Liver Function Tests (LFTs) Interpretation: A Complete Guide

The De Ritis Ratio (AST/ALT ratio) is a fundamental diagnostic tool for differentiating alcoholic liver disease from viral hepatitis. ALT is liver-specific, while AST is found in multiple tissues. In viral hepatitis, the ratio equals 1:1 because ALT is released in greater quantities than AST. In alcoholic liver disease, the ratio exceeds 2:1 due to mitochondrial damage releasing AST and pyridoxine deficiency reducing ALT production. Alcohol metabolism produces toxic metabolites that damage hepatocytes and deplete glutathione. For diagnosis, the ratio must exceed 2:1 with AST less than 300 U/L. This ratio, discovered in 1957, provides a simple yet powerful method for clinicians to determine the etiology of liver damage.

This lecture explains how to differentiate between various liver diseases using AST and ALT enzyme patterns: viral hepatitis (A, B, C) typically shows ALT > AST, while alcoholic liver disease shows AST ≥ ALT; ischemic liver disease causes extremely elevated AST and ALT levels (several thousand units); chronic conditions like NASH and autoimmune hepatitis also show ALT > AST but require additional diagnostic testing including serology and imaging.

AST (Aspartate Transaminase) and ALT (Alanine Transaminase) are key enzymes in liver function tests, with ALT being more liver-specific due to its cytosolic nature, while AST is found in multiple tissues including muscle and heart. The AST:ALT ratio (De Ritis ratio) is crucial for diagnosis: a ratio >2:1 indicates alcoholic liver disease (due to mitochondrial damage and vitamin B6 deficiency), while a ratio <1 suggests viral hepatitis or non-alcoholic fatty liver disease. Marked elevation (10x normal) indicates acute viral or toxic hepatitis, moderate elevation (2-5x) suggests chronic hepatitis, and mild elevation (<2x) may indicate fatty liver or drug-induced conditions.

Cholestasis shows elevated alkaline phosphatase and gamma-glutamyl transferase; hepatocellular injury shows elevated transaminases. AST/ALT ratio interpretation: hepatocellular injury (AST/ALT ≥1) occurs in alcoholic hepatitis, necrotizing hepatitis, decompensated cirrhosis, hepatic malignancy. Most other liver diseases (fatty liver, viral hepatitis, extrahepatic cholestasis) show AST/ALT ratio <1. Prehepatic: elevated indirect bilirubin, normal enzymes. Intrahepatic: elevated indirect and total bilirubin, elevated transaminases. Posthepatic: elevated total bilirubin, elevated biliary enzymes.

The MELD (Model for End-Stage Liver Disease) score is used to prioritize patients for liver transplantation and is calculated using bilirubin, INR, and creatinine. Higher scores indicate worse prognosis and higher priority for transplant. The Child-Pugh score assesses cirrhosis severity and prognosis using encephalopathy, ascites, INR, bilirubin, and albumin. Child-Pugh classes (A, B, C) indicate different levels of decompensation. The mnemonic 'BIC' (Bilirubin, INR, Creatinine) helps remember MELD components. Scores >40 indicate very poor prognosis with mortality approaching 71%. These scores are essential for clinical decision-making in cirrhotic patients.

The Child-Pugh score and MELD score are used to assess severity of liver cirrhosis and predict prognosis. The Child-Pugh score includes: (1) Encephalopathy - none (1 point), grade 1-2 (2 points), grade 3-4 (3 points). (2) Ascites - none (1 point), mild (2 points), moderate-severe (3 points). (3) Albumin - >3.5 g/dL (1 point), 2.8-3.5 g/dL (2 points), <2.8 g/dL (3 points). (4) Bilirubin - <2 mg/dL (1 point), 2-3 mg/dL (2 points), >3 mg/dL (3 points). (5) Prothrombin time - <4 seconds prolongation (1 point), 4-6 seconds prolongation (2 points), >6 seconds prolongation (3 points). The MELD score includes: (1) Creatinine - mg/dL. (2) INR. (3) Bilirubin - mg/dL. (4) Sodium - mmol/L. The Child-Pugh score is used to determine prognosis and transplant priority, while the MELD score is used to determine transplant priority.

The Child-Pugh classification assesses cirrhosis decompensation using five factors: albumin, bilirubin, ascites, encephalopathy, and prothrombin time. Each factor scores 1-3 points, with total scores of 5-6 (Class A), 7-9 (Class B), and 10-15 (Class C). MELD score (Model for End-Stage Liver Disease) uses bilirubin, INR, and creatinine and is the best predictor of short-term mortality, used for transplant prioritization.

This section details the essential risk stratification tools for managing liver disease patients undergoing surgery. The Child-Pugh score evaluates three biochemical markers (bilirubin, albumin, INR) and two clinical markers (ascites severity, hepatic encephalopathy severity), categorizing patients as A (mild), B (moderate), or C (severe). The MELD score uses creatinine, bilirubin, and INR (with sodium in some versions) to predict mortality, with scores below 10, 10-15, and above 15 corresponding roughly to Child-Pugh classes A, B, and C. Both systems correlate with perioperative morbidity and mortality but have limitations—they don't account for acute versus chronic status, surgical risk, cardiac/respiratory status, or hepatorenal syndrome. The recommended framework: for elective surgery without active liver disease, Child-Pugh A/MELD <10 allows cautious proceeding after optimizing extra-hepatic manifestations; Child-Pugh B/MELD 10-15 permits proceeding with caution acknowledging higher risk; Child-Pugh C/MELD >15 warrants deferring or canceling surgery and ensuring prior medical team consultation.

The Child-Pugh score is calculated using five variables: (1) Ascites (0 points if absent, 1 point if mild, 2 points if moderate, 3 points if severe/refractory); (2) Encephalopathy (0 points if absent, 1 point if grade 1-2, 2 points if grade 3-4); (3) Albumin (3 points if <2.8 g/dL, 2 points if 2.8-3.5 g/dL, 1 point if >3.5 g/dL); (4) INR (3 points if >2.3, 2 points if 1.7-2.3, 1 point if <1.7); (5) Bilirubin (3 points if >3.5 mg/dL, 2 points if 2.1-3.5 mg/dL, 1 point if <2.1 mg/dL). Scores of 5-6 indicate Child-Pugh B, 7-9 indicate Child-Pugh C. Child-Pugh C patients have poor prognosis and should generally avoid surgery unless absolutely necessary.

Drug-induced liver injury is diagnosed through a process of exclusion: clinicians rule out other causes of liver damage and then identify the specific agent responsible through temporal association (timing of exposure relative to symptoms) and expert adjudication. This diagnostic approach applies to both modern medicines and alternative medicines. However, patients often take multiple alternative medicines simultaneously, each containing numerous herbs, making it difficult to pinpoint which specific component caused harm.

Drug-induced liver injury (DILI) should be suspected when there is a mixed hepatocellular and cholestatic pattern of liver enzyme elevation. The diagnostic approach includes: viral hepatitis serology, autoimmune markers (ANA, AMA, anti-mitochondrial antibody, smooth muscle antibody), and imaging to rule out extrahepatic biliary obstruction. The key to diagnosis is often stopping the suspected drug and observing for improvement. A comprehensive workup should extend to include herpes viruses as 'moonlighters' of liver infections.

Drug-Induced Liver Injury (DILI) is liver damage caused by xenobiotics (drugs, herbs, supplements) after excluding other causes, with three main phenotypes: direct (predictable, dose-dependent, e.g., acetaminophen), idiosyncratic (unpredictable, immune-mediated, variable presentation), and immune-mediated (indirect, e.g., checkpoint inhibitors). DILI incidence ranges from 14-19 events per 100,000 inhabitants, with antibiotics and herbal supplements being the most common causes in Mexico. Diagnosis requires a systematic approach: clinical history, R value (alkaline phosphatase/transaminases ratio) to differentiate hepatocellular, mixed, or cholestatic patterns, and RUCAM causality assessment. Key diagnostic tools include Livertox database and liver biopsy when needed. Future approaches will leverage biomarkers, artificial intelligence, and genetic polymorphisms for personalized medicine.

Diagnosing drug-induced liver injury requires a diagnosis of exclusion with detailed patient history about medications and supplements. AASLD guidelines define significant injury as ALT >5x ULN or ALP >2x ULN on two tests 24 hours apart, or bilirubin >2.5 or INR >1.5. The R ratio (ALT/ULN ÷ ALP/ULN) classifies injury as hepatocellular (>5), cholestatic (<2), or mixed (2-5). Other causes must be excluded including viral hepatitis, Wilson disease, autoimmune liver disease, and alcohol use. NIH LiverTox website provides free lookup of reported liver injury cases for any medication or supplement.

Diagnosis of DILI requires meeting specific criteria: (1) Temporal relationship - symptoms must appear 5-90 days after drug initiation; (2) Improvement after drug discontinuation - liver enzymes should decrease by 50% within one month (for hepatocellular injury) or 108 days (for cholestatic injury); (3) Exclusion of alternative causes through thorough investigation, potentially including liver biopsy; (4) Positive response to rechallenge (though this is rarely performed due to ethical concerns). The RUCAM (Roussel Uclaf Causality Assessment Method) scoring system provides a standardized approach, with scores of 2 or more indicating probable DILI. These criteria help clinicians establish causality between drug exposure and liver damage.