Summary

1. Hepatocellular injury is characterized by disproportionate elevation of AST and ALT levels compared with alkaline phosphatase, while cholestatic injury shows disproportionate elevation of alkaline phosphatase compared with AST and ALT.
2. True normal ALT levels are significantly lower than traditional laboratory ranges, with optimal upper limits of 29-33 IU/l for males and 19-25 IU/l for females, and elevations above these thresholds correlate with increased liver-related mortality.
3. The evaluation of hepatocellular injury follows a systematic approach based on the magnitude of aminotransferase elevation, with specific diagnostic considerations for different levels of elevation.
4. Elevation of alkaline phosphatase requires confirmation of hepatic origin and systematic evaluation to differentiate between extrahepatic and intrahepatic causes of cholestasis.
5. Elevated total bilirubin should be fractionated to direct (conjugated) and indirect (unconjugated) bilirubin to determine the etiology of hyperbilirubinemia.
6. When evaluating medications as a potential cause of abnormal liver tests, specific patterns of injury, timeline of medication use, and clinical features can help establish the diagnosis of drug-induced liver injury (DILI).
7. When assessing abnormal liver tests, physical examination findings may provide clues to the etiology and severity of liver disease.
8. The presence of albumin and prothrombin time abnormalities with elevated liver chemistries indicates impaired hepatic synthetic function and suggests more severe liver disease.

Introduction

Accurate interpretation of liver chemistry tests is crucial for diagnosing and managing a wide range of hepatic disorders. Physicians must distinguish between hepatocellular and cholestatic injury patterns, recognize the limitations of traditional reference ranges, and systematically evaluate potential etiologies. This guide provides a facts that can help you develop a structured approach to interpreting liver chemistry tests, from differentiating injury patterns to recognizing the implications of abnormal synthetic function. By understanding these key concepts, physicians can enhance diagnostic accuracy and guide appropriate management strategies.

1) Hepatocellular injury is characterized by disproportionate elevation of AST and ALT levels compared with alkaline phosphatase, while cholestatic injury shows disproportionate elevation of alkaline phosphatase compared with AST and ALT.

The R ratio can quantify the pattern of liver injury: R = (ALT/ALT ULN)/(ALP/ALP ULN), where R > 5 indicates hepatocellular injury, R < 2 indicates cholestatic injury, and R between 2-5 indicates mixed pattern. AST is present in the liver, cardiac muscle, skeletal muscle, kidney, and brain, making ALT a more specific marker for hepatocellular injury. In alcoholic liver disease, the AST/ALT ratio is typically > 2:1 due to pyridoxine deficiency affecting ALT activity and mitochondrial injury affecting AST. In viral hepatitis and NAFLD, ALT levels typically exceed AST levels, but this pattern may reverse in cirrhosis of any etiology. The presence of elevated alkaline phosphatase of hepatic origin should be confirmed with GGT elevation or fractionation of alkaline phosphatase isoenzymes.

‍

2) True normal ALT levels are significantly lower than traditional laboratory ranges, with optimal upper limits of 29-33 IU/l for males and 19-25 IU/l for females, and elevations above these thresholds correlate with increased liver-related mortality.

Multiple population studies show that ALT levels above these lower thresholds correlate with increased liver-related mortality risk by 3-11x compared to those with normal values. There is a linear relationship between ALT level and BMI that should be considered when assessing patients for liver disease. Patients with AST/ALT levels between 30-39 IU/l have 8-9.5x increased risk of liver-related death compared to those with levels <20 IU/l. Normal ALT levels don't exclude significant liver disease; 9% of hepatitis C patients with normal ALT have bridging fibrosis and 11% have cirrhosis. Reference ranges for ALT vary widely between laboratories (31-72 U/l), creating inconsistency in identifying patients with underlying liver disease.

‍

3) The evaluation of hepatocellular injury follows a systematic approach based on the magnitude of aminotransferase elevation, with specific diagnostic considerations for different levels of elevation.

Borderline elevation (<2x ULN) warrants assessment for common conditions including NAFLD, alcohol, medications, and chronic viral hepatitis. Mild elevation (2-5x ULN) should include evaluation for hemochromatosis, autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency. Moderate elevation (5-15x ULN) requires evaluation for acute viral hepatitis (A, B, C) in addition to all the causes of mild elevation. Severe elevation (>15x ULN) or massive elevation (ALT >10,000 IU/l) should prompt investigation for acetaminophen toxicity, ischemic hepatopathy (shock liver), and autoimmune hepatitis. Fulminant hepatic failure, defined by acute liver injury, impaired synthetic function (elevated PT/INR), and hepatic encephalopathy, requires immediate referral to a liver specialist regardless of ALT level.

‍

4) Elevation of alkaline phosphatase requires confirmation of hepatic origin and systematic evaluation to differentiate between extrahepatic and intrahepatic causes of cholestasis.

Confirmation of hepatic origin should be done with GGT measurement or alkaline phosphatase fractionation, as ALP can also originate from bone, placenta, intestine, and kidney. Ultrasound is the first-line imaging for elevated alkaline phosphatase to detect biliary dilation suggesting extrahepatic obstruction. Primary biliary cholangitis (PBC) is diagnosed by positive anti-mitochondrial antibodies, present in >95% of patients. Primary sclerosing cholangitis (PSC) is diagnosed by a characteristic "beaded" appearance of bile ducts on MRCP or ERCP and is associated with inflammatory bowel disease. Isolated elevation of alkaline phosphatase with normal imaging should prompt consideration of drug-induced liver injury, infiltrative diseases (sarcoidosis, granulomatosis, amyloidosis), or vanishing bile duct syndrome.

5) Elevated total bilirubin should be fractionated to direct (conjugated) and indirect (unconjugated) bilirubin to determine the etiology of hyperbilirubinemia.

Elevated conjugated (direct) bilirubin implies hepatocellular disease or biliary obstruction in most settings and requires prompt evaluation. Isolated unconjugated hyperbilirubinemia is most commonly due to Gilbert's syndrome (affecting 3-7% of the population) or hemolysis. Gilbert's syndrome is a benign condition with mild unconjugated hyperbilirubinemia (<4 mg/dl) that increases with fasting and typically requires no treatment. Hemolysis rarely causes bilirubin levels >5 mg/dl unless coexistent renal or liver disease is present, and is characterized by reduced haptoglobin and elevated LDH and reticulocyte count. Dubin-Johnson and Rotor syndromes are rare inherited conditions causing conjugated hyperbilirubinemia with otherwise normal liver tests, including normal alkaline phosphatase and GGT.

‍

6) When evaluating medications as a potential cause of abnormal liver tests, specific patterns of injury, timeline of medication use, and clinical features can help establish the diagnosis of drug-induced liver injury (DILI).

Common drug classes associated with liver injury include antibiotics, antiepileptics, NSAIDs, statins, anti-tuberculosis drugs, and antiretroviral treatments. DILI can present with hepatocellular, cholestatic, or mixed patterns, and the pattern can help identify the offending agent. Acetaminophen toxicity typically causes massive ALT elevations (>10,000 IU/l) and requires prompt treatment with N-acetylcysteine. Statins rarely cause clinically significant hepatotoxicity despite common mild transaminase elevations and can be safely used in patients with chronic liver disease. Herbal supplements and complementary alternative medicines (including chaparral, ephedra, germander, green tea extract) are important causes of liver injury and should be specifically queried.

‍

7) When assessing abnormal liver tests, physical examination findings may provide clues to the etiology and severity of liver disease.

Stigmata of chronic liver disease (jaundice, ascites, splenomegaly, palmar erythema, spider angiomata) suggest advanced disease or cirrhosis. A firm liver edge on palpation suggests cirrhosis or infiltrative disorders, while an enlarged nodular liver suggests malignancy. Dupuytren contractures with parotid gland enlargement and testicular atrophy suggest alcoholic liver disease. Kayser-Fleischer rings (copper deposition in the cornea) are pathognomonic for Wilson disease, especially in patients with neurologic symptoms. Bronzing of the skin may suggest hereditary hemochromatosis, while decreased breath sounds may indicate alpha-1-antitrypsin deficiency with emphysema.

‍

8) The presence of albumin and prothrombin time abnormalities with elevated liver chemistries indicates impaired hepatic synthetic function and suggests more severe liver disease.

Albumin has a half-life of 3 weeks, so reduced levels (<3.5 g/dl) typically indicate liver disease of more than 3 weeks duration or other systemic illness. Prothrombin time is a more sensitive marker of acute liver dysfunction, as it may be prolonged within 24 hours of severe injury. Prolonged prothrombin time in the setting of liver disease indicates decreased synthesis of vitamin K-dependent clotting factors (II, VII, IX, X). Prothrombin time prolongation that corrects with vitamin K administration suggests cholestasis with malabsorption of fat-soluble vitamins rather than severe hepatocellular dysfunction. The combination of coagulopathy (INR >1.5) and encephalopathy defines acute liver failure and requires urgent referral to a liver transplant center.

‍

Source

Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. Am J Gastroenterol. 2017 Jan;112(1):18-35. doi: 10.1038/ajg.2016.517. Epub 2016 Dec 20. PMID: 27995906.

‍