Why is lactate dehydrogenase (LDH) elevated in cirrhosis?

Why Lactate Dehydrogenase is Elevated in Cirrhosis

LDH is elevated in cirrhosis primarily due to impaired hepatic clearance of lactate combined with accelerated glycolysis in the splanchnic circulation, hepatocyte damage from chronic inflammation and hypoxia, and the release of LDH from necrotic or damaged liver cells.

Primary Mechanisms of LDH Elevation

Impaired Lactate Clearance

• The healthy liver normally maintains a net splanchnic uptake of lactate through gluconeogenesis, but cirrhotic patients lose this capacity, leading to systemic lactate accumulation 1
• Lactate clearance is impaired by liver dysfunction in cirrhosis, which directly affects LDH levels since the liver cannot efficiently metabolize lactate 2
• Fasting lactate concentrations correlate directly with portal pressure and negatively with ICG clearance (a measure of hepatic function), demonstrating that worsening liver dysfunction progressively impairs lactate metabolism 1

Accelerated Splanchnic Glycolysis

• Cirrhotic patients exhibit accelerated glycolysis in the splanchnic region, which increases lactate production beyond the liver's diminished capacity to clear it 1
• This mechanism appears more important than decreased gluconeogenesis in explaining elevated lactate levels in chronic liver disease 1
• The combination of increased production and decreased clearance creates a "double hit" that elevates both lactate and LDH levels 1

Hepatocyte Hypoxia and Damage

• Hepatic hypoxic conditions exist in cirrhosis, particularly around the central vein, leading to increased LDH production by hepatocytes as an adaptive response to low oxygen concentrations 3, 4
• Microcirculatory disturbance in the cirrhotic liver creates zones of relative hypoxia, which upregulates LDH expression in hepatocytes 3
• The mosaic pattern of LDH distribution in cirrhotic hepatocytes reflects uneven oxygen delivery and variable degrees of cellular stress 4

Direct Hepatocyte Injury and Necrosis

• Lymphocyte-mediated liver cell damage in chronic active liver disease and primary biliary cirrhosis causes direct release of cytoplasmic LDH from damaged hepatocytes 5
• Hepatocyte necrosis releases tissue factor and intracellular enzymes including LDH into the circulation 2
• The degree of LDH elevation correlates with the severity of hepatocyte insufficiency and the extent of degenerative lesions 4

LDH Isoenzyme Pattern Changes

Specific Isoenzyme Shifts

• Micronodular cirrhosis shows increased LDG2 and LDG3 activity with decreased LDG5 activity, while macronodular cirrhosis demonstrates decreased LDG1 and LDG3 with increased LDG5 activity 4
• These isoenzyme pattern changes reflect the balance between degenerative and regenerative processes characteristic of different cirrhosis types 4
• In sterile cirrhotic ascites, LDH-1 activity is significantly higher compared to other causes of ascites, providing diagnostic utility 6

Diagnostic Implications

• The LDH isoenzyme profile can help establish the type of cirrhosis, degree of hypoxia, intensity of regeneration processes, and effectiveness of therapy 4
• Ascitic fluid LDH isoenzyme patterns differ between sterile cirrhotic ascites and complications like spontaneous bacterial peritonitis, where LDH-2 and LDH-3 activities are higher 6

Clinical Context and Prognostic Significance

Relationship to Disease Severity

• Lactate levels increase with cirrhosis severity and correlate with portal pressure, mean arterial blood pressure, and oxygen saturation 1
• In acute-on-chronic liver failure (ACLF), serum lactate is associated with the number of organ failures and mortality in critically ill cirrhotic patients 2
• The MELD-LA model (combining MELD score with lactate) is an excellent predictor of in-hospital mortality and outperforms MELD alone 2

Diagnostic Pitfalls

• Biomarkers including LDH are often elevated in cirrhotic patients both with and without infection, limiting their specificity for diagnosing sepsis 2
• Persistent elevation of LDH is a poor prognostic indicator regardless of whether infection is present 2
• When evaluating elevated LDH in cirrhosis, clinicians must assess hepatic function with a complete liver panel (ALT, AST, alkaline phosphatase, total and direct bilirubin, albumin, prothrombin time) to contextualize the finding 7

Practical Clinical Algorithm

When encountering elevated LDH in a cirrhotic patient:

1. Measure concurrent lactate levels to assess the severity of metabolic derangement and risk of ACLF 2
2. Obtain a complete liver panel to determine if LDH elevation reflects worsening hepatic synthetic function 7
3. Assess for infection with high clinical suspicion, as LDH elevation alone cannot distinguish infected from non-infected states 2
4. Evaluate for acute decompensation by checking for new or worsening ascites, hepatic encephalopathy, AKI, or hemodynamic changes 2
5. Consider MELD-LA scoring if the patient appears critically ill, as this provides superior prognostic information compared to MELD alone 2
6. Monitor serially rather than relying on a single value, as persistent elevation indicates poor prognosis 2