Clinical Significance of Growth Differentiation Factor-15 (GDF-15)
GDF-15 is a stress-responsive cytokine and inflammatory biomarker that serves as a powerful prognostic indicator across multiple disease states, particularly cardiovascular disease, heart failure, bleeding risk in atrial fibrillation, and metabolic disorders, with elevated levels consistently predicting increased mortality and adverse outcomes.
Primary Clinical Applications
Cardiovascular Disease and Heart Failure
GDF-15 functions as a marker of cell injury and inflammation in cardiac disease, belonging to the transforming growth factor-β cytokine superfamily 1. The American Heart Association recognizes GDF-15 as one of the most useful inflammatory biomarkers in heart failure pathophysiology 1.
Key mechanisms in cardiac disease:
- Released in response to myocardial ischemia-reperfusion injury 1
- Upregulated during tissue injury, oxidative stress, and sustained inflammatory responses that adversely affect cardiac structure and function 1
- Provides incremental prognostic value for death in patients with unstable angina/non-ST-elevation myocardial infarction beyond traditional markers 1
- Adds prognostic information beyond natriuretic peptides and cardiac troponins in acute coronary syndromes, atrial fibrillation, and heart failure 2
Bleeding Risk Assessment in Atrial Fibrillation
GDF-15 is incorporated into the ABC bleeding risk score, one of the most validated bleeding prediction tools for patients on anticoagulation 1. The ABC score uses age, biomarkers (including GDF-15 or cystatin C/CKD-EPI, high-sensitivity troponin T, and hemoglobin), and previous bleeding history to stratify patients into low (<1%), intermediate (1-2%), and high (>3%) annual bleeding risk categories 1.
This biomarker-based approach outperforms traditional clinical bleeding risk scores by capturing systemic stress responses that predispose to bleeding complications 1.
Metabolic Disease and Diabetes
GDF-15 plays a complex role in metabolic regulation:
- Acts as a potent anorectic factor with anti-inflammatory and tissue protective properties 1
- Increases upon fasting independently of leptin 1
- Elevated in obesity due to macrophage accumulation in adipose tissue 1
- Significantly upregulated in type 2 diabetes patients receiving metformin, correlating with reduced body mass 1
- Higher levels in metabolic dysfunction-associated steatotic liver disease compared to healthy controls 1
The current evidence suggests GDF-15 secretion represents a stress-induced compensatory mechanism to confer tissue protection 1.
Infectious Disease and Sepsis
GDF-15 demonstrates protective effects during acute infection:
- Upregulated in humans and mice during viral and bacterial infections 1
- Protective in bacterial (LPS) and viral (Poly I:C) sepsis models by enhancing disease tolerance through adrenergic signaling to the liver, resulting in hepatic triglyceride export and cardiac protection during acute inflammation 1
- IFN-γ is necessary for systemic GDF-15 upregulation during infection, which leads to upregulation of FGF21 and ketone bodies 1
Kidney Disease
Increased GDF-15 levels are linked to:
- Increased risk of incident chronic kidney disease 3
- Faster decline in kidney function across various renal disorders including diabetic nephropathy, IgA nephropathy, lupus nephritis, and kidney transplantation 3
- Nephroprotective activity associated with inflammation downregulation and upregulation of protective factors like Klotho in tubular cells 3
Prognostic Value
GDF-15 serum concentrations reflect a "systemic response" and are predictive of all-cause mortality across disease states 4. This makes it a powerful biomarker for:
- Risk stratification in cardiovascular disease 5, 2
- Monitoring disease progression in heart failure 1
- Assessing bleeding risk in anticoagulated patients 1
- Evaluating metabolic stress in diabetes and obesity 5
Immunoregulatory Functions
GDF-15 modulates immune responses by:
- Suppressing type 1 inflammatory responses while promoting type 2 responses 6
- Regulating effector function and recruitment of immune cells 6
- Affecting diverse mechanisms during inflammation and infection 6
Clinical Caveats
GDF-15 has diverse and partially opposing functions depending on cellular state and microenvironment 3. While most evidence supports a protective role, some reports suggest GDF-15 deficiency may be beneficial against vascular injury and inflammation in specific contexts 5.
The exact mechanisms underlying GDF-15's effects in various disease states are not yet fully understood, and its role appears context-dependent based on the specific pathological condition 3, 5.