The Acute-Phase Response and Hepatic Reprioritization
When the body experiences an inflammatory stimulus—such as from infection, trauma, or surgery—it initiates a systemic inflammatory response. This triggers a complex, coordinated physiological reaction known as the acute-phase response. A key component of this process involves a significant shift in liver function called hepatic reprioritization, where the liver alters its protein synthesis priorities.
The Shift from Visceral to Acute-Phase Proteins
During the acute-phase response, the liver decreases the synthesis of certain proteins and increases the synthesis of others.
Negative acute-phase proteins: These are the visceral proteins whose serum concentrations decrease during inflammation. The body lowers their production to conserve amino acids, which are then used to create other, more urgent proteins. The key visceral proteins affected include:
- Albumin: The most abundant protein in human serum, albumin has a long half-life of about 20 days. Systemic inflammation not only reduces its synthesis but also increases its degradation and promotes leakage from the bloodstream into surrounding tissues.
- Prealbumin (Transthyretin): With a much shorter half-life of 2-3 days, prealbumin is more responsive to acute changes. However, its levels are still significantly impacted by inflammatory states, making it a poor indicator of short-term nutritional intake alone.
- Transferrin: This protein transports iron and has a half-life of approximately 10 days. Like albumin, its levels decrease during inflammation.
Positive acute-phase proteins: These proteins see a rise in concentration during inflammation. Examples include C-reactive protein (CRP), fibrinogen, and various complement factors. Their elevated levels are essential for the body's immune defense, coagulation, and tissue repair processes.
The Misinterpretation of Visceral Protein Levels
For many years, low levels of visceral proteins like albumin and prealbumin were viewed as direct indicators of malnutrition. While poor nutritional intake can contribute to low levels, the powerful inhibitory effect of inflammatory cytokines on the liver's synthetic function means that inflammation is often the primary driver of these low levels in acutely ill or stressed patients. Studies have shown that even in some well-nourished individuals, significant inflammation can cause these protein levels to drop, leading to misdiagnosis of malnutrition. In fact, low visceral protein levels are now often considered markers of inflammation severity and prognostic indicators rather than pure nutritional markers.
The Interplay of Malnutrition and Inflammation
The relationship between malnutrition and inflammation is often a vicious cycle. Inflammation promotes malnutrition by causing anorexia and altering metabolism, leading to increased muscle catabolism. Meanwhile, malnutrition can compromise the immune system, leaving the body more vulnerable to infections that trigger further inflammation. This cycle can exacerbate adverse clinical outcomes, such as longer hospital stays and increased mortality. Effective management requires addressing both components simultaneously, as nutritional support alone is often ineffective at correcting low visceral protein levels in the presence of strong inflammation.
Interpretation in the Clinical Setting
Given this complex relationship, clinicians must interpret visceral protein levels cautiously. They should not be used as sole markers for diagnosing malnutrition or monitoring the effectiveness of nutritional support. Instead, a more comprehensive approach is needed, one that incorporates markers of inflammation, such as C-reactive protein (CRP), alongside a thorough nutritional assessment. For instance, a low prealbumin level coupled with a high CRP level strongly suggests an inflammatory state, rather than just inadequate nutritional intake.
Differentiating Inflammation vs. Malnutrition Effects
| Characteristic | Primary Effect of Malnutrition | Primary Effect of Acute Inflammation |
|---|---|---|
| Visceral Protein Level | May decrease gradually, especially with severe, long-term starvation. | Drops rapidly due to hepatic reprioritization, catabolism, and fluid shifts. |
| Serum Albumin | Maintained until extreme, severe starvation occurs; a long half-life makes it insensitive to acute changes. | Drops significantly and rapidly; levels are a marker of the inflammatory state's severity. |
| Prealbumin (Transthyretin) | Shows more sensitive decline reflecting recent protein-energy status. | Drops significantly and is unreliable as a nutritional indicator when CRP is elevated. |
| C-Reactive Protein (CRP) | Generally normal in the absence of infection or stress. | Rapidly and significantly increases; inversely correlated with albumin levels. |
| Nutritional Assessment | Reflects poor nutritional intake, weight loss, or inadequate absorption. | Reflects the body's systemic response to trauma, infection, or disease. |
| Intervention Response | Levels respond positively to nutritional repletion. | Levels do not reliably increase with nutritional support alone if inflammation persists. |
Conclusion
The effect of inflammation on visceral proteins is profound, causing a significant and rapid decrease in their circulating levels. This is not simply a sign of nutritional deficiency but an active, systemic response by the liver to reprioritize protein synthesis for immune function. Consequently, using visceral proteins like albumin and prealbumin as isolated markers for nutritional assessment is unreliable, particularly in acutely ill patients. A comprehensive assessment that considers both visceral protein levels and inflammatory markers, such as C-reactive protein, provides a far more accurate picture of a patient's overall clinical status. Addressing the underlying inflammation is often the most effective strategy for normalizing these protein levels and improving patient outcomes. For further research and analysis on this topic, the paper Systemic response to inflammation by Jensen in JPEN J Parenter Enteral Nutr is highly recommended.
