What protein is induced by vitamin K absence?

December 19, 2025 •

3 min read

It is a fact that vitamin K is crucial for the function of several proteins in the body. The specific protein induced by vitamin K absence is called PIVKA-II, also known as des-gamma-carboxy prothrombin (DCP). Its presence indicates impaired vitamin K-dependent carboxylation.

Quick Summary

PIVKA-II (des-gamma-carboxy prothrombin) is the protein induced by vitamin K absence, a result of defective carboxylation of precursor proteins. It is clinically significant as a marker for liver disease, notably hepatocellular carcinoma (HCC).

Key Points

PIVKA-II (DCP): The specific protein induced by the absence of vitamin K is PIVKA-II, or des-gamma-carboxy prothrombin.
Impaired Carboxylation: Its induction results from impaired carboxylation of glutamic acid residues, a vital process requiring vitamin K.
Inactive Proteins: The resulting PIVKA-II is an inactive precursor of prothrombin, one of the key vitamin K-dependent coagulation factors.
Liver Disease Indicator: Elevated PIVKA-II levels can indicate severe vitamin K deficiency or certain liver diseases, including hepatocellular carcinoma (HCC).
Warfarin's Effect: The anticoagulant warfarin blocks the vitamin K cycle, leading to a therapeutic and detectable increase in PIVKA-II.
Diagnostic Complement: PIVKA-II is often used alongside AFP as a complementary biomarker to improve diagnostic accuracy for HCC.

The Role of Vitamin K in Protein Synthesis

Vitamin K is a fat-soluble vitamin essential as a cofactor for the enzyme gamma-glutamyl carboxylase. This enzyme modifies certain proteins by converting glutamic acid residues into gamma-carboxyglutamic acid residues (Gla). These Gla residues are necessary for calcium binding and protein activation, a process facilitated by the vitamin K cycle.

The Vitamin K Cycle

The vitamin K cycle, primarily occurring in the liver, involves carboxylation, epoxidation, and reduction steps. Carboxylation by gamma-glutamyl carboxylase uses vitamin K hydroquinone and converts it to vitamin K epoxide. Vitamin K epoxide reductase (VKOR) then reduces the epoxide back to hydroquinone, allowing the cycle to continue. Interference with this cycle, such as by deficiency or antagonists like warfarin, disrupts proper carboxylation.

PIVKA-II: The Protein of Interest

PIVKA-II, also known as des-gamma-carboxy prothrombin (DCP), represents the undercarboxylated or uncarboxylated precursor proteins that build up when functional vitamin K is insufficient. Prothrombin (Factor II) is a key vitamin K-dependent protein for blood coagulation. When vitamin K is lacking, the liver releases these inactive prothrombin precursors, measured as PIVKA-II.

Why PIVKA-II Appears

Impaired vitamin K function prevents gamma-glutamyl carboxylase from properly carboxylating prothrombin precursors. This results in an inactive prothrombin molecule lacking Gla residues needed for calcium binding. The liver releases these incomplete proteins, causing PIVKA-II levels to rise in the blood during vitamin K deficiency.

Causes of Vitamin K Absence

Several factors can lead to increased PIVKA-II by reducing functional vitamin K.

Malabsorption: Conditions hindering fat-soluble vitamin absorption, like cystic fibrosis or celiac disease.
Anticoagulants: Vitamin K antagonists such as warfarin, which inhibit VKOR and block the vitamin K cycle, causing a rise in PIVKA-II.
Nutritional Deficiency: Though rare in healthy adults, severe malnutrition can lead to deficiency. Newborns are also vulnerable and receive prophylactic vitamin K.
Liver Disease: Conditions like cirrhosis or hepatocellular carcinoma (HCC) can impair the liver's ability to utilize vitamin K, increasing PIVKA-II.

Clinical Significance of PIVKA-II

Measuring PIVKA-II is useful for assessing vitamin K status and, increasingly, for liver conditions.

PIVKA-II as an HCC Marker

Elevated PIVKA-II correlates with hepatocellular carcinoma (HCC). Malignant liver cells often fail to carboxylate prothrombin correctly, raising PIVKA-II. It is used as a tumor marker, often with alpha-fetoprotein (AFP), particularly in Asia. PIVKA-II levels can also relate to tumor size, metastasis, and prognosis.

Comparison of Vitamin K-Dependent Proteins

The table below shows the differences between functional, carboxylated proteins and their undercarboxylated counterparts like PIVKA-II.


Feature	Normal (Carboxylated) Proteins	PIVKA-II (Undercarboxylated) Proteins
Function	Biologically active	Biologically inactive or reduced function
Residues	Contains Gla residues	Lacks or has fewer Gla residues
Calcium Binding	Binds calcium	Poor or no calcium binding
Production Location	Liver (factors II, VII, IX, X, C, S)	Liver, especially during deficiency or inhibition
Clinical Marker	Assesses normal coagulation	Marker for vitamin K deficiency
Liver Disease Role	Normal liver function component	Rises in liver dysfunction and HCC
Warfarin Treatment	Production inhibited	Levels increase

PIVKA-II vs. Other Markers

PIVKA-II is often used alongside AFP in diagnosing liver cancer. While AFP has limitations, PIVKA-II can help distinguish early HCC from other liver diseases. Combining PIVKA-II and AFP can improve diagnostic accuracy. PIVKA-II can also indicate the severity of liver insufficiency in conditions like hepatitis E.

Conclusion

PIVKA-II is the protein induced by vitamin K absence, an inactive prothrombin precursor resulting from impaired carboxylation. It signals vitamin K deficiency and is a significant biomarker for hepatocellular carcinoma, reflecting the liver's inability to modify the protein during malignancy. Understanding PIVKA-II's induction is crucial for diagnosing and managing vitamin K-related and liver conditions. For more scientific details, refer to resources like the NCBI Bookshelf.

Frequently Asked Questions

The primary protein is PIVKA-II (Protein Induced by Vitamin K Absence or Antagonist-II), which is also known as des-gamma-carboxy prothrombin (DCP).

Vitamin K acts as a cofactor for an enzyme that adds a carboxy group to specific proteins, a process called carboxylation. This modification is essential for these proteins to bind calcium and become functionally active.

PIVKA-II stands for Protein Induced by Vitamin K Absence or Antagonist-II. It is the inactive prothrombin precursor that is produced when the vitamin K-dependent carboxylation process is inhibited.

A high PIVKA-II level can indicate severe vitamin K deficiency, the use of vitamin K antagonist medications like warfarin, or the presence of a liver disorder such as hepatocellular carcinoma (HCC).

Yes, a deficiency of vitamin K directly inhibits the proper carboxylation of prothrombin, causing the accumulation of inactive precursors that are detected as PIVKA-II.

PIVKA-II levels are measured via a blood test, which typically requires a serum sample. The test can be used to monitor patients with known liver disease or those on warfarin therapy.

Prothrombin is the normal, active coagulation protein that has been correctly carboxylated with the help of vitamin K. PIVKA-II is the inactive, uncarboxylated precursor of prothrombin that is produced when vitamin K is absent or ineffective.

The most common medication to cause a significant increase in PIVKA-II is the anticoagulant warfarin, as it directly blocks the vitamin K recycling process. Broad-spectrum antibiotics can also interfere with gut bacteria that produce vitamin K2, potentially leading to an increase.