Myeloperoxidase Deficiency 

Updated: Oct 19, 2016
Author: Maureen M Petersen, MD; Chief Editor: Harumi Jyonouchi, MD 



Myeloperoxidase (MPO) is a human enzyme in the azurophilic granules of neutrophils and in the lysosomes of monocytes. Its major role is to aid in microbial killing. Although MPO received little clinical attention until 1966, the enzyme was first isolated in 1941, and deficiency of MPO was first described in 1954. Some patients with MPO deficiency have impaired microbial killing, but most are asymptomatic.

The condition was initially believed to be very rare with only 15 cases reported before the 1970s. However, modern laboratory techniques have allowed researchers to discover that MPO deficiency is actually more common than previously described but without clinical relevance.


Normal function of myeloperoxidase

MPO, a heme-containing protein, is found in the azurophilic granules of neutrophils and in the lysosomes of monocytes in humans; however, monocytes contain only about a third of the MPO present in neutrophils. When neutrophils become activated during phagocytosis, they undergo a process referred to as a respiratory burst. This respiratory burst causes production of superoxide, hydrogen peroxide, and other reactive oxygen derivatives, which are all toxic to microbes. During respiratory bursts, granule contents are released into the phagolysosomes and outside the cell, allowing released contents to come into contact with any microbes present. Experiments conducted in the 1960s showed that MPO catalyzes the conversion of hydrogen peroxide and chloride ions (Cl) into hypochlorous acid.[1] Hypochlorous acid is 50 times more potent in microbial killing than hydrogen peroxide.

MPO also directly chlorinates phagocytosed bacteria; thus, the MPO-hydrogen peroxide-Cl system seems to have an important role in microbial killing.[2] Although the exact mechanism by which microbial killing occurs is controversial, researchers are fairly certain that MPO is important for the process to optimally occur.

In addition to killing bacteria, the products of the MPO-hydrogen peroxide-Cl system are believed to play a role in killing fungi, parasites, protozoa, viruses, tumor cells, natural killer (NK) cells, red cells, and platelets. The MPO-hydrogen peroxide-Cl system is also believed to be involved in terminating the respiratory burst, because individuals with MPO deficiency have prolonged respiratory bursts. It may play a role in downregulating the inflammatory response by regulating NK cells, decreasing peptide binding to chemotactic receptors, and auto-oxidizing and inactivating products of polymorphonuclear leukocytes (PMNs), such as a1-proteinase inhibitor and chemotaxins.

Other functions of MPO include tyrosyl radical production and chlorination, generation of tyrosine peroxide, mediation of the adhesion of myeloid cells via b2-integrins, and oxidation of serum lipoproteins. MPO may have a role in atherosclerosis. Researchers have demonstrated that patients with stable coronary artery disease had an increased cardiovascular risk if plasma MPO levels were elevated.[3] A small study demonstrated that MPO deficiency may protect against cardiovascular disease.[4] MPO may also have a role in carcinogenesis and degenerative neurological diseases. The understanding of MPO biology remains incomplete; much more remains to be discovered.[5]

Normal myeloperoxidase production

MPO is a dimeric molecule, consisting of a pair of heavy-chain and light-chain protomers and 2 iron atoms. MPO is encoded by a single gene located on band 17q22-23. The mature enzyme is synthesized from a single polypeptide product. Therefore, the expression of the gene and the synthesis of MPO primarily occurs during the promyelocytic stage of myeloid development, concurrent with development of the azurophilic granules. The MPO gene encodes for a primary translational product, which is glycosylated to yield an enzymatically inactive precursor, apopro-MPO.

Apopro-MPO reversibly binds to chaperone proteins, calreticulin and calnexin, during protein maturation. This results in the subsequent binding of heme.[6] Heme insertion induces conformational changes in the protein yielding pro-MPO, an enzymatically active precursor.[7] Pro-MPO undergoes several complex conversions and eventually becomes mature MPO in the azurophilic granules, but the exact mechanisms are still poorly understood.

MPO should be distinguished from eosinophilic peroxidase (EPO), a different enzyme produced by a different gene. Although patients with MPO deficiency have decreased MPO activity in the neutrophils and monocytes, these patients usually have normal levels of EPO in eosinophils.

Pathophysiology of hereditary myeloperoxidase deficiency

Hereditary MPO deficiency was initially thought to follow the classic autosomal recessive pattern. A number of genetic mutations resulting in MPO deficiency have been identified, and many others may still be undiscovered. Researchers now believe that most patients are compound heterozygotes, which means that they have a different mutation on each allele, one from each parent. As with several other genetic diseases, numerous allele combinations can lead to the phenotype of MPO deficiency, which partially explains the variability of clinical features. Some mutations result in posttranslational defects; others (which are not yet clearly defined) seem to cause pretranslational defects, possibly due to structural alterations in the regulatory parts of the MPO gene. See Causes for a discussion of individual mutations that have been identified and their effects.

Some authors have proposed a bigenic model involving the interaction of 2 genes, such as a production gene and a regulatory gene. Overall, the genetic basis of this condition is now thought to be quite heterogeneous and complex. Undoubtedly, much remains to be discovered.

Pathophysiology of acquired myeloperoxidase deficiency

MPO deficiency in acquired cases is usually transient and generally resolves once the inciting condition improves. In addition, acquired MPO deficiency is usually partial and involves only a fraction of the PMNs.[8] The following conditions can lead to acquired MPO deficiency:

  • Pregnancy

  • Lead intoxication - Inhibits heme synthesis (a component of mature MPO)

  • Iron deficiency

  • Severe infection - Secondary to PMN activation and "consumption" of MPO

  • Thrombotic diseases

  • Renal transplantation

  • Diabetes mellitus

  • Neuronal lipofuscinosis

  • Drugs - Cytotoxic agents and some anti-inflammatory agents such as dapsone, 5-aminosalicylic acid, and sulfapyridine

  • Disseminated cancers - Probably related to administration of cytostatic agents

  • Several hematologic disorders and neoplasms especially those involving the maturation of granulocytes:

    • Acute myeloid leukemia (AML)

    • Chronic myeloid leukemia (CML)

    • Polycythemia vera

    • Hodgkin disease

    • Refractory megaloblastic anemia

    • Aplastic anemia

    • Myelofibrosis with myeloid metaplasia

    • Myelodysplastic syndromes

Microbial killing in myeloperoxidase deficiency

MPO-deficient neutrophils are normally able to phagocytose most microbes. However, the ability of MPO-deficient neutrophils to kill bacteria seems impaired to varying degrees. For organisms such as Staphylococcus aureus, Serratia species, and Escherichia coli, killing is initially impaired but then reaches normal levels after a period of time. This suggests that an apparently slower, alternative mechanism of killing can take over in MPO-deficient neutrophils.

The capacity to kill certain fungi, however, seems completely absent in MPO-deficient neutrophils. In vitro studies have shown that Candida albicans, Candida krusei, Candida stellatoidea, and Candida tropicalis cannot be killed by MPO-deficient PMNs. In contrast, an MPO-independent mechanism can kill Candida glabrata, Candida parapsilosis, and Candida pseudotropicalis. Even more interesting is that the hyphal elements of Aspergillus fumigatus and C albicans cannot be killed, but the spores of A fumigatus and the yeast phase of C albicans can be killed by an independent mechanism. This leads to the conclusion that bacterial killing may not necessarily be a problem for patients with MPO deficiency, but the killing of certain fungi may be a problem, depending on the severity of the deficiency.



United States

Incidence rates from screening studies range from 1 case per 1400-2000 population.


One series found the prevalence of total or subtotal MPO deficiency to be 1 case per 2727 population.[9] Prevalence rates in Japan have been reported to be much lower, with one study finding the prevalence of total and partial deficiency to be 1 case per 57,135 population and 1 case per 17,501 population, respectively.[10]

Until the 1970s, only 15 cases of MPO deficiency had been reported worldwide. Because most cases are asymptomatic, very few people were evaluated for the deficiency. However, modern laboratory techniques, particularly the wider application of automated flow cytometry for determining WBC differentials, have allowed the screening of large study populations to determine the true prevalence of MPO deficiency.[9]


European researchers evaluated patients with complete MPO deficiency and found that about half of the patients had infectious complications; the other half were asymptomatic. Approximately 10% of the cases involved life-threatening infectious complications. Other studies have reported that severe infections occur in fewer than 5% of patients with MPO deficiency; however, this frequency may be based on the inclusion of both complete and partial deficiencies. Generally, infections only occur in patients who have concomitant diabetes mellitus.


A group from Europe who studied patients with complete myeloperoxidase (MPO) deficiency found that about half had infectious complications, while the other half were asymptomatic. Infectious complications were life threatening in about 10% of cases.

Others have reported severe infections occurring in fewer than 5% of patients with MPO deficiency (this frequency may be based on the inclusion of both complete and partial deficiencies). Infections generally occur only in patients who have concomitant diabetes mellitus.




Recurrent infections

Most individuals with partial or total myeloperoxidase (MPO) deficiency have no increased frequency of infections, probably because MPO-independent mechanisms in the polymorphonuclear leukocytes (PMNs) can take over. In general, it is considered a relatively benign immunodeficiency and was removed from the Classification of Primary Immunodeficiency Disease by the Primary Immunodeficiency Disease Classification Committee of the International Union of the Immunologic Societies in 2005.

Severe infections are uncommon, occurring in fewer than 5% of patients with MPO deficiency. If infectious disease occurs, it is usually a fungal infection (particularly candidal, such as C albicans or C tropicalis) that occurs in a patient who also has diabetes mellitus. Patients without diabetes mellitus rarely have problems, although the reason for this is unknown. Possibly, MPO deficiency becomes clinically significant only in the presence of an additional defect in the host defense, or perhaps the MPO-independent system is defective in some patients with diabetes mellitus.

Physicians should entertain the diagnosis of MPO deficiency in cases of invasive fungal infection in a patient with no known predisposing immune defects (eg, chemotherapy, corticosteroid treatment) or in a patient with concomitant diabetes mellitus. Some consider peroxidase staining of the peripheral blood smear to be part of the complete evaluation of a patient with a suspected immunodeficiency.

Increased incidence of malignancy

A strong association between total MPO deficiency and malignancies has been reported by several independent investigators. In vitro, MPO-deficient neutrophils have decreased destruction of malignant cells demonstrating that the MPO system plays a central role in tumor surveillance.[8]

MPO is released from neutrophils in lung tissue in response to pulmonary insult including damage secondary to tobacco smoke exposure. MPO has been shown to convert the metabolites of benzo[a]pyrene from tobacco smoke into a highly reactive carcinogen. Researchers have demonstrated that decreased MPO can decrease lung cancer risk.[11]


Hereditary cases can be caused by a number of mutations, including R569W, Y173C, M251T, G501S, and R499C.

  • R569W: This is the most common defect identified to date. Tryptophan is substituted for arginine at codon 569. Tryptophan cannot form electrostatic bonds. Most patients described have been compound heterozygotes, but one has been homozygous for this mutation. The mutation results in a maturational arrest at the stage of apopro-MPO that is unprocessed, enzymatically inactive, and undelivered to the azurophilic granules.[12]

  • Y173C: Cysteine is substituted for tyrosine at codon 173. This leads to an additional site for intramolecular disulfide bonds, which presumably leads to abnormal folding of the protein. Apopro-MPO is converted into pro-MPO, which is malfolded. This malfolded pro-MPO seems to be sequestered by calnexin (a molecular chaperone) and retained in the endoplasmic reticulum. The trapped precursor then undergoes degradation in the endoplasmic reticulum. Pro-MPO is prevented from entering the secretory pathway and cannot proceed to become mature MPO in the azurophilic granules. Therefore, MPO deficiency resulting from this mutation occurs because of an abnormality of protein folding. Interestingly, abnormalities in protein folding have also been described in cystic fibrosis and protein C deficiency.

  • M251T: In this defect, mature subunits are formed, but their enzymatic activity is markedly low.

  • G501S: This mutation is a missense mutation within part of the heme-binding pocket. It has been identified in a Japanese patient with complete MPO deficiency.[13]

  • R499C: This mutation is a nonsynonymous mutation that results in an arginine to cysteine substitution in the exon 9 coding region. The mutation was identified in a Japanese patient with complete MPO deficiency. Further genetic analysis revealed mRNA was transcribed into an appropriate peptide sequence, but no MPO protein was evident on Western blot findings.[14]

  • As time goes on and more cases are analyzed, more mutations are being identified. Some pretranslational defects have been described that could be caused by mutations in the regulatory portion of the MPO gene or by the presence of mutations in other genes involved in the regulation of the MPO gene.

  • Acquired MPO deficiency is less common than the hereditary form. This condition can be transient. The enzyme defect is corrected when the underlying condition has resolved. In most cases of acquired deficiency, the deficiency is partial and affects only a proportion of neutrophils (see Pathophysiology).



Differential Diagnoses



Laboratory Studies

The presence of myeloperoxidase (MPO) can be determined using numerous techniques, including histochemical staining, immunocytochemistry, and flow cytometry. Depending on the assay used, one must ensure that eosinophilic peroxidase (EPO) from eosinophils does not cause false-positive results.[15]

The easiest technique is to perform direct visualization of neutrophils on a peripheral blood smear that has been stained for peroxidase. The clinician can ask the pathologist to examine the neutrophils for peroxidase when a peripheral smear is requested.[16]

Dihydrorhodamine 123 (DHR) assay, a flow cytometric assay, is often used to measure the presence of reactive oxygen intermediates in the work-up of a patient with suspected immunodeficiency. This assay is easier, more reliable, and more sensitive than nitroblue tetrazolium dye reduction assay in the diagnosis of chronic granulomatous disease (CGD). At this time, a DHR assay should not be used as a screen for MPO deficiency because of variable results and poor sensitivity in detecting partial MPO deficiency. If a DHR assay is consistent with a diagnosis of CGD but the clinical history is more consistent with MPO deficiency, further laboratory testing should be performed (eg, genetic sequencing or intracellular staining with anti-MPO antibody).[17]



Medical Care

In general, routine treatment with prophylactic antibiotics is not recommended because most patients with myeloperoxidase (MPO) deficiency have no increased incidence of infections.

  • Exercise caution in patients with concomitant diabetes mellitus. If infection does occur, initiate prompt and aggressive treatment with antimicrobials. Every effort should be made to identify causative agents and administer specific antimicrobial therapy.

  • If possible, avoid any treatments that might increase the likelihood of developing fungal infection (eg, use of broad-spectrum antibiotics, prolonged courses of antibiotics).