Myeloperoxidase Deficiency

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

Background

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.

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Pathophysiology

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:

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.

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Epidemiology

Frequency

United States

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

International

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]

Mortality/Morbidity

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.

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Prognosis

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.

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