Page 815 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 50 Disorders of Phagocyte Function 701

owing to the toxic effects of accumulating hydrogen peroxide on TABLE
−
NADPH oxidase. This brief burst of O 2 , however, appears to be 50.6 Summary of Myeloperoxidase Deficiency
sufficient for adequate microbial killing because the few patients
reported have not had problems with recurrent infections. However, Incidence 1 in 2000 (partial deficiency)
they do have congenital hemolytic anemia during periods of oxidant 1 in 4000 (total deficiency)
stress caused by diminished levels of glutathione reductase in erythro- Inheritance Autosomal recessive with variable
cytes. In glutathione synthetase deficiency, the respiratory burst expression; MPO gene on chromosome
proceeds normally. Patients have severe metabolic acidosis caused by 17 at q22−q23
elevated levels of 5-oxoproline, which is the product of the first step Molecular defect Defective posttranslational processing of
in glutathione synthesis and is present in increased levels because of an abnormal MPO precursor
a lack of feedback of GSH on the synthetic pathway. Patients with polypeptide; eosinophil peroxidase
glutathione synthetase deficiency also have intermittent neutropenia encoded by different gene and levels
(perhaps caused by the acidosis), as well as oxidant-induced hemoly- normal
sis. There are mild problems with recurrent infections. Therapy with
vitamin E (400 IU/day) has been found to be beneficial in patients Pathogenesis Partial or complete MPO deficiency leads
with severe glutathione synthetase deficiency with hemolysis and to diminished production of HOCl and
infections. HOCl-derived chloramines; MPO
products are necessary for rapid
killing of microbes (especially Candida
Myeloperoxidase Deficiency spp.) but not absolutely required
Clinical manifestations Usually clinically silent
MPO deficiency is the most common inherited disorder of phago- Disseminated candidiasis or fungal
17
cytes but is almost always asymptomatic. MPO is present in azuro- disease (rare; usually in conjunction
philic granules of neutrophils and monocytes, and catalyzes the with diabetes mellitus)
production of a potent antimicrobial agent, HOCl from chloride and Acquired deficiency in M2, M3, and M4
4,5
hydrogen peroxide (see Fig. 50.3, reaction 4). HOCl in turn reacts AMLs and myelodysplasia
with a variety of primary and secondary amines to form chloramines, Laboratory evaluation Deficiency of neutrophil and monocyte
some of which can be toxic. Moreover, HOCl is capable of activating peroxidase by histochemical analysis
latent metalloproteinases (e.g., collagenase) and inactivating (eosinophil peroxidase normal)
antiproteinases. Delayed, but eventually normal, killing of
Complete MPO deficiency is seen in approximately 1 in 4000 bacteria in vitro
individuals, and partial deficiency is even more common (1 in 2000 Failure to kill Candida albicans and
persons). The key features of MPO deficiency are summarized in hyphal forms of Aspergillus
Table 50.6. The disorder is inherited in an AR manner. In the few fumigatus in vitro
cases reported, several different mutations have been identified, which
generally appear to affect the posttranslational processing of a precur- Differential diagnosis Acquired partial MPO deficiency seen in
sor polypeptide for MPO. Acquired forms of MPO deficiency are M2, M3, and M4 AML; MDS; and
also seen. The gene that encodes for MPO is located on chromosome Batten disease
17 at q22–q23 near the breakpoint for the 15-to-17 translocation of Therapy None in asymptomatic patients
promyelocytic leukemia. Subpopulations of MPO-deficient cells can Aggressive treatment of fungal infections
be seen not only in the M3 (promyelocytic) form of acute myeloid when they occur
leukemia but also in the M2 and M4 forms. MPO-deficient cells are Control of blood glucose levels in
also seen in approximately 25% of patients with chronic myeloid diabetics
leukemia and myelodysplastic syndromes. Prognosis Usually excellent
One of the most curious features of MPO deficiency is the
remarkable lack of clinical symptoms in affected persons, given the AML, Acute myeloid leukemia; HOCl, hypochlorous acid; MDS, myelodysplastic
syndromes; MPO, myeloperoxidase.
prediction that severe MPO deficiency would cripple important
antimicrobial reactions catalyzed by HOCl. In vitro, an impressive
defect in killing Candida albicans and hyphal forms of Aspergillus
17
fumigatus is observed. Bacterial killing in vitro is also abnormal in
being somewhat slower than normal, but eventually it is complete. DISORDERS OF PHAGOCYTE ADHESION
MPO-deficient mice also exhibit abnormalities in host defense against AND CHEMOTAXIS
Candida and Klebsiella spp. Excessive or unusual infections in MPO-
deficient patients, however, are uncommon, except for rare individu- Since 1970, numerous investigators have found in vitro chemotactic
17
als who also have diabetes mellitus. In these individuals, disseminated abnormalities in neutrophils from patients with a wide variety of
fungal infections (usually candidiasis) are seen. clinical disorders associated with increased susceptibility to bacterial
3
The discrepancy between the in vitro and in vivo manifestations and fungal infections. In most circumstances, the chemotactic
of MPO deficiency in most patients can be explained in several ways. abnormality identified was only marginal and not always clearly
First, the respiratory burst in MPO-deficient neutrophils is substan- related to the clinical status of the patient. In other instances, clear
tially augmented, presumably from the absence of HOCl-mediated and major defects were identified in vitro that correlated with the in
toxic effects on the NADPH oxidase. Second, other products of the vivo propensity for infection. Extensive classification systems have
respiratory burst, together with the oxygen-independent antibacterial been devised to categorize the numerous acquired defects in chemo-
proteins, appear to have sufficient potency to compensate for the loss taxis. The problem in many of these reports is that it is unclear
of MPO-dependent reactions. Finally, residual amounts of MPO whether the infections were caused by the in vitro chemotactic
coupled with the normal levels of eosinophil peroxidase may provide abnormality or by the medical complications of the underlying dis-
at least some degree of peroxidative activity at the sites of infection. order (e.g., acidosis, malnutrition, or exposure to nosocomial infec-
Treatment is usually not required for MPO deficiency except in tions). A further complicating factor is that there are inherent
those individuals with fungal infections. In these patients, aggressive limitations in the in vitro chemotaxis assay, which is subject to labora-
use of antifungal antibiotics is indicated. The prognosis is excellent tory artifacts both as a result of neutrophil purification procedures as
in the majority of patients with MPO deficiency. well as the assay itself. Furthermore, the extent to which these in vitro