Abstract
A 26-month-old boy was admitted because of recurrent fever, generalized erythematous rash, and joint pain. The fever persisted, and the joint pain waxed and waned. The combination of fever, erythematous rash, and joint pain suggested that the patient suffered from a childhood chronic inflammatory illness such as systemic juvenile idiopathic arthritis (sJIA) or chronic infantile neurological cutaneous and articular syndrome (CINCA, alternatively called neonatal-onset multisystem inflammatory disease or NOMID). However, neither of the conditions could explain the unique clinical features and the extraordinary laboratory findings seen in this patient. The patient had characteristic facial features such as flat nasal bridge, frontal bossing, and prominent edema of the eyelids. Marked hepatomegaly was noted, but the spleen was absent. Unlike most of patients with asplenia, this patient did not have any form of congenital heart disease. His brother and sister were healthy. The mother had experienced two intrauterine fetal deaths.
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1 Case Report
A 26-month-old boy was admitted because of recurrent fever , generalized erythematous rash, and joint pain. The fever persisted, and the joint pain waxed and waned. The combination of fever, erythematous rash, and joint pain suggested that the patient suffered from a childhood chronic inflammatory illness such as systemic juvenile idiopathic arthritis (sJIA) or chronic infantile neurological cutaneous and articular syndrome (CINCA, alternatively called neonatal-onset multisystem inflammatory disease or NOMID). However, neither of the conditions could explain the unique clinical features and the extraordinary laboratory findings seen in this patient. The patient had characteristic facial features such as flat nasal bridge, frontal bossing, and prominent edema of the eyelids. Marked hepatomegaly was noted, but the spleen was absent. Unlike most of patients with asplenia , this patient did not have any form of congenital heart disease. His brother and sister were healthy. The mother had experienced two intrauterine fetal deaths.
The white cell count was 51,600/μL (normal range; 3300 to 8800), and the platelet count was 226 x 104/μL (normal range; 13–35). The marked leukocytosis and thrombocytosis both persisted throughout the course of the illness. He had significant anemia with erythrocyte count 1.48 x 106/μL (normal range; 4.30–5.50) and hemoglobin concentration 4.9 g/dL (normal range; 13.5–17.0). Peripheral blood smear showed numerous fragmented erythrocytes and erythroblasts (Fig. 7.1). Serum iron concentration was 64 μg/dL (normal range; 50–170). Lactate dehydrogenase (LDH) was 17,470 IU/L (normal range; 196–355), and aspartate aminotransferase (AST) was 442 IU/L (normal range; 9–42), but alanine aminotransferase (ALT) was within normal limits. Serum ferritin was 780 ng/mL (normal range; 26–280). Marked abnormalities were noted in parameters of both coagulation and fibrinolysis system, although he did not show apparent bleeding tendency or signs of accelerated coagulation. Fibrinogen was 109 mg/dL (normal range; 196–356), fibrin degradation product (FDP) was 300.1 μg/mL (normal range; <5), d-dimer was 186.1 μg/mL (normal range; <2.5), thrombin-antithrombin complex was 202.2 μg/L (normal range; <3), and plasmin-α2 plasmin inhibitor complex was 22.3 μg/mL (normal range; <0.8). Thrombomodulin was 12 ng/mL (normal range; <3.5) and von Willebrand factor was 580% (normal range; 60–170). Hyperlipidemia was another prominent finding, with triglyceride at 638 mg/dL (normal range; 32–115) and total cholesterol at 552 mg/dL (normal range; 32–115) with predominance of low-density lipoprotein cholesterol .
The appearance of his serum was peculiar. Freshly separated serum was always turbid with brownish tint (Fig. 7.2a). Hemolysate of the patient’s erythrocytes showed two distinct peaks of oxyhemoglobin (OxyHb) at 541 nm and 576 nm (Fig. 7.2b). In addition to the two peaks of OxyHb, the patient’s serum showed a third unique peak at 631 nm, which corresponded to methemoglobin (MetHb) (Fig. 7.2c). Both gross appearance of the serum and the absorption spectrum analysis suggested that heme in the form of OxyHb and MetHb was markedly increased in the patient’s serum. These results indicated that either massive hemolysis is constantly taking place in vivo or that Hb accumulated in the serum due to defects in Hb catabolic pathway. Haptoglobin (Hp) concentration was extremely elevated at 800–1200 mg/dL (normal range; 19–170), and a large amount of the Hb-Hp complex was detected in the patient’s urine sample. Repeated measurement of serum bilirubin concentration was always low at 0.1–0.3 mg/dL (normal range; 0.2–1.3). Hemopexin was undetectable by immunoelectrophoresis. Serum heme concentration was extremely high at 490 μM (normal range; <1 μM). Both direct and indirect Coombs’ tests were negative on repeated occasions. Putting all these data together, it was highly suggested that there is a certain abnormality in the process of hepatic uptake of Hb-Hp complex or in heme degradation pathway (Fig. 7.3).
Heme oxygenase (HO ) is an enzyme which plays a key role in heme degradation to biliverdin. Three isoforms of HO are known, including HO-1, HO-2, and HO-3 (Maines 1988). Among these isoforms, HO-1 is peculiar in that it is rapidly induced in response to various oxidative stresses (Nath 2006). In contrast, HO-2 is a constitutive isoform that is expressed under homeostatic conditions. HO-3 is not catalytically active, but is thought to work in oxygen sensing. Immunohistochemical analysis of the liver biopsy specimen showed that Kupffer cells did not produce HO-1 in the patient’s liver (Fig. 7.4). Exposure of Epstein-Barr virus-transformed lymphoblastoid cell line (LCL) derived from the patient to oxidative stress such as hemin, cadmium, or sodium arsenite did not induce HO-1 protein (Fig. 7.5a and b). HO-2 was constitutively expressed in both controls and the patient LCL. HO-1 gene analysis revealed that the patient had compound heterozygotes of HO-1 gene mutations (Yachie et al. 1999). The maternal allele lacked the second exon, and the paternal allele showed two base pair deletions within the third exon (Fig. 7.5c).
Pathological examination of the first case of HO-1 deficiency revealed characteristic tissue injury. Notably, cellular injury was confined to selected organs and cell types, including the kidney, the liver, circulating monocytes, and vascular endothelial cells . In the kidney, mild mesangial proliferation and thickening of the capillary loop were observed within the glomeruli (Fig. 7.6a). Electron microscopy revealed marked swelling of the endothelial cells and their detachment throughout the glomerular capillary (Fig. 7.6b). In addition to the glomerular damage, tubulointerstitial injury with tubular atrophy was significant. The liver was massively enlarged, and there was a significant amyloid accumulation resulting in marked atrophy of hepatocytes (Fig. 7.6c, d). Scattered foci of iron deposits were observed in both the kidney and the liver (Kawashima et al. 2002). Cytoplasm of the circulating monocytes was vacuolated, and monocyte surface antigens were significantly different from normal profiles, as described later.
After we reported the first case of human HO-1 deficiency, only five additional cases have been confirmed by HO-1 gene analysis (Radhakrishnan 2011a, b, and personal communication). Fever, absence of the spleen, hemolytic anemia , hematuria/proteinuria, and the absence of jaundice seem to be the common denominators of the disease. The common clinical and laboratory features are summarized in Tables 7.1 and 7.2, respectively. All cases from India (from the second to the sixth cases) had identical homozygous mutation. However, the disease onset and durations vary significantly depending on the case. Laboratory findings were characterized by marked increase of platelet. Levels of hepatic enzymes, such as LDH, AST, and ALT, were significantly elevated. Low to normal serum bilirubin and high Hp concentration in the presence of hemolysis seems to be the hallmark of the illness.
2 Diagnosis
Because only limited numbers of patients with HO-1 deficiency (OMIM#614034) are known, there are no established diagnostic criteria for this very rare disease. Combinations of (1) absence or hypoplasia of the spleen, (2) extremely elevated LDH and ferritin, (3) leukocytosis and thrombocytosis, and (4) hemolytic anemia without jaundice are highly suggestive of this disease. Although the age of onset among the six HO-1 deficiency cases varied, ranging from infancy to 15 years of age, laboratory data and clinical profiles were surprisingly uniform. Fever, hemolytic anemia, and hematuria/proteinuria were consistent findings. In all cases, bilirubin remained within normal range, while serum ferritin and LDH values were invariably high. Although the absence or hypoplasia of the spleen seems to be the hallmark of the illness, its functional significance in patients with HO-1 deficiency has not been determined.
Differential diagnosis includes various childhood inflammatory illnesses including sJIA and other autoinflammatory diseases such as CINCA or NOMID.
3 Biochemical Perspectives or Molecular Perspectives
Heme is a major component of Hb, the product of erythrocyte destruction. Heme is constantly produced in vivo and it is extremely toxic to cells (Balla et al. 2007). Therefore, constitutive mechanisms exist to cancel the toxic effect of heme. Serum Hp binds free Hb efficiently, and the Hb-Hp complex is promptly taken up by phagocytes and hepatocytes which express the receptors for the complex, now known as CD163 (Madsen et al. 2004).
Heme catabolic pathway within the liver is shown in Fig. 7.7. Of particular importance is the fact that HO-1 not only plays role as a catabolic enzyme of heme degradation pathway; it also induces molecules, including carbon monoxide (CO) , which exerts potent antioxidative functions (Nakahira et al. 2006). HO-1 deficiency will lead to significant reduction of these molecules and subsequent cellular and tissue injury. However, there are numerous questions to be answered regarding the pathogenesis and the biochemical and molecular perspectives of HO-1 deficiency. Some of these questions are shown below.
3.1 Question 1: Why Only Certain Organs and Cell Types Are Damaged in HO-1 Deficiency?
Of particular interest is the fact that only selected cells or organs are damaged in HO-1 deficiency. Several mechanisms may explain this. First of all, these susceptible cells seem to be the targets of constant oxidative stress exposure, both for anatomical and functional reasons. Vascular endothelial cells are the target of shear stress and are exposed to multiple oxidative stresses, including hemolysis, pH changes, and hypoxemia for obvious reasons. In the HO-1-deficient patient, secondary accumulation of heme proteins, cholesterol, and fragmented erythrocytes further aggravates the oxidative stresses. Renal tubular cells are constantly exposed to hematuria, proteinuria, and various other excretory substances in urine. Tissue macrophages and circulating monocytes are frequently turned on to exert their scavenger functions. In addition, they function as one of the central players of innate and acquired immunity. Second, while these cells may be particularly sensitive to oxidative injury, they may serve as a high-quality sensor of oxidative stress for the susceptible organs. Upon exposure to oxidative insults, these sensor cells rapidly induce antioxidative molecules. As a result, the organs are saved from critical damage. HO-1 may participate as a central molecule to neutralize the oxidative stress.
In normal rat and human kidneys, renal tubular epithelial cells express HO-1 selectively. Distal tubules express significantly more HO-1 than the proximal tubules in a normal kidney (Fig. 7.8a). However, significant level of HO-1 expression is induced within proximal tubules in patients with hematuria or proteinuria (Fig. 7.8b). Proximal tubular epithelial cells also produce significant levels of HO-1 upon various oxidative stimuli in vitro, indicating that these cells are inherently capable of responding to exogenous noxious insults (Yang et al. 2003).
3.2 Question 2: How Does the Hypoplasia of the Spleen Occur and What Is Its Functional Significance?
We do not know exactly why all the patients with HO-1 deficiency lacked functional spleen. One hypothesis is that HO-1 deficiency and subsequent vascular endothelial injury results in early (most likely in utero) vascular damage involving the splenic artery. Due to accumulating injured blood cells, the patients’ spleens are overworked. The continuing splenic overwork may lead to the enhanced oxidative damage to the splenic vasculatures which are already vulnerable to oxidative stress . It is intriguing in this respect that hypomorphic mutation of HO-1 in mice resulted in the progressive atrophy of the spleen due to fibrotic changes in the splenic artery (Kovtunovych et al. 2010). These assumptions will remain as such until cases of HO-1 deficiency with intact splenic function are discovered.
Regardless of the mechanism leading to splenic hypoplasia, splenic dysfunction helps the survival of damaged, but still functioning, blood cells and prevents the fatal outcome. In contrast, the presence of functionally intact spleen may accelerate the destruction of injured blood cells thereby leading to fatal hemolysis and thrombocytopenia.
3.3 Question 3: What Is the Mechanism of Accelerated Cell Injury Seen in HO-1 Deficiency?
Direct consequences of HO-1 deficiency include extensive cell injury due to lack of the enzyme and induction of cell dysfunction, in particular, scavenger functions of macrophages . As we cannot extrapolate that these are the universal features observed in every HO-1-deficient patient, we analyzed the functional significance of HO-1 deficiency using the LCL derived from the patient.
LCL of the HO-1-deficient patient (HO-1-deficient LCL) was extremely sensitive to hemin-induced cellular injury (Fig.7.9). Extreme sensitivity of HO-1-deficient LCL to hemin stimulation could not be reversed by the addition of apoferritin or bilirubin. Furthermore, ferritin production by HO-1-deficient LCL was comparable with that by control LCL with or without the addition of hemin. Although ferritin and bilirubin may act as antioxidant in certain situations, they do not contribute much to the protection of cells from hemin-induced cell injury, at high hemin concentrations. LCL transfected with HO-1 gene was significantly less sensitive to hemin-induced cellular injury (Yachie et al. 1999). These results support the notion that degradation of heme by HO-1 is directly responsible for the reversal of cellular injury.
3.4 Question 4: What Are the Functional Defects of Macrophages?
In addition to cellular injury to the resident macrophages, the patient exhibited peculiar findings indicating a disturbance of macrophage scavenger function. Asplenia was certainly a significant contribution to the reduced scavenging function in the patient, resulting in the overload by other reticuloendothelial systems, including circulating macrophages and the hepatic Kupffer cells. The patient’s peripheral blood monocytes exhibited some morphological characteristics, including prominent vacuolation and basophilic cytoplasm (Fig. 7.1b). These changes may reflect a persistent, systemic inflammatory reaction. In addition to morphological changes, the surface antigen expression by these monocytes was abnormal, i.e., expressions of HLA-DR and CD36 were significantly reduced as compared with normal monocytes (Yachie et al. 2002). CD14 expression was comparable to that in the control. The reduction in the antigen expression was constantly observed after repeated examinations, indicating that these changes reflect abnormal monocyte functions in the patient.
Consistent with the changes in the surface molecules, monocyte phagocytic functions were also impaired dramatically. Although phagocytosis of fluorescence-labeled latex beads did not change significantly, that of opsonized erythrocytes was almost completely abolished. These results indicate that reduction of surface molecules are directly related to the abolishment of receptor-mediated phagocytosis of opsonized erythrocytes by monocytes. Various hematological and biochemical abnormalities seen in the HO-1-deficient patient, including increased Hp concentration, abundance of fragmented erythrocytes and thrombocytosis, and hyperlipidemia, may all be explained by the reduced scavenging functions of phagocytes.
3.5 Question 5: What Is the Role of Damaged Endothelial Cells in the Regulation of the Coagulation/Fibrinolytic System?
Another distinct feature of the first human HO-1 deficiency case was the defective endothelial function, as represented by extremely abnormal parameters of coagulation/fibrinolysis. Unlike in cases of other hematological illnesses associated with disseminated intravascular coagulation , our patient exhibited extraordinarily elevated values for thrombin-antithrombin complex, FDP, and plasmin-α2 plasmin inhibitor complex. Paradoxically, the platelet numbers constantly increased. The data indicated that HO-1 or HO-1 products, such as CO , may be associated with the regulation of the coagulation/fibrinolytic system.
We recently demonstrated in in vitro cultures that a CO-releasing molecule suppressed TNF-α-induced upregulation of tissue factor and plasminogen activator inhibitor type 1 by human umbilical vein endothelial cells . It also suppressed mitogen-activated protein kinases and NK-κB signaling pathway activation by TNF-α. Lipopolysaccharide (LPS)-induced TNF-α production by circulating mononuclear cells was also significantly inhibited by the CO-releasing molecules (Maruyama et al. 2012). These results may explain the characteristic findings seen in the HO-1-deficient patient. At the same time, the data support the view that CO-releasing molecules may constitute a novel anticoagulative and anti-inflammatory therapy .
A summary of the macrophage activation and endothelial cell dysfunction is shown in Fig. 7.10. Lack of HO-1 resulted in unregulated activation of macrophages with excess inflammatory cytokine release. At the same time, HO-1 deficiency resulted in overproduction of tissue factor by endothelial cells and macrophages, leading to the abnormal activation of the coagulation/fibrinolysis system. The figure illustrates the role of HO-1 as an inhibitor of cytokine overproduction and endothelial cell dysfunction. It was intriguing that the HO-1-deficient patient did not run an acute catastrophic course. On the contrary, prolonged and sustained activation of macrophages, platelets, and endothelial cells led to exhaustion and dysfunction of these cells.
3.6 Question 6: What Is the Impact of HO-1 Deficiency on Macrophage Function?
Monocytes/macrophages are composed of at least two functionally distinct subsets, M1 and M2 (Geissmann et al. 2003). The different subsets of the monocyte/macrophage lineage differentiate in response to environmental stimuli. M1 macrophages are the “classical” macrophages, and they comprise the pro-inflammatory subset, whereas M2 macrophages are “alternatively” activated macrophages. They resolve inflammatory responses, perform scavenger functions, and promote tissue remodeling and repair. Interferon (IFN)-γ is the key cytokine driving the M1 pathway, whereas IL-4, IL-10, and steroids promote monocyte differentiation into M2 macrophages.
We reported previously that circulating monocytes produce significant levels of HO-1 during Kawasaki disease and infectious diseases, suggesting its anti-inflammatory role during these illnesses (Yachie et al. 2003). Furthermore, we investigated the profiles of cytokine mRNA expression in two subsets of circulating monocytes (Mizuno et al. 2005). In this study, freshly isolated CD16high/CCR2negative monocytes expressed significant levels of HO-1 mRNA in vivo. They produced little IL-10 upon stimulation with LPS. In contrast, the major subset of CD16low/CCR2positive monocytes did not express HO-1 mRNA in vivo, whereas they responded significantly to LPS and produced IL-10. The fractions of CD16high/CCR2negative monocytes increased during various acute inflammatory diseases, such as Kawasaki disease and influenza virus infection, suggesting that monocytes play anti-inflammatory roles through HO-1 production.
In macrophages and dendritic cells, CO reduces pro-inflammatory and increases anti-inflammatory cytokine secretion in response to LPS (Lee and Chau 2002). HO-1-mediated anti-inflammatory effects may therefore be closely linked to anti-inflammatory mechanisms, such as the suppression of the immune and inflammatory responses in macrophages via diminished antigen-presenting capacity and cytokine synthesis (Listopad et al. 2007). This is consistent with our finding in the HO-1-deficient patient, in whom the lack of HO-1 resulted in a marked rise in circulating heme and subsequent oxidative vascular and tissue injury, anemia, and chronic inflammation. Schaer et al. reported that macrophages express upregulated levels of CD163 in sepsis-induced hemophagocytic syndrome (Schaer et al. 2006). HO-1 is induced by CD163-mediated Hb-Hp complex uptake (Fig. 7.11) (Yamazaki et al. 2007). These macrophages expressed significant levels of HO-1, suggesting their role as a negative regulator of inflammation.
4 Therapy
No effective therapy is known. However, careful avoidance of various types of external stress, including infections, physical stresses, and medical interventions, may at least prolong the onset of the catastrophic episodes. There is no evidence to support the roles of anti-inflammatory drugs or immunosuppressive agents. Experiences with only limited numbers of HO-1-deficient patients indicate that once the onset of the inflammatory processes is triggered, it is extremely difficult to prevent the progression of the subsequent organ damage.
End-of-Chapter Questions
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1.
What are the common clinical findings of human HO-1 deficiency?
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2.
What are the common laboratory features of human HO-1 deficiency?
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3.
What could be the differential diagnosis of patients with HO-1 deficiency?
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4.
The ages of onset for each HO-1-deficient patient are significantly different. What are the possible reasons for this?
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Yachie, A. (2019). Heme Oxygenase-1 Deficiency. In: Oohashi, T., Tsukahara, H., Ramirez, F., Barber, C., Otsuka, F. (eds) Human Pathobiochemistry. Springer, Singapore. https://doi.org/10.1007/978-981-13-2977-7_7
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