Raised Serum Levels of Syndecan-1 (CD138), in a Case of Acute Idiopathic Systemic Capillary Leak Syndrome (SCLS) (Clarkson’s Disease)

Background

Systemic capillary leak syndrome (SCLS) (Clarkson’s disease) presents clinically with transient hemoconcentration, hypoalbuminemia, hypotension, and generalized edema, without known cause [1]. In 1960, Clarkson et al. first described an idiopathic form of this disorder characterized by repeated episodes of edema and hypotension associated with increased capillary permeability that resolved spontaneously [2]. Although triggers for acute episodes of SCLS have not yet been identified, they are frequently preceded by viral infections or intense physical exertion, suggesting a role for inflammatory mediators in acute SCLS [1].

Common complications of SCLS include hypotensive shock, acute kidney injury resulting from hypovolemia, and muscle compartment syndromes due to massive soft tissue edema, which can lead to mortality in untreated cases. Treatment for acute episodes of SCLS is supportive, including an intravenous infusion of crystalloids, colloids, and vasopressors to maintain adequate blood pressure, but with avoidance of excessive intravenous fluids that can exacerbate edema. Clinical observation and monitoring for the early signs and symptoms of an acute attack of SCLS, and treatment in a highly equipped intensive care unit (ICU) are all important measures to improve the chances of patient survival. A monoclonal gammopathy, typically IgG kappa, has been described in up to 90% of patients with acute SCLS [3,4]. From the published literature, most cases of SCLS present in middle-aged adults, and SCLS is equally reported in both sexes [5,6]. Although at least 300 cases of SCLS have been reported in the literature at this time, because the condition is rare and the diagnosis may be missed, it is likely that cases of SCLS are under-reported.

Findings from in vitro studies suggest that vascular endothelial hyperpermeability contributes to the clinical presentation of SCLS [7,8]. Also, serum samples from patients in the acute phase of SCLS, when added to normal microvascular endothelial cells in culture disrupted cell-cell contacts and induced morphological changes consistent with vascular barrier dysfunction [7,8]. Microvascular endothelial cells provide the foundation for the vasculature, and on their luminal side, the microvascular endothelial cells secrete endothelial surface glycocalyx (ESG), which is of critical importance for the stabilization of hemodynamic equilibrium [9]. The basal side of the endothelium, lined by a basement membrane, forms important contacts with the extracellular matrix. These microvasculature structures function as a barrier between the blood and the interstitial fluid. During acute episodes of SCLS, the microvascular endothelial barrier is highly permeable for fluid, plasma, and protein molecules of up to 900 kDa, which can enter into the interstitial space, causing edema [10]. The specific molecules that mediate endothelial hyperpermeability in SCLS are unknown.

Although a flu-like prodrome has been reported in up to 88% of cases of SCLS, specific infectious or other triggers for attacks can only be identified in approximately 60% of cases [3,5]. Common complications of acute attacks of SCLS include acute kidney failure (89%), muscle compartmental syndromes with rhabdomyolysis (43%), thromboses, pulmonary edema, and painful peripheral neuropathies. The five-year survival rate for SCLS has been reported to be between 73–78% [3,5].

This report is the second known case of SCLS in Norway [9]. In addition to reporting a rare condition, this report includes details of the medical history of the family members, in an attempt to identify predisposing factors for SCLS. In this case, a family history of lymphoproliferative disorders, cardiovascular disease, cancer, and diabetes was identified. A transient increase in the cell surface heparan sulfate proteoglycan, syndecan-1 (CD138) was identified during the acute presentation, which normalized during the recovery phase. These findings suggest that reduced ESG function could contribute to vascular endothelial hyperpermeability in SCLS.

Case Report

RELEVANT PAST MEDICAL HISTORY AND FAMILY HISTORY:

Examination of the patient’s prior medical history showed that she was born nine weeks before term, weighing 1,070 g. Pregnancy and delivery were complicated by toxemia, Rhesus incompatibility, and exchange transfusion. She had appendicitis at two-years-of-age, which was complicated by sepsis. From early childhood, she had repeated urinary tract infections with cystitis, and at least four episodes of cysto-pyelonephritis, but she had no permanent kidney damage. During her pregnancies an increased blood glucose was noted.

In her paternal family, there were several cases of premature death due to heart disease, cancer, and diabetes. Her mother had toxemia associated with all three pregnancies, and died at 76 years-of-age and had a weak serum IgM-lambda monoclonal gammopathy of undetermined significance (MGUS). Six of mother’s brothers and sisters died of cardiovascular disease, and one of the mother’s sisters died at 72-years-of-age of multiple myeloma after 12 years with a known IgA-kappa monoclonal gammopathy of undetermined significance (MGUS).

Discussion

The pathogenesis of systemic capillary leak syndrome (SCLS) (Clarkson’s disease) is not understood, and the site of the vascular endothelial hyperpermeability in SCLS remains unknown. Although transient increases in circulating vascular endothelial growth factor (VEGF), angiopoietin-2 (Angpt-2), and monocyte/macrophage-associated inflammatory mediators including C-X-C chemokine motif 10 (CXCL10), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 during acute episodes of SCLS suggest a role for these cytokines in the mechanism of vascular leak, the specific pathways resulting in vascular endothelial hyperpermeability in SCLS remain unknown. Preliminary study findings from our laboratory (unpublished data) suggest that individuals affected by SCLS have cutaneous hyper-responsiveness to inflammatory mediators that affect the microvasculature and that endothelial cells derived from patients with SCLS exhibit this behavior persistently in vitro.

The barrier function of the microvasculature is a complex physiological process in which adhesive cell-cell junction contacts prevent plasma and cell extravasation. Under normal homeostatic conditions, microvascular endothelial cells secrete endothelial surface glycocalyx (ESG), which fortifies the endothelial barrier via several mechanisms. ESG is a fibrous matrix rich in negatively-charged proteoglycans containing sialic and neuraminic acids, which prevent binding of circulating leukocytes and platelets. Vascular endothelial cells actively build and replenish the structural components of ESG, as well as blood group antigens and endothelial superoxide dismutase (eSOD). Components from plasma, including albumin, anti-thrombin, and calcium ions, are interspersed throughout the ESG meshwork, which helps to maintain intravascular osmotic pressure, coagulation, and platelet adhesion [13,14]. ESG also protects endothelial cells from shear stress induced by circulating blood, and ESG degradation due to endothelial cell damage may contribute to the severity of plasma leak in diverse clinical conditions including, dengue virus infection and heart failure [15–17].

Syndecan-1 (CD138) is a transmembrane proteoglycan component of ESG that binds to hyaluronan on the luminal side of the endothelial cell membrane and cytoskeletal components on the cytosolic side. In conditions associated with ESG disruption, for example, sepsis, trauma, and ischemia, syndecan-1 (CD138) is shed and circulates in the serum, reflecting both damage to the ESG and weakening of the endothelial barrier [18]. Damage to ESG promotes white blood cell and platelet adherence to the endothelial wall, initiating thrombosis. Plasma fluid leaks into the interstitial space through trans-endothelial cell pores and through widened intercellular gaps, which partially depend on the availability of syndecan-1 (CD138) [9].

In the case of the patient in this report, fluctuating levels of syndecan-1 (CD138) were found during the presentation of SCLS. Serum syndecan-1 (CD138) levels were within the normal range for the first several days of the acute presentation, peaked at five times the upper limit of normal on the sixth day, and then returned to baseline after that. An upper respiratory infection preceded the attack of SCLS in this patient, and it has previously been reported that viral membrane components, including neuraminidase, may lead to ESG disruption through digestion of neuraminic acids [19]. Therefore, viremia may have resulted in disruption of ESG in this patient. Serum syndecan-1 (CD138) levels increased to nearly ten times the upper limit of normal on days 9–12, which could reflect reperfusion injury resulting from mobilization of extravasated fluid during the recovery phase and restoration of intravascular volume, a phenomenon that has been described by previous clinical studies [20]. Syndecan-1 (CD138) levels returned to baseline during the convalescent phase, indicating the resolution of the acute endothelial dysfunction.

In this patient, several additional laboratory abnormalities were found during the acute phase in our patient that have not been previously reported in association with SCLS. Low levels of C3 and C4 were detected on the ninth day of the disease, which could reflect extravasation due to increased microvascular permeability, rather than complement consumption. Mannose-binding lectin (MBL) was low or undetectable in our patient. MBL adheres to mannose on the surface of many pathogens forming the complex, MBL-associated serine protease (MASP). MASP leads to the cleavage of C4 into C4a and C4b; C4b fragments then bind to microbes, initiating formation of C3-convertase. The subsequent complement cascade catalyzed by C3-convertase creates a membrane attack complex, which causes lysis of the pathogen as well as apoptosis and cell necrosis. MBL binds to glycoprotein in viruses and is instrumental in the first-line defense against infection [21]. MBL deficiency has been reported to be associated with recurrent infections in humans but has not previously been reported in SCLS. In the case of the patient in this report, MBL deficiency may have accounted for her history of frequent infections, including cystitis and pyelonephritis, as well as the frequent upper respiratory tract viral infections, such as the episode that triggered her attack of SCLS. Low levels of IgG and IgA, with normal levels of IgM, are findings that have previously been reported in cases of SCLS [22,23].

Finally, an important aspect of this case report was the discovery that several family members also had a history of monoclonal gammopathy of undetermined significance (MGUS). Although none of this patient’s relatives had a history of episodes of SCLS, to our knowledge, such familial clustering of paraproteinemia has not been previously reported in SCLS, and the pathophysiological significance of this finding requires further study [24].

Conclusions

This case report supports the view that damage to the microvascular endothelium and its ESG have a role in the pathogenesis of acute systemic capillary leak syndrome (SCLS) (Clarkson’s disease). This case also indicated that monitoring serum levels of syndecan-1 (CD138) might be used to monitor progression and resolution of episodes of SCLS. Further studies are needed to determine the mechanisms underlying the degradation of endothelial surface glycocalyx (ESG) and vascular damage in SCLS.