A child with abdominal pain, arthralgia, palpable skin rash, hepatosplenomegaly, and pancytopenia: Answers

Although the triad of purpura, arthritis, and abdominal pain is suggestive of Henoch-Schonlein purpura (HSP)/IgA vasculitis, this is likely the manifestation of an underlying secondary etiology.

Palpable purpura, arthritis, and abdominal pain point toward a diagnosis of IgA vasculitis but hepatosplenomegaly, low platelet count, and abdominal wall venous engorgement along with history of hematemesis suggest the possibility of an underlying liver disease. Many systemic conditions may be associated with secondary IgA vasculitis among which systemic inflammation, infections, neoplasm, and chronic liver diseases are common (Table 1). Considering the possibility of variceal bleeding in a child with hepatosplenomegaly, subsequent investigations focussed on finding any evidence of underlying liver disease. Abdominal sonography confirmed hepatosplenomegaly but did not find any obvious change in liver echo-texture. On the other hand, magnetic resonance imaging (MRI) of the abdomen revealed heterogenous liver and dilated portal veins. Upper GI endoscopy revealed early gastric varices and portal congestive gastropathy. Detailed work-up for liver disease revealed low serum ceruloplasmin (< 3 mg/dl) with high 24-h urinary copper excretion (271.85 μg/day). Slit lamp bio-microscopy showed evidence of Kayser-Fleischer rings in both eyes. Modified Leipzig score for this child was 7 and Ferenci score was 6, which were consistent with the diagnosis of Wilson disease [1]. This was further confirmed by whole exome sequence which showed pathogenic heterozygous mutation in the ATP7B gene.

The principal features of primary or secondary IgA vasculitis are increased deposition of “abnormal” IgA in various organs, particularly the kidney, and skin-triggering immune reaction. The abnormal O-glycosylated hinge region (Gd-IgA1) in IgA1 plays a key role in the pathogenesis of IgA vasculitis. Normally, IgA1 is produced in the bone marrow but aberrantly glycosylated IgA1 (Gd-IgA1) is produced in response to mucosal insult. Significantly high levels of Gd-IgA1 have been reported in patients with IgAN and their first-degree relatives [2]. Genome-wide association studies have identified a major locus on chromosome 22q12.2 influencing susceptibility to IgAN and variation in serum IgA level. IgG antibodies specific for N-acetylgalactosamine (GalNAc) residues in O-linked glycans of the hinge region of IgA1 heavy chains have been found in patients with IgAN. Although a low level of this anti-glycan IgG antibody may be present in healthy individuals, a high serum level is usually associated with disease severity [3]. The anti-glycan IgG antibody recognizes GalNAc-containing epitopes on the galactose-deficient hinge region O-glycans of IgA to form an immune complex (IgA1-IgG). Although this circulating immune complex is not unique to IgAN as it can be detected in healthy individuals and in HSP without nephritis, a large circulating antibody complex is associated with HSP nephritis [4]. Deposition of antibody to Gd-IgA1 (IgA or IgG) and/or immune complex (IgA1-IgG) in kidney mesangial cells leads to activation of inflammatory cells and complement system resulting in kidney manifestation of IgA vasculitis. The pathogenesis of secondary IgA vasculitis remains unclear. Currently, it is postulated that abnormal production or impaired clearance of IgA or immune complex plays an important role [5]. Liver damage not only impairs clearance but also has been shown to alter gut permeability resulting in easier passage of IgA formed against common food and microbial antigens into the blood stream [6, 7]. Similarly, diseases like irritable bowel syndrome, Crohn’s disease, inflammatory bowel disease, celiac disease, and other gastrointestinal tract diseases have also been associated with IgA nephropathy [8]. It has been shown that patients with secondary IgAN have high levels of circulating Gd-IgA1and IgA1-IgG complexes and glomerular deposition of Gd-IgA1 which suggest that secondary IgAN has a shared feature with primary IgAN [9].

There is no standard management strategy for secondary IgA vasculitis but improvement is often observed by treating the secondary etiology [10, 11]. Along with supportive care of the kidney, our child was started on standard treatment for Wilson disease which included d-penicillamine and zinc sulfate [1, 12]. Corticosteroid was weaned off and angiotensin-converting enzyme inhibitor (ACEI) was added to control the proteinuria. At 6 months of follow-up, he showed complete resolution of proteinuria, hematuria, and normalization of eGFR; thus, ACEI was stopped.