Background

Henoch-Schonlein purpura (HSP), an immune-mediated systemic vasculitis has an estimated incidence in European children of 22.1/100,000/year, with peak incidence between 4 and 6 years of age [7]. Characteristic symptoms and signs include palpable purpuric rash, abdominal pain, arthralgia and nephritis [3, 20]. Gastrointestinal signs and symptoms, including colicky abdominal pain, nausea, vomiting, diarrhoea or bleeding, occur in 30% of cases or more, although serious complications such as intussusception, perforation, or obstruction are unusual [20]. However, massive and potentially life-threatening gastrointestinal haemorrhage may occasionally occur [1, 25].

There have been recent reports of atypical HSP in which sometimes severe renal or gastrointestinal lesions occur before or without the skin rash, causing significant diagnostic difficulty [5, 6, 8, 15, 21, 23]. We present a patient with atypical HSP who suffered life-threatening massive gastrointestinal haemorrhage from multiple intestinal sites, in whom IVIG infusion rapidly induced resolution of all abnormalities.

Materials and methods

Immunohistochemical analysis was performed using standard techniques, as previously described [22]. Primary antibodies included T cell markers (CD3, 4 and 8) and HLA-DR (Dako, Ely, UK). FITC-conjugated antibodies were used to study the distribution of IgA, IgG and IgM (Dako), while C1q was localised with a polyclonal antibody (Dako) followed by TRITC-conjugated anti-rabbit antibody. Sulphated glycosaminoglycans (GAGs) were localised by specific histochemistry using poly-lysine gold at pH 1.2, as previously described [16], and HSPG was localised using monoclonal 10E4 (Seikagaku, Abingdon, UK).

Clinical presentation

A previously well 9-year-old girl presented with pallor, dizziness and abdominal pain, developing severe haematemesis and melaena. There was no history of URTI, rash, arthralgia, drug ingestion or allergy. Examination showed one oral aphthous ulcer, but no other skin lesions. She was tachycardic but normotensive, anaemic with Hb 4.7 g/dl, and had normal clotting. CRP was normal (1 mg/l), serum albumin reduced at 29 g/l and creatinine 45 μmol/l. Urinalysis was not available due to oliguria. She was transfused and treated with octreotide infusion (5 μg/kg/h). Upper endoscopy showed diffuse severe oozing haemorrhagic gastritis, while histology showed patchy chronic gastritis, but no H. pylori. Urease (CLO) test for H. pylori was also negative.

Treatment was initiated using sucralfate and intravenous omeprazole. Despite this, she bled again two days later, becoming shocked despite transfusion, octreotide and tranexamic acid, and her haemoglobin dropped from 10.2 to 5.5 g/dl. Investigations showed increased CRP (124 mg/l) and IgG (24.5 g/l, normal range 8–16 g/l), without elevation of IgA or IgM (both 0.6 g/l), while albumin had dropped to 24 g/l. Urgent isotope red cell scan showed bleeding at several sites, including stomach, small intestine and colon (Fig. 1). As urinalysis now demonstrated proteinuria and haematuria, a clinical diagnosis of HSP was made despite the absence of skin rash. As we considered corticosteroids contraindicated by severe gastritis, she was commenced on IVIG therapy at 2 g/kg/day. The bleeding terminated abruptly, and she has remained well since (over 2 years). All other investigations performed, including extensive virological screening, stool culture and microscopy, autoimmune panel and coeliac serology were normal. Repeated endoscopy showed resolving gastritis and mild duodenitis. Urgent immunohistochemical analysis, performed due to diagnostic uncertainty, showed focal subepithelial clusters of CD4 T cells in the stomach, while CD8 intraepithelial lymphocytes (IELs) were densely increased in the duodenum (Fig. 2). There was extensive extracellular IgA deposition in both stomach and duodenum, localising on small vessel endothelium (Fig. 2). Further evidence of vascular activation included HLA-DR expression and HSPG loss in small vessel endothelium. There was focal subepithelial IgG deposition in stomach and duodenum, partially co-localising with C1q. Epithelial expression of HSPG and sulphated GAGs were reduced in both stomach and duodenum (Fig. 2), and likely to induce intestinal protein leak as these strongly anionic molecules represent a constitutive charged barrier to albumin leakage in the intestine [4, 16].

Fig. 1
figure 1

Isotope red cell scan showing accumulation of tracer within the small intestine. Evidence of blood loss at several sites was seen during this procedure

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Fig. 2
figure 2

Mucosal findings in stomach and duodenum. a Gastric histology (original magnification, ×10) showing blood within the lumen, and relatively mild inflammatory infiltrate around the epithelium. b Higher power view (×40) showing infiltration of small dark mononuclear cells around the gastric epithelium. c Staining for CD3 T cells in gastric antrum, showing dense focal aggregation beneath the surface epithelium. These were predominantly CD4+ on serial section. d Focal deposition of IgG beneath the gastric epithelium. This partially co-localised with complement C1q on serial section. e Dense staining for IgA within gastric mucosa, with IgA deposition on endothelium of small vessels. f Duodenal biopsy (×10), showing villous blunting and patchy infiltration of mononuclear cells into the lamina propria and epithelium. g Focal IgA deposition on vascular endothelium within the duodenal lamina propria. h Distribution of sulphated glycosaminoglycans (GAGs—brown staining) within the duodenum, showing scanty expression on surface epithelium (×10). i A duodenal villus (×40), showing absent sulphated GAGs on the endothelium of a small vessel. This is indicative of vascular activation, and HLA-DR expression was also upregulated (not shown). j Dense increase in CD3+ T cells within the duodenal surface epithelium. k Serial section to j and l, stained for CD4+ cells, showing few CD4+ intraepithelial lymphocytes. l Serial section to j and k, stained for CD8+ T cells, showing that the majority of the intraepithelial lymphocytes were CD8 cells

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Discussion

This patient presented with severe multifocal gastrointestinal haemorrhage associated with mucosal IgA deposition and a massive increase in duodenal IELs. The dense IgA deposition on mucosal vessels, with concomitant renal involvement, are diagnostic of HSP [3, 20]. Previous reports of atypical HSP with predominant gastrointestinal involvement have shown that skin rash may develop late or indeed never appear [5, 6, 8, 15, 21, 23]. For our patient, we speculate that successful response to IVIG may have terminated her disease before skin lesions could develop. We learned that life-threatening intestinal complications of HSP may develop without skin rash, and emphasise the importance of urinalysis for proteinuria and haematuria in cases of unexplained gastrointestinal haemorrhage.

The pathogenesis of HSP shares features with IgA nephropathy, including reduced IgA1 glycosylation, possibly pathogen-induced [3, 20]. This predisposes to circulating IgA immune complexes, usually deposited in kidney, skin or gut [20]. The antigenic content of these complexes suggests possible derivation from gut contents, including dietary proteins such as gliadin [14]. Gastrointestinal lesions in HSP are characterised by focal vascular IgA deposition [12, 24], as in this case, and the formation of IgA anti-endothelial antibodies may occur [20]. The cytokine centrally involved in the isotype shift of mucosal B cells to IgA is transforming growth factor β1 (TGF-β1) [17]. It is thus notable that a polymorphism causing high TGF-β production is associated with HSP [27], and increased circulating TGF-β-producing Th3 cells have been identified in acute HSP with gastrointestinal and not renal involvement [26]. By contrast, polymorphisms for interleukin-1β (IL-1β) and IL-1 receptor antagonist genes have been associated with renal, but not gastrointestinal, involvement [2].

Most cases of HSP resolve spontaneously, but in severe or complicated cases several immunomodulatory therapies have been used successfully, including corticosteroids, azathioprine, cyclophosphamide, cyclosporine and plasmapheresis [2, 20]. We faced a therapeutic dilemma, as our patient had life-threatening multifocal gastrointestinal haemorrhage, but with severe gastritis, which we considered precluded the use of steroids. We chose IVIG on the basis of efficacy in other vasculitides, and noted prompt and complete cessation of her multifocal enteric bleeding. Similar prompt resolution of gastrointestinal HSP has been reported in a 56-year-old man with bloody diarrhoea [9], and in a 19-year-old man [19], a 10-year-old boy [13] and a 5-year-old girl [10] whose chronic abdominal HSP symptoms were unresponsive to corticosteroids. Important recent evidence identifies the central mechanism of action of IVIG to be sialylation of immunoglobulin Fc regions, altering interaction with Fc-γ receptors [11]. Whether such IVIG-induced glycosylation may extend to correcting the undersialylation of IgA1 characteristic of HSP [2, 20] is an intriguing question that warrants further study. While the response of renal HSP to IVIG may be less striking [18], consistent reports of a prompt gastrointestinal response to IVIG therapy suggest that this should be considered as an important therapeutic option in cases of HSP with severe abdominal symptoms.