Take a look at the Recent articles

Abstract

Aim: We report a case report that combines numerous Autoimmune manifestations (AIMs), some of which preceded the diagnosis of Gaucher disease (GD) – and this despite the presence of cardinal signs of GD hidden due to the associated AIMs.

Keywords

autoimmune manifestation, hyperpigmentation, autoantibodies

Introduction

Autoimmune manifestations (AIMs) can be observed during viral infections, cancers, toxic or drug intake and thus simulate autoimmune diseases. More recently, these AIMs are increasingly reported during Gaucher disease (GD), a genetic disorder belonging to lysosomal storage diseases defined by a deficiency in β glucocerebrosidase [1] and characterized by an activation of the immune system [2-6].

During GD, there is an activation of the immune system expressed by hypergammaglobulinemia [7,8], but also an increase in the incidence of autoantibodies that are exceptionally associated with clinical manifestations [9].

Case presentation

A 23-year-old woman with a history of chronic inflammatory bowel disease (IBD) (unclassifiable colitis) under treatment (corticosteroids and 5-Aminosalicylic acid ‘5-ASA’) for one year was hospitalized with clinical symptoms combining subicterus, type 1 splenomegaly and hepatomegaly with a hepatic arrow at 16 cm associated with an altered liver tests with cytolysis twice the normal and increased conjugated bilirubin.

Viral serologies B, C were negative. Hyperglobulinemia at 35 g/l was noted, predominantly on IgG. Anti-smooth muscle antibodies were positive at a significant level. Liver Doppler ultrasound and esophago-gastro-duodenal endoscopy did not reveal signs of portal hypertension. The liver biopsy revealed an appearance of moderately active chronic liver disease with a predominantly portal and periportal inflammatory infiltrate, which led to the diagnosis of autoimmune hepatitis (AIH) according to the International Autoimmune Hepatitis Group (IAIHG) criteria. This patient had hyperpigmentation plaques on the face and limbs (Figure 1), probably related to chronic hyperferritinemia. Photosensitivity, hair loss, oral ulcers, infiltrated purpuric lesions, and livedo in the legs, as well as arthritis of the left ankle, were also noted.     

Figure 1. Hyperpigmentation

Biologically, leukopenias with lymphopenia at 900 cells/mm³, fluctuating thrombocytopenia 85,000-90,000/mm³ were found on successive blood counts as well as a normocytic, non-regenerative anemia at 9 g/dl. The Coombs test was positive without signs of hemolysis. Hyperferritinemia (X10 N) was noted. Renal function and urinary sediment were normal, with negative 24-hour proteinuria. Autoimmunity assessment found antinuclear antibodies (ANA) + 1/320 DNA++, anti-Sm+++ antibodies, and a C3 level within normal limits. The chest image and cardiac Doppler ultrasound were unremarkable. The diagnosis of systemic lupus erythematosus (SLE) was made at this stage given the presence of more than 4/11 SLICC criteria and the patient, due to the association with active AIH, was treated with corticosteroid therapy combined with an immunosuppressant such as azathioprine (50 mg X3/day). Photoprotection and synthetic antimalarials such as hydroxychloroquine 200 mg X2/day had been combined to control the lupus disease.

The persistence of splenomegaly, anemia and thrombocytopenia, as well as hyperferritinemia and the appearance of diffuse bone pain, justified a bone marrow aspiration which revealed the presence of numerous typical Gaucher cells. GD was confirmed by the enzymatic assessment which revealed a collapse of the leukocyte activity of β-glucocerebrosidase (0.1 µmol/l/h) and genetic by the detection of two homozygous mutations: c.[259C>T]; [259C>T] (p.[Arg87Trp];[Arg87Trp]).

GD activity was demonstrated by elevated chitotriosidases and ferritin levels. GD lesion assessment revealed osteopenia, without bone deformities or bone infarction, in addition to organomegaly and cytopenia. The enzyme replacement therapy (imiglucerase at a dose of 60 IU/kg every 15 days) was initiated.

The outcome was favorable under enzyme replacement therapy, with disappearance of organomegaly, bone pain, normalization of hematometric parameters, and a decrease in chitotriosidase levels from the third month. A subsequent family history led to the diagnosis of GD with the same genetic mutation in three other sisters, two of whom were eligible for enzymotherapy replacement treatment. Seven years later, the patient gave birth to a healthy baby boy, followed by two early abortions.

During her follow-up, the patient presented with a right upper lobe pulmonary embolism with no triggering factors. The D-dimer level was 10 times normal, and venous Doppler ultrasound examinations revealed no thrombosis of the inferior vena cava or lower limbs. A thrombophilia assessment revealed significant anti-cardiolipin and anti-β2GPI antibodies, rechecked 12 weeks later, thus establishing the diagnosis of antiphospholipid antibody syndrome (APLS). A follow-up chest CT angiography revealed recanalization of the pulmonary arteries, and Doppler echocardiography found no evidence of embolic post-chronic pulmonary hypertension.

Three years later, the patient became pregnant again and received treatment combining aspirin 100 mg/day and enoxaparin at a curative dose, which allowed for uneventful pregnancy, delivery, and postpartum. During her regular checkups, the appearance of intense pruritus and cholestasis syndrome warranted a biliary MRI, which revealed the appearance of primary sclerosing cholangitis (PSC). The pruritus and biological cholestasis were improved and stabilized with treatment with ursodeoxycholic acid at an increasing dose.

The progression of the inflammatory colitis was marked by episodes of relapsing and remitting associated with extra-digestive manifestations such as pyoderma gangrenosum (Figure 2), despite optimized treatment, and the benefit of anti-TNF agents in this patient was raised.

Figure 2. Pyoderma Gangrenosum     

During follow-up, the patient developed vascular purpura in the lower limbs (Figure 3) associated with crusty and hemorrhagic rhinitis as well as sinusitis and paresthesias of the limbs. A skin biopsy at this level revealed an appearance of leukocytoclastic vasculitis with negative immunofluorescence. The ENT examination was unremarkable.  

Figure 3. Cutaneous signs of vasculitis in the form of purpuric lesions

CT scan of the sinuses demonstrated a non-destructive appearance of left maxillary sinusitis, while a CT scan of the chest was unremarkable. The electro-neuro-myogram ‘ENMG’ was unremarkable, as were the renal function tests, proteinuria, and urinary sediment. However, ANCAs were positive with anti-PR3 specificity, checked twice. The Five Factors Score ‘FFS’ score of 0 warranted corticosteroid therapy. Vitamin-calcium supplementation and diphosphonate courses were associated due to the bone risk of GD, comorbidities (bowel disease), and long-term corticosteroid treatment. 

Results and discussion

According to the literature, it has been established that during MG different autoantibodies can be observed. Indeed, the accumulation of residues in left-handed cells is associated with an inflammatory state, causing macrophage activation and secretion of cytokines [5,10] such as IL6, IL10 or IL2 associated with hyperactivity of the immune system and correlated with the development of mono or polyclonal gammopathy [11,12], which in turn promotes the appearance of autoantibodies [13,14]. Serratrice, et al. [15], highlighted a clear increase in the prevalence of antibodies in patients with type 1 MG compared to healthy patients with a predominance of antiphospholipid antibodies in 30% of patients but without thrombotic manifestations. The antinuclear antibodies ‘ANA’ were also more frequent in patients with type 1 GD but again without there being clinically evident AIDs.

Serratrice, et al. [15], have also demonstrated during their study which involved 40 patients with type 1 GD that there was no correlation between the presence of autoantibodies and the genotype of the disease, the treatment or the splenectomy except for anti-cardiolipin antibodies whose prevalence was higher in splenectomized patients. However, rare cases of AID associated with type 1 GD have been reported, such as autoimmune hemolytic anemia ‘AIHA’ [15], SAPL [16], or autoimmune thrombocytopenia ‘AIT’ [17,18]. Others exceptional associations have been reported such as rheumatoid arthritis [19],  Sjogren’s syndrome [20,21] and even proven lupus with class IV nephropathy [22]. Indeed, on 84 patients with type 1 GD Indeed, Rosenbaum et al demonstrated AIT in 3.5% of patients, 2.3% had AIHA but also the presence of a circulating lupus anticoagulant in 5.9% of cases associated with proven APS in one patient. ANA and anti-DNA were present in 8.3%. [22]. Preliminary results in this same cohort highlighted the presence of autoantibodies in 62.5% of patients, a decrease in antibody levels was observed in some patients after the start of enzyme treatment [23]. In our patient, the diagnosis of SLE rather delayed the diagnosis of GD even though the SLICC classification criteria were met. We have not found any data in the literature regarding an association between ANCA vasculitis and GD, especially since we do not have sufficient criteria for the diagnosis of systemic granulomatosis with polyangiitis.

Conclusion

Even if the presence of autoantibodies during GD is well established, it is most often asymptomatic. However, the case of our patient has proven that it is possible to have the association of different clinically and biologically evident pathologies during GD. This case report raises the hypothesis that AIDs during GD would be more than a fortuitous association and would constitute more the expression of an immunological disorder exposing to an increased risk of AID in the same way as that described for myeloma and certain cancers during GD. The diagnostic wandering induced by these AIDs when they first appear and take center stage is more anecdotal and, in our observation, would be attributable to common signs characterizing GD and AIDs (cytopenias, hypergammaglobulinemia, hyperferritinemia, bone, hepatic and digestive disorders).

Conflicts of interest

The author declares no conflict of interest.

References

1. Zimran A, Elstein D, vom Dahl S (1992) Gaucher disease. Clinical, laboratory, radiologic, and genetic features of 53 patients. Medicine 71: 337-353. [Crossref]
2. Mignot C, Doummar D, Maire I, De Villemeur TB, French Type 2 Gaucher Disease Study Group,  et al. (2006) Type 2 Gaucher disease: 15 new cases and review of the literature. Brain Dev 28: 39-48. [Crossref]
3. Sidransky E (2012) Gaucher disease: Insights from a rare Mendelian disorder. Discov Med 14: 273-281. [Crossref]
4. Stirnemann J, Vigan M, Hamroun D, Heraoui D, Rossi-Semerano L, et al. (2012) The French Gaucher’s disease registry: Clinical characteristics, complications and treatment of 562 patients. Orphanet J Rare Dis 7: 77. [Crossref]
5. Raghavan SS, Topol J, Kolodny EH (1980) Leukocyte beta-glucosidase in homozygotes and heterozygotes for Gaucher disease. Am J Hum Genet 32: 158-173. [Crossref]
6. Shoenfeld Y, Beresovski A, Zharhary D, Tomer Y, Swissa M, et al. (1995) Natural autoantibodies in sera of patients with Gaucher’s disease. J Clin Immunol 15: 363-372. [Crossref]
7. Pratt PW, Estern S, Kochwa S (1968) Immunoglobulin abnormalities in Gaucher’s disease. Report of 16 cases. Blood 31: 633-640. [Crossref]
8. Shoenfeld Y, Berliner S, Pinkhas J, Beutler E (1980) The association of Gaucher’s disease and dysproteinemias. Acta Haematol 64: 241-243. [Crossref]
9. Beutler E, Grabowski G (2011) Glucosylceramide lipidosis: Gaucher disease. New York: McGraw-Hill.
10. Pandey MK, Grabowski GA (2013) Immunological cells and functions in Gaucher disease. Crit Rev Oncog 18: 197-220. [Crossref]
11. Barak V, Acker M, Nisman B, Kalickman I, Abrahamov A, et al. (1999) Cytokines in Gaucher’s disease. Eur Cytokine Netw 10: 205-210. [Crossref]
12. Allen MJ, Myer BJ, Khokher AM, Rushton N, Cox TM, et al. (1997) Pro-inflammatory cytokines and the pathogenesis of Gaucher’s disease: Increased release of interleukin-6 and interleukin-10. QJM 90: 19-25. [Crossref]
13. Arends M, van Dussen L, Biegstraaten M, Hollak CEM (2013) Malignancies and monoclonal gammopathy in Gaucher disease; a systematic review of the literature. Br J Haematol 161: 832-842. [Crossref]
14. Burroughs S PR, Bartolomeo A, Greenstein R (1994) Hemolytic anemia in Gaucher Disease. Blood Cells Mol Dis 1994: 589A.
15. De Roux-Serratrice C, Serratrice J, San Marco M, Ené N, Ben Amri A, et al. (2006) Devenir des auto-anticorps au cours du traitement de la Maladie de Gaucher. Rev Médecine Interne 27: S317.
16. Haratz D, Manny N, Raz I (1990) Autoimmune hemolytic anemia in Gaucher’s disease. Klin Wochenschr 68: 94-95. [Crossref]
17. Sherer Y, Dulitzki M, Levy Y, Livneh A, Shoenfeld Y, et al. (2002) Successful pregnancy outcome in a patient with Gaucher’s disease and antiphospholipid syndrome. Ann Hematol 81: 161-163. [Crossref]
18. Lester TJ, Grabowski GA, Goldblatt J, Leiderman IZ, Zaroulis CG, et al. (1984) Immune thrombocytopenia and Gaucher’s disease. Am J Med 77: 569-571. [Crossref]
19. Khan A, Hanley DA, McNeil C, Boyd S (2015) Improvement in bone mineral density and architecture in a patient with gaucher disease using teriparatide. JIMD Rep 22: 23-28.  [Crossref]
20. Dayan B, Elstein D, Zimran A, Nesher G (2003) Decreased salivary output in patients with Gaucher disease. QJM 96:53-56. [Crossref]
21. Shvidel L, Sigler E, Shtalrid M, Feldberg E, Berrebi A, et al. (2007) Parotid gland involvement, the presenting sign of high-grade non-Hodgkin lymphoma in two patients with Gaucher disease and sicca syndrome. J Inherit Metab Dis 30: 825. [Crossref]
22. Matta MC, Soares DC, Kerstenetzky MS, Freitas ACP, Kim CA, et al. (2016) CD4+CD25 high Foxp3+ Treg deficiency in a Brazilian patient with Gaucher disease and lupus nephritis. Hum Immunol 77: 196-200. [Crossref]
23. Rosenbaum H, Hoffman R, Brenner B, Rowe J (2002) Immune and autoimmune phenomena in type 1 Gaucher disease. Blood 3623. [Crossref]