Exostosin-Positive Membranous Nephropathy and Autoimmune Hepatitis: Successful Remission with Immunosuppressive Therapy: A Case Report

Introduction

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. With the discovery of numerous novel antigens associated with MN, its nomenclature has shifted towards an antigen-based classification.¹ Exostosin-1 (EXT1) and Exostosin-2 (EXT2) are target antigens associated with autoimmune diseases, especially lupus nephritis (LN).² To the best of our knowledge, while MN has been described with autoimmune liver diseases, EXT-positive MN has not been previously described with autoimmune hepatitis (AIH).³ We report a case of successful remission of EXT-2-positive MN and AIH with immunosuppressive therapy.

Case Report

A 48-year-old obese female with a history of acquired thrombotic thrombocytopenic purpura (TTP) treated with steroids, plasmapheresis, and rituximab 3 years earlier, was referred for the evaluation of transaminitis, microscopic hematuria, and proteinuria. Labs were suggestive for aspartate aminotransferase (AST)-219 U/L (normal 0-32 U/L), alanine transaminase (ALT)-137 U/L (normal 0-33 U/L), alkaline phosphates-107 U/L (normal 35-104 U/L), and γ-glutamyl transferase (GGT)-76 U/L (normal 5-36 U/L). In the absence of identifiable risk factors for liver disease other than obesity, a liver biopsy was performed and showed portal inflammation with interface hepatitis consistent with AIH [Figure 1]. Concurrently, the patient was found to have microscopic hematuria and a urine albumin-to-creatinine ratio (ACR) of 1190 mg/g, hypoalbuminaemia, and normal estimated glomerular filtration rate (eGFR). Serology was positive for anti-nuclear antibodies (ANA) and high immunoglobulin G (IgG) levels of 2182 mg/dL (normal 700-1600 mg/dL), but otherwise negative. Prednisone and azathioprine (AZA) were started for AIH, and losartan was started for proteinuria. Kidney biopsy showed EXT-2 positive MN with tubular injury [Figure 2]. Due to the development of steroid-induced diabetes, she was switched from prednisone to budesonide. AZA was switched to mycophenolate mofetil (MMF), and losartan was continued. One and two years later, she achieved complete remission of MN and AIH, respectively, with resolution of proteinuria (ACR<20 mg/g) and hematuria, and normalization of IgG levels (1364 mg/dL) and liver enzymes (AST: 28 IU/L, ALT: 33 IU/L).

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Figure 1:

Hematoxylin and eosin stain of liver biopsy specimen showing plasma cell-dominated portal inflammation with interface hepatitis (red arrow), consistent with autoimmune hepatitis, 40x magnification. Image Courtesy of Dr. Satyapal Chahar.

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Figure 2:

Kidney biopsy findings in the patient with membranous nephropathy and autoimmune hepatitis. (a) Low power Masson-Trichrome image demonstrating cortical parenchyma with mild interstitial fibrosis and tubular atrophy, 50x magnification; (b) Jones methenamine silver stain showing thickened glomerular basement membranes with formation of punctate holes, 600x magnification; (c) Hematoxylin and eosin stain showing proximal tubules with prominent protein resorption droplets, 600x magnification; (d) Immunofluorescence for IgG in a mesangial and incomplete global granular capillary loop pattern, 600x magnification; (e) Immunohistochemical stain for EXT2 demonstrating strong positivity along the glomerular capillary loops, 600x magnification; (f) Ultrastructural photomicrograph demonstrating global subepithelial electron dense immune-type deposits along the glomerular basement membranes, 5000x magnification.

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Discussion

MN is characterized by thickening of the glomerular basement membrane (GBM) with deposition of immune complexes in the subepithelial space. These immune complexes consist of an immunoglobulin targeting a specific antigen, mostly derived from the podocytes, which causes severe podocyte damage, resulting in proteinuria.⁴ Since the discovery of phospholipase A2 receptor (PLA2R) antibodies in 2009, numerous novel antigens have been identified, leading to a better understanding of the underlying pathophysiology of MN.^5,6

EXTs are glycosyltransferases involved in heparan sulfate synthesis, a major component of the GBM, and are found in many tissues, including the podocytes. Sethi et al. discovered EXT-1 and EXT-2 as potential target antigens in MN in the context of autoimmune diseases, based on clinical and pathological findings, especially lupus.^2,7

MN has been reported in association with autoimmune liver diseases, including AIH, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and overlap syndrome (AIH with PBC or PSC). Dauvergne et al. reported 10 patients with MN in association with autoimmune liver disease. Interestingly, seven had a positive PLA2R on kidney biopsy, while four tested positive for anti-PLA2R antibodies.⁸ Nesheiwat et al. reported a case of MN in association with AIH, PBC, and acute Helicobacter Pylori infection.³ Stefanidis et al. reported a case of MN in association with Sjögren syndrome, polymyositis, and AIH.⁹ Hong et al. reported a case of MN in a patient with AIH-PBC overlap syndrome.¹⁰ Interestingly, most MN cases reported in the setting of autoimmune liver disease responded to medical therapy directed against the underlying liver disorder, mainly steroids and AZA. None of the reported cases were stained or positive for EXT.^3,9,10

Before biopsy, our patient was started on prednisone and AZA for AIH, and losartan for proteinuria. Unfortunately, the patient developed steroid-induced diabetes, prompting the switch to Budesonide, a treatment commonly used in the management of AIH in patients who are intolerant to steroids.¹¹ EXT positivity is speculated to be a subtype and activity marker in patients with Class 5 LN.¹² In addition, MMF has been suggested in some studies to be superior to AZA in the management of Class 5 LN.¹³ For the above reasons, AZA was switched to MMF; losartan was continued for proteinuria. Our patient achieved full remission for both MN and AIH with the above regimen, 1 and 2 years later, respectively. Our case adds to the growing literature on MN associated with autoimmune liver diseases, particularly AIH.