The Clinical Utility of Soluble Serum Biomarkers in Autoimmune Pancreatitis: A Systematic Review

Abstract

Autoimmune pancreatitis (AIP) is a rare etiological type of chronic pancreatitis. The clinical and radiological presentation of AIP often resembles that of pancreatic cancer. Identifying non-invasive markers for their early distinction is of utmost importance to avoid unnecessary surgery or a delay in steroid therapy. Thus, this systematic review was conducted to revisit all current evidence on the clinical utility of different serum biomarkers in diagnosing AIP, distinguishing AIP from pancreatic cancer, and predicting disease course, steroid therapy response, and relapse. A systematic review was performed for articles published up to August 2021 by searching electronic databases such as MEDLINE, Web of Science, and EMBASE. Among 5123 identified records, 92 studies were included in the qualitative synthesis. Apart from immunoglobulin (Ig) G4, which was by far the most studied biomarker, we identified autoantibodies against the following: lactoferrin, carboanhydrase II, plasminogen-binding protein, amylase-α2A, cationic (PRSS1) and anionic (PRSS2) trypsinogens, pancreatic secretory trypsin inhibitor (PSTI/SPINK1), and type IV collagen. The identified novel autoantigens were laminin 511, annexin A11, HSP-10, and prohibitin. Other biomarkers included cytokines, decreased complement levels, circulating immune complexes, N-glycan profile changes, aberrant miRNAs expression, decreased IgA and IgM levels, increased IgE levels and/or peripheral eosinophil count, and changes in apolipoprotein isoforms levels. To our knowledge, this is the first systematic review that addresses biomarkers in AIP. Evolving research has recognized numerous biomarkers that could help elucidate the pathophysiological mechanisms of AIP, bringing us closer to AIP diagnosis and its preoperative distinction from pancreatic cancer.

Challenges for clinicians treating autoimmune pancreatitis: Current perspectives

“…, parasitic diseases, chronic pancreatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or Sjogren’s syndrome)[ 4 , 35 , 65 , 70 - 73 ]. In addition, although LPSP with typical IgG4+ plasma cell abundance, a histological finding of type 1 AIP, was observed, the level of IgG4 in serum was sometimes lower than the cutoff value, so the level of IgG4 did not rise in all patients with type 1 AIP[74].Patients with increased IgG4 concentrations have high disease activity, a high incidence of jaundice at onset, and a number of extrapancreatic manifestations[ 74 , 75 ]. However, IgG4 Levels are not sufficiently correlated with the onset of complications or recurrence[ 11 , 74 , 76 , 77 ]; therefore, serological markers such as autotaxin are being studied for their relevance to relapse[ 78 ].…”

“…The c-antineutrophil cytoplasmic antibodies tends to be increased in some patients with type 2 AIP, which can help to distinguish type 1 from type 2[ 79 ]. However, despite research on various biomarkers ( e.g ., antibodies against the following: Carboanhydrase II, plasminogen-binding protein, lactoferrin, Alpha 2A amylase, cationic trypsinogen gene 1 (PRSS1) and PRSS2, and pancreatic secretory trypsin inhibitor/serine protease inhibitor, Kazal type 1 for the diagnosis of AIP and its differentiation from PDAC, verification of their specificity and sensitivity for commercialization is still insufficient[ 75 , 80 ].…”

“…However, one study reported that the combination of IgG4 > 100 mg/dL and CA19-9 < 74 U/mL was more likely to indicate AIP than PDAC (sensitivity of 94%, specificity of 100%)[ 83 ]. In addition, serum eosinophilia, raised total serum IgE levels, and serum microRNAs may be used to differentiate between AIP and PDAC[ 11 , 75 , 84 , 85 ].…”