Advances in the diagnosis and treatment of IgG4-associated sclerosing cholangitis
IgG4-associated sclerosing cholangitis (IgG4-SC) is a manifestation of IgG4-associated disease in the biliary system, often associated with type I autoimmune pancreatitis (AIP), IgG4-associated lacrimal glanditis, salpingitis and IgG4-associated retroperitoneal fibrosis. The disease is mainly characterized by elevated serum IgG4 levels, IgG4-positive plasma cell infiltration around the bile ducts and matted fibrosis formation. In terms of imaging, IgG4-SC is similar to primary sclerosing cholangitis (PSC), pancreatic head cancer and bile duct cancer.
I. Clinical manifestations
IgG4-SC is mainly seen in middle-aged and elderly men and is often seen for obstructive jaundice, most patients have autoimmune pancreatitis AIP. A study by Ghazale A et al. in 2008 showed that the initial clinical presentation of 58 patients with IgG4-SC was jaundice (77%), weight loss (53%), abdominal pain (26%), steatorrhea (15%) and first onset diabetes (8%). . In addition, IgG4-associated lacrimal glanditis, salpingitis and IgG4-associated retroperitoneal fibrosis are also common in patients with IgG4-SC. Meanwhile, a study by Korean scholars showed that 40% of IgG4-SC patients had a history of allergy such as dermatitis, eczema, asthma and sinusitis.
II. Laboratory indicators
Patients with IgG4-SC often have elevated liver enzymes, with elevated alkaline phosphatase and glutamine aminotransferase being the most common. Patients with biliary stenosis also have varying degrees of elevated serum bilirubin. An important serologic feature of IgG4-SC is elevated serum IgG4, a subgroup of IgG that accounts for about 5% of IgG in the normal population and has poor antigen affinity and lacks the ability to bind C1q complement. Elevated serum IgG4 levels are also seen in other diseases such as atopic dermatitis, filariasis, and aspergillosis. Serum IgG4 ≥135 mg/dl is one of the diagnostic criteria for IgG4-SC. Studies have reported that IgG4≥135
The AIP study found that 20% of patients did not have elevated serum IgG4 levels, and for suspected patients with normal serum IgG4 levels, IgG4/IgG ≥ 40% contributed to the diagnosis. patients with IgG4-SC also often had elevated peripheral blood eosinophils (≥ 600 cells/mm3) and serum IgE levels are elevated. In addition, elevated serum immunoglobulin IgG, positive antinuclear antibodies and positive rheumatoid factor were also seen in 56%, 44% and 16% of patients, respectively.
Imaging manifestations
Imaging is an important tool for the detection of IgG4-SC, and as research progresses, imaging-specific manifestations are playing an increasingly important role in the diagnosis and differential diagnosis of the disease. Imaging shows uniform thickening of the bile duct wall and inner and outer edges in a circular pattern, which is seen not only in the stenotic portion, but also in the morphologically normal portion under cholangiography.
Patients with IgG4-SC combined with AIP often have stenosis of the lower end of the common bile duct due to bile duct thickening and pancreatic swelling and compression, and the confluent bile duct stenosis is followed by bile duct dilatation, which is the main imaging feature of IgG4-SC. In contrast, PSC has band-like strictures, bead-like changes, dendritic images and diverticular protrusions under cholangiography.
IV. Histological manifestations
The main pathological features of IgG4-associated cholangitis are massive lympho-plasmacytic inflammatory reaction around the bile ducts, matted fibrosis formation and occlusive phlebitis, massive IgG4-positive plasma cell infiltration in the bile duct wall and immunohistochemistry showing >10 IgG4-positive cells/high magnification field [14]. It is worth mentioning that the bile duct epithelium is generally not damaged despite the dense inflammatory reaction around the bile duct.
V. Diagnosis
In 2009, the Mayo Clinic proposed five diagnostic criteria for IgG4-SC from histology, imaging, serology, other organ accumulation and response to treatment, referred to as HISORt criteria.In 2012, Japanese scholars proposed international diagnostic criteria for IgG4-SC, mainly diagnosing from four aspects: imaging manifestations, serological IgG4 levels, extrahepatic organ involvement and histological features IgG4-SC.
VI. Differential diagnosis
(a) Differential diagnosis of IgG4-associated sclerosing cholangitis and cholangiocarcinoma.
IgG4-associated sclerosing cholangitis is most importantly differentiated from cholangiocarcinoma, gallbladder cancer and pancreatic head cancer, especially cholangiocarcinoma.Taku Tabata [16] et al. retrospectively analyzed 6 patients with IgG4-associated cholangitis and 42 patients with bile duct cancer. The results suggested that obstructive jaundice was more common in patients with cholangiocarcinoma
(p<0.01), higher total bilirubin values
(ERCP showed that 83% of patients with hilar cholangiocarcinoma had complete obstruction of the hilar or hepatobiliary ducts (p<0.01). Low biliary strictures and bile duct wall thickening were more common in patients with IgG4-associated cholangitis (p<0.01). ghazale igg4="">140 mg/dl and IgG4>280 mg/dl were found in 10% and 1% of patients with malignancy, respectively. Abdul M [18] retrospectively analyzed 147 patients with cholangiocarcinoma (CCA) and 50 IgG4-associated cholangitis patients and showed that serum IgG4 levels in some CCA and PSC patients could reach more than two times the upper limit of normal. Therefore, serum IgG4 levels cannot be used as an exclusion diagnosis for CCA. Also, they found that the specificity of the diagnosis of IgG4-associated cholangitis was 100% when serum IgG4 was higher than 4 times the upper limit of normal. differentiation of IgG4-associated cholangitis from cholangiocarcinoma requires a thorough evaluation of serology, imaging and pathological tissues. Malignancy needs to be strictly excluded before diagnostic treatment with glucocorticoids.
(ii) Differential diagnosis of IgG4-associated cholangitis and PSC
IgG4-SC must be differentiated from PSC because of the completely different response to glucocorticoid therapy. Clinically, age << i="">40 years and the presence of inflammatory bowel disease suggest PSC,
The presence of AIP or other IgG4-associated disease suggests IgG4-SC; serologically, 9% of PSC patients also have elevated serum IgG4 levels. A recent study found that 15% of PSC patients had serum IgG4 (> 1.4 g/L). However, in serum IgG4 > 1.4 and < 2.8 g igg1="">0.24 significantly improved the specificity and positive predictive value for the diagnosis of IgG4-associated cholangitis. This can be of great help in the differential diagnosis of IgG4-SC and PSC. Histologically, IgG4-associated cholangitis showed matted fibrosis and occlusive phlebitis formation; in PSC, the inflammation in the bile duct lumen was more pronounced with erosions and yellow granulomas, forming onion skin-like changes. IgG4+ cytoplasmic cell infiltration or periportal fibroinflammatory nodule formation in liver puncture tissue suggests IgG4-SC, while the disappearance of bile ducts or the formation of annular fibrosis suggests PSC.
VII. Treatment
No randomized controlled trials have been conducted to analyze the hormonal treatment of IgG4-associated disease. Current treatment regimens are based on retrospective analyses and empirical treatments in large samples, and most of them are studies on AIP. There are two main widely accepted treatment regimens.
The first regimen, proposed by the Mayo Clinic, recommends starting treatment with prednisolone at 40/mg per day for 4 weeks, then reducing the dose by 5 mg per week for 7 weeks and withdrawing the hormone at the end of the 11-week course. The disadvantage of this regimen is that within 3 months of withdrawal, 50% of patients experience relapse.
Another retrospective analysis from 17 centers in Japan in 2009: this regimen recommends an initial treatment dose of 0.6 mg/kg/day for 2-4 weeks, with a gradual reduction to 5 mg/day over 3-6 months, and maintenance treatment at a dose of 2.5-5 mg/day for 3 years. It is worth mentioning that a retrospective study by Kamisawa et al. found that relapse occurred in 25% of patients despite receiving maintenance doses of hormone therapy.
Therapeutic response was defined as a significant improvement in biliary system strictures, a fall in liver enzymes to within twice the upper limit of normal, and a decrease in IgG4 and CA199 levels in patients after four weeks of hormone therapy. However, a study by Kamisawa et al. found that only 63% of patients’ serology returned to normal after treatment. A retrospective study by the Mayo Clinic also found that only 18 of 30 patients (60%) had improvement in biliary strictures and liver function abnormalities, and another 11 (37%) had only partial remission or were treatment-naïve.
The efficacy of glucocorticoids in IgG4-associated disease is mainly related to the degree of fibrosis in the affected organs, and untreated IgG4-associated disease progresses from lymphoplasmacytic inflammation to extensive fibrosis (especially when thyroid involvement and retroperitoneal fibrosis are present). related disease remain sensitive to hormonal therapy.
A 24-month retrospective study suggested that maintenance doses of hormone therapy reduced the probability of relapse to 32%, while complete interruption of hormone therapy was associated with a 70% probability of relapse (p=0.01). Kamisawa et al. found that the return to normal serum IgG4 levels was a predictor of relapse in patients on low-dose hormone maintenance therapy. The relapse rate was 30% in patients with persistently elevated serum IgG4 levels and only 10% in those who returned to normal.
7.2 Other drug therapy
Remedial drugs such as azathioprine, mescaline and methotrexate have also been used in the treatment of IgG4-associated disease in patients who are suboptimally treated or intolerant to hormonal therapy, but these drugs have been used empirically in small samples and no large clinical trials have been conducted to demonstrate their efficacy. Rituximab has also been used in some patients with refractory IgG4-associated disease with significant efficacy. After treatment, serum IgG4 levels decreased significantly in patients, while the remaining IgG subtypes were unaffected, and patients experienced significant clinical relief within a few weeks. The efficacy of rituximab is suggestive of the pathogenesis of the disease.