Antimitochondrial Antibody Titers Research Articles

Anti-Mitochondrial Antibody Titers Decrease Over Time in Primary Biliary Cholangitis Patients With Ursodeoxycholic Acid Therapeutic Response: A Cohort Study Followed Up to 28 Years.

BackgroundHow anti-mitochondrial antibody (AMA) and liver biochemistry levels change in primary biliary cholangitis (PBC) patients treated with ursodeoxycholic acid (UDCA) remains unclear.MethodsA 28-year cohort of 157 PBC patients was conducted. Patients with alkaline phosphatase (Alk-p) levels >1.67 × upper limit of normal after 1 year of UDCA treatment were considered nonresponders.ResultsAt baseline, of 157 (mean age: 54.41 years), 136 (86.6%) were female, 51 (32.5%) had cirrhosis, and 128 (81.5%) had detectable AMAs (immunoglobulin G). UDCA nonresponders (n=61) were younger and had higher Alk-p and total bilirubin levels and cirrhosis rates than UDCA responders (n=84). Alk-p levels and cirrhosis were negatively associated with UDCA response. Regardless of cirrhosis and UDCA response, most PBC patients had decreased Alk-p and γ-glutamyltransferase levels at last follow-up (up to 28.73 years) compared with baseline levels. Patients with baseline cirrhosis (2.78 ± 2.56 vs. 6.84 ± 9.00 mg/dL, p=0.024) and UDCA nonresponders (2.54 ± 2.19 vs. 4.51 ± 6.99 mg/dL, p=0.006) had increased total bilirubin levels while patients without cirrhosis (AST: 91.5 ± 84.5 vs. 58.9 ± 43.7 U/L, p<0.001; ALT: 107.3 ± 122.5 vs. 50.7 ± 36.8 U/L, p<0.001) and UDCA responders (AST: 83.8 ± 101.3 vs. 45.58 ± 38.42 U/L, p=0.014; ALT: 95.10 ± 144.6 vs. 39.12 ± 30.65 U/L, p=0.009) had decreased aminotransferase levels. Only UDCA responders had decreased AMA titers from 1 year after UDCA treatment (p=0.028) until the last follow-up (p<0.001).ConclusionsUDCA responders exhibited decreased AMA titers 1 year after treatment. Regardless of UDCA response, PBC patients showed improved cholestatic features, but only UDCA responders and patients without baseline cirrhosis exhibited attenuated hepatobiliary damage following UDCA treatment.

A great mimicker of primary biliary cholangitis.

A 59 year-old man without past medical history was referred with biochemical features of cholestasis (aspartate aminotransferase (AST) 117 U/L, alanine aminotransferase (ALT) 83 U/L, gamma-glutamyl transferase (GGT) 1307 U/L, alkaline phosphatase (AP) 1803 U/L, total bilirubin 0,7 mg/dL), a strongly positive antimitochondrial M2 antibody (AMA-M2) titer (88 U), weight loss and abdominal pain since several months. He did not take any medications, nor there was a history of alcohol abuse or sexual risk behavior. Upon presentation, clinical examination showed a rather cachectic patient (body mass index 19 kg/m²), without further abnormalities. As primary biliary cholangitis (PBC) was suspected, treatment with ursodeoxycholic acid had been initiated but did not improve the cholestasis nor the pain. Additional investigations didn’t reveal any other irregularities, except for a mildly dilated aortic sinus root of 42 mm. The histopathological findings of a liver biopsy are shown below (Figure 1). This showed granulomas with cholangitis and increased presence of neutrophils, which raised suspicion for an infectious cause.

The impact of undiagnosed primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune disease characterized by symptoms with a major impact on the quality of life. The aim of this study was to identify patients with undiagnosed PBC who are not under hepatology follow-up and to assess the clinical impact of lack of adequate treatment and surveillance. Adult patients with a positive antimitochondrial antibodies (AMA) titer were identified from local biochemistry records. Patients with probable PBC who were not known by the hepatology services were invited to accurately stage their disease and optimize medical management. A total of 214 AMA-positive patients were identified, 148 of whom had diagnostic criteria for PBC. Twenty-three patients were not known by the hepatology services, most of them followed by specialties other than gastroenterology. These patients had significantly higher liver stiffness compared to those followed by the hepatology services (14.3 kPa vs. 6.2 kPa; P = 0.009). A large percentage of untreated individuals reported fatigue (72.7%) and pruritus (27.3%). A substantial number of patients with PBC are not known to have hepatology services with a significant long-term impact from a lack of follow-up and therapy. Strategies must be established to identify these patients and reduce the disease's progressive nature.

Retrieval and treatment of patients with primary biliary cholangitis who are lost in the health system.

hepatitis C patients loss to follow-up in the health care system has been shown to have negative consequences. This study aimed to investigate this issue as regards primary biliary cholangitis. the databases (immunology, biochemistry, clinical reports, drug dispensation, appointments) of 4 reference hospitals in Spain (serving a population of 1,450,000 inhabitants) were analyzed. The diagnosis of primary biliary cholangitis was based on an antimitochondrial antibody titer ≥ 1:80, chronically elevated alkaline phosphatase, and the absence of other liver disease. Patients were classified as lost in the absence of reports indicating a diagnosis, specific medical follow-up, and/or treatment with bile salts. a total of 1372 patients with antimitochondrial antibody titers ≥ 1:80 were included between January 2010 and June 2019. A total of 697 (50.8 %) were classified as having primary biliary cholangitis, and 100 patients (14.3 %; 95 % CI: 11.8-17.2) were identified as lost. Of these, 30 were contacted and retrieved. The median age was 70 years, 93 % were female, median alkaline phosphatase was 185 IU/L, 10 % had pruritus, and 27 % had a transient elastography value > 9.5 kPa. The disease was confirmed and ursodeoxycholic acid was started in all 30 patients. Death was liver-related in 6 of the 100 patients classified as lost. up to 14.3 % of patients (1 out of 7) with a definitive diagnosis of primary biliary cholangitis remain undiagnosed, thus preventing monitoring and treatment. More than a quarter are at risk of advanced liver disease and its complications. Patients lost in the system must be identified and retrieved, and searching hospital databases is a suitable approach to meet this goal.

Cases of liver disease lost in the health system: a call to action.

We recently reported our experience searching for patients with primary biliary cholangitis (PBC) who were lost in the health system. Our search of databases in 4 hospitals, 3 of which were tertiary institutions, revealed that sufficient data were available to ensure a reliable diagnosis (i.e., cholestasis, positive antimitochondrial antibody titer, and no other liver disease) in 14.3 % (100/697) of PBC cases. However, patients remained undiagnosed, thus missing an opportunity to start early treatment and follow-up. Even more strikingly, of 30 rescued patients, 27 % had an elastography result indicating a poorer prognosis (> 9.5 kPa).

Correlation between anti-mitochondrial antibodies and clinical serological and cirrhotic markers of primary biliary cholangitis

Objective To explore the correlation between the level of anti-mitochondrial antibody (AMA) and clinical indicators of first visited primary biliary cholangitis (PBC) patients with positive AMA. Methods From January 2013 to December 2016, the clinical data of 1 323 patients with positive AMA and/or AMA-M2 detected for the first time were collected through the Information System of Peking University People′s Hospital. Among them, 183 were detected by indirect immunofluorescence assay, 431 were measured by immunoblotting, and 709 were determined by enzyme-linked immunosorbent assay (ELISA). Patients were divided into undiagnosed PBC group (non-PBC group, 973 cases) and newly diagnosed PBC group (new-PBC group, 350 cases including 268 cases of non-liver cirrhosis and 82 cases of liver cirrhosis); among 709 cases detected by ELISA, there were 567 cases in the non-PBC group and 142 cases in the new-PBC group (115 cases of non-liver cirrhosis PBC group and 27 cases of liver cirrhosis PBC group). Among 183 cases determined by indirect immunofluorescence assay, there were 118 cases in the non-PBC group and 65 cases in the new-PBC group. Among them 69 cases with low AMA titer (1∶40—1∶80) (53 cases of non-PBC group and 16 cases of new-PBC group), 95 cases with medium titer (1∶160—1∶320) (59 cases of non-PBC group and 36 cases of new-PBC group) and 19 cases with high titer (≥1∶640) (six cases of non-PBC group and 13 cases of new-PBC group). AMA levels among groups were compared, and its correlation with clinical serology and cirrhosis indicators of PBC including immunoglobulin (Ig)G, IgM, platelet, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltranspeptadase (GGT), alkaline phosphatase (ALP), serum total protein, serum albumin, total bilirubin (TBil), total cholesterol (TC), and aspartate aminotransferase to platelet ratio index (APRI) and fibrosis (Fib-4) was analysed. Mann-Whitney U test, Kruskal-Wallis test, and linear regression analysis were performed for statistical analysis. Results By ELISA method, the median titer of AMA-M2 of 709 patients was 53 RU/mL, the serum AMA and AMA-M2 levels of new-PBC group were both higher than those of non-PBC group (1∶320 vs. 1∶80, 180 RU/mL vs. 47 RU/mL), and the differences were statistically significant (χ2 = 14.111, Z = -7.531, both P 0.05). AMA-M2 value of patients in PBC with liver cirrhosis group was positively correlated with IgM level (r = 0.38, P = 0.039), but was not correlated with APRI and Fib-4 (all P > 0.05). The median of AMA value of 183 patients who underwent indirect immunofluorescence test was 1∶160. In non-PBC group, the IgM levels of patients with low, medium and high AMA titers gradually increased (the median levels were 1.2, 1.7 and 1.8 g/L, respectively); in new-PBC group, the levels of IgM, GGT and ALP of patients with low, medium and high AMA titers gradually increased (median IgM levels were 1.5, 3.7 and 4.1 g/L, respectively; GGT levels were 144, 182 and 317 U/L, respectively; and ALP levels were 137, 168 and 221 U/L, respectively), and the differences were statistically significant (χ2 =6.260, 7.081, 8.030, 15.226, all P<0.05). In non-PBC group, the median level of serum AMA-M2 of men was lower than that of women (41 RU/L vs. 50 RU/L), and the difference was statistically significant (Z = -2.945, P = 0.003). In new-PBC group, the median level of serum AMA-M2 of men tended to be lower than that of women (113 RU/mL vs. 206 RU/mL), but the difference was not statistically significant (P=0.257). Conclusion Serum AMA level is correlated with many clinical parameters and may be related with the disease severity in patients with PBC. Key words: Anti-mitochondrial antibody; Primary biliary cholangitis; Liver cirrhosis; Clinical significance

Analysis of the autoantibodies characteristics of 77 anti-soluble liver antigen positive patients with liver diseases

Objective To understand the characteristics and clinical significance of anti-soluble liver antigen antibody (anti-SLA) in patients with liver diseases. Methods Serum samples from seventy-seven patients with anti-SLA were collected from Beijing You'An Hospital during the period between January 2010 and December 2018. Anti-SLA, anti-liver cytosol type 1 antibody (anti-LC1), anti-glycoprotein 210 antibody(anti-gp210) and anti-nuclear body protein sp100 antibody(anti-sp100) were detected by immunoblotting; indirect immunofluorescence assay used for detecting anti-nuclear antibody (ANA), anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (SMA), and anti-liver kidney microsome antibody (anti-LKM). One-way analysis of variance was used to compare the ages of different anti-SLA groups. The non-parametric rank sum test was used to compare the liver function indexes and immunoglobulins in different intensity groups of anti-SLA. P<0.05 was considered statistically significant. Further comparisons were made between the two groups, the correction level α′=0.008 3, P<0.008 3 was considered statistically significant. Results The average age of 77 anti-SLA positive patients was (52.50±1.25) years old, 70 females (90.9%) and 7 males (9.1%). 80.5% of anti-SLA-positive patients (62/77 cases) were strongly positive at the time of initial diagnosis (+++ to ++++).The Alanine aminotransferase (ALT) level in the SLA++ group was higher than that in the SLA++++ group (232.7 U/L vs 65.6 U/L,χ2=7.751,P=0.005) and the immunoglobulin M(IgM) level in the SLA+++ group was lower than that in the SLA++++ group (1 270 mg/L vs 2 270 mg/L,χ2=8.337,P=0.004).There was no significant difference in age, other liver function and immunological indicators among the different groups.Seventy cases (90.9%) were both anti-SLA and ANA positive, 13 cases (16.9%) were positive with SMA, and none positive with anti-LKM and anti-LC1. Among anti-SLA positive patients, 58 cases were diagnosed with autoimmune hepatitis (AIH), 12 were AIH/primary biliary cholangitis (PBC) overlap syndrome (OS), 2 were drug-induced liver injury, 2 were chronic hepatitis B, and 3 were hepatitis A, hepatitis E and acquired immune deficiency syndrome (AIDS) with liver injury, respectively.Cases of AIH and AIH/PBC OS accounted for 90.9% (70/77 cases) of anti-SLA-positive patients, and 5 of 7 patients diagnosed with non-AIH (and OS) had elevated IgG, showing AIH feature.92.3% (12/13 cases) of anti-SLA with high titers of AMA were diagnosed as AIH/PBC overlap syndrome. Of the 77 anti-SLA-positive patients, 28 (36.4%) had advanced or end-stage liver disease, including decompensated cirrhosis (22 cases), chronic acute liver failure (4 cases), and liver transplantation (1 case) and death from liver failure (1 case). Conclusions Anti-SLA has high diagnostic specificity for AIH;anti-SLA positive in patients with PBC should be an important biomarker for the diagnosis of AIH/PBC overlap syndrome. Key words: Liver diseases; Hepatitis, autoimmune; Autoantibodies

3195 Autoimmune Hepatitis With Primary Biliary Cirrhosis: An Overlapping Syndrome of the Liver

INTRODUCTION: Autoimmune liver diseases consist of Primary Biliary Cirrhosis (PBC), Autoimmune Hepatitis (AIH) and Primary Sclerosing Cholangitis (PSC). Overlap syndromes are defined when there are characteristic features of AIH along with PBC and PSC. We report the presentation and management of an AIH-PBC overlap syndrome. CASE DESCRIPTION/METHODS: A 60-year-old Asian female with a past history of hypertension, presented with fatigue, myalgia, nausea, vomiting, and icterus for ten days. She denied the use of illicit drugs, alcohol consumption or family history of liver disease. On arrival, she had a temperature of 38.2°C, a pulse of 110 beats/minute, blood pressure of 100/70 mm Hg, and oxygen saturation of 97% on room air. Physical exam revealed icterus 1+, and mild tenderness in the right hypochondriac area. Laboratory investigations revealed leukocyte count of 15.2 K/ul, alanine transaminase of 1107 U/l, aspartate aminotransferase of 1010 U/l, alkaline phosphatase of 685 U/l, total bilirubin of 10 mg/dl with the direct component of 9 mg/dl, and gamma-glutamyl transferase of 666 U/l. Further workup revealed anti-nuclear antibody titer of 1:1000, antimitochondrial antibody (AMA) titer of 1:80 with negative peripheral antineutrophil cytoplasmic antibody and hepatitis serology. Ultrasound of the abdomen showed common-bile duct (CBD) stricture formation. The patient underwent endoscopic retrograde cholangiopancreatography with sphincterotomy and stenting. Liver biopsy showed interface hepatitis with portal tract inflammation. Brush border sampling from the CBD revealed lymphocytic and neutrophilic infiltrate. A diagnosis of AIH-PBC overlap syndrome was made. She was started on piperacillin/tazobactam 4.5 gm and metronidazole 400 mg along with with ursodeoxycholic acid (UDCA) 300 mg, thrice a day. After a month, the stent was removed and there was a resolution of symptoms with normalization of liver enzymes. DISCUSSION: The minimum criteria required for the diagnosis of AIH-PBC overlap syndrome include positive AMA and histology showing bile duct abnormality in an otherwise classical AIH (Table 1). Management is usually with UDCA, immunosuppressants, and corticosteroids. It is prudent to maintain a modest index of suspicion of overlap syndromes in patients such as ours. Early diagnosis and appropriate management are of paramount importance.

2339 Hemobilia-Associated Acute Cholecystitis Post-Percutaneous Liver Biopsy: A Unexpected Sequelae of a Known Complication

INTRODUCTION: Percutaneous liver biopsy is often a part of the diagnostic workup of unexplained abnormal liver enzymes. Known complications include hemobilia and unintentional perforation of an adjacent organ but rarely do these complications lead to sepsis. CASE DESCRIPTION/METHODS: We present a case of a 65-year old female being evaluated for abnormal liver enzymes (ALT 40 U/L, normal alkaline phosphatase) with a positive anti-mitochondrial (titer 1:1280) and anti-nuclear antibodies (titer 1:640). A percutaneous liver biopsy was performed under ultrasound guidance without any immediate complication. The biopsy revealed moderate-to-marked macrovesicula steatosis with focal centrilobular and periportal fibrosis (Stage 1 of 4). Five days later she presented to the emergency department with persistent RUQ pain, fevers and melena. Vitals notable for temperature of 39.3 °C. Physical examination revealed RUQ tenderness to palpation. The leukocyte count was 5.04 K/uL (predominantly neutrophils), AST 558 U/L, ALT 350 U/L, ALP 287 U/L, total bilirubin 1.9 mg/dL. CT abdomen demonstrated only cholelithiasis without other abnormalities. An abdominal ultrasound showed gallbladder sludge and wall thickening with a negative Murphy’s sign (Figure 1). Blood cultures were positive for Klebsiella pneumonia and IV antibiotics were started. Over the ensuing several days, the patient had worsening abdominal pain and developed melena. Imaging was remarkable for hyperdense material within the gallbladder. An endoscopic ultrasound was performed which revealed moderate amount of hyperechoic material in the gallbladder consistent with clotted blood. Given concern that an infected blood clot in gallbladder was a source of bacteremia, a laparoscopic cholecystectomy was performed. The surgical gallbladder specimen showed acute hemorrhagic acalculous cholecystitis. Postoperative course was uncomplicated and the patient was discharged home feeling back to normal. DISCUSSION: Hemobilia is a well-recognized complication of percutaneous liver biopsy, although this case is unusual because it appears to have led to acalculous cholecystitis and Klebsiella bacteremia. Blood, similar to sludge, can accumulate and mimic obstructive processes such as acute cholecystitis and acute pancreatitis. This case highlights the importance of early recognition of delayed complications of percutaneous liver biopsy.

2311 Syphilis Hepatitis Presenting as a Mimic of Primary Biliary Cholangitis

INTRODUCTION: Primary Biliary Cholangitis (PBC) is a progressive cholestatic liver disease defined by autoimmune destruction of intrahepatic bile ducts. Patients typically present with a cholestatic liver injury pattern. Anti-mitochondrial antibody (AMA) is present in 95% of PBC diagnoses thus, an AMA titer of 1:40 in addition to alkaline phosphatase (ALP) greater than 1.5 times the upper limit of normal is diagnostic of PBC (1). Syphilis is a sexually transmitted infectious disease caused by transmission of Treponema pallidum. The highest risk populations are men who have sex with men (MSM) and persons living with HIV. Syphilis has been further associated with HIV infection considering shared risk factors and transmission routes. While the staged progression of syphilis is well-documented, not all presentations are readily observed by clinicians considering the variability of the disease. One variation that is sparingly seen is syphilis presenting as acute hepatitis. CASE DESCRIPTION/METHODS: A 54 year-old man living with HIV presented to University of Kentucky Hospital with one week of abdominal pain, vomiting, and a diffuse non-pruritic rash. Upon admission he was noted to have a cholestatic liver injury pattern. Laboratory evaluation revealed AST 91, ALT 120, ALP 832, total bilirubin 6.4, and CD4 count 336. The acute hepatitis panel was negative. Abdominal CT and ultrasound failed to demonstrate biliary ductal dilation. Further investigation revealed an RPR titer 1:256 and an anti-mitochondrial M2 antibody IgG of 83.5U. The patient was treated for syphilis with doxycycline due an allergy to penicillin. Subsequently there was complete resolution of the cholestatic liver injury and a final diagnosis of syphilis hepatitis. DISCUSSION: In this report, we present a case of syphilis that presented similar to PBC with a consistent serologic pattern and a positive AMA. Other reports have recognized syphilis as a reversible cause of cholestatic liver injury. One study in particular, recognized a high false positive AMA rate in patients with syphilis (2). As, syphilis is a easily targeted cause of liver injury, we suggest testing high-risk patients with a presumed diagnosis of PBC.

New treatments/targets for primary biliary cholangitis.

SummaryPrimary biliary cholangitis (PBC) is an autoimmune, cholestatic, chronic liver disease that ultimately progresses towards cirrhosis and liver failure if untreated. While ursodeoxycholic acid has been established as standard of care for PBC in the last few decades, significant advances in second-line treatment options have recently been made and new therapeutic developments are currently under evaluation. The purpose of this article is to provide the clinician with an overview of the current treatment options and future opportunities for patients with PBC.

Immunological abnormalities in patients with primary biliary cholangitis.

Primary biliary cholangitis (PBC), an autoimmune liver disease occurring predominantly in women, is characterized by high titers of serum anti-mitochondrial antibodies (AMAs) and progressive intrahepatic cholestasis. The immune system plays a critical role in PBC pathogenesis and a variety of immune cell subsets have been shown to infiltrate the portal tract areas of patients with PBC. Amongst the participating immune cells, CD4 T cells are important cytokine-producing cells that foster an inflammatory microenvironment. Specifically, these cells orchestrate activation of other immune cells, including autoreactive effector CD8 T cells that cause biliary epithelial cell (BEC) injury and B cells that produce large quantities of AMAs. Meanwhile, other immune cells, including dendritic cells (DCs), natural killer (NK) cells, NKT cells, monocytes, and macrophages are also important in PBC pathogenesis. Activation of these cells initiates and perpetuates bile duct damage in PBC patients, leading to intrahepatic cholestasis, hepatic damage, liver fibrosis, and eventually cirrhosis or even liver failure. Taken together, the body of accumulated clinical and experimental evidence has enhanced our understanding of the immunopathogenesis of PBC and suggests that immunotherapy may be a promising treatment option. Herein, we summarize current knowledge regarding immunological abnormalities of PBC patients, with emphasis on underlying pathogenic mechanisms. The differential immune response which occurs over decades of disease activity suggests that different therapies may be needed at different stages of disease.

Histologically proven AMA positive primary biliary cholangitis but normal serum alkaline phosphatase: Is alkaline phosphatase truly a surrogate marker?

Background and aimsThe most highly directed and specific autoantibody in human immunopathology is the serologic hallmark of primary biliary cholangitis (PBC), antimitochondrial antibodies (AMAs). However the clinical significance of finding a positive AMA, with normal alkaline phosphatase (ALP) remains enigmatic. MethodsWe took advantage of 169 consecutive outpatients who were identified as having a positive AMA, but normal ALP levels between January 2012 and January 2018. A liver biopsy was performed on 67/169 of these AMA positive normal ALP patients. ResultsIn all 169 patients we reconfirmed the AMA and also performed anti-gp210 and anti-sp100, liver stiffness (LSM) assessed by vibration-controlled transient elastography (VCTE), an abdominal computed tomography (CT) scan, and either a magnetic resonance imaging (MRI) or ultrasound. The liver biopsies were reviewed by two unbiased observers. 87.6% of the 169 patients were females with a mean age of 46; the median AMA titer 1:320; an elevated serum IgM was found in 53.3%. Importantly, in patients with a liver biopsy, 55（82.1%）out of 67 had varying degrees of cholangitis activity, diagnostic of PBC. ConclusionIn patients who were AMA-positive but had normal ALP levels, more than 80% were associated with histological classic PBC. These data emphasize the importance of a positive AMA, even with a normal ALP and also question the role of ALP as a sole surrogate marker of cholangitis.

A Rare Case of Cholestasis

This is the case of 49-year-old woman with no past medical history who was found to have a rare case of cholangitis. A 49-year-old woman with no significant past medical history presented with a 1-month history of dull abdominal pain, early satiety, fatigue, pruritus, and weight loss. She had no history of drug, alcohol, or tobacco use, and no family history of hepatobiliary disease or autoimmunity. Her vital signs were within normal limits. Physical exam revealed mild jaundice without abdominal tenderness or ascites. Initial lab testing showed elevated liver enzymes in a cholestatic pattern, with AST/ALT 147/34 U/L, alkaline phosphatase 493U/L, and total bilirubin 6.8 mg/dl (direct 4.0 mg/dl). Imaging, including CT, ultrasound, and MRCP, was suggestive of mild inflammation of the pancreas and mild splenomegaly, as well as mild fatty infiltration of the liver without gallstones, ductal obstruction, or focal hepatic or gallbladder abnormalities. Infectious studies were negative for viral hepatitis and HIV. ESR and CRP were elevated concerning for autoimmune etiology. Anti-nuclear antibody (ANA, titer 1:1280) and anti-actin antibody were positive. Anti-mitochondrial antibody (AMA) titer was negative. Liver biopsy was performed and showed biliary pattern cirrhosis and florid biliary duct destruction consistent with autoimmune cholangitis. The patient was started on prednisone and ursodeoxycholic acid with resolution of symptoms 1 month later. AST was 45U/L, alkaline phosphatase 130U/L, and total bilirubin decreased to 1.2 mg/L. Autoimmune cholangitis (AIC) is a rare cause of cholestasis not commonly encountered in clinical practice. Maintaining it as a differential diagnosis will aid in prompt diagnosis and treatment. The patient met diagnostic criteria for AIC, which is characterized by the clinical, biochemical, and histologic features of primary biliary cirrhosis (PBC) but with negative AMA and positive ANA and/or anti-actin antibody. Like PBC, AIC has a female preponderance, a cholestatic liver enzyme pattern, and florid bile duct lesions on histology; both slowly progress to fibrosis and cirrhosis if left untreated. AIC is probably a heterogeneous syndrome that includes patients with AMA-negative PBC, small duct primary sclerosing cholangitis, autoimmune hepatitis with bile duct damage, and various transition states. Therapy consists of ursodeoxycholic acid and corticosteroids; liver transplantation is the treatment of choice for end-stage disease.

A Retrospective Analysis of Ten Patients with Normal Alkaline Phosphatase and Primary Biliary Cholangitis

Introduction: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease which can be diagnosed when a patient tests positive for positive antimitochondrial antibody (AMA) and has a high alkaline phosphatase (AP) without the need for undergoing a liver biopsy. However, medical literature has documented that PBC can occur among patients with normal AP. As a result in patients worked up for common liver conditions like hepatitis and fatty liver, an incidental diagnosis of concomitant PBC can be missed if AMA is not ordered. We routinely perform AMA on patients who are evaluated for liver disease based on either imaging studies or abnormal liver tests and over last ten years came across patients with positive AMA and normal or near normal liver tests. We want to present this case series to highlight the importance of working up patients thoroughly with a battery of liver tests and if AMA is positive doing a liver biopsy to confirm the diagnosis of PBC.2732 Figure 1. Results of the study showing patient demographics, AMA range, ALP levels, presence of other autoimmune diseases and Liver biopsy resultsMethods: The charts of 10 patients with normal cholestatic liver enzymes and AMA positivity who underwent liver biopsy between 2012-2017 were retrospectively analyzed. Records were reviewed, cause of death verified when applicable, and all available clinical and biochemical data were collected, including detailed reports of liver histology. Only patients naïve to ursodeoxycholic acid were included in this case series. Results: Among the patient population, eight were females; median age was 56 years; median AMA titer was 50.3(lab reference 0-20); extrahepatic autoimmune disorders were present in five of ten patients including systemic lupus erythmatosis, Rheumatoid arthritis, Sjogren's syndrome, scleroderma and undifferentiated connective tissue disorder(Table 1). Two patients had cirrhosis on liver biopsy. The liver histology findings revealed PBC in all ten patients: 4 patients had early PBC changes, 2 patients had PBC with cirrhosis; 2 patients had PBC stage 2/4; and one patient each had changes of PBC associated with HCV and nonalcoholic steatohepatitis. Conclusion: AMA positive patients with normal cholestatic liver enzymes should be considered for a liver biopsy to establish a diagnosis of PBC. Based on this case series and data recently published in the literature, AMA should be ordered in patients worked up for common liver diseases. In the future, cost analysis of ordering AMA and the downstream benefit of deferring decompensated liver disease among PBC patients should be done.

A case series evaluating the impact of Hepatitis C eradication using direct acting antivirals on primary biliary cholangitis-associated autoimmunity

BackgroundChronic Hepatitis C Virus (HCV) infection has been commonly linked to the development of autoimmunity, in part through activation of B cells. B cells are also postulated to play a pathogenic role in the autoimmune liver disease Primary Biliary Cholangitis (PBC). Patients with concurrent PBC and HCV infection carry an increased risk of more progressive disease, although the mechanism underlying this effect is poorly understood. Utilizing a case series of patients with concurrent PBC and HCV, the aim of this study was to evaluate for the potential impact of HCV eradication upon autoimmunity/autoantibody production.Case presentationA case series evaluating three patients with co-existing PBC-HCV infection receiving non-interferon based HCV treatments with direct-acting antivirals (DAA). One of three patient received Ursodeoxycholic acid (UDCA; 13 mg/kg/day) during the treatment period. Sustained virological response (SVR) to DAA’s was assessed using a HCV Quantitative Nucleic Acid Test (Abbott). Autoantibodies associated with autoimmune liver diseases (including PBC) and liver biochemistry, were measured before, during and after DAA treatment (Mitogen Advanced Diagnostics Laboratory, Calgary, Canada).All patients achieved an SVR, as determined by negative HCV RNA test 12 weeks post-DAA therapy. Titres of anti-mitochondrial antibodies (AMA-M2), anti- branched-chain 2-oxo-acid dehydrogenase complex and 2-oxo glutarate dehydrogenase complex (anti-3E-BPO), and anti- tripartite motif-containing protein 21 (TRIM21/Ro52) remained unchanged, despite successful HCV eradication. Two of the three patients exhibited a transient decrease in some autoantibody titres during DAA treatment, but these returned to baseline levels post-DAA therapy.ConclusionsWithin the limitations of a case series, our results suggest that HCV co-infection may not be a significant driver of PBC-related autoimmunity/autoantibody production. However, a larger n-value is required to truly assess for the effect of HCV eradication on autoantibody production.

Increased cholestatic enzymes in two patients with long-term history of ulcerative colitis: consider primary biliary cholangitis not always primary sclerosing cholangitis

Several hepatobiliary disorders have been reported in ulcerative colitis (UC) patients with primary sclerosing cholangitis (PSC) being the most specific. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis,...

Evidence for the association between IgG-antimitochondrial antibody and biochemical response to ursodeoxycholic acid treatment in primary biliary cholangitis.

Antimitochondrial antibody (AMA) is considered the serological hallmark of primary biliary cholangitis (PBC), while data regarding the profile of AMA during ursodeoxycholic acid (UDCA) treatment are scarce. Here, we assessed the influence of UDCA treatment on titers of AMA and factors relevant to its production. Serum IgA-AMA, IgM-AMA, IgG-AMA, B cell-activating factor of the tumor necrosis factor family (BAFF), and the frequency of circulating plasmablasts were detected in PBC patients, including those who received UDCA therapy for 24 weeks, healthy controls, chronic hepatitis B patients, and autoimmune hepatitis patients. Consecutive liver sections from controls and PBC patients were stained by immunohistochemistry for detection of intrahepatic CD38+ , IgA+ , IgM+ , and IgG+ cells. Significant decrease in titers of IgG-AMA was found only confined to PBC patients with biochemical response to UDCA treatment (P = 0.005), and similar pattern was also observed at week 24 in quantifying circulating plasmablasts (P = 0.025) and serum BAFF (P = 0.013). Notably, positive correlation between serum BAFF levels and titers of IgG-AMA, and the frequency of circulating plasmablasts were observed in PBC patients (r = 0.464, P = 0.034 and r = 0.700, P < 0.001, respectively). Additionally, in situ staining revealed significant accumulation of CD38+ and IgG+ cells within the portal tracts of PBC liver. Decreased titers of serum IgG-AMA are associated with biochemical response to UDCA treatment, implicating the potentiality of this hallmark in therapeutic response evaluation and the beneficial effect of UDCA on humoral immunity in PBC patients.

Polymorphisms of IL12RB2 May Affect the Natural History of Primary Biliary Cholangitis: A Single Centre Study.

Background. Recent GWAS in primary biliary cholangitis (PBC) showed strong associations with SNPs located within interleukin-12 receptor (IL12R) beta-2 (IL12RB2) gene. Aims. We assessed whether genetic variation of IL12RB2 is associated with laboratory and clinical features of PBC. Methods. Genomic DNA was isolated from 306 patients with PBC and 258 age/gender-matched controls. PBC-specific anti-mitochondrial antibodies (AMA) were tested in all subjects by ELISA. Two SNPs, rs3790567 and rs6679356, of IL12RB2 were genotyped using the MGB-TaqMan SNP assay. Results. Despite comparable age at diagnosis of cirrhotic and noncirrhotic PBC patients, allele A of rs3790567 and allele C of rs6679356 were overrepresented in the former rather than the latter group (p = 0.0009 and p = 0.002, resp.). The risk of cirrhosis at presentation increased when allele A and allele C coexisted. AMA-M2 titres were significantly higher in AA homozygotes of rs3790567 compared to GG homozygotes (132 ± 54 versus 103 ± 62, p = 0.02) and in rs6679356 when C allele was present (p = 0.038). There were no other significant associations between IL12RB2 polymorphisms and laboratory or clinical features. Conclusion. In this first study analyzing phenotypic features of PBC carriers of the IL12RB2 polymorphisms, we found that carriers are more frequently cirrhotic at diagnosis and have significantly higher titres of AMA.

Large-scale characterization study of patients with antimitochondrial antibodies but nonestablished primary biliary cholangitis.

Nearly half of the newly detected AMAs in clinical practice does not lead to a diagnosis of PBC. PBC is unrecognized in 13% of those cases. Only 1 in 6 patients with AMAs and normal ALP will develop PBC after 5 years. The mortality of AMA-positive patients without PBC is increased irrespective of the risk of PBC development. (Hepatology 2017;65:152-163).