Cholangiopathy After Severe COVID-19: Clinical Features and Prognostic Implications.

INTRODUCTION: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 virus, is a predominantly respiratory tract infection with the capacity to affect multiple organ systems. Abnormal liver tests, mainly transaminase elevations, have been reported in hospitalized patients. We describe a syndrome of cholangiopathy in patients recovering from severe COVID-19 characterized by marked elevation in serum alkaline phosphatase (ALP) accompanied by evidence of bile duct injury on imaging. METHODS: We conducted a retrospective study of COVID-19 patients admitted to our institution from March 1, 2020, to August 15, 2020, on whom the hepatology service was consulted for abnormal liver tests. Bile duct injury was identified by abnormal liver tests with serum ALP > 3x upper limit of normal and abnormal findings on magnetic resonance cholangiopacreatography. Clinical, laboratory, radiological, and histological findings were recorded in a Research Electronic Data Capture database. RESULTS: Twelve patients were identified, 11 men and 1 woman, with a mean age of 58 years. Mean time from COVID-19 diagnosis to diagnosis of cholangiopathy was 118 days. Peak median serum alanine aminotransferase was 661 U/L and peak median serum ALP was 1855 U/L. Marked elevations of erythrocyte sedimentation rate, C-reactive protein, and D-dimers were common. Magnetic resonance cholangiopacreatography findings included beading of intrahepatic ducts (11/12, 92%), bile duct wall thickening with enhancement (7/12, 58%), and peribiliary diffusion high signal (10/12, 83%). Liver biopsy in 4 patients showed acute and/or chronic large duct obstruction without clear bile duct loss. Progressive biliary tract damage has been demonstrated radiographically. Five patients were referred for consideration of liver transplantation after experiencing persistent jaundice, hepatic insufficiency, and/or recurrent bacterial cholangitis. One patient underwent successful living donor liver transplantation. DISCUSSION: Cholangiopathy is a late complication of severe COVID-19 with the potential for progressive biliary injury and liver failure. Further studies are required to understand pathogenesis, natural history, and therapeutic interventions.

Treatment of unresectable extrahepatic cholangiocarcinoma using hematoporphyrin photodynamic therapy: A prospective study.

BACKGROUND: The available evidence of Photodynamic therapy (PDT) combined with stent placement treatment for unresectable extrahepatic cholangiocarcinoma (EHCC) is still insufficient. It also remains unclear whether PDT influences systemic inflammatory response. AIM: To explore the clinical efficacy and safety of the combination treatment and the systemic inflammatory response in patients with EHCC. METHODS: Patients with unresectable EHCC underwent either the combined treatment using Hematoporphyrin PDT and stent placement (PDT+stent group, n=12) or stent-only (stent group, n=27). The primary end-point was overall survival. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were measured. Quality of life was assessed using the Karnofsky performance scale (KPS) every 3 months. RESULTS: Average survival time (13.8 vs. 9.6 months), and 6-month (91.7% vs. 74.1%), and 1-year (58.3% vs. 3.7%) survival rates of PDT+stent group were significantly increased compared with the stent group. KPS scores in the PDT+stent group were significantly improved. TNF-α and IL-6 levels were significantly increased in the PDT+stent group. CONCLUSION: Hematoporphyrin-PDT combined with stent placement is an effective and safe treatment for EHCC. The treatment might promote systemic inflammatory response.

Difference in clinical presentation, immunology profile and treatment response of type 1 autoimmune hepatitis between United Kingdom and Singapore patients.

BACKGROUND: Autoimmune hepatitis (AIH) is an immune-mediated liver disease of unknown etiology. Increasing incidence of AIH in Asian patients has been reported. However, the phenotypic difference of Asian patients in Europe and Asia has still not been explored. AIM: To evaluate the clinical presentation, biochemical and immunological profiles, treatment response and survival outcome of type 1 AIH from two tertiary liver transplant centres (United Kingdom and Singapore). METHOD: Patients who fulfilled the simplified diagnostic scoring criteria of AIH were included in the study. Patients with overlap syndrome were excluded. RESULTS: Totals of 40 Asian patients and 159 Caucasian patients from the University Hospital of Birmingham National Health Service Foundation Trust, UK, were compared with 57 Asian patients from Singapore General Hospital, Singapore. Asian patients from Singapore present significantly much later (median 55 vs. 32 years, p < 0.001), had higher MELD (p < 0.001) with lower albumin (p < 0.001) and higher bilirubin (p < 0.001) and lower ASMA positivity (p < 0.001) at diagnosis compared to UK Asian. Jaundice at presentation was much higher in Singapore Asian patients compared to UK Asian (53 vs. 30 %) but cirrhosis at diagnosis was more common in UK patients. Associated autoimmune conditions were less commonly seen in Singapore Asians. Comparing between UK cohorts, Asian patients present at younger age and have higher IgG level compared to Caucasian. Overall, 5-year transplant-free survival in all three cohorts was similar (p = 0.846). CONCLUSION: We demonstrate that AIH patients from Singapore present at older age with jaundice and have a low positivity of SMA. Despite these differences, transplant-free survival is similar in the two groups.

Persistent seropositivity for yellow fever in a previously vaccinated autologous hematopoietic stem cell transplantation recipient.

The duration of a protective level of yellow fever antibodies after autologous hematopoietic stem cell transplantation in a previously vaccinated person is unclear. The case of a patient who had previously been vaccinated for yellow fever and who remained seropositive for 22 months after autologous peripheral blood stem cell transplantation for malignant lymphoma is described herein.

Passenger Lymphocyte Syndrome in a Renal Transplant Recipient.

New onset anaemia within three months after renal transplantation though not very common sometimes present as diagnostic challenge to the renal physicians. Understanding the etiology is necessary for correct management and avoiding adverse graft outcome. Passenger lymphocyte syndrome (PLS) is a rare entity of immune haemolytic anaemia that sometimes occurs in recipient of minor ABO mismatched renal transplantation. In this case report we present an AB positive renal allograft recipient who received organ from an O positive donor and developed acute haemolytic anaemia and jaundice, 19 days after renal transplantation due to PLS.

Differentiating autoimmune pancreatitis from pancreatic cancer.

Differential diagnosis between autoimmune pancreatitis (AIP) and pancreatic cancer can be very difficult. The main clinical symptoms in patients with autoimmune pancreatitis are jaundice, weight loss, abdominal pain and new onset of diabetes mellitus. Unfortunately, the same symptoms could be observed in patients with pancreatic carcinoma too. Imaging methods as computed tomography (CT) scan, magnetic resonance imaging (MRI) and endosonography (EUS); together with serological examination (IgG4 and Ca 19-9) play the important role in differentiation autoimmune pancreatitis from pancreatic cancer. Extrapancreatic findings are distinctive in patients with autoimmune pancreatitis. In some cases the pancreatic biopsy is indicated, mainly in patients with focal or multifocal form of autoimmune pancreatitis. Response to steroids (decreased pancreatic or extrapancreatic lesion or damage) is distinctive to AIP. In clinical practice, CT scan seems to be the most reasonable tool for examining the patients with obstructive jaundice with or without present pancreatic mass. Stratification the patients with possible AIP versus pancreatic cancer is important. In patients with AIP it may avoid pancreatic resection, as well as incorrect steroid treatment in patients with pancreatic carcinoma.

Biliary obstruction results in PD-1-dependent liver T cell dysfunction and acute inflammation mediated by Th17 cells and neutrophils.

Biliary obstruction is a common clinical problem that is associated with intrahepatic inflammation and impaired immunity. PD-1 is well known to mediate T cell dysfunction but has been reported to promote and attenuate acute inflammation in various injury models. With the use of a well-established murine model of BDL, we studied the effects of intrahepatic PD-1 expression on LTC function, inflammation, and cholestasis. Following BDL, PD-1 expression increased significantly among LTCs. Increased PD-1 expression following BDL was associated with decreased LTC proliferation and less IFN-γ production. Elimination of PD-1 expression resulted in significantly improved proliferative capacity among LTC following BDL, in addition to a more immunostimulatory cytokine profile. Not only was LTC function rescued in PD-1(-/-) mice, but also, the degrees of biliary cell injury, cholestasis, and inflammation were diminished significantly compared with WT animals following BDL. PD-1-mediated acute inflammation following BDL was associated with expansions of intrahepatic neutrophil and Th17 cell populations, with the latter dependent on IL-6. PD-1 blockade represents an attractive strategy for reversing intrahepatic immunosuppression while limiting inflammatory liver damage.

Aggressive natural killer-cell leukemia with jaundice and spontaneous splenic rupture: a case report and review of the literature.

Aggressive natural killer cell leukemia/lymphoma (ANKL) is a rare aggressive form of NK-cell neoplasm. We report an uncommon case of 36-year-old male who showed jaundice and spontaneous splenic rupture. The diagnosis was established by the biopsy of liver and spleen. The monomorphous medium-size neoplastic cells infiltrated into portal areas and sinus of liver as well as the cords and sinus of the spleen. Necrosis, mitotic figures and significant apoptosis could be seen easily. These neoplastic cells demonstrated a typical immunophenotype of CD3ε+, CD56+, CD16+, Granzyme B+, TIA-1+. T-cell receptor γ (TCR-γ) gene rearrangement analysis showed germline configuration and the result of in situ hybridization for Epstein-Barr virus-encoded RNA (EBER-ISH) was positive. The patient has undergone an aggressive clinical course and died of multi-organ function failure 14 days later after admission. To the best of our knowledge, this is the first case of ANKL with spontaneous splenic rupture, and we should pay more attention to recognize it. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2048154883890867.

IgG4-positive sclerosing cholangitis following autoimmune pancreatitis with deranged CA19.9.

Sclerosing cholangitis is an autoimmune condition characterized by lymphocytic infiltration within the biliary epithelium leading to multifocal stricturing of the biliary tree. Primary sclerosing cholangitis (PSC) is the most common type encountered clinically. However, a similar process may occur in conjunction with autoimmune pancreatitis (AIP), known as AIP-associated sclerosing cholangitis (AIP-SC). This subtype is associated with an elevated IgG(4) level and the presence of a number of autoantibodies. AIP-SC shows good response to steroid treatment, distinguishing it clinically from PSC. The authors report a case of AIP-SC in a patient who had previously undergone a biliary bypass for AIP-induced chronic pancreatitis. The presentation of jaundice and grossly elevated tumor marker, CA19.9, raised the concern of malignancy. The uncertainty of the diagnosis was resolved when AIP-SC was confirmed on liver biopsy, with a concomitantly elevated serum IgG(4) level. The disease went into remission with steroid treatment.

Epidemiological, immunological and clinical characteristics of acute hepatitis C.

UNLABELLED: The aim of the study was to make a clinical and epidemiological and immunological characteristic of patients with acute hepatitis C infection (AHC). PATIENTS AND METHODS: The study included 178 patients with AHC; they were studied in terms of clinical course, biochemical constellations, T and B lymphocyte subpopulations, level of TNF-alpha in the blood serum, presence of autoantibodies, and the outcome of the disease in a five-year follow-up period. METHODS: anti-HCV (EIA), HCV-RNA (PCR), HCV genotyping; ALT, AST, AP, gamma-GT; ultrasonography and liver biopsy. RESULTS: AHC incidence increased six-fold between 2000 and 2006. The prevalence of the disease among intravenous drug-users (IDUs) was 46.07%. Young people (31.71 +/- 1.21) and males (67.98%) were prevalent. The genotype HCV-1 was prevalent. AHC ran with icterus in 70.22% of all cases, while it was anicteric in 29.78%; ALT-activity was high--it was mean 1007.94 +/- 59.87 U/l; intrahepatic cholestasis was found in 38.80%. A light form of the disease was found in 43.26%, mild--in 50.56%, and severe--in 6.18%, without reaching acute liver failure. In the acute stage of the disease, an increase of helper/inducer CD3+CD4+ (p = 0.001), memory T helper CD4+CD29+ (p < 0.0001), activated CD3+HLA-DR+ (p <0.0001), mature CD3+ T cells (p < 0.05), naive CD2+T (p < 0.01), and B-lymphocytes CD19+ (p < 0.001) was found, together with a non-significant increase of the suppressor/cytotoxic CD3+CD8+ T lymphocytes in comparison with the controls. The total killer CD56+ were reduced, as well as the MHC restricted killer cells CD8+CD56+. TNF-alpha was elevated in the serum in the light and mild forms (p < 0.0001). The participation of non-organ-specified antibodies (NOSAs) was minimal. Anti-MLA titer was 1/80 in two patients. Five years after the outset of AHC, a spontaneous viral clearance was established in 36.67% and chronic hepatitis in 63.33%. CONCLUSION: Despite the initially activated immune cellular response strongly correlating with a well expressed cytolytic syndrome around 2/3 of the AHC patients develop a chronic form of the disease.

Six consecutive cases of successful adult ABO-incompatible living donor liver transplantation: a proposal for grading the severity of antibody-mediated rejection.

BACKGROUND: The clinical symptoms, histological findings, and treatments for antibody-mediated rejection (AMR), which is the leading cause of graft loss in adult ABO-incompatible liver transplantation (ABO-I-LT), have rarely been discussed. METHODS: We performed adult living donor ABO-I-LT on six patients. We used anti-CD20 monoclonal antibody combined with plasma exchange preoperatively and intraportal or hepatic-arterial infusion, consisting of prostaglandin E1, corticosteroids, and protease inhibitor postoperatively to prevent AMR. Splenectomy was performed in patients 1, 4, 5 and 6 but not in patients 2 and 3. Weekly liver biopsies were performed after ABO-I-LT. When severe AMR was diagnosed, we performed plasma exchange combined with gamma-globulin bolus infusion (PE+IVIG). RESULTS: In patients 1-3, severe jaundice, rapid decreases in platelet counts, and severe coagulopathy were observed in the early postoperative period. Liver biopsies sampled after the onset of these clinical findings were characterized by severe periportal and lobular hemorrhagic and neutrophil infiltration, suggesting that severe AMR occurred. However, after the initiation of PE+IVIG, AMR was remedied in all three patients. In patients 4-6, severe AMR was not observed. Mild AMR characterized by mild portal hemorrhagic infiltration was observed in patient 4, and moderate AMR characterized by moderate periportal and lobular hemorrhagic infiltration was observed in patient 6. Patients 4-6 did not require PE+IVIG and their clinical course was uneventful. CONCLUSION: Given the experience of these six patients, we consider that AMR may be graded based on liver biopsy findings including hemorrhagic infiltration and neutrophil infiltration, as well as clinical findings. All six patients are currently doing well.

Acute hepatitis E with severe jaundice: report of three cases.

Hepatitis E virus (HEV) is the main cause of enterically transmitted non-A hepatitis worldwide. Infection is endemic in developing countries. Disease course is benign, and severe jaundice is rarely reported. Three patients presented to our department with symptomatic acute hepatitis. Two of them had recently travelled to endemic areas. Jaundice was very marked in all patients. HEV infection was documented by HEV antibodies and by HEV-RNA detection in serum and stools. In the autochthonous case, immunoglobulin-M was absent, and diagnosis was established on HEV-RNA amplification by real-time reverse transcriptase-PCR. Comprehensive investigation for concomitant causes of liver disease was negative in all patients. Histological features showed marked cholestasis with multiple bile plugs in dilated canaliculi. In conclusion, acute hepatitis E may be autochthonous in developed countries and patients may present with severe jaundice. HEV-RNA detection by real-time reverse transcriptase-PCR is a very efficacious diagnostic tool in anti-HEV immunoglobulin-M-negative cases.

Liver injury induced by a Japanese herbal medicine, sairei-to (TJ-114, Bupleurum and Hoelen Combination, Chai-Ling-Tang) R1.

The case is reported of a man who showed acute hepatitis with jaundice after he was given a Japanese herbal medicine, sairei-to (TJ-114, Bupleurum and Hoelen Combination, Chai-Ling-Tang). Unusually, the component thought to be responsible for the observed drug-induced liver injury was able to be identified. Lymphocyte migration inhibition testing indicated that the tuber of the perennial herbage Pinellia ternate was the causative agent.

The effect of jaundice on the generation of anti-gastrin antibodies in G17DT immunized patients with advanced pancreatic cancer.

AIM: The aim of this study was to determine the ability of G17DT to generate anti-gastrin antibodies in jaundiced patients with biliary obstruction due to advanced pancreatic cancer. METHODS: G17DT was administered to 41 patients with advanced pancreatic adenocarcinoma by intramuscular (i.m.) injection at a dose of 250mcg at weeks 0, 1 and 3 of the study. RESULTS: Thirty-five of 41 patients participating in the study were categorized as responders in terms of their gastrin-17 antibody response. There was no correlation between the maximum G17 antibody response and the bilirubin level at either week 0 or week 12. The median survival of patients from the time of the first injection of G17DT was 204 days with 25% of patients surviving for or=305 days. CONCLUSION: This study shows that G17DT administered to jaundiced patients with advanced pancreatic cancer is immunogenic and well tolerated.

Red blood cell alloantibodies and liver transplantation in Chinese patients.

Red blood cell (RBC) alloantibodies are present in up to 14% of white recipients of liver transplants and can cause severe delayed hemolysis. A retrospective survey showed 17 cases (8.8%) of RBC alloantibodies in 192 consecutive Chinese recipients of liver transplants, compared with a 3.7% background hospital incidence. The spectrum of RBC alloantibodies was different from that in white recipients, with no anti-D or anti-K antibodies but with a significant incidence of anti-Mi (29%) antibodies. There was significantly increased transfusion in RBC alloantibody positive cases. Delayed hemolysis also resulted in higher day-7 bilirubin levels. A total of 7 to 86 antigen-positive units were issued in five RBC alloantibody cases, including three early deaths. Seven cases in the RBC alloantibody negative group, but none in the positive group, were salvaged by regraft. Blood banks servicing transplant centers should be aware of ethnic patterns in RBC alloantibodies. Delayed hemolysis may jeopardize patient survival as a result of difficult postoperative stabilization, especially in cases requiring massive transfusion.

Type C-chronic hepatitis patients who had autoimmune phenomenon and developed jaundice during interferon therapy.

Of a total of 2342 patients with type-C chronic hepatitis treated with interferon (IFN) at this hospital, 3 patients developed jaundice during the course of IFN therapy, but all 3 of them exhibited negative conversion of hepatitis C virus (HCV)-RNA following readministration of IFN. All 3 patients were assessed as having "probable autoimmune hepatitis (AIH)" in accordance with the AIH scoring system, indicating association with an "autoimmune phenomenon". Readministration of IFN at a low-dose induced activation of the autoimmune phenomenon, leading to fulminant hepatocellular impairment. As a result, HCV-RNA content dropped dramatically, possibly contributing to the negative conversion of HCV-RNA noted following the readministration of IFN. At present, no adequate therapy has been established for type-C chronic hepatitis with autoimmune manifestations. However, in conclusion, our findings suggested that: IFN should be a frontline regiment: (1). if autoantibody titers are low or patients are rated as having "probable AIH" or lower in accordance with the AIH scoring system, indicating a strong link to chronic hepatitis or (2). if IFN is expected to be efficacious on the basis of genotype of HCV-RNA level; even if there is acute exacerbation of type-C chronic hepatitis, IFN should be re-administered in the HCV-RNA level has dropped subsequently.

Forced expression of murine IL-17E induces growth retardation, jaundice, a Th2-biased response, and multiorgan inflammation in mice.

IL-17 is a proinflammatory cytokine, and its in vivo expression induces neutrophilia in mice. IL-17E is a recently described member of an emerging family of IL-17-related cytokines. IL-17E has been shown to bind IL-17Rh1, a protein distantly related to the IL-17R, suggesting that IL-17E probably possesses unique biological functions. In this study, we have identified the murine ortholog of IL-17E and developed transgenic mice to characterize its actions in vivo. Biological consequences of overexpression of murine (m)IL-17E, both unique to IL-17E and similar to IL-17, were revealed. Exposure to mIL-17E resulted in a Th2-biased response, characterized by eosinophilia, increased serum IgE and IgG1, and a Th2 cytokine profile including elevated serum levels of IL-13 and IL-5 and elevated gene expression of IL-4, IL-5, IL-10, and IL-13 was observed in many tissues. Increased gene expression of IFN-gamma in several tissues and elevated serum TNF-alpha were also noted. In addition, IL-17E induces G-CSF production in vitro and mIL-17E-transgenic mice had increased serum G-CSF and exhibit neutrophilia, a property shared by IL-17. Moreover, exposure to mIL-17E elicited pathological changes in multiple tissues, particularly liver, heart, and lungs, characterized by mixed inflammatory cell infiltration, epithelial hyperplasia, and hypertrophy. Taken together, these findings suggest that IL-17E is a unique pleiotropic cytokine and may be an important mediator of inflammatory and immune responses.