Alison Winstanley

Presentation and Management of Post-treatment Relapse in Autoimmune Pancreatitis/Immunoglobulin G4-Associated Cholangitis

BACKGROUND & AIMS Autoimmune pancreatitis (AIP) is a multisystem disorder that often has extrapancreatic manifestations such as immunoglobulin G4-associated cholangitis (IAC). Patients respond rapidly to steroids but can relapse after therapy. We assessed the clinical management of relapse in a group of patients with AIP/IAC. METHODS We performed a prospective study of patients diagnosed with AIP from 2004-2007 who received steroids. Treatment outcome was defined clinically, radiologically, and biochemically as response to steroids, remission after steroids, failure to wean steroids, and relapse. Steroids +/- azathioprine (AZA) were used to treat patients who failed, relapsed, or could not be weaned from steroids. RESULTS Twenty-eight patients with AIP were studied; 23 (82%) had IAC. All patients responded within 6 weeks to prednisolone therapy. Twenty-three patients achieved remission after a median of 5 months of treatment (range, 1.5-17 months), whereas 5 patients (18%) could not be weaned because of a disease flare. Of the patients who achieved remission, 8 of 23 (35%) subsequently relapsed. Overall, 13 of 23 patients (57%) with AIP/IAC relapsed, compared with 0 of the 5 with isolated AIP (P = .04, Fisher exact test). Steroids were increased/restarted in all patients who relapsed; 10 also received AZA. Remission was achieved and maintained in 7 patients; they remain on AZA monotherapy at a median of 14 months (range, 1-27 months). CONCLUSIONS Relapse or failure to wean steroids occurred in 46% of patients with AIP. Patients with IAC are at particularly high risk of relapse. AZA appears to be effective in patients with post-treatment relapse or who cannot be weaned from steroids. To view this articles video abstract, go to the AGAs YouTube Channel.

Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2.

Liver disease is one of the leading causes of death worldwide. Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-derived eicosanoid prostaglandin E2 (PGE2) drives cirrhosis-associated immunosuppression. We observed elevated circulating concentrations (more than seven times as high as in healthy volunteers) of PGE2 in patients with acute decompensation of cirrhosis. Plasma from these and patients with end-stage liver disease (ESLD) suppressed macrophage proinflammatory cytokine secretion and bacterial killing in vitro in a PGE2-dependent manner via the prostanoid type E receptor-2 (EP2), effects not seen with plasma from patients with stable cirrhosis (Child-Pugh score grade A). Albumin, which reduces PGE2 bioavailability, was decreased in the serum of patients with acute decompensation or ESLD (<30 mg/dl) and appears to have a role in modulating PGE2-mediated immune dysfunction. In vivo administration of human albumin solution to these patients significantly improved the plasma-induced impairment of macrophage proinflammatory cytokine production in vitro. Two mouse models of liver injury (bile duct ligation and carbon tetrachloride) also exhibited elevated PGE2, reduced circulating albumin concentrations and EP2-mediated immunosuppression. Treatment with COX inhibitors or albumin restored immune competence and survival following infection with group B Streptococcus. Taken together, human albumin solution infusions may be used to reduce circulating PGE2 levels, attenuating immune suppression and reducing the risk of infection in patients with acutely decompensated cirrhosis or ESLD.

Hepatic sinusoidal obstruction syndrome (SOS) reduces the effect of oxaliplatin in colorectal liver metastases

Vreuls C P H, Van Den Broek M A, Winstanley A, Koek G H, Wisse E, Dejong C H, Olde Damink S W M, Bosman F T & Driessen A 
(2012) Histopathology 61, 314–318

Single nucleotide polymorphisms in the interferon-γ and interleukin-10 genes do not influence chronic hepatitis C severity or T-cell reactivity to hepatitis C virus

Abstract: Background: The mechanisms by which interferon‐γ (IFN‐γ) contributes to inter‐individual heterogeneity in the severity of chronic hepatitis C (CH‐C) are unknown. In 116 consecutive patients with CH‐C, we tested the hypothesis that host genetic factors regulating IFN‐γ production and activity influence the severity of liver damage and hepatitis C virus (HCV)‐specific T‐cell reactivity.

Marathon-induced ischemic colitis: why running is not always good for you

We present the case of a 31 year-old man who presented to the emergency department of University College Hospital London after collapsing upon finishing the London marathon. Contrast-enhanced multidetector computed tomography scanning revealed ischemic colitis of the cecum and ascending colon, which progressed to the development of clinical peritonism after 48 hours. This patient subsequently underwent a laparotomy and right hemicolectomy, with ileostomy formation, on the third day after admission. Operative and histologic findings confirmed ischemic colitis of the cecum and proximal colon. The postoperative recovery was uneventful, and he was discharged home well. Possible mechanisms of ischemia in marathon runners and those undergoing intense exercise include a combination of splanchnic vasoconstriction, dehydration, and hyperthermia, combined with mechanical forces. Most patients presenting with marathon-running-induced ischemic colitis respond to conservative treatment and the need for operative intervention is extremely rare.

Effect of toll‐like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma

Chronic liver disease is a predisposing factor for development of hepatocellular carcinoma (HCC). Toll‐like receptors play a crucial role in immunity against microbial pathogens and recent evidence suggests that they may also be important in pathogenesis of chronic liver disease. The purpose of this study was to determine whether TLR7 and TLR9 are potential targets for prevention and progression of HCC.

Glutathione S -transferase M1-null genotype as risk factor for SOS in oxaliplatin-treated patients with metastatic colorectal cancer

Background:Oxaliplatin is used as a neo-adjuvant therapy in hepatic colorectal carcinoma metastasis. This treatment has significant side effects, as oxaliplatin is toxic to the sinusoidal endothelial cells and can induce sinusoidal obstruction syndrome (SOS), which is related to decreased overall survival. Glutathione has an important role in the defence system, catalysed by glutathione S-transferase (GST), including two non-enzyme producing polymorphisms (GSTM1-null and GSTT1-null). We hypothesise that patients with a non-enzyme producing polymorphism have a higher risk of developing toxic injury owing to oxaliplatin.Methods:In the nontumour-bearing liver, the presence of SOS was studied histopathologically. The genotype was determined by a semi-nested PCR.Results:Thirty-two of the 55 (58%) patients showed SOS lesions, consisting of 27% mild, 22% moderate and 9% severe lesions. The GSTM1-null genotype was present in 25 of the 55 (46%). Multivariate analysis showed that the GSTM1-null genotype significantly correlated with the presence of (moderate–severe) SOS (P=0.026).Conclusion:The GSTM1-null genotype is an independent risk factor for SOS. This finding allows us, in association with other risk factors, to conceive a potential risk profile predicting whether the patient is at risk of developing SOS, before starting oxaliplatin, and subsequently might result in adjustment of treatment.

Radiofrequency ablation is effective for the treatment of high-grade dysplasia in Barrett's esophagus after failed photodynamic therapy.

Endoscopic radiofrequency ablation (RFA) is an effective treatment for high-grade dysplasia in Barretts esophagus in ablation-naïve patients, but no studies have evaluated its use in patients in whom ablative therapy has previously failed. We describe 14 patients with residual high-grade dysplasia following aminolevulinic acid or Photofrin (porfimer sodium) photodynamic therapy (PDT). An overall complete reversal of dysplasia was achieved in 86 % with a combination of RFA and rescue endoscopic mucosal resection. The median total follow-up is 19 months. The rate of strictures was 7 % (1/14) and there was a low rate of buried glands (0.5 % follow-up biopsies). These data suggest RFA is both safe and effective for eradication of high-grade dysplasia in patients in whom PDT has failed.

Cerebral involvement in IgG4-related disease

IgG4-related disease is a recently recognised multi-system disease. Common organ involvement includes the pancreas, biliary tree and salivary glands. Central nervous system involvement has been infrequently reported. In a single-centre cohort of 84 patients, we report cerebral involvement in three (4%) patients. Details of cerebral involvement in these patients are outlined, including pituitary involvement in two patients and a diffuse autoimmune-like encephalopathy in the other.

Bile duct-ligated mice exhibit multiple phenotypic similarities to acute decompensation patients despite histological differences.

Patients with decompensated cirrhosis are susceptible to infection. Innate immune dysfunction and development of organ failure are considered to underlie this. A rodent model of liver disease sharing these phenotypic features would assist in vivo study of underlying mechanisms and testing of therapeutics. We evaluated three models to identify which demonstrated the greatest clinical and immunological phenotypic similarity to patients with acutely decompensated (AD) cirrhosis.