A third of patients receiving Interferon-α (IFN-α) treatment for Hepatitis-C develop major depressive disorder (MDD). Conversely, anti-Tumor Necrosis Factor (TNF) therapies improve depression ...providing key empirical support for the "inflammatory theory" of depression. Heightened amygdala reactivity (particularly to negatively valanced stimuli) is a consistent finding within MDD; can predict treatment efficacy and reverses following successful treatment. However, whether IFN-α and anti-TNF enhance/attenuate depressive symptoms through modulation of amygdala emotional reactivity is unknown. Utilizing a prospective study design, we recruited 30 patients (mean 48.0 ± 10.5 years, 21 male) initiating IFN-α treatment for Hepatitis-C and 30 (mean 50.4 ± 15.7 years, 10 male) anti-TNF therapy for inflammatory arthritis. All completed an emotional face-processing task during fMRI and blood sampling before and after their first IFN-α (4-h) or anti-TNF (24-h) injection and follow-up psychiatric assessments for 3 months of treatment. IFN-α significantly increased depression symptoms (Hamilton Depression Rating Scale HAM-D) at 4 weeks (p < 0.001) but not 4-h after first dose (p > 0.1). Conversely, anti-TNF significantly improved depressive symptoms (Hospital Anxiety and Depression Rating Scale HADS) at both 24-h (P = 0.015) and 12 weeks (p = 0.018). In support of our a-priori hypothesis, both IFN-α and anti-TNF significantly modulated amygdala reactivity with IFN-α acutely enhancing right amygdala responses to sad (compared with neutral) faces (p = 0.032) and anti-TNF conversely decreasing right amygdala reactivity (across emotional valence) (p = 0.033). Furthermore, these changes predicted IFN-induced increases in HAM-D 4 weeks later (R
= 0.17, p = 0.022) and anti-TNF-associated decreases in HADS at 24-h (R
= 0.23, p = 0.01) suggesting that actions of systemic inflammation on amygdala emotional reactivity play a mechanistic role in inflammation-associated depressive symptoms.
Abstract
Objective.
Assessment of faecal calprotectin (fCal) test performance in primary care within an irritable bowel syndrome (IBS) diagnostic pathway.
Methods.
Study based on consecutively ...collected fCal data from 962 patients, aged 18-45, presenting to their general practitioner (GP) with persistent gastrointestinal symptoms.
Results.
Six hundred and eighty six (71%) patients had a negative (<50 μg/g) and 276 (29%) had a positive fCal. 28% (77/276) of the patients testing positive and 3% (17/686) of those testing negative had an organic diagnosis. At 50 μg/g the sensitivity of the test for organic disease was 82%, (95% confidence interval CI 73-89) and the specificity was 77% (95% CI 74-80), with negative predictive value (NPV) and positive predictive value (PPV) of 98% and 28%, respectively. A cut-off increase to 150 μg/g reduces the NPV by 1% whilst increasing the PPV to 71%. This would reduce colonoscopy and flexible sigmoidoscopy bookings by 10% at the cost of four missed cases of inflammatory bowel disease.
Conclusions.
This study provides the first evidence on the use of fCal testing in primary care. The low prevalence of organic disease in this setting has a significant impact on test performance. This suggests a need for change in cut-off value, to improve PPV whilst accepting a reduction in test sensitivity, if it is to be used as part of the pathway for management of patients with suspected IBS.
Background & Aims: Differentiating symptoms of irritable bowel syndrome (IBS) from those of organic intestinal disease is a familiar problem for physicians. The aim of this study was to assess the ...sensitivity, specificity, and odds ratios (ORs) of fecal calprotectin, small intestinal permeability, Rome I criteria, and laboratory markers of inflammation (erythrocyte sedimentation rate ESR, C-reactive protein CRP, blood count) in distinguishing organic from nonorganic intestinal disease. Methods: A total of 602 new referrals to a gastroenterology clinic who had symptoms suggestive of IBS or organic intestinal disease were studied for these parameters. All patients underwent invasive imaging (barium/endoscopic examination) and other investigations as appropriate, with physicians blinded to the results of fecal calprotectin and intestinal permeability. Results: A total of 263 patients were diagnosed with organic disease and 339 with IBS. At 10 mg/L, the sensitivity and specificity of calprotectin for organic disease were 89% and 79%, respectively, and that of intestinal permeability for small intestinal disease were 63% and 87%, respectively. Sensitivity of positive Rome criteria for IBS was 85% with a specificity of 71%. An abnormal calprotectin test had an OR for disease of 27.8 (95% confidence interval CI, 17.6–43.7; P < 0.0001) compared with ORs of 4.2 (95% CI, 2.9–6.1; P < 0.0001) and 3.2 (95% CI, 2.2–4.6; P < 0.0001) for elevated CRP and ESR values. An abnormal permeability test gave an OR of 8.9 (95% CI, 5.8–14.0; P < 0.0001) for small intestinal disease. The OR for IBS with positive Rome criteria was 13.3 (95% CI, 8.9–20.0). Conclusions: Fecal calprotectin, intestinal permeability, and positive Rome I criteria provide a safe and noninvasive means of helping differentiate between patients with organic and nonorganic intestinal disease.
GASTROENTEROLOGY 2002;123:450-460
Background & Aims: Prediction of relapse of inflammatory bowel disease has important implications for therapeutic stategies. We assessed whether measurement of intestinal permeability and ...inflammation could predict relapse of inflammatory bowel disease (IBD). Methods: Forty-three patients with Crohn's disease (CD) and 37 with ulcerative colitis (UC) in clinical remission provided a stool sample to be assayed for calprotectin (a neutrophil-specific marker), and patients with CD additionally underwent a small intestinal permeability test. Relapse was defined using clinical disease activity indices. Results: Twenty-five (58%) patients with CD and 19 (51%) with UC had a relapse over the 12-month period. Median calprotectin levels in the relapse groups (122 mg/L for CD, 123 mg/L for UC; normal <10 mg/L) differed significantly (P < 0.0001) from those of the nonrelapse groups (41.5 mg/L for CD, 29.0 mg/L for UC). At 50 mg/L, the sensitivity and specificity of calprotectin for predicting relapse in all patients with IBD were 90% and 83%, respectively. Permeability in the CD patients who relapsed (median, 0.075; normal <0.04) differed significantly (P = 0.004) from that in the nonrelapse group (median, 0.038). At the level of 0.05, the sensitivity and specificity of permeability in predicting relapse were 84% and 61%, respectively. Conclusions: Fecal calprotectin predicts clinical relapse of disease activity in patients with CD and UC, whereas small intestinal permeability is a useful predictor of relapse in patients with small intestinal CD.
GASTROENTEROLOGY 2000;119:15-22
The coronavirus disease 2019 (COVID-19) pandemic has been associated with significant morbidity and mortality. Following the introduction of vaccines, various side effects have been reported. Whilst ...those reported may be attributed to the vaccine itself, at times, it may simply incite an immunological phenomenon. We present a case series of two patients who presented with symptoms of yellowing of the eyes and the skin along with fatigue, and tiredness, following vaccination for COVID-19. The diagnosis of post COVID-19-vaccination related hepatitis is one of the fewer, less understood, yet reported side effects associated with significant morbidity. The diagnosis of COVID-19 vaccination-related cholangitis is an outcome reported here for the first time to the best of our knowledge. It was alarming that both patients did not have any significant past history of medical ailments. A prompt assessment followed by investigations including liver biopsy assisted in a timely understanding of the phenomenon with complete resolution of the symptoms.
AbstractMultiple genetic and environmental factors interact to determine an individual’s predisposition to non-alcoholic fatty liver disease and its phenotypic characteristics. Association studies ...have found a number of alleles associated with the development of non-alcoholic steatohepatitis. Our aim was to investigate whether multiple risk-associated alleles may be present in affected monozygotic twins, indicating underlying genetic predisposition to non-alcoholic steatohepatitis. We determined the genotype of 14 candidate gene polymorphisms (at 11 unlinked loci) in a set of monozygotic twins who presented with cirrhosis within 18 months of each other. Genotyping revealed multiple single nucleotide polymorphisms at 9 independent loci in genes PNPLA3, APOC3, GCKR, TRIB1, LYPLAL1, PPP1R3B, COL13A1, and EFCAB4B, previously implicated in contributing to non-alcoholic steatohepatitis pathogenesis. In conclusion, this case series illustrates the potential cumulative effect of multiple polymorphisms in the development and potential progression of a complex trait such as NASH cirrhosis.
A 60-year-old woman with a background of frailty, non-alcoholic fatty liver disease (NAFLD), cirrhosis and type 2 diabetes mellitus (T2DM), presented with worsening shortness of breath and a drop in ...oxygen saturation on sitting and standing up. Her chest X-ray demonstrated evidence of upper lobe venous diversion. Given the hypoxia, she had a computed tomography pulmonary angiography (CTPA) to rule out a pulmonary embolism. The only finding from the CTPA was pulmonary hypertension in the absence of any clots in the lungs. An ultrasound of the abdomen confirmed portal hypertension with splenomegaly and a cirrhotic liver, therefore, an initial diagnosis of portopulmonary hypertension and hepatopulmonary syndrome was made.
The patient declined an agitated saline contrast echocardiography. Based on frailty she was not deemed to be a suitable candidate for a liver transplant and was discharged with a package of care alongside home oxygen therapy with periodic review in the gastroenterology clinic. She was assessed as stable with no new concerns while on home oxygen and diuretics.
This case highlights challenges in diagnosing and managing patients with cirrhosis, portopulmonary hypertension and hepatopulmonary syndrome with a background of complex comorbidities and frailty.
Non-steroidal anti-inflammatory drugs cause small-bowel inflammation in about 60% of patients receiving these drugs long-term. The inflammation is associated with small intestinal bleeding, protein ...loss, ulcers and occasionally strictures. Treatment options for NSAID enteropathy include metronidazole, sulphasalazine and misoprostol, and some patients may require surgery. The diagnosis of NSAID enteropathy is not always straightforward. It is especially difficult to differentiate it from the ileitis associated with spondylarthropathy and, at times, that of Crohn's disease. An investigational algorithm is suggested for this purpose.
In the last decade a number of small-bowel diseases have been identified, where none were thought to exist, because of the increasing use of enteroscopy and new sensitive tests for intestinal inflammation. Optimal treatments of these conditions are still to be studied.
Background. HCV infection is associated with musculoskeletal manifestations such as chronic widespread pain, sicca syndrome, polyarthritis, and a reduced HRQOL. Little data is available on the effect ...of treatment on these manifestations. This study measured changes in extrahepatic symptoms and HRQOL before and after antiviral treatment in a large UK patient cohort. Methods. 118 patients completed HQLQ and rheumatological questionnaires before and after treatment with pegylated interferon-α and ribavirin, with specific regard to chronic widespread pain, sicca syndrome, and sustained virological response. Results. There was significant improvement in HQLQ domains of physical functioning, physical disability, social functioning, limitations and health distress due to hepatitis, and general health. There was significant deterioration in domains of positive well-being, health distress, and mental health. There was a significant decline prevalence of CWP (26.3% versus 15.3%, P=0.015). Sicca syndrome prevalence fell insignificantly (12.7% versus 11%). SVR was associated positively with all HRQOL changes and significantly with CWP remission. Conclusions. HCV antivirals significantly improve poor HRQOL scores and CWP. Before treatment, both were common, coassociated, and unaccounted for through mixed cryoglobulinemia alone. Although a role of the hepatitis C virus in CWP cannot be deduced by these results, symptomatic improvement via antiviral treatment exists for this subset of patients.
Abstract Background Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used clinically for hepatitis C treatment. Though effective, IFN-α induces marked behavioral changes that, ...when severe, can appear indistinguishable from major depression. Curiously, fatigue and motivational impairment evolve rapidly, suggesting acute engagement of immune-brain communicatory pathways, yet mood impairments typically emerge later, after weeks of treatment. Whether this reflects prolonged modulation of motivational processes underpinning fatigue or separate neurobiological mechanisms is currently unclear. Methods Here, we used quantitative magnetization transfer (qMT) imaging, an advanced microstructural neuroimaging technique sensitive to effects of inflammation, in a prospective study design to measure acute brain changes to IFN-α and relate these to later development of discrete behavioral changes. Twenty-three patients initiating IFN-α treatment for hepatitis C underwent qMT imaging and blood sampling at baseline and 4 hours after their first IFN-α injection. Comprehensive behavioral and psychological assessments were completed at both scanning sessions and at treatment weeks 4, 8, 12, and 24. Results IFN-α injection stimulated an acute inflammatory cytokine response and evoked fatigue that peaked between 4 and 12 weeks, preceding mood change by 4 weeks. In the brain, IFN-α induced an acute change in striatal microstructure that additionally predicted development of fatigue but not mood symptoms. Conclusions Our findings highlight qMT as an in vivo biomarker of central effects of peripheral inflammation. We demonstrate exquisite sensitivity of the striatum to IFN-α, implicate striatal perturbation in IFN-α-induced fatigue, and dissociate this from mechanisms underlying IFN-α-induced mood symptoms, providing empirical support for distinct neural substrates mediating actions on motivation and mood.
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