Acute effects of interferon-alpha on cellular anabolic and catabolic processes are associated with the development of fatigue during Interferon-alpha-based therapy for Hepatitis-C: A preliminary study.

INTRODUCTION: Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used to treat Hepatitis-C virus (HCV) infection. Though clinically effective, IFN-α frequently induces functionally impairing mood and motivation symptoms, particularly fatigue. Unlike mood impairment, which typically emerges after weeks of treatment, fatigue tends to emerge and evolve rapidly, typically within hours of the first IFN-α injection. Despite being a major source of functional impairment during IFN-α and other immune-based therapies, the biological mechanisms underlying fatigue remain poorly understood. Here, we aimed to identify acute immune-response signatures to IFN-α that could predict the later development of fatigue. METHODS: In this exploratory study, we analyzed whole blood transcriptomics in a longitudinal sample of 27 HCV patients initiating IFN-α and Ribavirin therapy. Blood samples were obtained at baseline and 4½ hours after the first IFN-α dose and transcriptomic data was obtained using Affymetrix Human Gene 1.1 ST Array Strips. Gene expression data visualization and quality control were assessed using Partek Genomics Suite V6.6 and protein-protein interaction networks using STRING and Ingenuity Pathway Analysis (IPA). A Fatigue Visual Analogue Scale (fVAS) was utilized to record fatigue symptoms at baseline, 4½ hours and 4 weeks after initiation of treatment. RESULTS: IFN-α was associated with an upregulation of 526 transcripts and a downregulation of 228 genes, indicating a rapid transcriptomic response in whole blood within 4½ hours of injection. 93 genes were significantly positively correlated with changes in fatigue, with gene expression changes measured from baseline to 4.5 h and increases in fatigue assessed from baseline to week 4 on the fVAS. We identified a novel network of predominantly cytosolic ribosomal units and ubiquitin proteins implicated in modulating mTOR signaling that was associated with the development of fatigue 4 weeks after initiation of IFN-α treatment (p = 0.0078). CONCLUSION: Our findings suggest that acute activation of this anabolic/catabolic network by IFN-α may predispose to the experience of fatigue similar to evidence found in cancer-related fatigue. Further investigation is warranted to confirm the exploratory nature of these observations.

Interferon and anti-TNF therapies differentially modulate amygdala reactivity which predicts associated bidirectional changes in depressive symptoms.

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 (R2 = 0.17, p = 0.022) and anti-TNF-associated decreases in HADS at 24-h (R2 = 0.23, p = 0.01) suggesting that actions of systemic inflammation on amygdala emotional reactivity play a mechanistic role in inflammation-associated depressive symptoms.

Factor analyses differentiate clinical phenotypes of idiopathic and interferon-alpha-induced depression.

The discovery that prolonged administration of interferon-alpha (a pro-inflammatory cytokine) readily precipitates depressive symptoms has played a key role in development of the inflammation theory of major depressive disorder (MDD). However, it remains unclear whether the clinical phenotype of patients with inflammation-associated depression significantly overlaps with, or can be distinguished from that of patients with 'idiopathic' depression. Here we explored the Hamilton depression scale factor structure of 172 patients undergoing interferon-alpha treatment for hepatitis-C at the point of transition to a depressive episode of DSM IV defined major depression severity. The resulting factor structure was first compared with a model derived from 6 previous studies of 'idiopathic' MDD (Cole et al., 2004). This confirmatory factor analysis revealed that the factor structure of HAMD scores in our interferon-alpha treated cohort did not plausibly fit that previously described for 'idiopathic' MDD. Instead, subsequent exploratory factor analysis revealed a distinct four factor model with a novel primary factor grouping cognitive symptoms of depression and anxiety (HAMD items 1, 2, 9, 10, 11, 15). The second sleep disorder factor (items 4, 5, 6) replicated previous findings in 'idiopathic' depression. A third and unique factor grouped somatic symptoms and function (items 7, 12, 13, 14 and item 1). The final factor (also common in idiopathic depression studies), grouped gastrointestinal symptoms and weight loss (items 12 and 16). Severe depression items (3, 8, and 17) were excluded from analysis due to very low variance. At transition, interferon-alpha induced major depressive episodes therefore appears to have more associated anxiety features that covary with depressed mood than classical or 'idiopathic' MDD and a low likelihood of severe features such as suicidal ideation. Identification of this clinical phenotype may help identify patients with an inflammatory depression etiology and support the development of more effective and personalized therapies.

Palliative long-term abdominal drains in refractory ascites due to end-stage liver disease: A case series.

BACKGROUND: Ascites, the commonest complication of cirrhosis, leads to frequent hospitalisations. Refractory ascites confers a median survival of 6 months without liver transplantation. In many, the management remains palliative (large-volume paracentesis). Despite calls for improvement, palliative and end-of-life care is not yet integrated into end-stage liver disease. Long-term abdominal drains are a palliative strategy in malignant ascites, but not end-stage liver disease. CASE PRESENTATION: A retrospective, single centre, case series review was performed of patients undergoing long-term abdominal drain placement for refractory ascites secondary to end-stage liver disease at a large teaching hospital between August 2011 and March 2013. Case management: Patients with end-stage liver disease and refractory ascites, where liver transplantation was not an option, were considered for long-term abdominal drains. Seven patients underwent successful long-term abdominal drain insertion after multi-professional assessment. Case outcome: Following long-term abdominal drain insertion, mean hospital attendances reduced to 1 (0-4) from 9 (4-21), with none for ascites management. Median survival after long-term abdominal drain insertion was 29 days (8-219). The complication rate was low and none life threatening. CONCLUSION: Palliative and end-of-life care needs in end-stage liver disease remain under-addressed. Our data suggest that long-term abdominal drains may be a safe and effective palliative intervention in end-stage liver disease. Prospective randomised controlled trials comparing large-volume paracentesis versus long-term abdominal drains in refractory ascites secondary to end-stage liver disease are warranted.

Interferon-α acutely impairs whole-brain functional connectivity network architecture - A preliminary study.

Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used to treat Hepatitis C infection. Though clinically effective, IFN-α rapidly impairs mood, motivation and cognition, effects that can appear indistinguishable from major depression and provide powerful empirical support for the inflammation theory of depression. Though inflammation has been shown to modulate activity within discrete brain regions, how it affects distributed information processing and the architecture of whole brain functional connectivity networks have not previously been investigated. Here we use a graph theoretic analysis of resting state functional magnetic resonance imaging (rfMRI) to investigate acute effects of systemic interferon-alpha (IFN-α) on whole brain functional connectivity architecture and its relationship to IFN-α-induced mood change. Twenty-two patients with Hepatitis-C infection, initiating IFN-α-based therapy were scanned at baseline and 4h after their first IFN-α dose. The whole brain network was parcellated into 110 cortical and sub-cortical nodes based on the Oxford-Harvard Atlas and effects assessed on higher-level graph metrics, including node degree, betweenness centrality, global and local efficiency. IFN-α was associated with a significant reduction in global network connectivity (node degree) (p=0.033) and efficiency (p=0.013), indicating a global reduction of information transfer among the nodes forming the whole brain network. Effects were similar for highly connected (hub) and non-hub nodes, with no effect on betweenness centrality (p>0.1). At a local level, we identified regions with reduced efficiency of information exchange and a sub-network with decreased functional connectivity after IFN-α. Changes in local and particularly global functional connectivity correlated with associated changes in mood measured on the Profile of Mood States (POMS) questionnaire. IFN-α rapidly induced a profound shift in whole brain network structure, impairing global functional connectivity and the efficiency of parallel information exchange. Correlations with multiple indices of mood change support a role for global changes in brain functional connectivity architecture in coordinated behavioral responses to IFN-α.

Monozygotic twins with NASH cirrhosis: cumulative effect of multiple single nucleotide polymorphisms?

 Multiple 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.

Diagnostic accuracy and clinical application of faecal calprotectin in adult patients presenting with gastrointestinal symptoms in primary care.

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.

Gender differences in hepatitis C seroprevalence and suboptimal vaccination and hepatology services uptake amongst substance misusers.

Injecting drug users are the principal at risk group for blood borne viruses. The aim was to assess the feasibility of screening substance misusers for blood borne viruses, and to offer appropriate vaccinations/referral to hepatology services. This was a nurse led prospective 6-month study based at a large Substance Misuse Service in south east England. Of the 196 consecutive individuals assessed, 81 were eligible for HBV immunization of whom only 33.3% completed a vaccination course. Prevalence of positive serological markers were: anti-HBc 14.4%, HBsAg 1.5%, and HCV antibody 37.9%. Compared to men, women were more likely to accept blood borne virus testing (83.3% vs. 62.3%), have ever injected (89.6% vs. 76.3%), overdose (54.2% vs. 23.6%), be anti-HBc positive (27.5% vs. 8.8%), drink alcohol above national recommended guidelines (41.7% vs. 25.7%), and have a positive HCV serology (55% vs. 30.4%) (P ≤ 0.05 for all). Of the 73 individuals identified with a positive HBsAg and or HCV antibody, only 14 (19.1%) were known to hepatology services and 8 (20%) of those eligible subsequently accepted a specialist referral. In conclusion, serological markers for blood borne viruses remain high in substance misusers (anti-HBc 14.4%, HCV antibody 37.9%), with women more likely to be positive. Overall, only 33.3% and 20%, respectively, complete HBV vaccination and accept a hepatology referral. A multidisciplinary approach is paramount to address both the blood borne viruses and the substance misuse and realignment of hepatitis services to Substance Misuse Services may offer such a strategy.

Shortness of breath due to portopulmonary hypertension and hepatopulmonary syndrome: diagnostic challenges and complex management approach in frail patients.

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.

COVID-19 Vaccination-Induced Cholangiopathy and Autoimmune Hepatitis: A Series of Two Cases.

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.

Norepinephrine-enhancing antidepressant exposure associated with reduced antiviral effect of interferon alpha on hepatitis C.

RATIONALE: Major depressive disorder is a common consequence of exposure to the pro-inflammatory cytokine interferon alpha, which is treated effectively with antidepressant medication. Antidepressant mode of action may conflict with interferon alpha's mechanism in treating hepatitis C however. OBJECTIVES: The purpose of this study is to prospectively explore, in a large naturalistic cohort, whether antidepressant exposure influenced end of treatment response of hepatitis C to interferon alpha. METHODS: Two hundred thirty-nine patients infected with chronic hepatitis C and due to receive treatment were recruited. All participants initiated peg-interferon-2-alpha 180 µg weekly sub-cutaneously plus oral ribavirin 800-1200 mg daily. Participants were assessed for DSM-IV major depression at baseline and four weekly during treatment. RESULTS: 32.6 % of the cohort was exposed to an antidepressant (serotonin-reuptake inhibitor: other categorised antidepressants 49:29). At baseline, 3.8 % had major depression and 55.2 % developed major depression during interferon alpha treatment. Exposure to an antidepressant not classified as a serotonin-reuptake inhibitor, of which all were norepinephrine-enhancing (OR 0.15, 95 % CI 0.04-0.60) and having a past history of psychiatric disorder (OR 4.41, 95 % CI 1.39-13.96) independently reduced the likelihood of end of treatment response. Serotonin-reuptake inhibitor exposure did not influence end of treatment response (OR 1.21, 95 % CI 0.35-4.19), neither did major depression at baseline (OR 2.31, 95 % CI 0.55-9.60) or during treatment (OR 0.69, 95 % CI 0.36-1.33). CONCLUSIONS: Our findings support a lack of conflict of therapeutic mechanism of serotonin-reuptake inhibitor antidepressants with interferon alpha in treating hepatitis C, which may include inflammatory influence. This appears not to be true for norepinephrine-enhancing antidepressant types and warrants investigation using more direct methods.

Acute Changes in Striatal Microstructure Predict the Development of Interferon-Alpha Induced Fatigue.

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.

Psychomotor retardation and vulnerability to interferon alpha induced major depressive disorder: Prospective study of a chronic hepatitis C cohort.

BACKGROUND: Major depressive disorder (MDD) is a common consequence of interferon alpha (IFNα) treatment and important supporting evidence of a role of inflammation in the aetiology of depression. OBJECTIVE: This study aimed to expand the knowledge of baseline clinical vulnerability characteristics to IFNα induced MDD, particularly exploring sub-threshold depressive symptoms. METHODS: A prospective cohort of chronic HCV patients undergoing treatment with pegylated-IFNα and ribavirin was studied. MDD was assessed using the Structured Clinical Interview for DSM-IV (SCID-I). Depressive symptoms and severity were assessed at baseline and monthly with the Hamilton Depression Rating Scale (HAMD). Subjects with MDD or taking antidepressant treatment at baseline were excluded. RESULTS: 278 patients were assessed for this cohort with a final study sample of 190. 94.2% had contracted HCV through intravenous drug use. During six months IFNα treatment, 53.2% of patients transitioned to DSM-IV threshold MDD. In the multivariate logistic analysis, independent factors significantly associated with development of MDD were younger age (OR 0.96, 95% CI 0.93-1.00, p=0.028), past history of MDD (OR 3.82, 95% CI 1.63-8.92, p=0.002), baseline HAMD items psychomotor retardation (OR 15.21, 95% CI 1.33-173.41, p=0.032) and somatic symptoms (general) (OR 2.96, 95% CI 1.44-6.08, p=0.003), and HCV genotype 2 (OR 2.27, 95% CI 1.07-4.78, p=0.032). CONCLUSIONS: During IFNα treatment, the rate of transition to MDD was high in this cohort. Psychomotor retardation and somatic symptoms may represent a greater inflamed state pre-treatment. This iatrogenic model of MDD may offer important insights into wider depression aetiology.

The substitution of endoscopic ultrasound for endoscopic retrograde cholangio-pancreatography: implications for service development and training.

OBJECTIVES: Choledocholithiasis and other benign conditions of the biliary tree are difficult to define clinically. Endoscopic retrograde cholangio-pancreatography (ERCP) is increasingly being replaced as the investigation of choice by other imaging modalities. The aim of this study was to measure the impact of substituting endoscopic ultrasound (EUS) for ERCP in terms of case throughput and the proportion of therapeutic ERCPs performed. METHODS: Over a 12-month period, cases with a low/medium likelihood for biliary pathology were triaged to EUS rather than ERCP. Data were collected on the proportion of ERCPs performed with diagnostic or therapeutic intent and compared with data from the preceding 12-month period. RESULTS: In the 12 months to April 2001, 518 cases were referred for ERCP; 140 underwent EUS and 378 underwent ERCP. The proportions of diagnostic and therapeutic ERCP were 14% and 86%, respectively. Benign biliary disease represented 33% of all referrals for EUS, and calculi were identified in 6% of these cases. During the preceding year, 637 ERCPs were performed. The proportion of diagnostic (33%) and therapeutic (67%) cases differed from the index year (P < 0.001). CONCLUSIONS: The substitution of EUS for ERCP results in significant quantitative and qualitative change to ERCP practice, which has direct consequences for training and service development.

HCV triple therapy in co-infection HIV/HCV is not associated with a different risk of developing major depressive disorder.

INTRODUCTION: Hepatitis C (HCV) treatment options have changed with the development of direct activity antivirals (DAAs) and the availability of triple therapies have improved HCV cure rates. A common neuropsychiatric side effect of pegylated-interferon and ribavirin treatment is major depressive disorder (MDD), however little is known about such adverse events with protease inhibitor-based triple therapy. The aim of this study was to assess the rate of MDD in co-infected HIV HCV patients undergoing different HCV treatments. METHODS: All participants were co-infected HIV HCV attending the Royal Sussex County Hospital Brighton hepatology outpatient clinic between 2010 and 2014. Participants were assessed for DSM-IV MDD and depression severity (using the Hamilton depression scale (HAMD)) at baseline and monthly after treatment initiation. HIV and HCV stages, genotype, reinfection and standard demographic variables were recorded. Influence of HCV stage (acute vs. chronic) and type of treatment (classic vs triple), emergence of MDD and clearance outcomes were analyzed using repeated measures and logistic regression models. RESULTS: Fifty participants with a mean age of 42.65 years (SD=10.32) were included; most were male (98%). The majority had contracted HCV genotype 1 (64%) or 4 (26%). The HCV stage and treatment groups were matched for age and depression at baseline. No significant differences were found on virological outcomes considering HCV stage and treatment. From baseline to SVR, there was a significant increase in HAMD scores, F(4,36)=10.09, p<.001; this was not significantly influenced by HCV stage, F(4,35)=0.54, p=.708 or HCV treatment group, F(4,35)=0.60, p=.664. Those with chronic HCV were more likely to transition to MDD than acute infection (OR 7.77, 95% CI 2.04-29.54, p=.003). No differences were found for depression emergence by HCV treatment group (OR 0.83, 95% CI 0.22-3.13, p=.787). CONCLUSIONS: HCV triple therapy was not associated with a different risk of emergence of MDD versus classic treatment. MDD should be assessed before therapy initiation and monitored throughout treatment for any HCV treatment regime. Future research could usefully clarify mechanisms of MDD emergence and risk factors for this.

Measuring the response of extrahepatic symptoms and quality of life to antiviral treatment in patients with hepatitis C.

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.

Pre-treatment waking cortisol response and vulnerability to interferon α induced depression.

Depressive disorder is a common consequence of interferon α treatment. An understanding of the aetiological processes involved is evolving. HPA axis abnormalities are clearly described in community depressive disorder and represent vulnerability to depression development. We explored whether pre-treatment HPA axis abnormalities influence depression emergence during interferon α treatment. We examined waking HPA axis response via salivary cortisol sampling in 44 non-depressed, chronic hepatitis C infected patients due to commence standard interferon α treatment. Hamilton depression scales and the structured clinical interview for DSM-IV major depressive disorder status were administered monthly during treatment. Major depressive disorder developed in 26 of 44 subjects during interferon-α treatment. The pre-treatment waking cortisol response over 1h was significantly greater in the subsequent switch to depression group (F=4.23, p=0.046). The waking cortisol response pre-treatment with interferon α appears greater in those subsequently switching to depressive disorder during treatment. This waking response may join other vulnerability factors for depression emergence in this group. This model could prove a valuable tool in understanding non-iatrogenic depressive disorder in the general population and notably the role of cytokines.

Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease.

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.