Heterogeneity of treatment response to beta-blockers in the treatment of portal hypertension: A systematic review.

BACKGROUND: It has been suggested that a relevant proportion of patients do not respond to nonselective beta-blockers (NSBB)s, which raises questions regarding the need for individualized therapy. The existence of potential heterogeneity in the treatment response can be assessed using the variability ratio (VR) of the outcome measurement (in this case, HVPG) between the treated and placebo groups. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the potential heterogeneity in the portal pressure response to NSBBs. METHODS: After a systematic search, we quantified the heterogeneity of treatment response with the VR between the treatment and control groups, with VR > 1 indicating potential heterogeneity. We used a similar approach to compare carvedilol with propranolol and statins with placebo. RESULTS: We identified 18 studies that included 965 patients. A comparison between beta-blockers and placebo showed a pooled VR of 0.99 (95% CI:0.87-1.14), which suggests a homogeneous HVPG response to NSBB at the individual patient level (ie, no evidence to support that some patients responded to beta-blockers and others did not). For the comparison between carvedilol and propranolol, pooled VR was 0.97 (95% CI 0.82-1.14), suggesting that carvedilol achieves a greater average response (rather than an increase in the proportion of responders). There was no evidence of a heterogeneous response to statins. CONCLUSION: Our analysis did not support the existence of a heterogeneous patient-by-patient response to NSBBs in cirrhosis. These findings challenge the concept of personalized therapy based on portal pressure response and indicate that routine portal pressure measurement may not be necessary to guide NSBB therapy.

The patient generated subjective global assessment short form is a useful screening tool to detect risk for malnutrition in patients with cirrhosis.

BACKGROUND AND AIMS: Malnutrition is a modifiable risk factor for morbidity and mortality in cirrhosis. Nutrition risk screening is recommended in cirrhosis nutrition guidelines, but is not routinely completed in practice. The patient-generated subjective global assessment short form (PG-SGA SF) is a patient-completed screen that has potential to be a substitute for more time and resource intensive nutrition screens. The aim of this cross-sectional study was to compare the PG-SGA SF and three other patient-completed screens against the nutrition assessment reference method in cirrhosis, the Royal Free Hospital subjective global assessment (RFH-SGA). We also explored whether being classified "at-risk" on a nutritional screening tool was associated with clinical outcomes of unplanned hospitalization or death. METHODS: Patients completed four nutrition screening tools with or without support from a caregiver. The RFH-SGA was carried out by a blinded registered dietitian. The four screening tools were compared against the RFH-SGA to calculate sensitivity, specificity, and positive and negative predictive value. RESULTS: A total of 121 patients were included. The PG-SGA SF screened the highest number of patients positive for malnutrition risk (52%), was the most accurate, and had the highest sensitivity. Being at risk for malnutrition on the PG-SGA SF was associated with a higher risk of unplanned hospitalization (unadjusted sHR 2.78 (95% CI 1.3-5.9), p = 0.009). CONCLUSIONS: The PG-SGA SF identifies malnutrition risk at similar or superior rates to other patient-generated screening tools in patients with cirrhosis. Our findings support its potential as a patient completed solution for identifying malnutrition risk in cirrhosis.

Noninvasive assessment oesophageal varices: impact of the Baveno VI criteria.

PURPOSE OF REVIEW: In 2015, as a consequence of the high development in noninvasive tests, Baveno VI consensus recommended for the first time the use of a prediction rule (liver stiffness <20kPa and platelet count > 150000) to identify patients at low risk of having varices and that could circumvent endoscopy. These became known as the Baveno VI criteria. We review here the data validating Baveno VI criteria and we discuss the attempts of expanding these criteria. RECENT FINDINGS: We report 28 studies assessing the performance of Baveno VI criteria showing a pooled 99% negative predictive value for ruling out high-risk varices. Performance is not affected by the cause of cirrhosis. Different attempts at expanding these criteria show suboptimal performance. Nonelastography-based criteria require further validation. SUMMARY: Baveno VI criteria can be safely used to avoid endoscopy in a substantial proportion of patients with compensated cirrhosis. The progressive change in approach to the management of compensated cirrhosis, progressively focusing on treating portal hypertension with beta-blockers independently of the presence of varices, might render these criteria less relevant.

Test-Retest Reliability and Consistency of HVPG and Impact on Trial Design: A Study in 289 Patients from 20 Randomized Controlled Trials.

BACKGROUND AND AIMS: Portal hypertension (PH) is a major driver for cirrhosis complications. Portal pressure is estimated in practice by the HVPG. The assessment of HVPG changes has been used for drug development in PH. This study aimed at quantifying the test-retest reliability and consistency of HVPG in the specific context of randomized controlled trials (RCTs) for the treatment of PH in cirrhosis and its impact on power calculations for trial design. APPROACH AND RESULTS: We conducted a search of published RCTs in patients with cirrhosis reporting individual patient-level data of HVPG at baseline and after an intervention, which included a placebo or an untreated control arm. Baseline and follow-up HVPGs in the control groups were extracted after digitizing the plots. We assessed reliability and consistency and the potential impact of study characteristics. We retrieved a total of 289 before and after HVPG measurements in the placebo/untreated groups from 20 RCTs. The time span between the two HVPG measurements ranged between 20 minutes and 730 days. Pre-/post-HVPG variability was lower in studies including only compensated patients; therefore, modeled sample size calculations for trials in compensated cirrhosis were lower than for decompensated cirrhosis. A higher proportion of alcohol-associated cirrhosis and unicentric trials was associated with lower differences between baseline and follow-up measurements. The smallest detectable difference in an individual was 26% and 30% in compensated and decompensated patients, respectively. CONCLUSIONS: The test-retest reliability of HVPG is overall excellent. Within-individual variance was higher in studies including higher proportions of decompensated patients. These findings should be taken into account when performing power analysis for trials based on the effects on HVPG or when considering HVPG as a tool to guide therapy of PH.

Single Topic Conference on Autoimmune Liver Disease from the Canadian Association for the Study of the Liver.

Autoimmune liver disease (AILD) spans a spectrum of chronic disorders affecting the liver parenchyma and biliary system. Three main categories of AILD are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). This review condenses the presentation and discussions of the Single Topic Conference (STC) on AILD that was held in Ottawa, Ontario, in November 2019. We cover generalities regarding disease presentation and clinical diagnosis; mechanistic themes; treatment paradigms; clinical trials, including approaches and challenges to new therapies; and looking beyond traditional disease boundaries. Although these diseases are considered autoimmune, the etiology and role of environmental triggers are poorly understood. AILDs are progressive and chronic conditions that affect survival and quality of life. Advances have been made in PBC treatment because second-line treatments are now available (obeticholic acid, bezafibrate); however, a significant proportion still present suboptimal response. AIH treatment has remained unchanged for several decades, and data suggest that fewer than 50% of patients achieve a complete response and as many as 80% develop treatment-related side effects. B-cell depletion therapy to treat AIH is in an early stage of development and has shown promising results. An effective treatment for PSC is urgently needed. Liver transplant remains the best option for patients who develop decompensated cirrhosis or hepatocellular carcinoma within specific criteria, but recurrent AILD might occur. Continued efforts are warranted to develop networks for AILD aimed at assessing geo-epidemiological, clinical, and biochemical differences to capture the new treatment era in Canada.

Clinical utility and outcome analysis of faecal calprotectin in Hawkes Bay District Health Board.

AIM: An audit to review the outcome in the use of faecal calprotectin (FCP) to differentiate irritable bowel syndrome (IBS) from active inflammatory bowel disease (IBD) patients, and to detect active flares in known IBD patients in the local Hawkes Bay District Health Board (HBDHB) population from October 2013 to October 2014. METHOD: Retrospective review of all FCP specimens requested in the HBDHB region from October 2013 to October 2014. Their indication, final diagnosis from clinical records, and endoscopic results are reviewed. RESULTS: There were 104 FCP registrations during this period. They were ordered by gastroenterologists (67%), followed by medical specialists (31%), GPs (4%) and surgeons (2%). There were 85 FCP samples requested to differentiate IBS from active IBD. Thirty were diagnosed with IBS. The mean FCP level for the 30 patients was 27.23 mcg/g (range 14.1-41.4), which was exclusive of 50 mcg/g. Using the null value of 50 mcg/g from international studies, its p-value was <0.001. There were 19 FCP samples requested to detect a flare in known IBD patients. Seven patients were diagnosed with an active flare endoscopically. The mean FCP for the 7 patients was 378.4 mcg/g (range 275.1-481.8). This was exclusive of 250mcg/g. Using the null value of 250 from international studies, its p-value was 0.007). CONCLUSION: The use of FCP is effective to both differentiate IBS from active IBD patients, and to detect flares in known IBD patients in the HBDHB population.

Type 2 diabetes: a risk factor for liver mortality and complications in hepatitis B cirrhosis patients.

BACKGROUND AND AIM: The effect of type 2 diabetes mellitus (DM) on morbidity and mortality among hepatitis B virus (HBV) cirrhosis patients is poorly defined. We assess the effect of DM on the HBV cirrhosis outcomes and survival. METHODS: A retrospective study of HBV cirrhosis patients who sought care at a sole public hospital in a geographically defined region, from year 2000 to 2012. Cirrhosis complications, liver transplantations, and mortality were reviewed. Primary outcome is the composite of liver-related and overall mortality or orthotopic liver transplantation (OLT). RESULTS: Two hundred twenty-three patients entered into the final analysis; 50 patients (22.4%) have DM at cirrhosis diagnosis. Seventy-two percent of DM patients have DM for more than 5 years at cirrhosis diagnosis. The incidence of hepatocellular carcinoma (HCC) was 25.4 and 60.5 per 1000 patient-years for non-DM and DM patients, respectively (P = 0.006). In multivariate analysis, DM was a predictor of HCC (hazard ratio [HR] 2.36, [1.14-4.85], P = 0.02), hepatic complications (HR 2.04, [1.16-3.59], P = 0.01), liver mortality or OLT (HR 2.26, [1.05-4.86], P = 0.04), and overall mortality or OLT (HR 2.25, [1.96-4.22], P = 0.01). Insulin and/or sulphonylurea use and poor diabetic control (glycosylated hemoglobin ≥ 7.0%) were predictors of HCC and cirrhosis complications (all P < 0.05). The 5-year liver-related mortality or OLT rate was 23.4% for DM patients and 9.4% for non-DM patients, respectively (P = 0.009). CONCLUSION: The presence of DM and poor diabetic control at cirrhosis diagnosis significantly increase the rate of cirrhosis complications and reduced survival in patients with HBV cirrhosis. Improving diabetic control should be essential part of the cirrhosis care in these patients.

Symptom presentations and other characteristics of colorectal cancer patients and the diagnostic performance of the Auckland Regional Grading Criteria for Suspected Colorectal Cancer in the South Auckland population.

AIM: This study reviews the presenting symptoms of colorectal cancer in the ethnically diverse Middlemore Hospital referral population of South Auckland, New Zealand. The performance of the newly introduced Auckland Regional Grading Criteria as prediction tool for selecting colorectal cancer cases referred from primary care was evaluated in this group. METHOD: Retrospective review of all colorectal cancer (CRC) cases diagnosed between January 2006 and January 2011. Information extracted from case note review was used to grade patients using the Auckland Regional Grading Criteria. RESULTS: A total of 799 patients were included. The commonest symptoms were: rectal bleeding (25.5-42.3%) and change in bowel habit (20.6-26.8%). Low-risk symptoms including abdominal pain (16.3-46.8%) and weight loss (18.4-26.1%) were not uncommon. 64.4% of Maori and 64.9% of Pacific patients had stage III or IV cancers. Pacific patients had more stage IV disease, 37.7% (p<0.001) and were less likely to undergo tumour resection, 26.0% (p<0.001). The Auckland Regional Grading Criteria would miss 24.7% of the patients with CRC in the referral population. CONCLUSION: While rectal bleeding and change in bowel habit are frequent presenting symptoms, low-risk atypical symptoms including constipation, weight loss and abdominal pain were not uncommon. Significant proportion of Pacific patients present with late-stage disease. The current Auckland Regional grading criteria would miss significant proportion of our study population with colorectal cancer.