Liver Stiffness by Transient Elastography Predicts Liver-Related Complications and Mortality in Patients with Chronic Liver Disease

Background

Liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) is a validated method for noninvasively staging liver fibrosis. Most hepatic complications occur in patients with advanced fibrosis. Our objective was to determine the ability of LSM by TE to predict hepatic complications and mortality in a large cohort of patients with chronic liver disease.

Methods

In consecutive adults who underwent LSM by TE between July 2008 and June 2011, we used Cox regression to determine the independent association between liver stiffness and death or hepatic complications (decompensation, hepatocellular carcinoma, and liver transplantation). The performance of LSM to predict complications was determined using the c-statistic.

Results

Among 2,052 patients (median age 51 years, 65% with hepatitis B or C), 87 patients (4.2%) died or developed a hepatic complication during a median follow-up period of 15.6 months (interquartile range, 11.0–23.5 months). Patients with complications had higher median liver stiffness than those without complications (13.5 vs. 6.0 kPa; P<0.00005). The 2-year incidence rates of death or hepatic complications were 2.6%, 9%, 19%, and 34% in patients with liver stiffness <10, 10–19.9, 20–39.9, and ≥40 kPa, respectively (P<0.00005). After adjustment for potential confounders, liver stiffness by TE was an independent predictor of complications (hazard ratio [HR] 1.05 per kPa; 95% confidence interval [CI] 1.03–1.06). The c-statistic of liver-stiffness for predicting complications was 0.80 (95% CI 0.75–0.85). A liver stiffness below 20 kPa effectively excluded complications (specificity 93%, negative predictive value 97%); however, the positive predictive value of higher results was sub-optimal (20%).

Conclusions

Liver stiffness by TE accurately predicts the risk of death or hepatic complications in patients with chronic liver disease. TE may facilitate the estimation of prognosis and guide management of these patients.     

Influence of Hepatitis C Virus and IL28B Genotypes on Liver Stiffness

Objective

Liver fibrosis has been associated with hepatitis C virus (HCV) genotype and genetic variation near the interleukin 28B (IL28B) gene, but the relative contribution is unknown. We aimed to investigate the relation between HCV genotypes, IL28B and development of liver stiffness.

Patients and Methods

This cross-sectional study consists of 369 patients with chronic hepatitis C (CHC). Liver stiffness was evaluated using transient elastograhy (TE). Factors associated with development of liver fibrosis were identified by logistic regression analysis.

Results

We identified 369 patients with CHC. 235 were male, 297 Caucasians, and 223 had been exposed to HCV through intravenous drug use. The overall median TE value was 7.4 kPa (interquartile range (IQR) 5.7–12.1). HCV replication was enhanced in patients carrying the IL28B CC genotype compared to TT and TC (5.8 vs. 5.4 log₁₀ IU/mL, p = 0.03). Patients infected with HCV genotype 3 had significantly higher TE values (8.2 kPa; IQR, 5.9–14.5) compared to genotype 1 (6.9 kPa; IQR, 5.4–10.9) and 2 (6.7 kPa; IQR, 4.9–8.8) (p = 0.02). Within patients with genotype 3, IL28B CC genotype had the highest TE values (p = 0.04). However, in multivariate logistic regression, using various cut-off values for fibrosis and cirrhosis, only increasing age (odds ratio (OR) 1.09 (95% confidence interval (CI), 1.05–1.14 per year increment)), ALT (OR 1.01 (95% CI, 1.002–1.011), per unit increment) and HCV genotype 3 compared to genotype 1 (OR 2.40 (95% CI, 1.19–4.81), were consistently associated with cirrhosis (TE>17.1 kPa).

Conclusions

Age, ALT and infection with HCV genotype 3 were associated with cirrhosis assessed by TE. However, IL28B genotype was not an independent predictor of fibrosis in our study.     

Deficiency in Thrombopoietin Induction after Liver Surgery Is Associated with Postoperative Liver Dysfunction

Background and Aims

Thrombopoietin (TPO) has been implicated in the process of liver regeneration and was found to correlate with hepatic function in patients with liver disease. With this investigation we aimed to determine if perioperative TPO levels were associated with postoperative outcome in patients undergoing liver resection.

Methods

Perioperative TPO was analyzed prior to liver resection as well as on the first and fifth postoperative day in 46 colorectal cancer patients with liver metastasis (mCRC) as well as 23 hepatocellular carcinoma patients (HCC). Serum markers of liver function within the first postoperative week were used to define liver dysfunction.

Results

While circulating TPO levels significantly increased one day after liver resection in patients without liver cirrhosis (mCRC) (P < 0.001), patients with underlying liver disease (HCC) failed to significantly induce TPO postoperatively. Accordingly, HCC patients had significantly lower TPO levels on POD1 and 5. Similarly, patients with major resections failed to increase circulating TPO levels. Perioperative dynamics of TPO were found to specifically predict liver dysfunction (AUC: 0.893, P < 0.001) after hepatectomy and remained an independent predictor upon multivariate analysis.

Conclusions

We here demonstrate that perioperative TPO dynamics are associated with postoperative LD. Postoperative TPO levels were found to be lowest in high-risk patients (HCC patients undergoing major resection) but showed an independent predictive value. Thus, a dampened TPO increase after liver resection reflects a poor capacity for hepatic recovery and may help to identify patients who require close monitoring or intervention for potential complications.     

Transient Elastography-Based Liver Profiles in a Hospital-Based Pediatric Population in Japan

Background & Aims

The utility of transient elastography (FibroScan) is well studied in adults but not in children. We sought to assess the feasibility of performing FibroScans and the characteristics of FibroScan-based liver profiles in Japanese obese and non-obese children.

Methods

FibroScan examinations were performed in pediatric patients (age, 1–18 yr) who visited Osaka City University Hospital. Liver steatosis measured by controlled attenuation parameter (CAP), and hepatic fibrosis evaluated as the liver stiffness measurement (LSM), were compared among obese subjects (BMI percentile ≥90%), non-obese healthy controls, and non-obese patients with liver disease.

Results

Among 214 children examined, FibroScans were performed successfully in 201 children (93.9%; median, 11.5 yr; range, 1.3–17.6 yr; 115 male). CAP values (mean±SD) were higher in the obese group (n = 52, 285±60 dB/m) compared with the liver disease (n = 40, 202±62, P<0.001) and the control (n = 107, 179±41, P<0.001) group. LSM values were significantly higher in the obese group (5.5±2.3 kPa) than in the control (3.9±0.9, P<0.001), but there were no significant differences in LSM between the liver disease group (5.4±4.2) and either the obese or control group. LSM was highly correlated with CAP in the obese group (ρ = 0.511) but not in the control (ρ = 0.129) or liver disease (ρ = 0.170) groups.

Conclusions

Childhood obesity carries a high risk of hepatic steatosis associated with increased liver stiffness. FibroScan methodology provides simultaneous determination of CAP and LSM, is feasible in children of any age, and is a non-invasive and effective screening method for hepatic steatosis and liver fibrosis in Japanese obese children.     

Relationship between Cerebral Microbleeds and Liver Stiffness Determined by Transient Elastography

Background & Aims

Liver fibrosis is a multifactorial disease that can affect the development of cerebral small vessel diseases (SVDs) including cerebral microbleeds (CMBs), leukoaraiosis, and silent infarctions. Transient elastography can accurately assess the degree of liver fibrosis by measuring liver stiffness (LS). In the present study, we investigated the association between SVDs and LS values.

Methods

We recruited 300 participants (mean age 56 years, 170 men) who underwent a comprehensive medical health check-up between January 2011 and December 2012. Transient elastography was taken on the right lobe of the liver through intercostal space with patients lying in the dorsal decubitus position with the right arm in maximal abduction. Mild and significant fibrosis were defined as LS values >5.6 and >8.0 kPa, respectively. The presence of each SVD was determined using the FLAIR, GRE MR imaging as well as T1-, T2-weighted MR images. We tested whether the presence and burden of each type of SVD were different by LS values.

Results

Of the different types of SVDs, only the presence (p = 0.001) and number of CMBs (p<0.001) were positively associated with LS values. Multivariate analysis revealed that significant fibrosis (>8.0 kPa) was an independent predictor of CMBs (odds ratio 6.079, 95% confidence interval 1.489–24.819, p = 0.012). However, leukoaraiosis and silent infarctions were not associated with LS values (all p>0.05).

Conclusions

The degree of liver fibrosis, as assessed using transient elastography, was independently associated with the presence and burden of CMBs in healthy, asymptomatic participants. Understanding the link between the brain and liver may advance future research on the pathomechanisms of CMBs.     

Use of Liver Stiffness Measurement for Liver Resection Surgery: Correlation with Indocyanine Green Clearance Testing and Post-Operative Outcome

Background

Liver stiffness measurement (LSM) using transient elastography has recently become available for the assessment of liver fibrosis. Whether LSM can predict the functional liver reserve in patients undergoing liver resection is not certain.

Aim

To correlate liver stiffness measurement (LSM) with indocyanine green (ICG) clearance test and liver biochemistry, and to determine its usefulness in predicting postoperative outcomes in patients undergoing liver resection.

Patients and Methods

Transient elastography and ICG clearance test were performed pre-operatively in 44 patients with hepatocellular carcinoma. The LSM and ICG retention rate at 15 minutes (R15) were correlated with pre-operative factors and post-operative outcomes.

Results

There was significant correlation between ICG R15 and LSM. In patients with LSM ≥11 kPa vs <11 kPa, there was significantly higher ICG R15 (17.1% vs 10.0% respectively, p = 0.025). For patients with ICG R15≥10% compared to those <10%, there was significantly higher LSM (12.0 vs 7.6 kPa respectively, p = 0.015). Twenty-eight patients proceeded to resection. There was a significant correlation between LSM and the peak INR after liver resection (r = 0.426, p = 0.024). There was a significant correlation between ICG R15 and the post-operative peak AST level (r = −0.414, p = 0.029) and peak ALT level (r = −0.568, p = 0.002). The operative time was a significant independent factor associated with post-operative complications and peak INR.

Conclusion

LSM correlated well with ICG R15 in patients undergoing liver resection, and predicted early post-operative complications. Addition of LSM to ICG R15 testing may provide better prognostic information for patients undergoing resection.     

Liver Lobe Volumes and the Ratios of Liver Lobe Volumes to Spleen Volume on Magnetic Resonance Imaging for Staging Liver Fibrosis in a Minipig Model

Objective

To investigate liver lobe volumes and the ratios of liver lobe volumes to spleen volume measured with magnetic resonance imaging (MRI) for quantitatively monitoring and staging liver fibrosis.

Methods

Animal study was approved by Institutional Animal Care and Use Committee. Sixteen minipigs were prospectively used to model liver fibrosis, and underwent abdominal gadolinium-enhanced MRI on 0, 5^th, 9^th, 16^th and 21^st weekend after modeling this disease staged by biopsy according to METAVIR classification system. On MRI, volume parameters including left lateral liver lobe volume (LLV), left medial liver lobe volume (LMV), right liver lobe volume (RV), caudate lobe volume (CV), and spleen volume (SV) were measured; and LLV/SV, LMV/SV, RV/SV and CV/SV were calculated. Statistical analyses were performed for staging this fibrosis.

Results

LLV and CV increased with increasing stage of fibrosis (r = 0.711, 0.526, respectively; all P < 0.05). RV and LMV increased from stage 0 to 2 and decreased from 2 to 4; and RV/SV decreased from 0 to 1, increased from 1 to 2, and decreased from 3 to 4 (all P > 0.05). LLV/SV, LMV/SV and CV/SV decreased from stage 0 to 4 (r = -0.566, -0.748 and -0.620, respectively; all P < 0.05). LLV, CV, LLV/SV, LMV/SV, RV/SV, and CV/SV could distinguish stage 0–1 from 2–4 and 0–2 from 3–4 (all P < 0.05). Among these parameters, LLV and LMV/SV could best classify stage ≥2 and ≥3, respectively (area under receiver operating characteristic curve = 0.893 and 0.946, respectively).

Conclusion

LLV and LMV/SV complement each other in staging liver fibrosis, and both parameters should be used to stage this disease.     

Aortic Stiffness in Lone Atrial Fibrillation: A Novel Risk Factor for Arrhythmia Recurrence

Background

Recent community-based research has linked aortic stiffness to the development of atrial fibrillation. We posit that aortic stiffness contributes to adverse atrial remodeling leading to the persistence of atrial fibrillation following catheter ablation in lone atrial fibrillation patients, despite the absence of apparent structural heart disease. Here, we aim to evaluate aortic stiffness in lone atrial fibrillation patients and determine its association with arrhythmia recurrence following radio-frequency catheter ablation.

Methods

We studied 68 consecutive lone atrial fibrillation patients who underwent catheter ablation procedure for atrial fibrillation and 50 healthy age- and sex-matched community controls. We performed radial artery applanation tonometry to obtain central measures of aortic stiffness: pulse pressure, augmentation pressure and augmentation index. Following ablation, arrhythmia recurrence was monitored at months 3, 6, 9, 12 and 6 monthly thereafter.

Results

Compared to healthy controls, lone atrial fibrillation patients had significantly elevated peripheral pulse pressure, central pulse pressure, augmentation pressure and larger left atrial dimensions (all P<0.05). During a mean follow-up of 2.9±1.4 years, 38 of the 68 lone atrial fibrillation patients had atrial fibrillation recurrence after initial catheter ablation procedure. Neither blood pressure nor aortic stiffness indices differed between patients with and without atrial fibrillation recurrence. However, patients with highest levels (≥75^th percentile) of peripheral pulse pressure, central pulse pressure and augmentation pressure had higher atrial fibrillation recurrence rates (all P<0.05). Only central aortic stiffness indices were associated with lower survival free from atrial fibrillation using Kaplan-Meier analysis.

Conclusion

Aortic stiffness is an important risk factor in patients with lone atrial fibrillation and contributes to higher atrial fibrillation recurrence following catheter ablation procedure.     

Carpal Tunnel Syndrome Assessment with Ultrasonography: Value of Inlet-to-Outlet Median Nerve Area Ratio in Patients versus Healthy Volunteers

Objective

To evaluate the diagnostic value of the Inlet-to-outlet median nerve area ratio (IOR) in patients with clinically and electrophysiologically confirmed carpal tunnel syndrome (CTS).

Methods

Forty-six wrists in 46 consecutive patients with clinical and electrodiagnostic evidence of CTS and forty-four wrists in 44 healthy volunteers were examined with ultrasonography. The cross-sectional area (CSA) of the median nerve was measured at the carpal tunnel inlet (the level of scaphoid-pisiform) and outlet (the level of the hook of the hamate), and the IOR was calculated for each wrist. Ultrasonography and electrodiagnostic tests were performed under blinded conditions. Electrodiagnostic testing combined with clinical symptoms were considered to be the gold standard test. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic value between the inlet CSA and IOR.

Results

The study population included 16 men and 30 women (mean age, 45.3 years; range, 18–83 years). The control population included 18 men and 26 women (mean age, 50.4 years; range, 18–79 years). The mean inlet CSA was 8.7 mm² in healthy controls and 14.6mm² in CTS group (P<0.001). The mean IOR in healthy volunteers (1.0) was smaller than that in patients (1.6, P<0.001). Receiver operating characteristic analysis revealed a diagnostic advantage to using the IOR rather than the inlet CSA (P<0.01). An IOR cutoff value of ≥ 1.3 would yield 93% specificity and 91% sensitivity in the diagnosis of CTS.

Conclusion

The IOR of median nerve area promises to be an effective means in the diagnosis of CTS. A large-scale, randomized controlled trial is required to determine how and when this parameter will be used.     

Assessment of Clinical Signs of Liver Cirrhosis Using T1 Mapping on Gd-EOB-DTPA-Enhanced 3T MRI

Objectives

To assess the differences between normal and cirrhotic livers by means of T1 mapping of liver parenchyma on gadoxetic acid (Gd-EOB-DTPA)-enhanced 3 Tesla (3T) MR imaging (MRI).

Methods

162 patients with normal (n = 96) and cirrhotic livers (n = 66; Child-Pugh class A, n = 30; B, n = 28; C, n = 8) underwent Gd-EOB-DTPA-enhanced 3T MRI. To obtain T1 maps, two TurboFLASH sequences (TI = 400 ms and 1000 ms) before and 20 min after Gd-EOB-DTPA administration were acquired. T1 relaxation times of the liver and the reduction rate between pre- and post-contrast enhancement images were measured.

Results

The T1 relaxation times for Gd-EOB-DTPA-enhanced MRI showed significant differences between patients with normal liver function and patients with Child-Pugh class A, B, and C (p < 0.001). The T1 relaxation times showed a constant significant increase from Child-Pugh class A up to class C (Child-Pugh class A, 335 ms ± 80 ms; B, 431 ms ± 75 ms; C, 557 ms ± 99 ms; Child-Pugh A to B, p < 0.001; Child-Pugh A to C, p < 0.001; Child-Pugh B to C, p < 0.001) and a constant decrease of the reduction rate of T1 relaxation times (Child-Pugh class A, 57.1% ± 8.8%; B, 44.3% ± 10.2%, C, 29.9% ± 6.9%; Child-Pugh A to B, p < 0.001; Child-Pugh A to C,p < 0.001; Child-Pugh B to C, p < 0.001).

Conclusion

Gd-EOB-DTPA-enhanced T1 mapping of the liver parenchyma may present a useful method for determining severity of liver cirrhosis.     

Incidence of Liver Damage of Uncertain Origin in HIV Patients Not Co-Infected with HCV/HBV

Background and Aims

Several studies have reported that a significant number of HIV patients not co-infected with HCV/HBV develop liver damage of uncertain origin (LDUO). The objective of our study was to evaluate the incidence of and risk factors for the development of LDUO in HIV infected patients not co-infected with HCV/HBV.

Methods

Prospective longitudinal study that included HIV-infected patients free of previous liver damage and viral hepatitis B or C co-infections. Patients were followed up at 6-monthly intervals. Liver stiffness was measured at each visit. Abnormal liver stiffness (ALS) was defined as a liver stiffness value greater than 7.2 kPa at two consecutive measurements. For patients who developed ALS, a protocol was followed to diagnose the cause of liver damage. Those patients who could not be diagnosed with any specific cause of liver disease were diagnosed as LDUO and liver biopsy was proposed.

Results

210 patients matched the inclusion criteria and were included. 198 patients completed the study. After a median (Q1–Q3) follow-up of 18 (IQR 12–26) months, 21 patients (10.6%) developed ALS. Of these, fifteen patients were diagnosed as LDUO. The incidence of LDUO was 7.64 cases/100 patient-years. Histological studies were performed on ten (66.6%) patients and all showed liver steatosis. A higher HOMA-IR value and body mass index were independently associated with the development of LDUO.

Conclusion

We found a high incidence of LDUO in HIV-infected patients associated with metabolic risk factors. The leading cause of LDUO in our study was non-alcoholic fatty liver disease.     

Quantitative Liver MRI Combining Phase Contrast Imaging,Elastography, and DWI: Assessment of Reproducibility and Postprandial Effect at 3.0 T

Purpose

To quantify short-term reproducibility (in fasting conditions) and postprandial changes after a meal in portal vein (PV) flow parameters measured with phase contrast (PC) imaging, liver diffusion parameters measured with multiple b value diffusion-weighted imaging (DWI) and liver stiffness (LS) measured with MR elastography (MRE) in healthy volunteers and patients with liver disease at 3.0 T.

Materials and Methods

In this IRB–approved prospective study, 30 subjects (11 healthy volunteers and 19 liver disease patients; 23 males, 7 females; mean age 46.5 y) were enrolled. Imaging included 2D PC imaging, multiple b value DWI and MRE. Subjects were initially scanned twice in fasting state to assess short-term parameter reproducibility, and then scanned 20 min. after a liquid meal. PV flow/velocity, LS, liver true diffusion coefficient (D), pseudodiffusion coefficient (D*), perfusion fraction (PF) and apparent diffusion coefficient (ADC) were measured in fasting and postprandial conditions. Short-term reproducibility was assessed in fasting conditions by measuring coefficients of variation (CV) and Bland-Altman limits of agreement. Differences in MR metrics before and after caloric intake and between healthy volunteers and liver disease patients were assessed.

Results

PV flow parameters, D, ADC and LS showed good to excellent short-term reproducibility in fasting state (CV <16%), while PF and D* showed acceptable and poor reproducibility (CV = 20.4% and 51.6%, respectively). PV flow parameters and LS were significantly higher (p<0.04) in postprandial state while liver diffusion parameters showed no significant change (p>0.2). LS was significantly higher in liver disease patients compared to healthy volunteers both in fasting and postprandial conditions (p<0.001). Changes in LS were significantly correlated with changes in PV flow (Spearman rho = 0.48, p = 0.013).

Conclusions

Caloric intake had no/minimal/large impact on diffusion/stiffness/portal vein flow, respectively. PC MRI and MRE but not DWI should be performed in controlled fasting state.     

Estimated Glomerular Filtration Rate,All-Cause Mortality and Cardiovascular Diseases Incidence in a Low Risk Population: The MATISS Study

Background

Chronic kidney disease (CKD) independently increases the risk of death and cardiovascular disease (CVD) in the general population. However, the relationship between estimated glomerular filtration rate (eGFR) and CVD/death risk in a general population at low risk of CVD has not been explored so far.

Design

Baseline and longitudinal data of 1465 men and 1459 women aged 35-74 years participating to the MATISS study, an Italian general population cohort, were used to evaluate the role of eGFR in the prediction of all-cause mortality and incident CVD.

Methods

Bio-bank stored sera were used to evaluate eGFR at baseline. Serum creatinine was measured on thawed samples by means of an IDMS-calibrated enzymatic method. eGFR was calculated by the CKD-EPI formula.

Results

At baseline, less than 2% of enrolled persons had eGFR < 60 mL/min/1.73m² and more than 70% had a 10-year cardiovascular risk score < 10%. In people 60 or more years old, the first and the last eGFR quintiles (<90 and ≥109 mL/min/1.73m², respectively) were associated to an increased risk for both all-cause mortality (hazard ratio 1.6, 95% confidence interval 1.2-2.1 and 4.3, 1.6-11.7, respectively) and incident CVD (1.6, 1.0-2.4 and 7.0, 2.2-22.9, respectively), even if adjusted for classical risk factors.

Conclusions

These findings strongly suggest that in an elderly, general population at low risk of CVD and low prevalence of reduced renal filtration, even a modest eGFR reduction is related to all-cause mortality and CVD incidence, underlying the potential benefit to this population of considering eGFR for their risk prediction.     

A Prospective Cohort Study Examining the Associations of Dietary Calcium Intake with All-Cause and Cardiovascular Mortality in Older Chinese Community-Dwelling People

Background

Most epidemiological studies of calcium intake and mortality risk have been conducted in populations with moderate to high calcium intake, and limited studies have focused on populations with low habitual calcium intake (i.e., mean dietary calcium intake <700 mg/d).

Objective

This study investigated the association between dietary calcium intake and death from all causes and cardiovascular disease in Chinese population with low habitual calcium intake.

Design

Data from 3,139 Chinese men and women in a population-based prospective cohort study, aged >=65 years and free of heart diseases or stroke at baseline, were analyzed. Primary outcome measures, identified from the death registry, were death from all causes and cardiovascular disease. Dietary calcium intake assessed using a validated food frequency questionnaire was categorized into sex-specific quartiles. Data on use of supplemental calcium (yes or no) including individual calcium supplements and other calcium containing supplement were collected. Cox regression models adjusted for demographic and lifestyle variables were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI).

Results

During a median of 9.1 years of follow-up, 529 all-cause deaths (344 men, 185 women) and 114 (74 men, 40 women) deaths from cardiovascular disease were identified. An inverse trend between dietary calcium intake and mortality was observed. Compared with the lowest quartile (<458 mg/d for men, <417 mg/d for women), the highest quartile of dietary calcium intake (>762 mg/d for men, >688 mg/d for women) had a significantly reduced risk of all-cause mortality (multivariate HR=0.63, 95% CI=0.49-0.81, P _trend<0.001) but an insignificant decreased risk of cardiovascular mortality (multivariate HR=0.70, 95% CI=0.41-1.21, P _trend=0.228). Similar inverse association was observed when the analyses were stratified on calcium supplemental use.

Conclusions

Higher intake of dietary calcium was associated with reduced risk of all-cause mortality and possibly cardiovascular mortality in Chinese older people with low habitual calcium intake.     

Medication Monitoring in a Nurse-Led Respiratory Outpatient Clinic: Pragmatic Randomised Trial of the West Wales Adverse Drug Reaction Profile

Objective

To assess the clinical effect of medication monitoring using the West Wales Adverse Drug Reaction (ADR) Profile for Respiratory Medicine.

Design

Single-site parallel-arm pragmatic trial using stratified randomisation.

Setting

Nurse-led respiratory outpatient clinic in general hospital in South Wales.

Participants

54 patients with chronic respiratory disease receiving bronchodilators, corticosteroids or leukotriene receptor antagonists.

Intervention

Following initial observation of usual nursing care, we allocated participants at random to receive at follow up: either the West Wales ADR Profile for Respiratory Medicine in addition to usual care (‘intervention arm’ with 26 participants); or usual care alone (‘control arm’ with 28 participants).

Main Outcome Measures

Problems reported and actions taken.

Results

We followed up all randomised participants, and analysed data in accordance with treatment allocated. The increase in numbers of problems per participant identified at follow up was significantly higher in the intervention arm, where the median increase was 20.5 [inter-quartile range (IQR) 13–26], while that in the control arm was −1 [−3 to +2] [Mann-Whitney U test: z = 6.28, p<0.001]. The increase in numbers of actions per participant taken at follow up was also significantly higher in the intervention arm, where the median increase was 2.5 [1]–[4] while that in the control arm was 0 [−1.75 to +1] [Mann-Whitney U test: z = 4.40, p<0.001].

Conclusion

When added to usual nursing care, the West Wales ADR Profile identified more problems and prompted more nursing actions. Our ADR Profile warrants further investigation as a strategy to optimise medication management.

Trial Registration

Controlled-trials.com ISRCTN10386209     

Effect of Meal Ingestion on Liver Stiffness in Patients with Cirrhosis and Portal Hypertension

Background and Aims

Liver stiffness is increasingly used in the non-invasive evaluation of chronic liver diseases. Liver stiffness correlates with hepatic venous pressure gradient (HVPG) in patients with cirrhosis and holds prognostic value in this population. Hence, accuracy in its measurement is needed. Several factors independent of fibrosis influence liver stiffness, but there is insufficient information on whether meal ingestion modifies liver stiffness in cirrhosis. We investigated the changes in liver stiffness occurring after the ingestion of a liquid standard test meal in this population.

Methods

In 19 patients with cirrhosis and esophageal varices (9 alcoholic, 9 HCV-related, 1 NASH; Child score 6.9±1.8), liver stiffness (transient elastography), portal blood flow (PBF) and hepatic artery blood flow (HABF) (Doppler-Ultrasound) were measured before and 30 minutes after receiving a standard mixed liquid meal. In 10 the HVPG changes were also measured.

Results

Post-prandial hyperemia was accompanied by a marked increase in liver stiffness (+27±33%; p<0.0001). Changes in liver stiffness did not correlate with PBF changes, but directly correlated with HABF changes (r = 0.658; p = 0.002). After the meal, those patients showing a decrease in HABF (n = 13) had a less marked increase of liver stiffness as compared to patients in whom HABF increased (n = 6; +12±21% vs. +62±29%,p<0.0001). As expected, post-prandial hyperemia was associated with an increase in HVPG (n = 10; +26±13%, p = 0.003), but changes in liver stiffness did not correlate with HVPG changes.

Conclusions

Liver stiffness increases markedly after a liquid test meal in patients with cirrhosis, suggesting that its measurement should be performed in standardized fasting conditions. The hepatic artery buffer response appears an important factor modulating postprandial changes of liver stiffness. The post-prandial increase in HVPG cannot be predicted by changes in liver stiffness.     

Glucose-Induced Glucagon-Like Peptide 1 Secretion Is Deficient in Patients with Non-Alcoholic Fatty Liver Disease

Background & Aims

The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD). However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients.

Methods

N = 52 patients (n = 16 NAFLD and n = 36 Non-alcoholic steatohepatitis (NASH) patients) and n = 50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration.

Results

Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001). In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH.

Conclusions

Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.     

Emphysema Predicts Hospitalisation and Incident Airflow Obstruction among Older Smokers: A Prospective Cohort Study

Background

Emphysema on CT is common in older smokers. We hypothesised that emphysema on CT predicts acute episodes of care for chronic lower respiratory disease among older smokers.

Materials and Methods

Participants in a lung cancer screening study age ≥60 years were recruited into a prospective cohort study in 2001–02. Two radiologists independently visually assessed the severity of emphysema as absent, mild, moderate or severe. Percent emphysema was defined as the proportion of voxels ≤ −910 Hounsfield Units. Participants completed a median of 5 visits over a median of 6 years of follow-up. The primary outcome was hospitalization, emergency room or urgent office visit for chronic lower respiratory disease. Spirometry was performed following ATS/ERS guidelines. Airflow obstruction was defined as FEV1/FVC ratio <0.70 and FEV1<80% predicted.

Results

Of 521 participants, 4% had moderate or severe emphysema, which was associated with acute episodes of care (rate ratio 1.89; 95% CI: 1.01–3.52) adjusting for age, sex and race/ethnicity, as was percent emphysema, with similar associations for hospitalisation. Emphysema on visual assessment also predicted incident airflow obstruction (HR 5.14; 95% CI 2.19–21.1).

Conclusion

Visually assessed emphysema and percent emphysema on CT predicted acute episodes of care for chronic lower respiratory disease, with the former predicting incident airflow obstruction among older smokers.     

Causes and Outcomes of Acute Liver Failure in China

Objectives

No extensive investigation has been performed and thus no representative data are available regarding acute liver failure (ALF) in China. This study aims to investigate the causes and outcomes of ALF in China and establish a prognostic model.

Methods

Patients diagnosed as ALF in seven hospitals in different areas of China from January 2007 to December 2012 were retrospectively selected.

Results

Of the 177 patients included in this study, 112 (63.28%) eventually died. The common causes of ALF were drug toxicity (43.50%), indeterminate etiology (29.38%) and acute viral hepatitis (11.30%). Additionally, traditional Chinese herbs predominated in the causes of drug-induced ALF (30/77). No patients in this study received liver transplantation. In the established model for predicting death in ALF, four variables were finally selected out, including age (P=0.01), the entry hepatic encephalopathy grade (P=0.04), international normalized ratio (P<0.01) and arterial blood ammonia (P=0.02). Using a threshold value of 0.5683, this model had a sensitivity of 95.24% and a specificity of 91.30%.

Conclusions

Traditional Chinese medicine was a major cause of ALF in China. The spontaneous mortality of ALF was high, whereas the rate of liver transplantation was significantly low. The established prognostic model of ALF had superior sensitivity and specificity.     

Procalcitonin Identifies Cell Injury,Not Bacterial Infection,in Acute Liver Failure

Background

Because acute liver failure (ALF) patients share many clinical features with severe sepsis and septic shock, identifying bacterial infection clinically in ALF patients is challenging. Procalcitonin (PCT) has proven to be a useful marker in detecting bacterial infection. We sought to determine whether PCT discriminated between presence and absence of infection in patients with ALF.

Method

Retrospective analysis of data and samples of 115 ALF patients from the United States Acute Liver Failure Study Group randomly selected from 1863 patients were classified for disease severity and ALF etiology. Twenty uninfected chronic liver disease (CLD) subjects served as controls.

Results

Procalcitonin concentrations in most samples were elevated, with median values for all ALF groups near or above a 2.0 ng/mL cut-off that generally indicates severe sepsis. While PCT concentrations increased somewhat with apparent liver injury severity, there were no differences in PCT levels between the pre-defined severity groups–non-SIRS and SIRS groups with no documented infections and Severe Sepsis and Septic Shock groups with documented infections, (p = 0.169). PCT values from CLD patients differed from all ALF groups (median CLD PCT value 0.104 ng/mL, (p ≤0.001)). Subjects with acetaminophen (APAP) toxicity, many without evidence of infection, demonstrated median PCT >2.0 ng/mL, regardless of SIRS features, while some culture positive subjects had PCT values <2.0 ng/mL.

Summary/Conclusions

While PCT appears to be a robust assay for detecting bacterial infection in the general population, there was poor discrimination between ALF patients with or without bacterial infection presumably because of the massive inflammation observed. Severe hepatocyte necrosis with inflammation results in elevated PCT levels, rendering this biomarker unreliable in the ALF setting.