Basal cortisol levels do not predict adrenal responsiveness in acute decompensated cirrhosis.

OBJECTIVE: Morning total cortisol (TC) levels have been shown to predict adrenal dysfunction (AD) in the general population, but their utility in cirrhosis is unknown. METHODS: A retrospective cohort study was performed including all noncritically ill patients at our institution between 2011 and 2022 admitted with acute decompensated cirrhosis who underwent standard-dose adrenocorticotropic hormone (ACTH) stimulation testing. Adrenal dysfunction was defined as an increase in TC (delta TC) level <9 µg/dl 60 minutes after ACTH dosing. Spearman correlation was utilized to assess the relationship between binding globulins and cortisol levels. Multivariate regression analysis was performed to determine if basal TC level or common clinical parameters were predictive of AD. RESULTS: One hundred and nineteen patients were included, with a median model for end-stage liver disease score of 18. Albumin levels did not correlate with basal TC levels (ρ = 0.127; P = 0.169); basal TC did not correlate with delta TC (ρ = 0.050; P = 0.591). The degree of hypoalbuminemia did not alter these relationships. On multivariate regression, only albumin level [odds ratio (OR) = 0.418; 95% confidence interval (CI), 0.196-0.890; P = 0.024] and MELD score (OR, 1.094; 95% CI, 1.019-1.174; P = 0.014) were predictive of AD. Basal TC levels were not predictive of AD (OR = 0.991; 95% CI, 0.903-1.088; P = 0.855) or delta TC (ß = 0.000; 95% CI -0.147 to 0.147; P = 0.999). CONCLUSION: Baseline TC levels do not predict ACTH stimulation testing response in patients with acute decompensated cirrhosis. Clinicians should avoid utilizing an isolated morning cortisol result as a screening method for AD in this population.

The Many Faces of Primary Sclerosing Cholangitis: Controversy Abounds.

Primary sclerosing cholangitis (PSC) is notoriously challenging to manage given its heterogeneity with regard to diagnosis, management, and progression. The lack of disease-modifying therapy and variable rate of onset of cirrhosis, portal hypertension-related decompensating events, jaundice, pruritus, biliary complications, and need for liver transplantation is deeply unsettling to clinicians and patients alike. Recent updated practice guidance by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver endeavored to highlight some of these challenges. However, these references only briefly address clinical dilemmas that providers face on a daily basis. This review aims to further discuss these controversial topics, including providing insight into the utility of ursodeoxycolic acid, the significance of alkaline phosphatase normalization, when to consider PSC variants and mimickers, and the implications of continuous hepatobiliary malignancy screening. In particular, there has been a growing body of literature raising concern about repeat exposure to gadolinium-containing contrast. Patients with PSC are potentially at risk for large lifetime exposure to gadolinium related to frequent magnetic resonance imaging scans and whether this carries any negative long-term adverse effects remains unknown.

Relative adrenal insufficiency in the non-critically ill patient with cirrhosis: A systematic review and meta-analysis.

BACKGROUND & AIMS: Characterization of relative adrenal insufficiency (RAI) in cirrhosis is heterogeneous with regard to studied patient populations and diagnostic methodology. We aimed to describe the prevalence and prognostic importance of RAI in non-critically ill patients with cirrhosis. METHODS: A systematic review and meta-analysis was performed using MeSH terms and Boolean operators to search five large databases (Ovid-MEDLINE, ScienceDirect, Web of Science, Cochrane Library and ClinicalTrials.gov). The population of interest was patients with cirrhosis and without critical illness. The primary outcome was the pooled prevalence of RAI as defined by a peak total cortisol level <18 µg/dl, delta total cortisol <9 µg/dl or composite of the two thresholds in response either a standard-dose or low-dose short synacthen test. Odds ratios and standardized mean differences from random-effects models estimated important clinical outcomes and patient characteristics by adrenal functional status. RESULTS: Twenty-two studies were included in final analysis, comprising 1991 patients with cirrhosis. The pooled prevalence of RAI was 37% (95% CI 33-42%). The prevalence of RAI varied by Child-Pugh classification, type of stimulation test used, specific diagnostic threshold and by severity of illness. Ninety-day mortality was significantly higher in patients with RAI (OR 2.88, 95% CI 1.69-4.92, I2 = 15%, p < 0.001). CONCLUSIONS: Relative adrenal insufficiency is highly prevalent in non-critically ill patients with cirrhosis and associated with increased mortality. Despite the proposed multifactorial pathogenesis, no studies to date have investigated therapeutic interventions in this specific population.

Adrenal Insufficiency in Cirrhosis.

Hypothalamus-pituitary-adrenal axis assessment in patients with cirrhosis is challenging. The phenotype of fatigue, hypotension, electrolyte disarray, and abdominal pain characterizing primary adrenal insufficiency (AI) overlaps significantly with decompensated liver disease. Reliance on total cortisol assays in hypoproteinemic states is problematic, yet abnormal stimulated levels in cirrhosis are associated with poor clinical outcomes. Alternative measures including free plasma or salivary cortisol levels have theoretical merit but are limited by unclear prognostic significance and undefined cirrhosis-specific reference ranges. Further complicating matters is that AI in cirrhosis represents a spectrum of impairment. Although absolute cortisol deficiency can occur, this represents a minority of cases. Instead, there is an emerging concept that cirrhosis, with or without critical illness, may induce a "relative" cortisol deficiency during times of stress. In addition, the limitations posed by decreased synthesis of binding globulins in cirrhosis necessitate re-evaluation of traditional AI diagnostic thresholds.

Abnormal cholesterol metabolism underlies relative adrenal insufficiency in decompensated cirrhosis.

BACKGROUND AND AIMS: Relative adrenal insufficiency (RAI) in patients with cirrhosis is associated with increased mortality. Although the pathogenesis of RAI remains unclear, disordered cholesterol metabolism may contribute. METHODS: We performed a prospective cohort study of 96 non-critically ill subjects with decompensated cirrhosis at a tertiary care centre. Subjects were administered 250 µcg cosyntropin, with RAI defined as an increase in total cortisol <9 µg/dL. High-density lipoprotein (HDL) levels and serum cholesterol esterification percentage (%CE), a validated surrogate marker of lecithin-cholesterol acyltransferase (LCAT) activity, were measured to assess the relationship between disordered cholesterol metabolism and the presence of RAI. Subjects were followed until death, liver transplantation or a maximum of 6 months. RESULTS: Subjects with RAI had decreased levels of HDL (18 vs 29 mg/dL, P < .01) and %CE (64% vs 66%, P = .03). Correlation was seen between HDL and %CE (r = 0.7, R2  = 0.49; P < .01) and each integer decrease in %CE predicted an approximately 2% increase in the probability of RAI. Transplant-free survival was reduced in subjects with RAI at both 6 months (43% vs 71%, P = .01) and 90 days (54% vs 81%, P < .01). CONCLUSIONS: Disruption in cholesterol metabolism contributes to the development of RAI in cirrhosis, as decreased LCAT activity leads to reduced HDL trafficking to the adrenal gland.

Management of Portal Vein Thrombosis in Cirrhosis.

While portal vein thrombosis (PVT) is a frequently encountered complication in the cirrhosis population, its management can be challenging for even the most experienced clinicians. Multiple factors must be considered with regards to management, including the degree of underlying portal hypertension and liver dysfunction, risks of therapies including anticoagulation and transjugular intrahepatic portosystemic shunt placement, and extent of the thrombosis. Interpreting the available literature to determine the best treatment strategy for any individual patient can be especially challenging given the lack of prospective, randomized controlled trials and the heterogeneity of cohorts studied. This review will provide an overview of PVT in the cirrhosis population, including necessary steps in evaluation and the potential benefits and drawbacks of different treatment approaches.

Pearls and pitfalls in nonalcoholic fatty liver disease: tricky results are common.

Interpretation of diagnostic and surveillance laboratory results and imaging in liver disease is fraught with misinterpretation and/or uncertainty. Nonalcoholic fatty liver disease (NAFLD) represents an ever-growing proportion of liver disease cases but presents unique challenges for the clinician. Given the necessity of excluding other etiologies of liver disease, NAFLD can at times represent a challenging diagnosis as non-invasive assessment and biopsy are imperfect tests with important limitations. Similarly, cautious review of laboratory reports is necessary to avoid missing abnormal pathophysiology. The presence of lab values within the standard reference range may be concerning in the setting of chronic liver disease ("abnormally normal") and conversely results flagged as abnormal may not necessarily be of great concern ("normally abnormal"). This review provides a framework for the clinician to review common diagnostic challenges in NAFLD and enhance patient care.

Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases.

BACKGROUND: Given the lack of long-term prospective studies, it is challenging for clinicians to make informed decisions about screening and treatment decisions regarding the risk of hepatocellular carcinoma (HCC) in patients with non-alcoholic steatohepatitis (NASH) who do not have cirrhosis. AIM: To characterise the pooled risk of HCC in the non-cirrhosis population. METHODS: Published studies were identified through April 2016 in MEDLINE, Scopus, Science Citation Index, AMED and the Cochrane Library. Two independent reviewers screened citations and extracted data. Random effect odds ratios (OR) were calculated to obtain aggregate estimates of effect size between NASH and non-NASH groups. Between-study variability and heterogeneity were assessed. RESULTS: Nineteen studies with 168 571 participants were included. Eighty-six per cent of included subjects had cirrhosis. The prevalence of HCC in non-cirrhotic NASH was 38.0%; among other aetiologies in non-cirrhotics, it was 14.2% (P < 0.001). Non-cirrhotic NASH subjects were at greater odds of developing HCC than non-cirrhotic subjects of other aetiologies (OR 2.61, 95% CI 1.27-5.35, P = 0.009). When examining all NASH subjects either with or without cirrhosis, those with NASH as the underlying liver disease did not have a significantly increased risk of HCC (OR 1.43, 95% CI 0.77-2.65, P = 0.250). CONCLUSIONS: In non-cirrhotic subjects, those with NASH have a higher risk of HCC compared to other aetiologies of liver disease. Further study investigating the risk factors of HCC among non-cirrhotic NASH patients is needed.

Nonadherence to Biologic Therapies in Inflammatory Bowel Disease.

BACKGROUND: Nonadherence to medications is common with patients with inflammatory bowel disease (IBD). The aim of this study was to assess adherence to biologic medications prescribed for IBD and to identify risk factors for biologic nonadherence. METHODS: This was a single center retrospective cohort study investigating IBD patient adherence to biologic therapies over a 2-year period from September 2014 to September 2016. Specialty pharmacy and infusion center records were obtained and a modified medication possession ratio was calculated. Patient characteristics associated with nonadherence in a univariate model were placed into a multivariate logistic regression to assess independent predictors of nonadherence. RESULTS: Three hundred sixty-five patients met inclusion criteria; 63 patients were on vedolizumab. Three hundred and one patients (82%) had Crohn's disease. The pooled 24-month adherence rate was 66%; adherence to individual biologic therapy included vedolizumab 83%, infliximab 70%, adalimumab 57%, and certolizumab pegol 50%. Facility-administered biologics were independently associated with higher adherence than self-administered biologics (OR 2.39, 95% CI 1.50 - 3.80). Additional risk factors for nonadherence included younger age (OR 1.22, 95% CI 1.01-1.47) and noncommercial insurance (OR 1.78, 95% CI 1.01 - 3.13). CONCLUSIONS: This is the first study to assess adherence to vedolizumab in IBD patients, which was higher than 3 other commonly prescribed biologic medications. Self-administered injections were strongly associated with biologic nonadherence. Younger age and noncommercial insurance also were associated with biologic nonadherence. Modality of administration should be taken into account when selecting a biologic agent for treatment of IBD.

Effects of experienced disgust on habituation during repeated exposure to threat-relevant stimuli in blood-injection-injury phobia.

Despite growing evidence implicating disgust in the etiology of blood-injection-injury (BII) phobia, the relevance of disgust for exposure-based treatment of BII phobia remains largely unknown. Individuals with BII phobia were randomly assigned to a disgust (view vomit videos) or neutral activation (view waterfall videos) condition. They were then exposed to 14 videotaped blood draws, during which fear and disgust levels were repeatedly assessed. Participants then engaged in a behavioral avoidance test (BAT) consisting of exposure to threat-relevant stimuli. Examination of outcome comparing the identical first and last blood-draw clips revealed that fear and disgust toward blood draws was significantly reduced in both groups. Disgust levels were also found to be more intense for the video stimuli relative to fear levels whereas the opposite was true for BAT stimuli. Contrary to predictions, the disgust induction did not enhance reductions in negative responses to the target video or reduce behavioral avoidance. Growth curve analyses did show that individuals with BII phobia exposed to the disgust induction showed greater initial fear levels during repeated exposure than those in the neutral condition. However, this effect was not consistently observed across different analytic approaches. Changes in fear during exposure were also found to be independent of changes in disgust but not vice versa, and greater initial fear levels during repeated exposure to threat was associated with fear and disgust levels during the BAT. The implications of these findings for conceptualizing the role of disgust in etiology and treatment of BII phobia are discussed.