The Long-Term Effect of Weight Loss on the Prevention of Progression to Cirrhosis among Patients with Obesity and MASH-Related F3 Liver Fibrosis.

This multi-center retrospective study examined the effect of weight loss on the prevention of progression to cirrhosis in a sample exclusively composed of patients with obesity and MASH-related F3 liver fibrosis. Adult patients with obesity and biopsy-confirmed MASH-related F3 liver fibrosis (n = 101) from two liver transplant centers in the US were included in the study. A higher proportion of patients who did not progress to cirrhosis achieved >5% weight loss at follow-up (59% vs. 30%, p = 0.045). In multivariable analysis, patients with >5% weight loss at follow-up had a lower hazard of developing cirrhosis compared to patients with no weight loss or weight gain (HR: 0.29, 95%, CI: 0.08-0.96); whereas, diabetes (HR: 3.24, 95%, CI: 1.21-8.67) and higher LDL levels (HR: 1.02, 95%, CI: 1.01-1.04) were associated with higher hazards of progression to cirrhosis. Weight loss >5% has the potential to prevent disease progression to cirrhosis in patients with obesity and MASH-related F3 liver fibrosis. The realization of this benefit requires weight loss maintenance longer than one year. Larger prospective studies are needed to determine how weight loss impacts other patient-centered outcomes such as mortality, hepatic decompensation, and hepatocellular carcinoma in patients with obesity and MASH-related F3 liver fibrosis.

A comparison between patients with various etiologies of cirrhosis and examination of cardiac risk factors limiting survival to liver transplantation.

BACKGROUND & AIMS: Objectives of this retrospective cohort study were to assess differences in patient survival between etiologies of cirrhosis while on the waitlist for liver transplantation (LT), and to identify cardiac risk factors that predict survival failure while on the waitlist for LT. METHODS: This single-center retrospective cohort design included adult patients who were listed for LT at a tertiary academic hospital with a high-volume liver transplant center. RESULTS: Of the 653 patients listed for LT during the study period, 507 (77.6%) survived to transplant and 146 (22.4%) died or clinically deteriorated prior to transplant. Cumulative incidence of death or clinical deterioration did not differ statistically between patient groups (log rank p = .11). In multivariate analysis, compared to patients with NAFLD, there were no significant differences between patients with alcoholic cirrhosis (HR .95, 95%, CI, .62-1.45), cryptogenic cirrhosis (HR 1.31, 95%, CI, .77-2.23), or hepatitis C cirrhosis (HR 1.12, 95%, CI, .66-1.90). However, higher MELD scores (HR = 1.52, 95% CI, 1.12-1.19), severe coronary artery disease (HR = 2.09 95% CI, 1.23-3.55), and tricuspid regurgitation (HR = 2.62, 95% CI, 1.31-5.26) were independently associated with increased risk for survival failure to LT. CONCLUSIONS: The presence of severe coronary artery disease and tricuspid regurgitation at the time of listing for transplant are associated with survival failure while on the LT waitlist across etiologies of liver disease. Diagnostic assessment of coronary and valvular disease should be considered in all patients undergoing evaluation for LT, such as cardiac catheterization and/or stress echocardiogram.

Acute Liver Failure Guidelines.

Acute liver failure (ALF) is a rare, acute, potentially reversible condition resulting in severe liver impairment and rapid clinical deterioration in patients without preexisting liver disease. Due to the rarity of this condition, published studies are limited by the use of retrospective or prospective cohorts and lack of randomized controlled trials. Current guidelines represent the suggested approach to the identification, treatment, and management of ALF and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence was reviewed using the Grading of Recommendations, Assessment, Development and Evaluation process to develop recommendations. When no robust evidence was available, expert opinions were summarized using Key Concepts. Considering the variety of clinical presentations of ALF, individualization of care should be applied in specific clinical scenarios.

Bi-directional Relationship Between Celiac Disease and Liver Chemistries: A Systematic Review and Meta-Analysis.

AIMS: Previous studies have reported conflicting results regarding prevalence of elevated LC (2-70%) in celiac disease (CD). This systematic review and meta-analysis assessed the prevalence of elevated LC at time of CD diagnosis and associated response to GFD. We also report the prevalence of CD in patients with unexplained elevation of LC. METHODS: Studies assessing LC (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) in CD patients were eligible. Studies with < 50 cases or in pediatric populations were excluded. RESULTS: In total, 20 studies assessing prevalence of elevated LC in 4,265 participants with newly diagnosed CD (mean age = 35.6 ± 6.5 years, 69.8% female) were included. Pooled prevalence of elevated LC was 18.7% (95% CI 13.8-24.8; I2 = 95%). Normalization of elevated LC was seen in 83.1% (95% CI 73.4-89.7; I2 = 79%, 11 studies) of patients after GFD. On meta-regression, age at CD diagnosis, gender, and Marsh grading were not associated with elevated LC. Among 979 participants (7 studies) with unexplained elevation of LC, pooled seroprevalence and biopsy-proven CD was 6.4% (95% CI 2.9-10.3, I2 = 71%) and 4.5% (95% CI 2.6-7.7, I2 = 67%), respectively. CONCLUSION: Elevated LC are seen in approximately one-fifth of patients at CD diagnosis with majority normalizing after GFD. Age, gender, and degree of intestinal damage are not predictive of elevated LC. In the appropriate clinical scenario, liver tests should be serially monitored in CD reserving workup for additional causes after a trial of GFD. Patients with unexplained elevation of liver tests should be screened for celiac disease.

Therapies for non-alcoholic fatty liver disease: A 2022 update.

The incidence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing and lifestyle interventions to treat this disease by addressing the underlying metabolic syndrome are often limited. Many pharmacological interventions are being studied to slow or even reverse NAFLD progression. This review for hepatologists aims to provide an updated understanding of the pathogenesis of NAFLD, current recommended therapies, and the most promising treatment options that are currently under development.

Cardiac risk factors limiting survival to liver transplantation in patients with nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) describes the hepatic manifestations of metabolic syndrome, which is estimated to affect 25% of adults, and currently represents the second most common indication for liver transplant in the United States. Studies have shown that patients with NAFLD are at an increased risk for heart failure, arrhythmia, and coronary artery disease (CAD), which may impact outcomes of liver transplantation. However, it remains unclear whether the presence of cardiac disease affects survival prior to liver transplant. If so, this would represent an important opportunity to optimize cardiac status and improve outcomes before liver transplant. AIM: To identify cardiac factors that impact survival to liver transplantation in patients with NAFLD and on the transplant waitlist. METHODS: The aim of this study was to identify cardiac risk factors that limit survival to transplant in patients with NAFLD. We performed a retrospective analysis of patients with NAFLD listed for liver transplant at a tertiary academic medical center in the United States from January 2015 to January 2021, identified through United Network of Organ Sharing registry. Exclusion criteria included a concurrent etiology of liver disease and removal from the transplant list due to chemical dependency, lack of social support, improvement in liver disease, or being lost to follow-up. We manually reviewed patient charts including electrocardiogram, echocardiogram, and cardiac catheterization reports as well as physician notes to identify cardiac disease states (i.e., heart failure, arrhythmia, valvular disease and CAD) and other related diagnoses. We performed a survival analysis by Cox proportional hazards regression model to analyze the association between cardiac factors at the time listed for transplant and death or clinical deterioration prior to transplant. RESULTS: Between January 2015 and January 2021, 265 patients with nonalcoholic fatty liver disease were listed for liver transplant at our institution. Our patient sample had a median age of 63 and an even distribution between sexes. The median Model for End-Stage Liver Disease (MELD) score was 17 and the median body mass index was 31.6. Of these 265 patients, 197 (74.3%) survived to transplant and 68 (25.7%) died or clinically deteriorated prior to transplant. The presence of mild or moderate CAD represented a hazard ratio of 2.013 (95%CI 1.078-3.759, P = 0.029) for death or clinical deterioration when compared to patients without CAD, after adjustment for age, sex, and MELD. MELD represented an adjusted hazard ratio of 1.188. CONCLUSION: Mild or moderate CAD represents a hazard for waitlist mortality prior to liver transplant in patients with NAFLD. Aggressive management of CAD may be needed to improve patient outcomes.

Disease progression in patients with PI*ZZ alpha-1 antitrypsin deficiency.

BACKGROUND AND OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is an uncommon but underdiagnosed cause of cirrhosis and lacks medical treatment options. It is important to recognize risk factors that contribute to disease progression and liver transplantation. We aimed to assess if age, sex, or smoking status was associated with liver or lung disease progression. METHODS: Forty-three patients with ZZ-AATD cirrhosis were consecutively sampled from an Institutional Review Board-approved registry of 240 patients with AATD of any genotype seen as outpatients in the Cleveland Clinic between 1999 and 2019. To determine the association between risk factors and lung or liver disease progression, linear mixed-effects models with fixed effects for linear time, risk factor, and time-by-risk factor interaction, and the random intercepts for intra-patient correlation were used. RESULTS: Based on the mixed-effects model analysis, there was a significant association between liver disease progression and smoking history, and no association with age or sex. There was no association between lung disease progression and age, sex, or smoking history. However, smoking history was significantly associated with lower forced expiratory volume values. CONCLUSION: This study found that in a cohort of patients with PI*ZZ genotype AATD (ZZ-AATD) and cirrhosis, smoking history was associated with liver disease progression, whereas age and sex were not.

Alpha-1 antitrypsin deficiency is under-recognized in individuals with cirrhosis undergoing liver transplantation.

OBJECTIVE: Under-recognition of alpha-1 antitrypsin deficiency (AATD) is well documented in AATD-lung disease but is rarely reported in patients with liver cirrhosis requiring liver transplantation. This report examines the frequency of newly diagnosed AATD based on pathologic examination of explanted livers following liver transplantation, trends in diagnosis over time, and prognostic correlates of under-recognition outcomes following liver transplantation. METHODS: This study retrospectively reviewed 1473 pathology reports from adult patients (>18 years) undergoing liver transplantation at Cleveland Clinic between 2004 and 2017. Pathology reports of explanted livers exhibiting periodic acid-Schiff, diastase-resistant inclusion bodies (PAS+G) suggestive of AATD were included and medical records were reviewed regarding demographics, AATD genotype, alternative etiologies for cirrhosis, presence of emphysema, and survival outcomes. Kaplan-Meier estimates of survival outcomes were compared between patients diagnosed pre-liver transplantation and that newly diagnosed post-liver transplantation. RESULTS: Of 1473 explanted liver pathology reports examined, 117 (7.9%) showed PAS+G suggestive of AATD. The diagnosis of AATD in these 117 patients was established pre-liver transplantation in 36 (30.8%, group 1) and in 46 (39.3%) post-liver transplantation (group 2a). Testing for AATD was not undertaken in 35 (29.9%) of patients despite having PAS+G on explanted livers (group 2b). Post-liver transplantation survival analysis showed a trend (P = 0.098) towards enhanced survival in group 1 vs. group 2 at 10 years. CONCLUSIONS: This study shows that diagnosis of AATD is overlooked and frequently delayed in patients with cirrhosis undergoing liver transplantation. The observed trend towards higher survival in patients diagnosed with AATD pre-liver transplantation suggests the opportunity to enhance outcomes by earlier recognition of AATD.

Update on viral hepatitis in pregnancy.

Pregnant women with acute viral hepatitis are at higher risk of morbidity and death than pregnant women with chronic viral hepatitis. The risk of death is highest with acute viral hepatitis E, and the rate of transmission to the baby may be highest with hepatitis B virus (HBV) infection. Managing viral hepatitis in pregnancy requires assessing the risk of transmission to the baby, determining the gestational age at the time of infection and the mother's risk of decompensation, and understanding the side effects of antiviral drugs.

Prevalence of celiac disease in cirrhosis and outcome of cirrhosis on a gluten free diet: a prospective study.

BACKGROUND & AIMS: Current consensus suggests CD to be a multi-systemic disease that could affect any organ system including the liver. It remains under-diagnosed in the US and its prevalence and management in cirrhotic patients has not been studied. Our aim was (1) to estimate the prevalence of CD in cirrhosis, (2) to characterize cirrhotic patients with abnormal celiac serology and normal small bowel biopsy and (3) to evaluate the effect of a GFD on the liver. METHODS: A total of 204 consecutive patients with biopsy proven cirrhosis scheduled for an upper endoscopy (EGD) to assess and treat gastro-esophageal varices (GEV) at the Cleveland Clinic between 5/1/2008 and 5/30/2010 were enrolled in the study and followed for 2 years. RESULTS: CD affects 2.5% of cirrhotic patients and more than twice the prevalence in the general population. Abnormal EMA >1/10 and high hTTG levels >20 IU can be used to diagnose CD in cirrhosis. Sensitivities and specificities are 100% for EMA and 80% and 94% for hTTG, respectively. After a GFD, patients with CD showed a return to normal levels of their celiac serology, small bowel biopsy and liver enzyme abnormalities. CONCLUSIONS: CD is at least twice more common in cirrhotic patients than in the general population and GFD improves liver tests. CD can occur coincidentally with other liver disorders and screening may be warranted during the evaluation of patients with cirrhosis. Abnormal EMA and high hTTG levels can be used to diagnose CD in cirrhosis.

A multicenter, prospective, randomized comparison of a novel signal transmission capsule endoscope to an existing capsule endoscope.

BACKGROUND: MiroCam, a capsule endoscope, uses a novel transmission technology, electric-field propagation, which uses the human body as a conduction medium for data transmission. OBJECTIVE: To compare the ability of the MiroCam (MC) and PillCam (PC) to identify sources of obscure GI bleeding (OGIB). DESIGN: Prospective, multicenter, comparative study. SETTING: Six academic hospitals. PATIENTS: A total of 105 patients with OGIB. INTERVENTION: Patients ingested both the MC and PC capsules sequentially in a randomized fashion. MAIN OUTCOME MEASUREMENTS: Concordance of rates in identifying a source of OGIB, operational times, and rates of complete small-bowel examination. RESULTS: Data analysis resulted in 43 (48%) "abnormal" cases identifying a source of OGIB by either capsule. Twenty-four cases (55.8%) were positive by both capsules. There was negative agreement in 46 of 58 cases (79.3%). The κ index was 0.547 (χ(2) = 1.32; P = .36). In 12 cases, MC positively identified a source that was not seen on PC, whereas in 7 cases, PC positively identified a source that was not seen on MC. MC had a 5.6% higher rate of detecting small-bowel lesions (P = .54). MC captured images at 3 frames per second for 11.1 hours, and PC captured images at 2 frames per second for 7.8 hours (P < .0001). Complete small-bowel examination was achieved in 93.3% for MC and 84.3% for PC (P = .10). LIMITATIONS: Readers were not blinded to the particular capsule they were reading. CONCLUSION: A positive diagnostic finding for OGIB was identified by either capsule in 48% of cases. The concordance rate between the 2 capsules was comparable to that of prior studies in identifying sources of small-bowel bleeding. The longer operational time of the MC may result in higher rates of complete small-bowel examination, which may, in turn, translate into a higher rate of detecting small-bowel lesions. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00878982.).

Diagnosis of celiac disease in adults based on serology test results, without small-bowel biopsy.

BACKGROUND & AIMS: Celiac disease is underdiagnosed, with nonspecific symptoms and high morbidity. New diagnostic factors are needed. We aimed to estimate the frequency at which adult patients with positive results from serology tests are referred for small-bowel biopsies and to identify factors that improve the diagnosis of celiac disease. METHODS: We performed a retrospective analysis of data from 2477 subjects who received serology tests for celiac disease between 2005 and 2007. We analyzed results for total levels of IgA, IgA against human tissue transglutaminase (hTTG), IgA and IgG against gliadin, as well as dilution titers of IgA against endomysial antibodies (EMA). Biopsy samples were analyzed by pathologists experienced in detecting mucosal changes associated with celiac disease and graded according to the Marsh system. RESULTS: Of the 2477 patients, 610 (25%) had abnormal results from serology tests, and 39% of these patients (240 of 610) underwent small-bowel biopsy analyses. Of these patients, 50 (21%) had biopsy findings consistent with celiac disease (Marsh 3 lesions) and were placed on gluten-free diets. Titers of IgA hTTG greater than 118 U identified patients with celiac disease with a 2% false-positive rate. Titers of 21 to 118 U, in combination with an EMA dilution titer of 1:160 or greater, had a positive predictive value of 83% for celiac disease. IgA hTTG levels less than 20 U, in combination with an EMA dilution titer less than 1:10, had a negative predictive value of 92% for celiac disease. CONCLUSIONS: Serum levels of IgA hTTG greater than 118 U, or 21 to 118 U in combination with an EMA dilution titer of 1:160 or greater, can be used to identify adult symptomatic patients with celiac disease, in the absence of a small-bowel biopsy.

Hepatic encephalopathy: suspect it early in patients with cirrhosis.

As viral hepatitis and nonalcoholic fatty liver disease continue to increase in prevalence, we will see more cases of hepatic encephalopathy. Primary care physicians are often the first to suspect it, as they are familiar with the patient's usual mental and physical status. This serious complication typically occurs in patients with severe comorbidities and requires multidisciplinary evaluation and care.

Histological abnormalities of the small bowel mucosa in cirrhosis and portal hypertension.

AIM: To study the small bowel (SB) mucosa on biopsy in cirrhotic patients with portal hypertension and in non-cirrhotic controls and grade findings according to the Marsh criteria. METHODS: We prospectively enrolled 51 consecutive patients undergoing an upper endoscopy for their routine medical care. Twenty five patients with cirrhosis and portal hypertension were compared to 26 controls. We obtained coeliac serology and multiple upper small bowel biopsies on all 51 patients. A GI pathologist interpreted biopsies and graded findings according to the Marsh criteria. We assessed equivalence in Marsh grade between cirrhotic and non-cirrhotic controls using the Mann-Whitney test for equivalence. RESULTS: Gender, ethnicity and age were similar between both groups. Marsh grades were equivalent between the groups. Grade of 0 was present in 96% and grade of 1 was present in 4% of both groups and there was no villus atrophy or decrease in villus/crypt ratio in patients with portal hypertension. CONCLUSION: This study provides evidence for the lack of villus atrophy in patients with cirrhosis and portal hypertension, and supports the continuous reliance on the Marsh criteria when the diagnosis of coeliac disease is to be made in the presence of cirrhosis.

The liver in pregnancy: disease vs benign changes.

Liver dysfunction in a pregnant woman may be caused by the pregnancy, it may be unrelated to the pregnancy, or it may be a chronic condition that existed before the pregnancy. In any case, the clinical clues of liver dysfunction in pregnancy are not specific, and certain "abnormalities" in liver function tests may represent benign changes of pregnancy. On the other hand, prompt recognition of the signs of liver disease in pregnant patients leads to timely management and may save the life of both mother and baby.

Long-term management of alcoholic liver disease.

Despite the epidemics of viral hepatitis C and nonalcoholic fatty liver disease, alcohol remains one of the major causes of liver disease. Commonly, hepatitis C and other liver diseases are found in association with alcohol consumption. This association in many instances is noted to accelerate the progression of liver disease. In many respects, the long-term management of alcoholic liver disease is not dissimilar from the long-term management of patients with cirrhosis from other etiologies. One major element is the abstinence of alcohol use. The ability to maintain sobriety has a major impact on the outcome of patients with alcoholic cirrhosis because maintaining abstinence can lead to significant regression of fibrosis and possibly early cirrhosis. Similarities in managing patients with cirrhosis due to alcohol or cirrhosis from other causes include vaccination to prevent superimposed viral hepatitis and screening for esophageal varices and hepatocellular carcinoma with subsequent appropriate therapy.