Effects of larazotide acetate, a tight junction regulator, on the liver and intestinal damage in acute liver failure in rats

Background and Aim The epithelial cells are the strongest determinants of the physical intestinal barrier. Tight junctions (TJs) hold the epithelial cells together and allow for selective paracellular permeability. Larazotide acetate (LA) is a synthetic octapeptide that reduces TJ permeability by blocking zonulin receptors. In this study, we aimed to investigate the effects of LA, a TJ regulator, on the liver and intestinal histology in the model of acute liver failure (ALF) in rats. Materials and Methods The thioacetamide (TAA) group received intraperitoneal (ip) injections of 300 mg/kg TAA for 3 days. The TAA+LA(dw) (drinking water) group received prophylactic 0.01 mg/mL LA orally for 7 days before the first dose of TAA. The LA(dw) group received 0.01 mg/mL LA orally. The TAA + LA(g) (gavage) group received prophylactic 0.01 mg/mL LA via oral gavage for 7 days before the first dose of TAA. The LA(g) group received 0.01 mg/mL LA via oral gavage. While liver tissue was evaluated only with light microscopy, intestinal samples were examined with light and electron microscopy. Results Serum ammonia, AST, and ALT levels in the TAA group were significantly higher than in control groups (all p < 0.01). Serum ALT levels in the TAA + LA(dw) group were significantly lower than in the TAA group ( p < 0.05). However, serum ammonia and ALT levels did not differ between the TAA and other groups. Serious liver damage in the TAA group was accompanied by marked intestinal damage. There was no significant difference between the TAA and TAA + LA(dw) groups and TAA and TAA + LA(g) groups for liver damage scores. However, intestinal damage scores significantly decreased in the TAA + LA(dw) group compared to the TAA group. In the TAA + LA(dw) group, fusion occurred between the surface epithelial cells of neighboring villi and connecting regions formed as epithelial bridges between the villi. Conclusion Our findings suggest that LA reduced intestinal damage by acting on TJs in the TAA-induced ALF model in rats.

Anesthetic Management of a Patient With Citrullinemia Type I During Dental Treatment

We report a case involving intravenous sedation for third molar extractions in a 32-year-old man with citrullinemia type I (CTLN1), a genetic disorder that affects the urea cycle. The patient was diagnosed with CTLN1 after he exhibited seizures soon after birth and was intellectually disabled because of persistent hyperammonemia, although his recent serum ammonia levels were fairly well controlled. We planned to minimize his preoperative fasting, continue his routine oral medications, and monitor his serum ammonia levels at least twice. Sedation with midazolam and a propofol infusion was planned to suppress his gag reflex and reduce protein hypercatabolism due to stress. Epinephrine-containing local anesthetics, which enhance protein catabolism, were avoided, replaced by plain lidocaine for blocks and prilocaine with felypressin for infiltration anesthesia. No significant elevation in ammonia levels was observed. In patients with CTLN1, sedation can be useful for preventing hyperammonemia. Patients who develop symptomatic hyperammonemia may require urgent/emergent treatment involving other medical specialists. Therefore, preoperative endocrinology consultation, perioperative monitoring of serum ammonia levels, and preemptively coordinating for appropriate care in the event hyperammonemia occurs should all be considered.

Electroacupuncture Synergistically Inhibits Proinflammatory Cytokine Production and Improves Cognitive Function in Rats with Cognitive Impairment due to Hepatic Encephalopathy through p38MAPK/STAT3 and TLR4/NF-κB Signaling Pathways

Objective. To investigate the effect of electroacupuncture (EA) on cognitive dysfunction in rats with hepatic encephalopathy and its underlying mechanism. Methods. Fifty Wistar rats were randomly divided into a normal group (n = 10) and model group (n = 40). Rat models of hepatic encephalopathy were established by administration of carbon tetrachloride and thioacetamide for a total of 12 weeks. At the 9th week after modeling, rats with cognitive impairment in the model group were identified by conducting the Morris water maze test, which were then randomly divided into a control group (CCl4) and treatment groups including EA group (CCl4 + EA), lactulose group (CCl4 + Lac), and EA plus lactulose group (CCl4 + CM), with 9 rats in each group. At the end of the 9th week, rats in CCl4 + Lac and CCl4 + CM groups had lactulose gavage at a dose of 10 mL/kg body weight, while normal control and CCl4 groups had gavage with the same volume of normal saline once a day for 21 days until the end of the experiment. Rats in CCl4 + EA and CCl4 + CM groups underwent acupuncture at Baihui (GV[DU]20), Shenting (GV[DU]24), and Zusanli (ST36) acupoints, among which EA at Baihui and Shenting acupoints were given once daily for 30 min lasting for 21 consecutive days. The effect of the treatment was measured by the Morris water maze test for learning and memory ability and magnetic resonance spectroscopy (MRS) for neuronal metabolism in the hippocampus of rats with hepatic encephalopathy. Pathological change in the rat hippocampus was observed by HE staining, while serum ammonia and liver function markers were detected. Western blot and real-time fluorescent quantitative PCR were used to detect the expressions of specific genes and proteins in the brain tissue. Results. Compared with those in the control group, rats undergoing EA had significantly shortened escape latency and increased number of platform crossing. H&E staining confirmed that EA improved brain tissue necrosis and ameliorated nuclear pyknosis in rats with hepatic encephalopathy. Significantly decreased levels of serum ammonia, alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (TBil), and total bile acid (TBA) were observed in rats undergoing EA, as well as improved levels of total protein (TP) and albumin (ALB). In addition, EA inhibited the brain expressions of TNF-α, IL-1β, IL-6, iNOS, TLR4, MyD88, NF-κB, p38MAPK, phosphorylated (p)-p38MAPK, STAT3, and p-STAT3 genes, as well as protein expressions of TNF-α, IL-6, TLR4, MyD88, NF-κB, p38MAPK, p-p38MAPK, STAT3, and p-STAT3. MRS showed increased Glx/Cr and decreased NAA/Cr, Cho/Cr and mI/Cr in the control group, and EA significantly reversed such changes in Glx/Cr and mI/Cr values. Conclusion. EA ameliorated the production of excessive proinflammatory cytokines in the hippocampus of rats with cognitive dysfunction secondary to hepatic encephalopathy, which also gave rise to subsequent changes such as reduced blood ammonia level, brain-protective activated astrocytes, and lower degree of brain tissue injury. The p38MAPK/STAT3 and TLR4/MyD88/NF-κB signaling pathways may be involved. EA can also improve the metabolism of NAA and Cho in the rat hippocampus and thereby improve learning and memory abilities.

Serum ammonia use: unnecessary, frequent and costly

Background/objectiveWhile ammonia plays a role in the complex pathophysiology of hepatic encephalopathy (HE), serum ammonia is unreliable for both diagnosis of, and correlation with, neurological symptoms in patients with cirrhosis. We aimed to quantify ordering, cost and appropriate use of serum ammonia in a major Midwestern healthcare system.Design/methodSerum ammonia ordering in adult patients presenting to a large Midwestern health system was evaluated from 1 January 2015 to 31 December 2019.ResultsSerum ammonia ordering was prevalent, with 20 338 tests ordered over 5 years. There were no differences in the number of inappropriate serum ammonia tests per 100 000 admissions for chronic liver disease over time (Pearson’s correlation coefficient=−0.24, p=0.70). As a proportion of total ammonia tests ordered, inappropriate tests increased over time (Pearson’s correlation coefficient=0.91, p=0.03). Inappropriate ordering was more common at community hospitals compared with the academic medical centre (99.3% vs 87.6%, p<0.001).ConclusionDespite evidence that serum ammonia levels are unreliable for the diagnosis of HE and are not associated with severity of HE in individuals with cirrhosis, ordering remains prevalent, contributing to waste and potential harm.

Early Tumor Response and Safety of Atezolizumab Plus Bevacizumab for Patients with Unresectable Hepatocellular Carcinoma in Real-World Practice

The aim of this study was to investigate the early tumor response and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma in real-world practice. Forty patients with Child-Pugh class A liver function and eastern cooperative oncology group performance status 0 or 1 were enrolled. The objective response rate (ORR) at six weeks after the start of treatment, changes in α-fetoprotein (AFP) and des-γ-carboxyprothrombin, incidence of adverse events (AEs), and changes in albumin-bilirubin (ALBI) score and serum ammonia level, were evaluated. Among 40 patients, 24 had histories of prior molecular targeted agents (MTAs). The ORR was 22.5% based on mRECIST. Multivariate analysis showed that an AFP ratio <1.0 at three weeks (odds ratio 39.2, 95% confidence interval CI 2.37–649.0, p = 0.0103) was the only significant factor for predicting early response. There was no significant difference in the frequency of AEs between patients receiving first-line treatments and others. Fatigue, proteinuria, and ascites were more frequent in patients who experienced prior treatment. No decrease in ALBI score or increase in serum ammonia level was observed. Our study demonstrated that AFP may be useful in assessing early response and that this treatment is safe, including in patients with prior MTA treatments.

A Case Series on Suspected Remdesivir Induced Hyperammonemia

Remdesivir is a broad spectrum anti-viral drug that has shown to inhibit SARS-CoV-2. In absence of any effective treatment for SARS-CoV-2 infection (COVID-19), Remdesivir has been tried for a compassionate use in severe COVID-19. Remdesivir has shown promise in the management of patients with COVID-19 although recent studies have shown concerns with its effectiveness and safety in practice. Despite this there is a need to document potential Adverse drug Reaction (ADR) to guide future decisions. We describe 2 cases of Suspected Remdesivir-induced hyperammonemia (SRIH) in patients with normal liver function. Serum ammonia levels was raised much above the baseline after a fortnight of therapy. After completion of the therapy, there was gradual improvement and normalization of serum ammonia levels. This suggested a causal relationship which was possibly due to the administration of Remdesivir drug. With the increasing use, physicians should be aware of this potential ADR of Remdesivir and evaluate ammonia levels in patients taking Remdesivir who present with alterations in mental status.

Recurrent Altered Mental State Associated with Nonhepatic Hyperammonemia Presented in an Elderly Female Patient: Probable Late-Onset Urea Cycle Disorder

Altered mentality associated with hyperammonemia is usually diagnosed in patients with liver disease. Nonhepatic hyperammonemia may be present in critically ill patients or may be caused by high protein diets or certain drugs. Urea cycle disorders (UCDs) rarely present with altered mentality with hyperammonemia in adult patients. An 82-year-old female visited our hospital with complaints of abnormal behavior and confusion. Routine blood tests revealed elevated serum ammonia. Her mentality and serum ammonia level normalized after lactulose enema and she was discharged thereafter. However, she was later re-admitted because of recurrent altered mentality. Amino acid analysis revealed that serum levels of ornithine and glutamine increased significantly, whereas the levels of alanine and glutamic acid increased slightly, and the levels of arginine, lysine, and citrulline were normal, which were probably caused by reduced activity of the mitochondrial ornithine carrier-1. Although our patient was not diagnosed genetically, this case illustrates the under-recognized fact that UCD can occur in a senile age. Clinical suspicion of UCDs in patients with hyperammonemia is critical for early diagnosis and to prevent the significant neurologic sequelae.

Reye's Syndrome

Reye's syndrome is a rare and potentially fatal pediatric illness defined as acute noninflammatory encephalopathy with fatty liver failure. It rarely occurs in elderly patients and is equally distributed between the sexes [1]. It has been usually associated with acute viral infections and the use of salicylate [1- 3]. There is no specific test to diagnose the disease. However, the most common lab finding is an early rise in serum ammonia levels occurring within 1 to 2 days of mental status changes [4-8]. Treatment of the Reye’s syndrome is mainly supportive and requires close monitoring best accomplished in an intensive care unit setting [9,10].

Prevalence of Hepatic Encephalopathy from a Commercial Medical Claims Database in the United States

Introduction. Hepatic encephalopathy (HE), a complication of cirrhosis, is associated with increased healthcare resource utilization and mortality, and impaired quality of life. Information on the prevalence of HE in the US general population is limited. Methods. Prevalence of HE was estimated by sequential stepwise data analysis of the Symphony Health anonymized patient-level data (APLD) claims database. First, patients ≥ 18 years with International Classification of Diseases ninth/tenth edition, clinical modification (ICD-9/10-CM), and codes for cirrhosis from 2018 medical and hospital claims were used to estimate prevalence of cirrhosis within the data set and number of patients with cirrhosis in the US general population. Second, patients diagnosed with cirrhosis in the APLD data set from 2015–2016 with an HE ICD-9/10-CM code within 1 year of cirrhosis diagnosis were used to deduce the prevalence of HE within the data set and estimate the number of patients with HE in the US general population. Last, US DiagnosticSource data on serum ammonia level laboratory results measured within ±2 days of a confirmed HE event were merged with the APLD HE data set, then applied to the US general population. Results. Medical and hospital claims data were available for 272,256 patients with cirrhosis in 2018. An estimated 536,856 US adults had a diagnosis of cirrhosis (prevalence of 0.21%) in 2018. This proportion applied to the estimated number of patients with cirrhosis in the United States resulted in a prevalence estimate of 201,858 cirrhosis patients with HE in 2018. When factoring in serum ammonia data, prevalence was conservatively estimated as approximately 196,000 cirrhosis patients with HE and serum ammonia levels > 21 μ mol / L . Conclusions. In this longitudinal cohort–based study, it was estimated that ≈202,000 patients had HE in the United States in 2018, representing a considerable burden to society and payers.

Real-World Experience of the One-Year Efficacy of Rifaximin Add-On to Lactulose Is Superior to Lactulose Alone in Patients with Cirrhosis Complicated with Recurrent Hepatic Encephalopathy in Taiwan

Background: Hepatic encephalopathy (HE), a neuropsychiatric complication of decompensated cirrhosis, is associated with high mortality and high risk of recurrence. Rifaximin add-on to lactulose for 3 to 6 months is recommended for the prevention of recurrent episodes of HE after the second episode. However, whether the combination for more than 6 months is superior to lactulose alone in the maintenance of HE remission is less evident. Therefore, the aim of this study is to evaluate the one-year efficacy of rifaximin add-on to lactulose for the maintenance of HE remission in Taiwan. Methods: We conducted a real-world single-center retrospective cohort study to compare the long-term efficacy of rifaximin add-on to lactulose (group R + L) versus lactulose alone (group L, control group). Furthermore, the treatment efficacy before and after rifaximin add-on to lactulose was also analyzed. The primary endpoint of our study was time to first HE recurrence (Conn score ≥ 2). All patients were followed up every three months until death, and censored at one year if still alive. Results and Conclusions: 12 patients were enrolled in group R + L. Another 31 patients were stratified into group L. Sex, comorbidity, ammonia level, and ascites grade were matched while age, HE grade, and model for end-stage liver disease (MELD) score were adjusted in the multivariable logistic regression model. Compared with group L, significant improvement in the maintenance of HE remission and decreased episodes and days of HE-related hospitalizations were demonstrated in group R + L. The serum ammonia levels were significantly lower at the 3rd and 6th month in group 1. Concerning changes before and after rifaximin add-on in group R + L, mini-mental status examination (MMSE), episodes of hospitalization, and variceal bleeding also improved at 6 and 12 months. Days of hospitalization, serum ammonia levels also improved at 6th month. Except for concern over price, no patients discontinued rifaximin due to adverse events or complications. The above results provide evidence for the one-year use of rifaximin add-on to lactulose in reducing HE recurrence and HE-related hospitalization for patients with decompensated cirrhosis.