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Lapenna L, Merli M, Cilla M, Cossiga V, Floreani A, Invernizzi F, Toniutto P, Burra P. Sex differences in hepatic encephalopathy: addressing the knowledge gap. Dig Liver Dis 2025:S1590-8658(25)00322-6. [PMID: 40288916 DOI: 10.1016/j.dld.2025.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 04/02/2025] [Accepted: 04/06/2025] [Indexed: 04/29/2025]
Abstract
Hepatic encephalopathy (HE) is a brain dysfunction caused by liver insufficiency and/or portal-systemic shunting with a significant impact on patients' quality of life and healthcare systems. This narrative review was elaborated by the Special Interest Group (SIG) "Gender in Hepatology" of the Italian Association for the Study of the Liver (AISF) and addresses the underexplored area of sex differences in HE, examining epidemiological trends, clinical manifestations and potential underlying mechanisms. Current evidence suggests that men and women may experience different prevalence rates, risk factors and disease progression due to biological and psychosocial factors. However, these differences remain poorly understood, with limited research on sex-specific outcomes, treatment adherence and psychological effects. Emerging data on body composition, gut microbiota and experimental models highlight potential mechanisms contributing to these differences. Given the evolving epidemiology of liver disease, this review highlights the need for targeted studies and sex-specific approaches in the management of HE to advance personalised medicine and improve outcomes.
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Affiliation(s)
- Lucia Lapenna
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
| | - Manuela Merli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy
| | - Marta Cilla
- Department of Internal Medicine and Hepatology, San Raffaele Hospital, Milan, Italy
| | - Valentina Cossiga
- Diseases of the Liver and Biliary System Unit, Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy
| | | | - Federica Invernizzi
- Department of Internal Medicine and Hepatology, San Raffaele Hospital, Milan, Italy
| | - Pierluigi Toniutto
- Hepatology and Liver Transplantation Unit, Academic Hospital, University of Udine, Udine, Italy
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
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Broca F, Dufrenoy M, Martin M. [Management of hepatic encephalopathy: A general review]. Rev Med Interne 2025; 46:211-219. [PMID: 39516076 DOI: 10.1016/j.revmed.2024.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 09/13/2024] [Accepted: 10/05/2024] [Indexed: 11/16/2024]
Abstract
Hepatic encephalopathy is a severe complication with high mortality in patients with hepatopathy and/or portosystemic shunts, partly due to the presence of hyperammonemia because of defective hepatic detoxification. Diagnosis is essentially clinical, characterized by various neuropsychiatric symptoms, possibly associated with hyperammonemia. Complementary tests, such as electroencephalogram to identify metabolic encephalopathy, or specific abnormalities on cerebral magnetic resonance imagery, may also support the diagnosis. Management is essentially based on treatment of triggering factors such as ionic disorders or sepsis, and symptomatic therapy with non-absorbable disaccharides (notably lactulose) or polyethylene glycol, possibly combined with rifaximin. Progression varies according to the initial severity and management of hepatic encephalopathy, but this condition is potentially reversible with treatment.
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Affiliation(s)
- Florent Broca
- Service de médecine interne, CHU La Milétrie, Poitiers, France; Faculté de médecine et de pharmacie, université de Poitiers, Poitiers, France.
| | - Mylène Dufrenoy
- Service de médecine interne, CHU La Milétrie, Poitiers, France; Faculté de médecine et de pharmacie, université de Poitiers, Poitiers, France.
| | - Mickaël Martin
- Service de médecine interne, CHU La Milétrie, Poitiers, France; Faculté de médecine et de pharmacie, université de Poitiers, Poitiers, France; Inserm U1313, université de Poitiers, Poitiers, France.
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3
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Tapper EB, Chen X, Parikh ND. Testosterone Replacement Reduces Morbidity and Mortality for Most Patients With Cirrhosis. Clin Gastroenterol Hepatol 2025:S1542-3565(25)00200-9. [PMID: 40097035 DOI: 10.1016/j.cgh.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 01/15/2025] [Accepted: 02/05/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND & AIMS Many men with cirrhosis have low testosterone levels. This is associated with sarcopenia, anemia, and poor quality of life. Data are lacking, however, regarding the clinical impact of testosterone replacement. METHODS We conducted an emulated clinical trial evaluating the impact of testosterone replacement among men who were diagnosed with hypogonadism at the same time as their diagnosis of cirrhosis (new user design). We used nationally representative Medicare data (2008-2020) to examine the risk of death, decompensation events, and fractures in patients who did or did not receive testosterone. We balanced treated and untreated with inverse probability of treatment weighting and evaluated outcomes using an intention-to-treat design. RESULTS A total of 282 patients (7.4%) with testicular hypofunction and cirrhosis received testosterone replacement after diagnosis. Patients started on testosterone spent 28.6% of patient-days on therapy, and patients not started would spend 0.5% of patient-days on therapy (P < .0001). Testosterone use was associated with lower mortality (subdistribution hazard ratio [sHR], 0.92; 95% confidence interval [CI], 0.85-0.99). Testosterone also led to a lower risk of new decompensation events (sHR, 0.92; 95% CI, 0.86-0.99) and especially for ascites requiring paracentesis (sHR, 0.82; 95% CI, 0.76-0.89) and variceal hemorrhage (sHR, 0.67; 95% CI, 0.54-0.85) with less effect on hepatic encephalopathy requiring hospitalization (sHR, 0.92; 95% CI, 0.84-1.01) and fractures (sHR, 0.99; 95% CI, 0.91-1.08) and without increased risk of hepatocellular carcinoma (sHR, 1.09; 95% CI, 0.91-1.3). There was substantial heterogeneity of treatment effect across baseline subgroups. CONCLUSION In our target trial emulation of a nationally representative cohort of older patients with cirrhosis and hypogonadism, testosterone use improved clinical outcomes.
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Affiliation(s)
- Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.
| | - Xi Chen
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
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Bloom PP, Bassis CM, Crossette E, Silber JL, Norman JM, Young VB, Lok AS. Safety and efficacy of a defined bacterial consortium, VE303, to treat HE. Hepatol Commun 2025; 9:e0650. [PMID: 39969428 PMCID: PMC11841841 DOI: 10.1097/hc9.0000000000000650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 12/24/2024] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Novel therapies are needed to treat HE, and microbiome modulation is a promising target. VE303 is a defined consortium of 8 purified, clonal bacterial strains, known to produce metabolites that may be beneficial in HE. We evaluated the safety and efficacy of VE303 to treat HE. METHODS We performed a single-center, randomized, placebo-controlled trial of VE303 in adult patients with a history of overt HE (NCT04899115). Eligible patients were taking lactulose and rifaximin, had no recent systemic antibiotics, and had MELD ≤20. All patients received 5 days of oral vancomycin followed by randomization to 14 days of VE303 or placebo (2:1). The primary endpoints were incidence of serious adverse events and change in psychometric HE score (PHES) from baseline to 4 weeks after treatment. Stool samples underwent metagenomic sequencing and metabolite quantification. RESULTS Eighteen patients completed the trial, 56% men, with a mean age of 59 years and a mean MELD of 11. Patients who received VE303 had a mean change in PHES of +1.5 versus -1.0 in those who received a placebo (p=0.20). Two of the 12 patients who received VE303 had at least 1 serious adverse event (all overt HE hospitalizations), compared with 0/6 patients who received a placebo. In the patients who received VE303, 2 of 8 strains engrafted in >50% of patients. Both VE303 strain engraftment and increased stool butyrate production had a trend toward improved PHES. CONCLUSIONS VE303 was well tolerated in patients with cirrhosis and a history of overt HE, leading to the engraftment of certain VE303 strains and a higher percentage of patients with improved PHES.
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Affiliation(s)
- Patricia P. Bloom
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Christine M. Bassis
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
| | | | | | | | - Vincent B. Young
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA
| | - Anna S.F. Lok
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
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Kawaratani H, Namisaki T, Kondo Y, Tatsumi R, Kawabe N, Tanabe N, Sakamaki A, Hoshikawa K, Uchida Y, Endo K, Kawaguchi T, Oikawa T, Ishizu Y, Hige S, Takami T, Terai S, Ueno Y, Mochida S, Koike K, Yoshiji H. Real-World Setting of Efficacy and Safety of 3 Years of Rifaximin Administration in Japanese Patients with Hepatic Encephalopathy: A Multicenter Retrospective Study. J Clin Med 2025; 14:1358. [PMID: 40004887 PMCID: PMC11856843 DOI: 10.3390/jcm14041358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/09/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Rifaximin is a therapeutic agent for patients with hepatic encephalopathy (HE); however, there is little data on the effects of its long-term (>1 year) administration in Japanese patients with cirrhosis. The effects and safety of 3-year rifaximin treatment on HE was investigated in Japan. Methods: A total of 190 Japanese patients with cirrhosis who were continuously administered rifaximin for more than 1 year suffered overt or covert HE, which was diagnosed by a physician. Laboratory data were collected at baseline, 3, 6, 12, 18, 24, 30, and 36 months following rifaximin administration. We examined the cumulative overt HE incidences, overall survival rates, and hepatic functional reserves following rifaximin treatment. The occurrence of adverse events was also assessed. Results: The levels of ammonia improved significantly after 3 months of rifaximin administration, which continued for 3 years. Serum albumin and prothrombin activity also significantly improved 3 years after initiation of rifaximin treatment. Cumulative overt HE incidences were 12.1%, 19.7%, and 24.9% at 1, 2, and 3 years, respectively. The survival rates following rifaximin treatment were 100%, 88.9%, and 77.8% at 1, 2, and 3 years, respectively. In contrast, renal function and electrolytes did not change following rifaximin administration. Only three (1.6%) patients discontinued rifaximin therapy because of severe diarrhea after 1 year of rifaximin administration. No other serious adverse events were observed. Conclusions: Three years of continuous rifaximin (RFX) treatment was both effective and safe for patients with hepatic encephalopathy. Liver function improved and did not worsen during treatment.
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Affiliation(s)
- Hideto Kawaratani
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (H.K.)
| | - Tadashi Namisaki
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (H.K.)
| | - Yasuteru Kondo
- Department of Hepatology, Sendai Tokushukai Hospital, Sendai 981-3116, Japan;
| | - Ryoji Tatsumi
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo 060-0033, Japan; (R.T.); (S.H.)
| | - Naoto Kawabe
- Department of Gastroenterology and Hepatology, Fujita Health University School of Medicine, Nagoya 454-8509, Japan;
| | - Norikazu Tanabe
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, Ube 755-8611, Japan; (N.T.); (T.T.)
| | - Akira Sakamaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 950-2181, Japan; (A.S.); (S.T.)
| | - Kyoko Hoshikawa
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan; (K.H.); (Y.U.)
| | - Yoshihito Uchida
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan; (Y.U.); (S.M.)
| | - Kei Endo
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Yahaba 028-3695, Japan;
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan;
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
| | - Shuhei Hige
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo 060-0033, Japan; (R.T.); (S.H.)
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, Ube 755-8611, Japan; (N.T.); (T.T.)
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 950-2181, Japan; (A.S.); (S.T.)
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan; (K.H.); (Y.U.)
| | - Satoshi Mochida
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan; (Y.U.); (S.M.)
| | | | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (H.K.)
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Bloom PP. The Misdiagnosis and Underdiagnosis of Hepatic Encephalopathy. Clin Transl Gastroenterol 2025; 16:e00784. [PMID: 39635997 PMCID: PMC11845192 DOI: 10.14309/ctg.0000000000000784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 10/30/2024] [Indexed: 12/07/2024] Open
Abstract
Patients with cirrhosis are at risk of developing hepatic encephalopathy (HE), which can present with a wide range of symptoms, including confusion, lethargy, inappropriate behavior, and altered sleep patterns. In addition to HE, patients with cirrhosis are at risk of developing mild cognitive impairment, dementia, and delirium, which have features closely resembling HE. Given the similar presentation of these conditions, misdiagnosis can and does occur. Mild cognitive impairment is common in individuals aged 50 years and older and can progress to dementia in those affected. Dementia and HE are both characterized by sleep disturbance and cognitive dysfunction, thus differentiating these conditions can be difficult. Furthermore, delirium can disrupt sleep patterns, and liver disease is recognized as a risk factor for its development. As HE is a cirrhosis-related complication, determining if a patient has undiagnosed cirrhosis is critical, particularly given the large number of patients with asymptomatic, compensated cirrhosis. Separately, underdiagnosis of minimal HE can occur even in patients with diagnosed liver disease, related, in part, to lack of testing. Given the availability of effective therapies for managing symptoms and preventing future episodes, accurate diagnosis of HE is essential.
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Affiliation(s)
- Patricia P. Bloom
- Division of Gastroenterology and Hepatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
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Wang S, Zhang L, Li J, Feng J, Gao J, Huang R. Hepatic encephalopathy and spontaneous bacterial peritonitis are associated with increased liver-related readmissions in cirrhosis. Front Med (Lausanne) 2025; 12:1417222. [PMID: 39958824 PMCID: PMC11825766 DOI: 10.3389/fmed.2025.1417222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 01/20/2025] [Indexed: 02/18/2025] Open
Abstract
Introduction Liver disease remains a significant global health concern. In China, the number of patients with liver cirrhosis is estimated to reach 7 million. In addition to the high risk of death, cirrhosis leads to several severe complications. Patients with cirrhosis have significantly longer hospital stays and higher total hospital costs than those without cirrhosis. We aimed to investigate the predictors of readmission among patients with cirrhosis in China. Materials and methods We conducted a retrospective study to evaluate adult patients with cirrhosis. Data on various sociodemographic, clinical, and hospitalization characteristics were collected. We defined the primary endpoint as the first liver-related readmission occurring within 30-90 days of initial hospitalization. Adult patients with cirrhosis admitted to our hospital between January 2009 and December 2022 were included. Differences between groups were analyzed using Student's t-test and chi-square test. Logistic and multiple linear regression analyses were performed to identify predictors associated with readmission and the length of the first hospitalization. Results In total, 1,285 patients were diagnosed with cirrhosis. Among these patients, 767 (59.7%) were males, and the mean age was 58.9 ± 12.3 years. Seventy-two (5.6%) and 154 (12.0%) patients were readmitted within 30 and 90 days, respectively. Compared with those who were not readmitted, patients readmitted at 30-day and 90-day had a higher proportion of males, ascites, spontaneous bacterial peritonitis, electrolyte abnormalities, higher Child-Pugh-Turcotte scores, longer initial hospital stays, and higher initial hospitalization costs. Logistic regression analysis indicated that hepatic encephalopathy, spontaneous bacterial peritonitis, diabetes, and ascites were predictors of 30- and 90-day readmission. Hypertension and spontaneous bacterial peritonitis were significant predictors of the length of the first hospitalization. Conclusion Patients with cirrhosis presenting with hepatic encephalopathy, ascites, and spontaneous bacterial peritonitis may have a higher risk of rehospitalization.
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Affiliation(s)
- Shan Wang
- Peking University Hepatology Institute, Peking University People’s Hospital, Beijing, China
- Department of Liver Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Lin Zhang
- Peking University Hepatology Institute, Peking University People’s Hospital, Beijing, China
| | - Jin Li
- The First Department of Neurology, The Third People’s Hospital of Liaoyang, Liaoyang, China
| | - Jiajun Feng
- Department of Marketing, School of Business, Renmin University of China, Beijing, China
| | - Jie Gao
- Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing, China
| | - Rui Huang
- Peking University Hepatology Institute, Peking University People’s Hospital, Beijing, China
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Protopapas AA, Tsankof A, Papagiouvanni I, Kaiafa G, Skoura L, Savopoulos C, Goulis I. Outpatient management after hospitalisation for acute decompensation of cirrhosis: A practical guide. World J Hepatol 2024; 16:1377-1394. [PMID: 39744202 PMCID: PMC11686542 DOI: 10.4254/wjh.v16.i12.1377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 10/24/2024] [Accepted: 11/20/2024] [Indexed: 11/29/2024] Open
Abstract
Acute decompensation in cirrhotic patients signifies the onset of clinically evident events due to portal hypertension. The transition from compensated to decompensated cirrhosis involves hemodynamic changes leading to multiorgan dysfunction, managed predominantly in outpatient settings with regular monitoring. The mortality risk is elevated in decompensated patients. Therefore, diligent outpatient management should focus on regular medical follow-ups, medication adjustments, patient education, addressing emergent issues and evaluation for liver transplantation. The ultimate goal is to improve quality of life, prevent disease progression, reduce complications, and assess possible recompensation. This guide provides valuable recommendations for medical experts managing decompensated cirrhotic patients post-hospitalization.
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Affiliation(s)
- Adonis A Protopapas
- First Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 54636, Greece.
| | - Alexandra Tsankof
- First Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Ioanna Papagiouvanni
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Georgia Kaiafa
- First Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Lemonia Skoura
- Department of Microbiology, Aristotle University οf Thessaloniki, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Christos Savopoulos
- First Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Ioannis Goulis
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
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Hurtado-Díaz-de-León I, Tapper EB. Systems of care that improve outcomes for people with hepatic encephalopathy. Metab Brain Dis 2024; 40:50. [PMID: 39621162 DOI: 10.1007/s11011-024-01430-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 10/31/2024] [Indexed: 12/11/2024]
Abstract
Hepatic encephalopathy (HE) is a critical neuropsychiatric complication of liver cirrhosis with a significant impact on patient quality of life and survival. The global prevalence of cirrhosis and associated HE necessitates a comprehensive understanding of the condition and effective systems of care to optimize outcomes. This review addresses the epidemiology, classification, diagnosis, and management of HE, with an emphasis on systems of care that improve outcomes for people with HE. Current diagnostic challenges include differentiating cognitive deficits attributable to HE from those caused by other etiologies, highlighting the need for accurate diagnostic methods. Traditional psychometric tests, while valuable for diagnosing covert HE (CHE), are limited in their ability to predict overt HE (OHE) due to various confounding factors. As a result, non-psychometric tools have been developed to provide outcome-based predictions aligned with the clinical course of HE. The management of HE includes addressing precipitating factors, pharmacologic interventions to reduce ammonia levels, and supportive care, with lactulose and rifaximin playing a central role. Preventive strategies with the use of remote monitoring in the outpatient management of HE, integrating technology for real-time tracking of therapy compliance and symptom evolution, could contribute to reducing hospital readmissions and improving patient care.
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Affiliation(s)
- Ivonne Hurtado-Díaz-de-León
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
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10
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Muallem A, Kandel L, Ackerman Z. Prognosis of Cirrhotic Patients After Osteoporotic Femoral Neck Fracture. J Clin Med 2024; 13:6701. [PMID: 39597844 PMCID: PMC11595005 DOI: 10.3390/jcm13226701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/01/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024] Open
Abstract
Introduction and Objectives: Osteoporotic hip fractures in cirrhotic subjects are associated with increased post-fracture mortality. Our aim was to identify unfavorable factors that were associated with increased post-fracture mortality. Patients and Methods: We employed a retrospective evaluation of the short- and long-term prognosis of cirrhotic patients that were admitted with a hip fracture to our institution. Results: A total of 77 cirrhotic and 81 control patients were included. The majority of the patients who died either during the initial three months or during one year of follow-up after the hip fracture were cirrhotic. The patients that did not survive the three-month period suffered from decompensated cirrhosis. The variables that were associated upon multivariate analysis with increased one-year all-cause mortality in both the control and cirrhotic patients were the presence of either cirrhosis, congestive heart failure or low hemoglobin levels upon admission. The variables that were associated upon univariate analysis with increased one-year all-cause mortality only in the cirrhotic patients were the patient's age, the presence of hepatic encephalopathy, as well as the levels of serum albumin, PT (in %) and FIB-4. Our multivariate analysis disclosed that the admission level of PT (in %) was the only parameter that was associated with one-year all-cause mortality among the cirrhotic patients (adjusted OR 0.962, CI: 0.928-0.996, p = 0.029). Conclusions: Patients with decompensated cirrhosis are at an increased risk of dying during the first year after an osteoporotic hip fracture. Cirrhotic patients with osteoporosis who are at risk of hip fractures should be identified and measures to prevent this complication should be implemented.
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Affiliation(s)
- Aviya Muallem
- Department of Orthopedic Surgery, Hadassah-Hebrew University Medical Center, Mount Scopus Campus and the Hebrew University-Hadassah Medical School, Jerusalem, Israel; (A.M.); (L.K.)
- Department of Medicine, Hadassah-Hebrew University Medical Center, Mount Scopus Campus and the Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Leonid Kandel
- Department of Orthopedic Surgery, Hadassah-Hebrew University Medical Center, Mount Scopus Campus and the Hebrew University-Hadassah Medical School, Jerusalem, Israel; (A.M.); (L.K.)
| | - Zvi Ackerman
- Department of Medicine, Hadassah-Hebrew University Medical Center, Mount Scopus Campus and the Hebrew University-Hadassah Medical School, Jerusalem, Israel
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11
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Tapper EB, Saleh ZM, Nikirk S, Bajaj J, Chen X, Lok ASF. Medically Tailored Meals for Patients With Cirrhosis and Hepatic Encephalopathy: The BRAINFOOD Proof-of-concept Trial. J Clin Exp Hepatol 2024; 14:101439. [PMID: 38882178 PMCID: PMC11176801 DOI: 10.1016/j.jceh.2024.101439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 04/27/2024] [Indexed: 06/18/2024] Open
Abstract
Background and aims Guidelines recommend that patients with hepatic encephalopathy (HE) receive a high-protein diet (roughly 1 g/kg actual body weight). Concommitant sodium restriction, low health literacy, and food insecurity limit patients' ability to meet this goal. We aimed to determine the feasibility of home-delivered high-protein medically tailored meals (MTMs) for patients with a recent episode of overt HE. Methods We enrolled patients with prior overt HE on active HE therapy in a 6-month trial of MTM. All received 21 home-delivered meals/week with protein snacks (mid-day and bedtime) for 12 weeks. Patients completed follow-up at week 24. The primary outcome was feasibility. Additional outcomes included change in protein and micronutrient intake (measured using 24 h dietary recalls performed by dieticians), cognitive function (Animal Naming Test [ANT]; EncephalApp Stroop), physical function (Liver Frailty Index [LFI]), and quality of life (Short Form-8 Health Survey [SF-8]). Healthcare utilization was also assessed. Results Ten patients competed the study with >90% of MTM consumed. Protein intake rose from 74.6 ± 25.1 g at baseline to 93.8 ± 24.3 g on MTM (P = 0.04). Branched-chain amino acids also increased-valine 3.73 ± 1.26 g to 5.17 ± 1.28 g, isoleucine 3.32 ± 1.18 to 4.69 ± 1.55, leucine 5.83 ± 2.00 to 7.49 ± 2.07, all P < 0.001. The LFI score improved from 4.42 ± 0.32 to 3.96 ± 0.82 by the end of the MTM phase (P = 0.03). SF-8 quality-of-life scores improved from 55.5 ± 15.5 at baseline to 64.7 ± 18.3 after the MTM phase, to 64.4 ± 19.1 at the end of the study (P = 0.1). EncephalApp Stroop time improved from 227 ± 94 to 194 ± 58s by the end of the MTM phase (P = 0.08). ANT scores were similarly non-significantly improved. Conclusion Home-delivered MTMs are feasible, increase protein consumption, and may improve patient wellbeing. A randomized trial is needed.
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Affiliation(s)
- Elliot B Tapper
- Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - Zachary M Saleh
- Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - Sam Nikirk
- Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - Jasmohan Bajaj
- Department of Internal Medicine, Virginia Commonwealth University, Richmond VA, USA
| | - Xi Chen
- Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - Anna S-F Lok
- Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
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12
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Hassan NF, El-Ansary MR, El-Ansary AR, El-Saied MA, Zaki OS. Unveiling the protective potential of mirabegron against thioacetamide-induced hepatic encephalopathy in rats: Insights into cAMP/PPAR-γ/p-ERK1/2/p S536 NF-κB p 65 and p-CREB/BDNF/TrkB in parallel with oxidative and apoptotic trajectories. Biochem Pharmacol 2024; 229:116504. [PMID: 39179118 DOI: 10.1016/j.bcp.2024.116504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 08/12/2024] [Accepted: 08/20/2024] [Indexed: 08/26/2024]
Abstract
Hepatic encephalopathy (HE) is one of the most prevalent and severe hepatic and brain disorders in which escalation of the oxidative, inflammatory and apoptotic trajectories pathologically connects acute liver injury with neurological impairment. Mirabegron (Mira) is a beta3 adrenergic receptor agonist with proven antioxidant and anti-inflammatory activities. The current research pointed to exploring Mira's hepato-and neuroprotective impacts against thioacetamide (TAA)-induced HE in rats. Rats were distributed into three experimental groups: the normal control group, the TAA group, received TAA (200 mg/kg/day for three consecutive days) and the Mira-treated group received Mira (10 mg/kg/day; oral gavage) for 15 consecutive days and intoxicated with TAA from the 13th to the 15th day of the experimental period. Mira counteracted hyperammonemia, enhanced rats' locomotor capability and motor coordination. It attenuated hepatic/neurological injuries by its antioxidant, anti-apoptotic as well as anti-inflammatory potentials. Mira predominantly targeted cyclic adenosine monophosphate (cAMP)/phosphorylated extracellular signal-regulated kinase (p-Erk1/2)/peroxisome proliferator-activated receptor gamma (PPARγ) dependent pathways via downregulation of p S536-nuclear factor kappa B p65 (p S536 NF-κB p 65)/tumor necrosis alpha (TNF-α) axis. Meanwhile, it attenuated nuclear factor erythroid 2-related factor (Nrf2) depletion in parallel with restoring of the neuroprotective defensive pathway by upregulation of cerebral cAMP/PPAR-γ/p-ERK1/2 and p-CREB/BDNF/TrkB besides reduction of GFAP immunoreactivity. Mira showed anti-apoptotic activity through inhibition of Bax immunoreactivity and elevation of Bcl2. To summarize, Mira exhibited a hepato-and neuroprotective effect against TAA-induced HE in rats via shielding antioxidant defense and mitigation of the pathological inflammatory and apoptotic axis besides upregulation of neuroprotective signaling pathways.
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Affiliation(s)
- Noha F Hassan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Mona R El-Ansary
- Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Amira R El-Ansary
- Department of Internal Medicine, Faculty of Medicine, Misr University for Science and Technology, Giza, Egypt
| | - Mohamed A El-Saied
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Omnia S Zaki
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt.
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13
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Flamm SL. Key Insights and Clinical Pearls in the Identification and Management of Cirrhosis and Its Complications. Am J Med 2024; 137:929-938. [PMID: 38788826 DOI: 10.1016/j.amjmed.2024.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 04/02/2024] [Accepted: 05/16/2024] [Indexed: 05/26/2024]
Abstract
Cirrhosis is a prevalent, chronic condition with an asymptomatic compensated phase, in which patients may feel well, and a decompensated phase that begins with the onset of complications (eg hepatic encephalopathy, ascites, and/or variceal bleeding). Because patients with cirrhosis may appear healthy with normal liver enzymes, alkaline phosphatase, and serum bilirubin levels, awareness of clinical signals is important. For example, patients with thrombocytopenia should be evaluated for chronic liver disease and cirrhosis. Early recognition and management of cirrhosis-related complications (eg hepatic encephalopathy, ascites, and/or variceal bleeding) are important, given their association with hospitalization and poor prognosis (eg increased odds of short-term mortality). Hepatic encephalopathy can be the most subtle cirrhosis-related complication and associated cognitive impairment may be misdiagnosed. Because hepatic encephalopathy can be associated with hospital readmissions, reducing readmission rates after hepatic encephalopathy-related hospitalizations is critical. This includes incorporating ongoing therapy (eg rifaximin plus lactulose) in postdischarge management plans to reduce the risk of hepatic encephalopathy recurrence. Strategies that mitigate cirrhosis progression and prevent the development of cirrhosis-related complications are key to improving patient outcomes.
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Affiliation(s)
- Steven L Flamm
- Section of Gastroenterology and Hepatology, Rush University Medical School, Chicago, Ill.
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14
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Deljavan Ghodrati A, Comoglu T. Rifaximin and alternative agents in the management of irritable bowel syndrome: A comprehensive review. Arch Pharm (Weinheim) 2024; 357:e2400356. [PMID: 39041415 DOI: 10.1002/ardp.202400356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/29/2024] [Accepted: 07/01/2024] [Indexed: 07/24/2024]
Abstract
Rifaximin, a broad-spectrum antibiotic, boasts a unique chemical composition and pharmacokinetic profile, rendering it highly effective in treating irritable bowel syndrome (IBS). Its minimal systemic absorption confines its impact to the gastrointestinal (GI) tract, where it yields significant therapeutic benefits. This review examines rifaximin's physico-chemical attributes and its role in managing IBS symptoms. Its molecular structure facilitates intestinal lumen retention postoral administration, minimizing systemic exposure and adverse effects. This targeted action is crucial in addressing the gut microbiota's role in IBS pathophysiology. By modifying microbial populations and their metabolite production, rifaximin mitigates symptoms like bloating, irregular bowel habits, and abdominal pain associated with IBS. It achieves this by reducing pathogenic bacteria and altering bacterial metabolism, enhancing mucosal and immune function. Clinical trials affirm rifaximin's superiority over placebo and conventional therapies in alleviating overall IBS symptoms and addressing small intestine bacterial overgrowth (SIBO). Despite its promising efficacy and sustained symptom relief, further research is essential to optimize long-term effectiveness and dosing regimens. Rifaximin stands as a vital treatment option for IBS due to its distinctive properties and clinical utility; yet, ongoing investigation is imperative for maximizing its therapeutic benefits.
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Affiliation(s)
- Aylin Deljavan Ghodrati
- Department of Pharmaceutical Technology, Ankara University Faculty of Pharmacy, Ankara, Turkey
- Graduate School of Health Sciences, Ankara University, Ankara, Turkey
| | - Tansel Comoglu
- Department of Pharmaceutical Technology, Ankara University Faculty of Pharmacy, Ankara, Turkey
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15
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Bloom PP, Fisher CJ, Tedesco N, Kamdar N, Garrido-Trevino L, Robin J, Asrani SK, Lok AS. HEAR-MHE study: Automated speech analysis identifies minimal hepatic encephalopathy and may predict future overt hepatic encephalopathy. Hepatology 2024:01515467-990000000-01026. [PMID: 39264936 DOI: 10.1097/hep.0000000000001086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 08/16/2024] [Indexed: 09/14/2024]
Abstract
BACKGROUND AND AIMS HE is a major cause of poor quality of life in patients with cirrhosis. A simple diagnostic test to identify minimal hepatic encephalopathy (MHE) and predict future overt HE (OHE) is lacking. We aimed to evaluate if analysis of speech patterns using a modern speech platform (1) correlates with validated HE tests, (2) correlates with MHE, and (3) predicts future OHE. APPROACH AND RESULTS In a two-center prospective cohort study of 200 outpatients with cirrhosis and 50 controls, patients underwent baseline speech recording and validated HE diagnostic testing with psychometric HE score. Patients were followed for 6 months to identify episodes of OHE. Seven hundred fifty-two speech variables were extracted using an automated speech analysis platform, reflecting the acoustic, lexical, and semantic aspects of speech. Patients with cirrhosis were median 63 years old (IQR 54, 68), 49.5% (99) were female. Over 100 speech variables were significantly associated with psychometric HE score ( p <0.05 with false discovery rate adjustment). A three-variable speech model (2 acoustic, 1 speech tempo variable) was similar to animal naming test in predicting MHE (AUC 0.76 vs. 0.69; p =0.11). Adding age and MELD-Na improved the accuracy of the speech model (AUC: 0.82). A combined clinical-speech model ("HEAR-MHE model") predicted time to OHE with a concordance of 0.74 ( p =0.06). CONCLUSIONS Automated speech analysis is highly correlated with validated HE tests, associated with MHE, and may predict future OHE. Future research is needed to validate this tool and to understand how it can be implemented in clinical practice.
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Affiliation(s)
- Patricia P Bloom
- Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Caitlyn J Fisher
- Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Nicholas Tedesco
- Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Neil Kamdar
- Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Stanford University, Stanford, California, USA
| | | | | | - Sumeet K Asrani
- Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA
| | - Anna S Lok
- Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
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16
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Solano QP, Chen X, Parikh ND, Tapper EB. Racial and Ethnic Disparities in Outcomes After the Development of Ascites: A National Cohort Study. Dig Dis Sci 2024; 69:3214-3219. [PMID: 39080087 DOI: 10.1007/s10620-024-08572-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 07/17/2024] [Indexed: 09/22/2024]
Abstract
INTRODUCTION Ascites, a severe complication of cirrhosis, significantly impacts patient morbidity and mortality especially in Black patients. Access to disease optimizing care has been proposed as a potential driver of this disparity. In this study, we evaluate TIPS utilization across racial and ethnic groups. METHODS We examined data from a 20% random sample of US Medicare enrollees with continuous Part D coverage. We required 180 days of continuous outpatient enrollment prior to cirrhosis diagnosis and all patients had ≥1 paracentesis within 180 days of their cirrhosis diagnosis. Time zero was the date of the first paracentesis. We assessed the likelihood of TIPS placement. Analyses were conducted to determine the independent associations between each outcome and race/ethnicity. RESULTS 5915 patients (average age 68.2, 64.4% male) were included in the analysis. 439 (7.4%) patients were identified as Black, 223 (3.8%) as Hispanic, and 4942 (83.6%) as white. When compared to white patients in a multivariable analysis, Black patients were less likely to receive a TIPS procedure (hazard ratio 0.4; 95% confidence interval (CI) 0.2-0.8) and had less days alive outside of the hospital (-100.5; 95% CI -189.4 - -11.6). There were no significant differences in transplant-free survival or number of paracenteses per year between ethnic and racial groups. CONCLUSION Black patients are less likely to receive a TIPS procedure when controlling for common patient- and disease-specific variables. Access to optimal specialized services may be a significant driver for disparities in outcomes of patients with cirrhosis between racial and ethnic groups.
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Affiliation(s)
- Quintin P Solano
- Division of Internal Medicine, University of Michigan, Ann Arbor, USA
| | - Xi Chen
- Division of Gastroenterology and Hepatology, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA
| | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA.
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17
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Smith ML, Wade JB, Wolstenholme J, Bajaj JS. Gut microbiome-brain-cirrhosis axis. Hepatology 2024; 80:465-485. [PMID: 36866864 PMCID: PMC10480351 DOI: 10.1097/hep.0000000000000344] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/10/2023] [Indexed: 03/04/2023]
Abstract
Cirrhosis is characterized by inflammation, degeneration, and fibrosis of liver tissue. Along with being the most common cause of liver failure and liver transplant, cirrhosis is a significant risk factor for several neuropsychiatric conditions. The most common of these is HE, which is characterized by cognitive and ataxic symptoms, resulting from the buildup of metabolic toxins with liver failure. However, cirrhosis patients also show a significantly increased risk for neurodegenerative diseases such as Alzheimer and Parkinson diseases, and for mood disorders such as anxiety and depression. In recent years, more attention has been played to communication between the ways the gut and liver communicate with each other and with the central nervous system, and the way these organs influence each other's function. This bidirectional communication has come to be known as the gut-liver-brain axis. The gut microbiome has emerged as a key mechanism affecting gut-liver, gut-brain, and brain-liver communication. Clinical studies and animal models have demonstrated the significant patterns of gut dysbiosis when cirrhosis is present, both with or without concomitant alcohol use disorder, and have provided compelling evidence that this dysbiosis also influences the cognitive and mood-related behaviors. In this review, we have summarized the pathophysiological and cognitive effects associated with cirrhosis, links to cirrhosis-associated disruption of the gut microbiome, and the current evidence from clinical and preclinical studies for the modulation of the gut microbiome as a treatment for cirrhosis and associated neuropsychiatric conditions.
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Affiliation(s)
- Maren L Smith
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
- Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - James B Wade
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jennifer Wolstenholme
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
- Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
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18
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Twohig PA, Peeraphatdit TB, Samson K, Schissel M, Smith L, Ashford A, Freese L, McCashland T. A Prospective Multimodal Education Intervention for Providers Does Not Increase Hepatic Encephalopathy Treatment Rates. Dig Dis Sci 2024; 69:1996-2007. [PMID: 38652390 DOI: 10.1007/s10620-024-08445-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 04/09/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Over 50% of hospitalizations from hepatic encephalopathy (HE) are preventable, but patients often do not receive medical treatment. AIMS To use a multimodal education intervention (MMEI) to increase HE treatment rates and to evaluate (1) trends in HE treatment, (2) predictors of receiving treatment, and (3) the impact of treatment on hospitalization outcomes. METHODS Prospective single-center cohort study of patients hospitalized with HE from April 1, 2020-September 30, 2022. The first 15 months were a control ("pre-MMEI"), the subsequent 15 months (MMEI) included three phases: (1) prior authorization resources, (2) electronic order set, and (3) in-person provider education. Treatment included receiving any drug (lactulose or rifaximin), or combination therapy. Treatment rates pre- vs. post-MMEI were compared using logistic regression. RESULTS 471 patients were included. There were lower odds of receiving any drug post-MMEI (p = 0.03). There was no difference in receiving combination therapy pre- or post-MMEI (p = 0.32). Predictors of receiving any drug included alcohol-related or cryptogenic cirrhosis (p's < 0.001), and the presence of ascites (p = 0.005) and/or portal hypertension (p = 0.003). The only significant predictor of not receiving any drug treatment was having autoimmune cirrhosis (p < 0.001). Patients seen by internal medicine (p = 0.01) or who were intoxicated (p = 0.02) were less likely to receive rifaximin. Any treatment was associated with higher 30-day liver disease-specific readmission (p < 0.001). CONCLUSION This MMEI did not increase HE treatment rates, suggesting that alternative strategies are needed to identify and address barriers to treatment.
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Affiliation(s)
- Patrick A Twohig
- Division of Gastroenterology & Hepatology, University of Nebraska Medical Center, 982000 Medical Center Drive, Omaha, NE, 68198-2000, USA.
| | - Thoetchai Bee Peeraphatdit
- Division of Gastroenterology & Hepatology, University of Nebraska Medical Center, 982000 Medical Center Drive, Omaha, NE, 68198-2000, USA
| | - Kaeli Samson
- Department of Biostatistics, University of Nebraska Medical Center, 984375 Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Makayla Schissel
- Department of Biostatistics, University of Nebraska Medical Center, 984375 Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Lynette Smith
- Department of Biostatistics, University of Nebraska Medical Center, 984375 Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Allison Ashford
- Departments of Internal Medicine & Hospital Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Laura Freese
- Departments of Internal Medicine & Hospital Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Timothy McCashland
- Department of Biostatistics, University of Nebraska Medical Center, 984375 Nebraska Medical Center, Omaha, NE, 68198, USA
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19
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Ge J, Buenaventura A, Berrean B, Purvis J, Fontil V, Lai JC, Pletcher MJ. Applying human-centered design to the construction of a cirrhosis management clinical decision support system. Hepatol Commun 2024; 8:e0394. [PMID: 38407255 PMCID: PMC10898661 DOI: 10.1097/hc9.0000000000000394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 12/13/2023] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND Electronic health record (EHR)-based clinical decision support is a scalable way to help standardize clinical care. Clinical decision support systems have not been extensively investigated in cirrhosis management. Human-centered design (HCD) is an approach that engages with potential users in intervention development. In this study, we applied HCD to design the features and interface for a clinical decision support system for cirrhosis management, called CirrhosisRx. METHODS We conducted technical feasibility assessments to construct a visual blueprint that outlines the basic features of the interface. We then convened collaborative-design workshops with generalist and specialist clinicians. We elicited current workflows for cirrhosis management, assessed gaps in existing EHR systems, evaluated potential features, and refined the design prototype for CirrhosisRx. At the conclusion of each workshop, we analyzed recordings and transcripts. RESULTS Workshop feedback showed that the aggregation of relevant clinical data into 6 cirrhosis decompensation domains (defined as common inpatient clinical scenarios) was the most important feature. Automatic inference of clinical events from EHR data, such as gastrointestinal bleeding from hemoglobin changes, was not accepted due to accuracy concerns. Visualizations for risk stratification scores were deemed not necessary. Lastly, the HCD co-design workshops allowed us to identify the target user population (generalists). CONCLUSIONS This is one of the first applications of HCD to design the features and interface for an electronic intervention for cirrhosis management. The HCD process altered features, modified the design interface, and likely improved CirrhosisRx's overall usability. The finalized design for CirrhosisRx proceeded to development and production and will be tested for effectiveness in a pragmatic randomized controlled trial. This work provides a model for the creation of other EHR-based interventions in hepatology care.
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Affiliation(s)
- Jin Ge
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California—San Francisco, San Francisco, California, USA
| | - Ana Buenaventura
- School of Medicine Technology Services, University of California—San Francisco, San Francisco, California, USA
| | - Beth Berrean
- School of Medicine Technology Services, University of California—San Francisco, San Francisco, California, USA
| | - Jory Purvis
- School of Medicine Technology Services, University of California—San Francisco, San Francisco, California, USA
| | - Valy Fontil
- Family Health Centers, NYU-Langone Medical Center, Brooklyn, New York, USA
| | - Jennifer C. Lai
- Department of Medicine, Division of Gastroenterology and Hepatology, University of California—San Francisco, San Francisco, California, USA
| | - Mark J. Pletcher
- Department of Epidemiology and Biostatistics, University of California—San Francisco, San Francisco, California, USA
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20
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Elhence H, Dodge JL, Lee BP. Association of Renin-Angiotensin System Inhibition With Liver-Related Events and Mortality in Compensated Cirrhosis. Clin Gastroenterol Hepatol 2024; 22:315-323.e17. [PMID: 37495200 PMCID: PMC11232660 DOI: 10.1016/j.cgh.2023.07.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/26/2023] [Accepted: 07/13/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND & AIMS While renin-angiotensin system inhibition lowers the hepatic venous gradient, the effect on more clinically meaningful endpoints is less studied. We aimed to quantify the relationship between renin-angiotensin system inhibition and liver-related events (LREs) among adults with compensated cirrhosis. METHODS In this national cohort study using the Optum database, we quantified the association between angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) use and LREs (hepatocellular carcinoma, liver transplantation, ascites, hepatic encephalopathy, or variceal bleeding) among patients with cirrhosis between 2009 and 2019. Selective beta-blocker (SBB) users served as the comparator group. We used demographic and clinical features to calculate inverse-probability treatment weighting-weighted cumulative incidences, absolute risk differences, and Cox proportional hazard ratios. RESULTS Among 4214 adults with cirrhosis, 3155 were ACE inhibitor/ARB users and 1059 were SBB users. In inverse probability treatment weighting-weighted analyses, ACE inhibitor/ARB (vs SBB) users had lower 5-year cumulative incidence (30.6% [95% confidence interval (CI), 27.8% to 33.2%] vs 41.3% [95% CI, 34.0% to 47.7%]; absolute risk difference, -10.7% [95% CI, -18.1% to -3.6%]) and lower risk of LREs (adjusted hazard ratio [aHR], 0.69; 95% CI, 0.60 to 0.80). There was a dose-response relationship: compared with SBB use, ACE inhibitor/ARB prescriptions ≥1 defined daily dose (aHR, 0.65; 95% CI, 0.56 to 0.76) were associated with a greater risk reduction compared with <1 defined daily dose (aHR, 0.87; 95% CI, 0.71 to 1.07). Results were robust across sensitivity analyses such as comparing ACE inhibitor/ARB users with nonusers and as-treated analysis. CONCLUSIONS In this national cohort study, ACE inhibitor/ARB use was associated with significantly lower risk of LREs in patients with compensated cirrhosis. These results provide support for a randomized clinical trial to confirm clinical benefit.
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Affiliation(s)
- Hirsh Elhence
- Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Jennifer L Dodge
- Department of Population Public Health Sciences, University of Southern California, Los Angeles, Los Angeles, California; Division of Gastroenterology and Liver Diseases, University of Southern California, Los Angeles, California
| | - Brian P Lee
- Division of Gastroenterology and Liver Diseases, University of Southern California, Los Angeles, California.
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21
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Nady R, Ahmed RR, Moustafa N, Abdul-Hamid M. TNF-α blockage by etanercept restores spatial learning and reduces cellular degeneration in the hippocampus during liver cirrhosis. Tissue Cell 2023; 85:102249. [PMID: 37865039 DOI: 10.1016/j.tice.2023.102249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 09/29/2023] [Accepted: 10/16/2023] [Indexed: 10/23/2023]
Abstract
Hepatic encephalopathy (HE) is one of the most debilitating cerebral complications of liver cirrhosis. The one-year survival of patients with liver cirrhosis and severe encephalopathy is less than 50%. Recent studies have indicated that neuroinflammation is a new player in the pathogenesis of HE, which seems to be involved in the development of cognitive impairment. In this study, we demonstrated neurobehavioral and neuropathological consequences of liver cirrhosis and tested the therapeutic potential of the tumor necrosis factor-α (TNF-α) inhibitor, etanercept. Sixty male adult Wistar albino rats (120-190 g) were allocated into four groups, where groups I and IV served as controls. Thioacetamide (TAA; 300 mg/kg) was intraperitoneally injected twice a week for five months to induce liver cirrhosis in group II (n = 20). Both TAA and etanercept (2 mg/kg) were administered to group III (n = 20). At the end of the experiment, spatial learning was assessed using Morris water maze. TNF-α was detected in both serum and hippocampus. The excised brains were also immunohistochemically stained with glial fibrillary acidic protein (GFAP) to estimate both the number and integrity of hippocampal astrocytes. Ultrastructural changes in the hippocampus were characterized by transmission electron microscopy. The results showed that blocking TNF-α by etanercept was accompanied by a lower TNF-α expression and a higher number of GFAP-positive astrocytes in the hippocampus. Etanercept intervention alleviated the neuronal and glial degenerative changes and impeded the deterioration of spatial learning ability. In conclusion, TNF-α is strongly involved in the development of liver cirrhosis and the associated encephalopathy. TNF-α blockers may be a promising approach for management of hepatic cirrhosis and its cerebral complications.
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Affiliation(s)
- Rehab Nady
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni Suef 62511, Egypt
| | - Rasha R Ahmed
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni Suef 62511, Egypt
| | - Nadia Moustafa
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni Suef 62511, Egypt
| | - Manal Abdul-Hamid
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni Suef 62511, Egypt.
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Ward JA, Yerke J, Lumpkin M, Kapoor A, Lindenmeyer CC, Bass S. Evaluation of a protocol for rifaximin discontinuation in critically ill patients with liver disease receiving broad-spectrum antibiotic therapy. World J Hepatol 2023; 15:1226-1236. [DOI: 10.4254/wjh.v15.i11.1226] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 09/05/2023] [Accepted: 10/23/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Rifaximin is frequently administered to critically ill patients with liver disease and hepatic encephalopathy, but patients currently or recently treated with antibiotics were frequently excluded from studies of rifaximin efficacy. Due to overlapping spectrums of activity, combination therapy with broad-spectrum antibiotics and rifaximin may be unnecessary. A pharmacist-driven protocol was piloted to reduce potentially overlapping therapy in critically ill patients with liver disease. It was hypothesized that withholding rifaximin during broad-spectrum antibiotic therapy would be safe and reduce healthcare costs.
AIM To determine the clinical, safety, and financial impact of discontinuing rifaximin during broad-spectrum antibiotic therapy in critically ill liver patients.
METHODS This was a single-center, quasi-experimental, pre-post study based on a pilot pharmacist-driven protocol. Patients in the protocol group were prospectively identified via the medical intensive care unit (ICU) (MICU) protocol to have rifaximin withheld during broad-spectrum antibiotic treatment. These were compared to a historical cohort who received combination therapy with broad-spectrum antibiotics and rifaximin. All data were collected retrospectively. The primary outcome was days alive and free of delirium and coma (DAFD) to 14 d. Safety outcomes included MICU length of stay, 48-h change in vasopressor dose, and ICU mortality. Secondary outcomes characterized rifaximin cost savings and protocol adherence. Multivariable analysis was utilized to evaluate the association between group assignment and the primary outcome while controlling for potential confounding factors.
RESULTS Each group included 32 patients. The median number of delirium- and coma-free days was similar in the control and protocol groups [3 interquartile range (IQR 0, 8) vs 2 (IQR 0, 9.5), P = 0.93]. In multivariable analysis, group assignment was not associated with a reduced ratio of days alive and free of delirium or coma at 14 d. The protocol resulted in a reduced median duration of rifaximin use during broad-spectrum antibiotic therapy [6 d control (IQR 3, 9.5) vs 1 d protocol (IQR 0, 1); P < 0.001]. Rates of other secondary clinical and safety outcomes were similar including ICU mortality and 48-h change in vasopressor requirements. Overall adherence to the protocol was 91.4%. The median estimated total cost of rifaximin therapy per patient was reduced from $758.40 (IQR $379.20, $1200.80) to $126.40 (IQR $0, $126.40), P < 0.01.
CONCLUSION The novel pharmacist-driven protocol for rifaximin discontinuation was associated with significant cost savings and no differences in safety outcomes including DAFD.
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Affiliation(s)
- Jessica A Ward
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Jason Yerke
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Mollie Lumpkin
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Aanchal Kapoor
- Department of Critical Care Medicine, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Christina C Lindenmeyer
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Stephanie Bass
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
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Bloom PP, Tapper EB. Lactulose in cirrhosis: Current understanding of efficacy, mechanism, and practical considerations. Hepatol Commun 2023; 7:e0295. [PMID: 37820287 PMCID: PMC10578757 DOI: 10.1097/hc9.0000000000000295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 09/04/2023] [Indexed: 10/13/2023] Open
Abstract
HE is a complication of cirrhosis characterized by neuropsychiatric and motor dysfunction, and results in decreased quality of life and increased mortality. Lactulose is a synthetic disaccharide used to treat HE since 1966, though many questions about its use remain unanswered. Lactulose reverses minimal HE, prevents overt HE, improves quality of life, increases the rate of recovery from overt HE, and improves survival rates. Lactulose's clinical effect appears to be derived from its impact on intestinal microbes, likely a result of its enteric acidifying effect, positive pressure on beneficial taxa, and improvement of gut barrier function. There are several practical considerations with lactulose including (1) a need to avoid excessive bowel movements and subsequent dehydration, (2) treatment titration protocols need further investigation, (3) baseline or treatment-induced gastrointestinal side effects limit adherence in some cases, and (4) the utility of monitoring stool consistency or pH remains unknown. Further research is needed to optimize our use of this effective treatment for HE.
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Aby ES, Shen TH, Murugappan MN, Stenehjem DD, Leventhal TM. High rifaximin out-of-pocket costs are associated with decreased treatment retention among patients with hepatic encephalopathy. Hepatol Commun 2023; 7:e0215. [PMID: 37534941 PMCID: PMC10553020 DOI: 10.1097/hc9.0000000000000215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 06/07/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND AND AIMS Hepatic encephalopathy (HE) is associated with significant morbidity and mortality for those with cirrhosis. Despite the known benefits of rifaximin use for HE, treatment retention remains low. This study aimed to evaluate the impact of out-of-pocket (OOP) rifaximin cost on treatment retention among commercially insured patients in the United States. METHODS Adult patients with cirrhosis and HE were identified from the IBM MarketScan claims database. Those who began rifaximin treatment between January 1, 2011, and December 1, 2021 were included. Regression models were used to analyze the relationship between patients' 30-day OOP rifaximin cost and rifaximin retention (≥80% eligible days with rifaximin supply) at 180, 360, and 540 days. Models were controlled for patient demographic and clinical characteristics including age, sex, comorbid conditions, Charlson comorbidity index (CCI), and lactulose use. RESULTS A total of 6839 adult patients were included. Most patients were between 55 and 64 years (57.1%), male (60.4%), and living in urban settings (84.6%). Treatment retention was low for all time periods; retention rates for rifaximin were 42%, 25%, and 16% at 180, 360, and 540 days, respectively. In multivariable analysis, 30-day OOP costs of ≥ $150 were associated with a decreased likelihood of rifaximin retention at 180, 360, and 540 days [relative risk (RR) = 0.67, RR = 0.62, and R = 0.60, respectively]. Younger age was associated with reduced treatment retention for all time periods. Metastatic cancer and depression were associated with reduced treatment retention at 180 days (RR = 0.70 and RR = 0.87, respectively). CONCLUSIONS Rates of rifaximin treatment retention are low despite the known benefits of rifaximin use for breakthrough HE. High 30-day OOP cost is associated with reduced rifaximin treatment retention.
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Affiliation(s)
- Elizabeth S. Aby
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
| | - Tsung-Hua Shen
- Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota, College of Pharmacy, Minneapolis, Minnesota, USA
| | - Meena N. Murugappan
- Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota, College of Pharmacy, Minneapolis, Minnesota, USA
| | - David D. Stenehjem
- Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota, College of Pharmacy, Minneapolis, Minnesota, USA
| | - Thomas M. Leventhal
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
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25
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Zacharias HD, Kamel F, Tan J, Kimer N, Gluud LL, Morgan MY. Rifaximin for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2023; 7:CD011585. [PMID: 37467180 PMCID: PMC10360160 DOI: 10.1002/14651858.cd011585.pub2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/21/2023]
Abstract
BACKGROUND Hepatic encephalopathy describes the spectrum of neuropsychiatric changes that may complicate the course of cirrhosis and detrimentally affect outcomes. Ammonia plays a key role in its development. Rifaximin is a non-absorbable antibiotic that inhibits urease-producing bacteria and reduces absorption of dietary and bacterial ammonia. OBJECTIVES To evaluate the beneficial and harmful effects of rifaximin versus placebo, no intervention, or non-absorbable disaccharides for: (i) the prevention of hepatic encephalopathy, and (ii) the treatment of minimal and overt hepatic encephalopathy, in people with cirrhosis, both when used alone and when combined with a non-absorbable disaccharide. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Clinical Trials Register, CENTRAL, MEDLINE, Embase, three other databases, the reference lists of identified papers, and relevant conference proceedings. We wrote to authors and pharmaceutical companies for information on other published, unpublished, or ongoing trials. Searches were performed to January 2023. SELECTION CRITERIA We included randomised clinical trials assessing prevention or treatment of hepatic encephalopathy with rifaximin alone, or with a non-absorbable disaccharide, versus placebo/no intervention, or a non-absorbable disaccharide alone. DATA COLLECTION AND ANALYSIS Six authors independently searched for studies, extracted data, and validated findings. We assessed the design, bias risk, and participant/intervention characteristics of the included studies. We assessed mortality, serious adverse events, health-related quality of life, hepatic encephalopathy, non-serious adverse events, blood ammonia, Number Connection Test-A, and length of hospital stay. MAIN RESULTS We included 41 trials involving 4545 people with, or at risk for, developing hepatic encephalopathy. We excluded 89 trials and identified 13 ongoing studies. Some trials involved participants with more than one type of hepatic encephalopathy or more than one treatment comparison. Hepatic encephalopathy was classed as acute (13 trials), chronic (7 trials), or minimal (8 trials), or else participants were considered at risk for its development (13 trials). The control groups received placebo (12 trials), no/standard treatment (1 trial), or a non-absorbable disaccharide (14 trials). Eighteen trials assessed rifaximin plus a non-absorbable disaccharide versus a non-absorbable disaccharide alone. We classified 11 trials as at high risk of overall bias for mortality and 28 for non-mortality outcomes, mainly due to lack of blinding, incomplete outcome data, and selective reporting. Compared to placebo/no intervention, rifaximin likely has no overall effect on mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.50 to 1.38; P = 48, I2 = 0%; 13 trials, 1007 participants; moderate-certainty evidence), and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.99, 95% CI 0.49 to 1.97; P = 0.97, I2 = 0%; 10 trials, 786 participants; low-certainty evidence). However, there is likely a reduction in the overall risk of mortality when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.69, 95% CI 0.55 to 0.86; number needed to treat for an additional beneficial outcome (NNTB) = 22; P = 0.001, I2 = 0%; 14 trials, 1946 participants; moderate-certainty evidence). There is likely no effect on the overall risk of serious adverse events when comparing rifaximin to placebo/no intervention (RR 1.05, 95% CI 0.83 to 1.32; P = 68, I2 = 0%; 9 trials, 801 participants; moderate-certainty evidence) and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.97, 95% CI 0.66 to 1.40; P = 85, I2 = 0%; 8 trials, 681 participants; low-certainty evidence). However, there was very low-certainty evidence that use of rifaximin plus a non-absorbable disaccharide may be associated with a lower risk of serious adverse events than use of a non-absorbable disaccharide alone (RR 0.66, 95% CI 0.45 to 0.98; P = 0.04, I2 = 60%; 7 trials, 1076 participants). Rifaximin likely results in an overall effect on health-related quality of life when compared to placebo/no intervention (mean difference (MD) -1.43, 95% CI -2.87 to 0.02; P = 0.05, I2 = 81%; 4 trials, 214 participants; moderate-certainty evidence), and may benefit health-related quality of life in people with minimal hepatic encephalopathy (MD -2.07, 95% CI -2.79 to -1.35; P < 0.001, I2 = 0%; 3 trials, 176 participants). The overall effect on health-related quality of life when comparing rifaximin to non-absorbable disaccharides is very uncertain (MD -0.33, 95% CI -1.65 to 0.98; P = 0.62, I2 = 0%; 2 trials, 249 participants; very low-certainty evidence). None of the combined rifaximin/non-absorbable disaccharide trials reported on this outcome. There is likely an overall beneficial effect on hepatic encephalopathy when comparing rifaximin to placebo/no intervention (RR 0.56, 95% CI 0.42 to 0.77; NNTB = 5; P < 0.001, I2 = 68%; 13 trials, 1009 participants; moderate-certainty evidence). This effect may be more marked in people with minimal hepatic encephalopathy (RR 0.40, 95% CI 0.31 to 0.52; NNTB = 3; P < 0.001, I2 = 10%; 6 trials, 364 participants) and in prevention trials (RR 0.71, 95% CI 0.56 to 0.91; NNTB = 10; P = 0.007, I2 = 36%; 4 trials, 474 participants). There may be little overall effect on hepatic encephalopathy when comparing rifaximin to non-absorbable disaccharides (RR 0.85, 95% CI 0.69 to 1.05; P = 0.13, I2 = 0%; 13 trials, 921 participants; low-certainty evidence). However, there may be an overall beneficial effect on hepatic encephalopathy when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.58, 95% CI 0.48 to 0.71; NNTB = 5; P < 0.001, I2 = 62%; 17 trials, 2332 participants; low-certainty evidence). AUTHORS' CONCLUSIONS Compared to placebo/no intervention, rifaximin likely improves health-related quality of life in people with minimal hepatic encephalopathy, and may improve hepatic encephalopathy, particularly in populations with minimal hepatic encephalopathy and when it is used for prevention. Rifaximin likely has no overall effect on mortality, serious adverse events, health-related quality of life, or hepatic encephalopathy compared to non-absorbable disaccharides. However, when used in combination with a non-absorbable disaccharide, it likely reduces overall mortality risk, the risk of serious adverse events, improves hepatic encephalopathy, reduces the length of hospital stay, and prevents the occurrence/recurrence of hepatic encephalopathy. The certainty of evidence for these outcomes is very low to moderate; further high-quality trials are needed.
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Affiliation(s)
- Harry D Zacharias
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Fady Kamel
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Jaclyn Tan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Nina Kimer
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Lise Lotte Gluud
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
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26
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Dutta N, Kc M, Wang Q, Lim N. Impact of Gastroenterology Consultation on the Clinical Outcomes of Patients Admitted With Hepatic Encephalopathy. Cureus 2023; 15:e41610. [PMID: 37565113 PMCID: PMC10409643 DOI: 10.7759/cureus.41610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2023] [Indexed: 08/12/2023] Open
Abstract
Introduction Hepatic encephalopathy (HE) is a common complication of cirrhosis and a common reason for hospital admission. We aimed to determine whether expert consultation from gastroenterology (GI) leads to better clinical outcomes for inpatients with HE. Methods A retrospective review was performed of all adult patients (age ≥ 18) admitted with HE to a tertiary care hospital between January 2013 and April 2018. Patients who received a GI consult were compared to patients who did not receive a GI consult (No consult group). The primary outcome was hospital length of stay (LOS); secondary outcomes were rates of 30-day hospital readmission and 90-day mortality. Multivariate analysis was conducted to adjust for known confounders. Results Four hundred and twenty-five patients (814 encounters) were included in the study; of these, 236 patients had received a GI consultation for HE. Patients in the GI consult group were younger (mean age 55 vs 58 years, p= 0.02) and had higher Model For End-Stage Liver Disease-sodium (MELD-Na) score (mean MELD-Na 23.5 vs 17.5, p<0.01) compared to patients who did not receive GI consultation. The precipitants of HE were significantly different between the groups: there was more spontaneous bacterial peritonitis (SBP) and GI bleeding (GIB) in the GI consult group and more lactulose non-adherence in the no consult group. There was no difference in the etiology of liver disease between the two groups. Median LOS for the GI consult group was six days vs three days in the no consult group (p<0.01); the incidence rate ratio was 1.79 (95%CI 1.59-2.02, p<0.01) on multivariate analysis. There was no difference in 30-day readmission or 90-day mortality between the two groups. Conclusion GI consultation for patients with HE admitted to a hospital medicine service may be associated with longer LOS. In selected patients admitted with HE, GI consultation may not be necessary to achieve good clinical outcomes.
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Affiliation(s)
- Nirjhar Dutta
- Division of Hospital Medicine, University of Minnesota, Minneapolis, USA
| | - Mandip Kc
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, USA
| | - Qi Wang
- Clinical and Translational Science Institute, University of Minnesota, Minneapolis, USA
| | - Nicholas Lim
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, USA
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27
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Ismond KP, Spiers JA, Tandon P. Identifying opportunities for hepatic encephalopathy self-management: A mixed methods systematic review and synthesis. CANADIAN LIVER JOURNAL 2023; 6:215-233. [PMID: 37503524 PMCID: PMC10370725 DOI: 10.3138/canlivj-2022-0025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 08/20/2022] [Indexed: 07/29/2023]
Abstract
Background Hepatic encephalopathy (HE) in cirrhosis is an extremely challenging complication for patients and care partners. To identify potentially modifiable factors to enhance HE self-management strategies, we conducted a synthesis of quantitative and qualitative research about real-world HE behaviours, knowledge, and experiences. Methods Using the EPPI-Centre's mixed methods synthesis procedure, a systematic literature search in five databases was completed; methods of selected articles underwent critical appraisal followed by descriptive analysis and coded line-by-line of content. Through refutational translation, the findings from the quantitative and qualitative syntheses were juxtaposed to highlight congruencies, incongruencies, or gaps. These findings informed generation of cross-analytical themes that were transformed into action statements. Results The quantitative narrative review of synthesis (n = 17) generated four themes (patients had low awareness of HE and low treatment adherence rates, physicians had a non-uniform approach to non-pharmaceutical therapies). Meta-aggregation of qualitative data from six articles yielded three themes (patients and care partners had low levels of HE awareness, were unfamiliar with HE self-management, and were adherent to treatments). Comparison of findings revealed three congruencies, two gaps, and one incongruency. The combined synthesis yielded two self-management themes: universal patient-oriented cirrhosis HE education and ensuring each health care encounter systematically addresses HE to guarantee health care is continuously modified to meet their needs. Conclusions By drawing on elements of Bloom's Taxonomy and distributed knowledge networks, deliberate patient-oriented HE messaging at all health care encounters is greatly needed to improve health outcomes and reduce care burdens related to HE.
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Affiliation(s)
- Kathleen P Ismond
- Division of Gastroenterology, Liver Unit, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Jude A Spiers
- Faculty of Nursing, University of Alberta, Edmonton, Alberta, Canada
| | - Puneeta Tandon
- Division of Gastroenterology, Liver Unit, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
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28
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Abstract
Importance Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9 per 100 000 people. Observations The most common causes of cirrhosis in the US, which can overlap, include alcohol use disorder (approximately 45% of all cases of cirrhosis), nonalcoholic fatty liver disease (26%), and hepatitis C (41%). Patients with cirrhosis experience symptoms including muscle cramps (approximately 64% prevalence), pruritus (39%), poor-quality sleep (63%), and sexual dysfunction (53%). Cirrhosis can be diagnosed by liver biopsy but may also be diagnosed noninvasively. Elastography, a noninvasive assessment of liver stiffness measured in kilopascals, can typically confirm cirrhosis at levels of 15 kPa or greater. Approximately 40% of people with cirrhosis are diagnosed when they present with complications such as hepatic encephalopathy or ascites. The median survival time following onset of hepatic encephalopathy and ascites is 0.92 and 1.1 years, respectively. Among people with ascites, the annual incidence of spontaneous bacterial peritonitis is 11% and of hepatorenal syndrome is 8%; the latter is associated with a median survival of less than 2 weeks. Approximately 1% to 4% of patients with cirrhosis develop hepatocellular carcinoma each year, which is associated with a 5-year survival of approximately 20%. In a 3-year randomized clinical trial of 201 patients with portal hypertension, nonselective β-blockers (carvedilol or propranolol) reduced the risk of decompensation or death compared with placebo (16% vs 27%). Compared with sequential initiation, combination aldosterone antagonist and loop diuretics were more likely to resolve ascites (76% vs 56%) with lower rates of hyperkalemia (4% vs 18%). In meta-analyses of randomized trials, lactulose was associated with reduced mortality relative to placebo (8.5% vs 14%) in randomized trials involving 705 patients and reduced risk of recurrent overt hepatic encephalopathy (25.5% vs 46.8%) in randomized trials involving 1415 patients. In a randomized clinical trial of 300 patients, terlipressin improved the rate of reversal of hepatorenal syndrome from 39% to 18%. Trials addressing symptoms of cirrhosis have demonstrated efficacy for hydroxyzine in improving sleep dysfunction, pickle brine and taurine for reducing muscle cramps, and tadalafil for improving sexual dysfunction in men. Conclusions and Relevance Approximately 2.2 million US adults have cirrhosis. Many symptoms, such as muscle cramps, poor-quality sleep, pruritus, and sexual dysfunction, are common and treatable. First-line therapies include carvedilol or propranolol to prevent variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists and loop diuretics for ascites, and terlipressin for hepatorenal syndrome.
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Affiliation(s)
- Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor
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29
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Díaz LA, Pages J, Mainardi V, Mendizabal M. Inpatient Hepatology Consultation: A Practical Approach for Clinicians. Med Clin North Am 2023; 107:555-565. [PMID: 37001953 DOI: 10.1016/j.mcna.2023.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
Cirrhosis is the end-stage of chronic liver disease and constitutes a leading cause of potential years of working life lost, especially in the Americas and Europe. Its natural history is characterized by an asymptomatic phase called compensated cirrhosis, followed by a rapidly progressive phase characterized by liver-related complications termed decompensated cirrhosis. Complications could be related to portal hypertension and/or liver dysfunction, including ascites, portal hypertensive gastrointestinal bleeding, encephalopathy, and jaundice. This review will discuss some of the most important precipitants of hepatic decompensation, including acute variceal bleeding, spontaneous bacterial peritonitis, and hepatic encephalopathy.
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Affiliation(s)
- Luis Antonio Díaz
- Department of Gastroenterology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Josefina Pages
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Provincia de Buenos Aires, Argentina
| | - Victoria Mainardi
- Hepatology and Liver Transplant Unit, Hospital Central de Las Fuerzas Armadas, Montevideo, Uruguay
| | - Manuel Mendizabal
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Provincia de Buenos Aires, Argentina.
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30
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Paik JM, Eberly KE, Kabbara K, Harring M, Younossi Y, Henry L, Verma M, Younossi ZM. Non-alcoholic fatty liver disease is associated with greater risk of 30-day hospital readmission in the United States (U.S.). Ann Hepatol 2023; 28:101108. [PMID: 37088421 DOI: 10.1016/j.aohep.2023.101108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/30/2023] [Accepted: 04/14/2023] [Indexed: 04/25/2023]
Abstract
INTRODUCTION AND OBJECTIVES Data about 30-day readmission for patients with chronic liver disease (CLD) and their contribution to CLD healthcare burden are sparse. Patterns, diagnoses, timing and predictors of 30-day readmissions for CLD from 2010-2017 were assessed. MATERIALS AND METHODS Nationwide Readmission Database (NRD) is an all-payer, all-ages, longitudinal administrative database, representing 35 million discharges in the US population yearly. We identified unique patients discharged with CLD including hepatitis B (HBV) and C (HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) from 2010 through 2017. Survey-weight adjusted multivariable were used. RESULTS From 2010 to 2017, the 30-day readmission rate for CLD decreased from 18.4% to 17.8% (p=.008), while increased for NAFLD from 17.0% to 19. 9% (p<.001). Of 125,019 patients discharged with CLD (mean age 57.4 years, male 59.0%) in 2017, the most common liver disease was HCV (29.2%), followed by ALD (23.5%), NAFLD (17.5%), and HBV (4.3%). Readmission rates were 20.5% for ALD, 19.9% for NAFLD, 16.8% for HCV and 16.7% for HBV. Compared to other liver diseases, patients with NAFLD had significantly higher risk of 30-day readmission in clinical comorbidities adjusted model (Hazard ratio [HR]=1.08 [95% confidence interval 1.03-1.13]). In addition to ascites, hepatic encephalopathy, higher number of coexisting comorbidities, comorbidities associated with higher risk of 30-day readmission included cirrhosis for NALFD and HCV; acute kidney injury for NAFLD, HCV and ALD; HCC for HCV, and peritonitis for ALD. Cirrhosis and cirrhosis-related complications was the most common reason for 30-day readmission, followed by sepsis. However, a large proportion of patients (43.7% for NAFLD; 28.4% for HCV, 39.0% for HBV, and 29.1% for ALD) were readmitted for extrahepatic reasons. Approximately 20% of those discharged with CLD were readmitted within 30 days but the majority of readmissions occurred within 15 days of discharge (62.8% for NAFLD, 63.7% for HCV, 74.3% for HBV, and 72.9% for ALD). Among readmitted patients, patients admitted ≤30-day had significantly higher cost and risk of in-hospital mortality for patients with NAFLD (+5.69% change [95% confidence interval, 2.54%-8.93%] and odds ratio (OR)=1.58 [1.28-1.95]) and HCV (+9.85% change [6.96%-12.82%] and OR=1.31, 1.08-1.59. CONCLUSIONS Early readmissions for CLD are prevalent causing economic and clinical burden to the US healthcare system, especially NAFLD readmissions. Closer surveillance and attention to both liver and extrahepatic medical conditions immediately after CLD discharge is encouraged.
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Affiliation(s)
- James M Paik
- Inova Medicine, Inova Health System, Falls Church, VA, United States; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States
| | - Katherine E Eberly
- Inova Medicine, Inova Health System, Falls Church, VA, United States; Center for Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA, United States
| | - Khaled Kabbara
- Inova Medicine, Inova Health System, Falls Church, VA, United States; Center for Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA, United States
| | - Michael Harring
- Inova Medicine, Inova Health System, Falls Church, VA, United States; Center for Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA, United States
| | - Youssef Younossi
- Center for Outcomes Research in Liver Diseases, Washington DC, United States; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States
| | - Linda Henry
- Center for Outcomes Research in Liver Diseases, Washington DC, United States
| | - Manisha Verma
- Inova Medicine, Inova Health System, Falls Church, VA, United States; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States
| | - Zobair M Younossi
- Inova Medicine, Inova Health System, Falls Church, VA, United States; Center for Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA, United States; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States.
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Jain S, Parrotte S, Anyanwu C, Fairchild AH. Cirrhosis and Sarcopenia. Semin Intervent Radiol 2023; 40:3-8. [PMID: 37152802 PMCID: PMC10159715 DOI: 10.1055/s-0043-1764281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
Sarcopenia is a progressive muscle wasting syndrome involving loss in skeletal muscle mass, strength, and function. It is closely associated with cirrhosis and its complications with up to more than half of cirrhotic patients demonstrating imaging findings of sarcopenia. The pathogenesis of this syndrome remains complex, including multiple factors involved in skeletal muscle homeostasis, systemic inflammation, and energy dysregulation. Many modalities exist in assessing and measuring sarcopenia. The use of cross-sectional imaging, such as computed tomography and magnetic resonance imaging, with accurate and clinically proven assessment software should be considered the gold standard. Sarcopenia has become the focus of ongoing extensive research with initial findings highlighting increased mortality and complication rates in patient with cirrhosis and hepatocellular carcinoma. Additional studies have demonstrated reversal and improved survival in sarcopenic patients who have undergone transjugular intrahepatic portosystemic shunt placement. Thus, accounting for sarcopenia can help risk stratify patients prior to interventional procedures to allow for better outcomes and improved survival.
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Affiliation(s)
- Shivani Jain
- Department of Interventional Radiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Samantha Parrotte
- Department of Interventional Radiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Chikamuche Anyanwu
- Department of Interventional Radiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Alexandra H. Fairchild
- Department of Interventional Radiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
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Jesudian AB, Gagnon-Sanschagrin P, Heimanson Z, Bungay R, Chen J, Guérin A, Bumpass B, Borroto D, Joseph G, Dashputre AA. Impact of rifaximin use following an initial overt hepatic encephalopathy hospitalization on rehospitalization and costs. J Med Econ 2023; 26:1169-1177. [PMID: 37664993 DOI: 10.1080/13696998.2023.2255074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/30/2023] [Accepted: 08/31/2023] [Indexed: 09/05/2023]
Abstract
AIM To assess the impact of rifaximin (± lactulose) use following discharge of an initial overt hepatic encephalopathy (OHE) hospitalization on OHE rehospitalizations and healthcare costs in a real-world setting. METHODS Adults (18-64 years) with an OHE hospitalization were identified from MarketScan® Commercial claims (Q4'15-Q2'20), classified into two mutually exclusive treatment cohorts (i.e. rifaximin and no rifaximin treatment), and further stratified into four subgroups based on decreasing quality of care (QoC; i.e. Type 1 - rifaximin without delay post-discharge; Type 2 - rifaximin with delay post-discharge; Type 3 - lactulose only post-discharge; Type 4 - no rifaximin/lactulose treatment post-discharge). The impact of rifaximin use on 30-day and annualized OHE hospitalizations and healthcare costs were assessed between cohorts and by the QoC subgroup. RESULTS Characteristics were similar between the rifaximin (N = 1,452; Type 1: 1,138, Type 2: 314) and no rifaximin (N = 560; Type 3:337, Type 4: 223) treatment cohorts. The 30-day risk of OHE rehospitalization was lower for the rifaximin vs. no rifaximin treatment cohort (odds ratio 0.56, p < .01) and increased with decreasing QoC. The annual rate of OHE hospitalizations was 59% lower for the rifaximin treatment cohort (incidence rate ratio 0.41, p < .01) and increased with decreasing QoC. Compared to the no rifaximin treatment cohort, the rifaximin treatment cohort had higher pharmacy costs, lower medical costs, and no difference in total healthcare costs. LIMITATIONS This was a claims-based study subject to common data limitations such as billing inaccuracies or omissions in coded claims. Total healthcare costs were reported from a payer's perspective, which do not capture indirect costs associated with patient burden. CONCLUSIONS Initiation of rifaximin after an OHE hospitalization was associated with reduced OHE hospitalizations both in the 30-days following and annually. Further, reduced medical costs offset increased pharmacy costs, and no annual cost differences were observed between cohorts.
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Affiliation(s)
- Arun B Jesudian
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA
| | | | | | | | | | | | | | | | - George Joseph
- Bausch Health, Bridgewater, NJ, USA
- BioNTech US Inc, Cambridge, MA, USA
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Aspinall RJ, Hudson M, Ryder SD, Richardson P, Farrington E, Wright M, Przemioslo RT, Perez F, Kent M, Henrar R, Hickey J, Shawcross DL. Real-world evidence of long-term survival and healthcare resource use in patients with hepatic encephalopathy receiving rifaximin-α treatment: a retrospective observational extension study with long-term follow-up (IMPRESS II). Frontline Gastroenterol 2022; 14:228-235. [PMID: 37056320 PMCID: PMC10086718 DOI: 10.1136/flgastro-2022-102221] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 10/02/2022] [Indexed: 11/12/2022] Open
Abstract
Objective To describe survival of patients with hepatic encephalopathy (HE), up to 5 years after initiation of rifaximin-α (RFX) treatment. Design/Method A retrospective, observational extension study within 9 National Health Service secondary/tertiary UK care centres. All patients had a clinical diagnosis of HE, were being treated with RFX and were included in the previous IMPRESS study which reported the 1-year experience. Demographics, clinical outcomes, selected cirrhosis-related complications, hospital admissions and attendances up to 5 years from RFX initiation were extracted from patient medical records and hospital electronic databases. The primary outcome measure was survival at 5 years post-initiation of RFX treatment. Results The study included 138 patients. The survival rate at 5 years post-initiation of RFX was 35% (95% CI 28.2% to 44.4%) overall and 36% (95% CI 26.1% to 45.4%) for patients with alcohol-related liver disease. Median survival from RFX initiation was 2.8 years (95% CI 2.0 to 3.8; n=136). Among 48 patients alive at 5 years, 69% remained on RFX treatment at the end of the observation period, 74% reported no cirrhosis-related complications and 24% (9/37) had received a liver transplant. Between 1 and 5 years post-initiation, total numbers of liver-related emergency department visits, inpatient admissions, intensive care unit admissions and outpatient visits were 84, 194, 3 and 709, respectively; the liver-related 30-day readmission rate was 37%. Conclusion Within UK clinical practice, RFX use in HE was associated with a 35% survival rate with high treatment adherence, 76% transplant-free survival rate, minimal healthcare resource and low rates of complications at 5 years post-initiation.
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Affiliation(s)
- Richard J Aspinall
- Department of Gastroenterology & Hepatology, Portsmouth Hospitals University NHS Trust, Portsmouth, UK
| | - Mark Hudson
- Formerly Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK
| | - Stephen D Ryder
- NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Paul Richardson
- Department of Gastroenterology and Hepatology, Royal Liverpool & Broadgreen University Hospitals NHS Trust, Liverpool, UK
| | - Elizabeth Farrington
- Department of Gastroenterology & Hepatology, Royal Cornwall Hospital, Cornwall, UK
| | - Mark Wright
- Department of Hepatology, University Hospital Southampton, Southampton, UK
| | | | - Francisco Perez
- Department of Gastroenterology, University Hospital of North Durham, Durham, UK
| | - Melanie Kent
- Department of Gastroenterology, University Hospital of North Durham, Durham, UK
| | | | | | - Debbie L Shawcross
- Institute of Liver Studies, Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
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Liu YB, Chen MK. Epidemiology of liver cirrhosis and associated complications: Current knowledge and future directions. World J Gastroenterol 2022; 28:5910-5930. [PMID: 36405106 PMCID: PMC9669831 DOI: 10.3748/wjg.v28.i41.5910] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 09/30/2022] [Accepted: 10/19/2022] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis causes a heavy global burden. In this review, we summarized up-to-date epidemiological features of cirrhosis and its complications. Recent epidemiological studies reported an increase in the prevalence of cirrhosis in 2017 compared to in 1990 in both men and women, with 5.2 million cases of cirrhosis and chronic liver disease occurring in 2017. Cirrhosis caused 1.48 million deaths in 2019, an increase of 8.1% compared to 2017. Disability-adjusted life-years due to cirrhosis ranked 16th among all diseases and 7th in people aged 50-74 years in 2019. The global burden of hepatitis B virus and hepatitis C virus-associated cirrhosis is decreasing, while the burden of cirrhosis due to alcohol and nonalcoholic fatty liver disease (NAFLD) is increasing rapidly. We described the current epidemiology of the major complications of cirrhosis, including ascites, variceal bleeding, hepatic encephalopathy, renal disorders, and infections. We also summarized the epidemiology of hepatocellular carcinoma in patients with cirrhosis. In the future, NAFLD-related cirrhosis will likely become more common due to the prevalence of metabolic diseases such as obesity and diabetes, and the prevalence of alcohol-induced cirrhosis is increasing. This altered epidemiology should be clinically noted, and relevant interventions should be undertaken.
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Affiliation(s)
- Yuan-Bin Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei Province, China
| | - Ming-Kai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei Province, China
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35
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Tapper EB, Zhao Z, Mazumder N, Parikh ND. Incidence of, Risk Factors for, and Outcomes After Ascites in a Population-Based Cohort of Older Americans. Dig Dis Sci 2022; 67:5327-5335. [PMID: 35262903 PMCID: PMC10905652 DOI: 10.1007/s10620-022-07454-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/14/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND The incidence of, risk factors for, and outcomes after the development of ascites are poorly described for contemporary patients with cirrhosis. METHODS We examined data for a 20% random sample of US Medicare enrollees with cirrhosis and Part D prescription coverage from 2008 to 2019, excluding patients with heart failure and diuretic use prior to cirrhosis. Among 63,364 persons with cirrhosis, we evaluated the incidence of ascites using an Aalen-Johansen estimator. We evaluated risk factors for ascites, mortality, and mortality after ascites using multistate modeling. We determined the associations with each outcome for an array of medication exposures including nonselective beta-blockers, antiviral therapy, statins, rifaximin, anticoagulants, and metformin. RESULTS The cumulative incidence of ascites was 5.1%, 9.5%, and 10.7% and 1, 3, and 5 years overall. The corresponding data for ascites requiring paracentesis were 1%, 2.1%, and 2.4%. Persons aged < 65 years, with alcohol-related cirrhosis, varices, or HE, are most likely to develop ascites. The risk of ascites was higher for persons taking any NSBB (including carvedilol) but lower for those taking atorvastatin (but not other statins) and antiviral therapy for Hepatitis C. Incident ascites was associated with increased risk of death, HR 27.6 95%CI(21.7-35.1). Survival following ascites was 1.08 years (interquartile range, IQR, 0.26-2.75), 0.38 years (IQR0.1-1.3) for those requiring paracentesis. Lipophilic statins were the only medications associated with lower mortality after ascites requiring paracentesis. CONCLUSIONS Ascites is associated with a high risk of death. Very few candidate therapies are associated with the reduction in the risk of ascites and mortality after ascites development.
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Affiliation(s)
- Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, 3912 Taubman, SPC 5362, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA.
| | - Zhe Zhao
- Division of Gastroenterology and Hepatology, University of Michigan, 3912 Taubman, SPC 5362, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA
| | - Nik Mazumder
- Division of Gastroenterology and Hepatology, University of Michigan, 3912 Taubman, SPC 5362, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, 3912 Taubman, SPC 5362, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA
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36
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Adrenal histological and functional changes after hepatic encephalopathy: From mice model to an integrative bioinformatics analysis. Acta Histochem 2022; 124:151960. [PMID: 36202047 DOI: 10.1016/j.acthis.2022.151960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 09/28/2022] [Indexed: 11/15/2022]
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Amin AN, Nguyen PH, Tapper EB. Missed diagnosis of cirrhosis in the inpatient setting. J Hosp Med 2022; 17 Suppl 1:S1-S7. [PMID: 35972039 PMCID: PMC9387549 DOI: 10.1002/jhm.12918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 07/05/2022] [Accepted: 07/05/2022] [Indexed: 11/07/2022]
Abstract
Cirrhosis accounts for a large number of deaths in the United States and worldwide, leading to an increasing burden on the healthcare system. Cirrhosis is, however, a progressive disease with different potential complications related to liver dysfunction and portal hypertension. Often, patients may present with complications of cirrhosis without having been diagnosed previously. It is pertinent that clinicians recognize these signs to place patients on an appropriate course of management to help delay or avoid further disease progression while avoiding deleterious outcomes and unnecessary utilization. We will discuss the epidemiology of liver disease, cirrhosis, and its complications (hepatic encephalopathy, ascites, and varices). In this study, we will discuss the rationale and impact of missing these diagnoses on the healthcare system and patient.
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Affiliation(s)
- Alpesh N. Amin
- Department of Medicine, University of California, Irvine
| | | | - Elliot B. Tapper
- Division of Gastroenterology and Hepatology, University of Michigan
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38
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Bloom PP, Donlan J, Torres Soto M, Daidone M, Hohmann E, Chung RT. Fecal microbiota transplant improves cognition in hepatic encephalopathy and its effect varies by donor and recipient. Hepatol Commun 2022; 6:2079-2089. [PMID: 35384391 PMCID: PMC9315114 DOI: 10.1002/hep4.1950] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/23/2022] [Accepted: 03/12/2022] [Indexed: 01/25/2023] Open
Abstract
Early data suggest fecal microbiota transplant (FMT) may treat hepatic encephalopathy (HE). Optimal FMT donor and recipient characteristics are unknown. We assessed the safety and efficacy of FMT in patients with prior overt HE, comparing five FMT donors. We performed an open-label study of FMT capsules, administered 5 times over 3 weeks. Primary outcomes were change in psychometric HE score (PHES) and serious adverse events (SAEs). Serial stool samples underwent shallow shotgun metagenomic sequencing. Ten patients completed FMT administration and 6-month follow-up. Model for End-Stage Liver Disease (MELD) score did not change after FMT (14 versus 14, p = 0.51). Thirteen minor adverse events and three serious adverse events (two unrelated to FMT) were reported. One SAE was extended-spectrum beta-lactamase Escherichia coli bacteremia. The PHES improved after three doses of FMT (+2.1, p < 0.05), after five doses of FMT (+2.9, p = 0.007), and 4 weeks after the fifth dose of FMT (+3.1, p = 0.02). Mean change in the PHES ranged from -1 to +6 by donor. Two taxa were identified by random forest analysis and confirmed by linear regression to predict the PHES- Bifidobacterium adolescentis (adjusted R2 = 0.27) and B. angulatum (adjusted R2 = 0.25)-both short-chain fatty acid (SCFA) producers. Patients who responded to FMT had higher levels of Bifidobacterium as well as other known beneficial taxa at baseline and throughout the study. The FMT donor with poorest cognitive outcomes in recipients had the lowest fecal SCFA levels. Conclusion: FMT capsules improved cognition in HE, with an effect varying by donor and recipient factors (NCT03420482).
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Affiliation(s)
- Patricia P. Bloom
- Division of GastroenterologyUniversity of MichiganAnn ArborMichiganUSA
| | - John Donlan
- Harvard Medical SchoolBostonMassachusettsUSA
| | | | - Michael Daidone
- Division of GastroenterologyMassachusetts General HospitalBostonMassachusettsUSA
| | - Elizabeth Hohmann
- Division of Infectious DiseaseMassachusetts General HospitalBostonMassachusettsUSA
| | - Raymond T. Chung
- Division of GastroenterologyMassachusetts General HospitalBostonMassachusettsUSA
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Tapper EB, Essien UR, Zhao Z, Ufere NN, Parikh ND. Racial and ethnic disparities in rifaximin use and subspecialty referrals for patients with hepatic encephalopathy in the United States. J Hepatol 2022; 77:377-382. [PMID: 35367057 DOI: 10.1016/j.jhep.2022.02.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/25/2022] [Accepted: 02/08/2022] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS Rifaximin use in combination with lactulose is associated with a decreased risk of overt hepatic encephalopathy (HE). We sought to determine whether race and ethnicity were associated with rifaximin prescriptions. METHODS We examined data for a 20% random sample of United States Medicare enrollees with cirrhosis and hepatic encephalopathy treated with outpatient lactulose and Part D prescription coverage from 2011-2019. Beginning at the time of first diagnosis, we evaluated time to first prescription of rifaximin accounting for competing risks (Fine-Gray, yielding subdistribution hazard ratios [sHRs]) and cumulative rifaximin exposure using a gamma hurdle model (yielding exposure length ratios). We aimed to determine the association of race and ethnicity with each outcome, adjusting for demographics, clinical factors, and other features of clinical management. RESULTS Overall, 29,095 patients were diagnosed with HE and treated with lactulose, of whom 13,272 were prescribed rifaximin. Compared to White patients, Black patients were least likely to receive any prescription for rifaximin (sHR 0.70; 95% CI 0.65-0.76). Asian and Hispanic patients were also less likely to receive rifaximin compared to White patients. Black patients also received fewer doses of rifaximin (exposure length ratio 0.90; 95% CI 0.82-0.98). Hispanic patients also received fewer doses (0.88; 95% CI 0.80-0.98). Out-of-pocket spending on rifaximin per person-year was higher for Black and Hispanic than White patients. Out-of-pocket medication spending was associated with reduced odds of filling a rifaximin prescription. Black and Hispanic patients were least likely to be referred to a gastroenterologist. CONCLUSION In a national cohort of patients with HE, we observed stark racial and ethnic disparities in the use of rifaximin, an approved therapy for the improvement of HE-specific outcomes. Access to gastroenterologists and cost controls may reduce disparities. LAY SUMMARY Hepatic encephalopathy is a serious problem that can affect people with cirrhosis. When someone develops hepatic encephalopathy, there are 2 main treatments. The first-line treatment is called lactulose. If episodes of hepatic encephalopathy happen on lactulose, another treatment called rifaximin is recommended. In this study, we found that compared to White patients, Black and Hispanic patients are less likely to be prescribed rifaximin, receive fewer rifaximin refills, spend more on rifaximin, and have less access to subspecialists who are familiar with rifaximin. We conclude that efforts to address the cost of rifaximin and access to gastroenterologists could help improve these disparities.
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Affiliation(s)
- Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, United States.
| | - Utibe R Essien
- Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, PA, United States
| | - Zhe Zhao
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, United States
| | - Nneka N Ufere
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, United States
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, United States
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40
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Changing Epidemiology of Cirrhosis and Hepatic Encephalopathy. Clin Gastroenterol Hepatol 2022; 20:S1-S8. [PMID: 35940729 PMCID: PMC9531320 DOI: 10.1016/j.cgh.2022.04.036] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 02/07/2023]
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Miwa T, Hanai T, Nishimura K, Sakai Y, Imai K, Suetsugu A, Takai K, Shiraki M, Katsukura N, Shimizu M. Survival benefit of L-carnitine supplementation in patients with cirrhosis. JPEN J Parenter Enteral Nutr 2022; 46:1326-1334. [PMID: 35511698 DOI: 10.1002/jpen.2386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/29/2022] [Accepted: 04/23/2022] [Indexed: 11/10/2022]
Abstract
BACKGROUND L-carnitine supplementation is effective in improving muscle cramps, hyperammonemia, and hepatic encephalopathy in patients with cirrhosis. However, limited evidence is available on the effect of L-carnitine supplementation on the survival of patients with cirrhosis. METHODS In this retrospective study, 674 patients with cirrhosis admitted to Gifu University Hospital or Chuno Kosei Hospital between October 2011 and December 2018 were enrolled. L-carnitine supplementation was defined as the use of L-carnitine for more than 30 consecutive days during the follow-up period. Propensity score matching was applied to create comparable groups between L-carnitine-treated and untreated patients. Mortality was evaluated using the Cox proportional hazards model. RESULTS Among the patients, 93 were excluded. Of the remaining 581 patients, 71 (12%) received L-carnitine supplementation. Propensity matching identified 189 patients (63 L-carnitine-treated and 126 untreated patients) with comparable baseline characteristics in both groups. Of the matched patients, 33 (52%) L-carnitine-treated and 74 (59%) untreated patients died during the median follow-up period of 36.3 months. Overall survival was significantly higher in L-carnitine-treated patients than in untreated patients (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.43-0.99). A subgroup analysis showed that the survival benefit of L-carnitine supplementation was prominent in patients with Child-Pugh class B or C (HR, 0.39; 95% CI, 0.23-0.68), albumin levels ≤3.5 g/dL (HR, 0.59; 95% CI, 0.37-0.95), and ammonia levels ≥90 μg/dL (HR, 0.50; 95% CI, 0.26-0.97) and those without sarcopenia (HR, 0.56; 95% CI, 0.35-0.90). CONCLUSION L-carnitine supplementation may improve survival in patients with cirrhosis. CLINICAL RELEVANCY STATEMENT Carnitine is a vitamin-like compound that regulates lipid and energy metabolism. Although it has been recognized that L-carnitine supplementation improves hyperammonemia, hepatic encephalopathy, sarcopenia, and frailty in patients with cirrhosis, the relationship between L-carnitine supplementation mortality remains unknown. The results of our study provide the first evidence that L-carnitine supplementation may improve survival in patients with cirrhosis. L-carnitine supplementation may shed a new light on the nutritional intervention for patients with cirrhosis. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Takao Miwa
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tatsunori Hanai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.,Center for Nutrition Support & Infection Control, Gifu University Hospital, Gifu, Japan
| | - Kayoko Nishimura
- Center for Nutrition Support & Infection Control, Gifu University Hospital, Gifu, Japan
| | - Yuko Sakai
- Department of Nutrition, Chuno Kosei Hospital, Seki, Japan
| | - Kenji Imai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Atsushi Suetsugu
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Koji Takai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.,Division for Regional Cancer Control, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Makoto Shiraki
- Department of Gastroenterology, Chuno Kosei Hospital, Seki, Japan
| | - Naoki Katsukura
- Department of Gastroenterology, Chuno Kosei Hospital, Seki, Japan
| | - Masahito Shimizu
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
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Tapper EB, Ufere NN, Huang DQ, Loomba R. Review article: current and emerging therapies for the management of cirrhosis and its complications. Aliment Pharmacol Ther 2022; 55:1099-1115. [PMID: 35235219 PMCID: PMC9314053 DOI: 10.1111/apt.16831] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/24/2022] [Accepted: 02/06/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND Cirrhosis is increasingly common and morbid. Optimal utilisation of therapeutic strategies to prevent and control the complications of cirrhosis are central to improving clinical and patient-reported outcomes. METHODS We conducted a narrative review of the literature focusing on the most recent advances. RESULTS We review the aetiology-focused therapies that can prevent cirrhosis and its complications. These include anti-viral therapies, psychopharmacological therapy for alcohol-use disorder, and the current landscape of clinical trials for non-alcoholic steatohepatitis. We review the current standard of care and latest developments in the management of hepatic encephalopathy (HE), ascites and hepatorenal syndrome. We evaluate the promise and drawbacks of chemopreventative therapies that have been examined in trials and observational studies which may reduce the risk of hepatocellular carcinoma and cirrhosis complications. Finally, we examine the therapies which address the non-pain symptoms of cirrhosis including pruritis, muscle cramps, sexual dysfunction and fatigue. CONCLUSION The improvement of clinical and patient-reported outcomes for patients with cirrhosis is possible by applying evidence-based pharmacotherapeutic approaches to the prevention and treatment of cirrhosis complications.
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Affiliation(s)
- Elliot B. Tapper
- Division of Gastroenterology and HepatologyUniversity of MichiganAnn ArborMichiganUSA
| | - Nneka N. Ufere
- Liver Center, Division of Gastroenterology, Department of MedicineMassachusetts General HospitalBostonMassachusettsUSA
| | - Daniel Q. Huang
- Department of Medicine, Yong Loo Lin School of MedicineNational University of SingaporeSingapore
- Division of Gastroenterology and Hepatology, Department of MedicineNational University Health SystemSingapore
- NAFLD Research CenterDivision of Gastroenterology and Hepatology. University of California at San DiegoLa JollaCaliforniaUSA
| | - Rohit Loomba
- NAFLD Research CenterDivision of Gastroenterology and Hepatology. University of California at San DiegoLa JollaCaliforniaUSA
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Deprescribing zolpidem reduces falls and fractures in patients with cirrhosis. JHEP Rep 2022; 4:100478. [PMID: 35493764 PMCID: PMC9052149 DOI: 10.1016/j.jhepr.2022.100478] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 02/14/2022] [Accepted: 03/07/2022] [Indexed: 12/27/2022] Open
Abstract
Background & Aims Benzodiazepines are associated with an increased risk of harm in patients with cirrhosis. However, stopping benzodiazepines must be done with care to avoid withdrawal or other unintended consequences. The impact of deprescribing on patients with cirrhosis is unknown. Methods We emulated a hypothetical 3-year trial of benzodiazepine deprescription among Medicare enrollees with compensated cirrhosis who lacked other life-limiting diagnoses. All received continuous benzodiazepine prescriptions for the 6-months prior to their diagnosis of cirrhosis. During a 90-day landmark period following their diagnosis of cirrhosis, patients were classified as complete deprescribers (no benzodiazepines dispensed), continuous users, or partial deprescribers. We used inverse probability treatment weighting to compare complete deprescribers to continuous users of traditional benzodiazepines and zolpidem. Outcomes accounted for competing risk of mortality and included incident decompensation (hepatic encephalopathy, ascites, or variceal bleeding), fractures, falls, and alcohol-related hospitalizations. Results There were 1,651 and 1,463 continuous users of traditional benzodiazepines and zolpidem, respectively, and 728 complete deprescribers. Patients were aged a median of 68 years, 24% had alcohol-related cirrhosis. There was no difference in the risk of death or decompensation for continuous users and deprescribers. Among deprescribers of traditional benzodiazepines, there was no improvement in the risk of falls or fractures. However, compared to continuous zolpidem users, deprescribers had a lower risk of falls (23.2% vs. 31%, p = 0.04) and fractures (21% vs. 29%, p = 0.02). Conclusions Deprescribing zolpidem reduces the risk of falls and fractures. However, deprescribing benzodiazepines does not improve the risk of decompensation. Efforts to safely address the indications for benzodiazepines such as insomnia and anxiety are urgently needed. Lay summary Many people with cirrhosis have anxiety, depression, and sleep disorders. Increasingly, patients with cirrhosis are treated with sedating medications called benzodiazepines, including valium, alprazolam (‘Xanax’), clonopin, and the sleep-aid zolpidem (‘Ambien’), which can cause falls, broken bones, and maybe other brain disorders. For this reason, many researchers are interested in trials of ‘deprescribing’ (stopping) benzodiazepines. However, no trials have been performed. We used health record data to simulate a trial of deprescribing. We found that stopping benzodiazepines may reduce the chance of falls or broken bones, but it does not improve survival or liver health.
Benzodiazepines are frequently and increasingly prescribed to patients with cirrhosis. Benzodiazepines may increase the risk of falls and fractures and hepatic encephalopathy. Trials of benzodiazepine deprescribing have not been undertaken. In this emulated clinical trial, benzodiazepine deprescribing did not decrease the risk of cirrhosis decompensation. Zolpidem deprescribing was strongly associated with reduced falls and fractures.
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An Electronic Decision Support Intervention Reduces Readmissions for Patients With Cirrhosis. Am J Gastroenterol 2022; 117:491-494. [PMID: 35020619 PMCID: PMC9034761 DOI: 10.14309/ajg.0000000000001608] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 11/23/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Rifaximin use in combination with lactulose is associated with a decreased risk of overt hepatic encephalopathy (HE). METHODS We prospectively evaluated the impact of an interruptive electronic medical record alert to indicate rifaximin for patients with cirrhosis and HE on lactulose. RESULTS The intervention was associated increased rifaximin utilization, particularly for nongastroenterology and hospitalist services odds ratio 1.20 95% confidence interval (1.09-1.31). For patients with HE, the intervention was associated with a lower readmission risk-adjusted subdistribution hazard ratio 0.63 95% confidence interval (0.48-0.82). DISCUSSION An interruptive alert in the electronic ordering system was associated with a lower risk of readmissions.
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Tapper EB, Kenney B, Nikirk S, Levine DA, Waljee AK. Animal Naming Test Is Associated With Poor Patient-Reported Outcomes and Frailty in People With and Without Cirrhosis: A Prospective Cohort Study. Clin Transl Gastroenterol 2022; 13:e00447. [PMID: 35080516 PMCID: PMC8806368 DOI: 10.14309/ctg.0000000000000447] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 12/06/2021] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Cognitive dysfunction is a major driver of care complexity, poor patient-reported outcomes, and frailty for people with cirrhosis. The performance and clinical associations of the animal naming test (ANT) in the general population are unknown. We evaluated ANT performance in a representative sample of older Americans with and without chronic liver disease (CLD). METHODS We analyzed 6,661 subjects enrolled in the 2010-2016 Health and Retirement Survey, a representative cohort of >30,000 US adults. Average age of participants was 75 years. We evaluated 3 subject subgroups: (i) without CLD, (ii) noncirrhosis CLD, and (iii) cirrhosis. We determined the association between the ANT (overall) and S-ANT1 <10 (adjusted for age and education) and health status, basic and instrumental activities of daily living, healthcare utilization (care hours received and hospitalizations), and frailty measures (hand grip and walk speed). RESULTS Overall, 8.2% of the sample had noncirrhotic CLD and 1.3% had cirrhosis. CLD or cirrhosis was not independently associated with ANT. Poor ANT performance was associated with poor health status and frailty overall. An S-ANT <10 was associated with fair-poor self-reported health (odds ratio [OR] 1.37; 95% confidence interval [CI]: 1.20-1.56), care hours received (incidence rate ratio [IRR] 2.39; 95% CI: 1.79-3.19), and hospitalizations (IRR 1.14; 95% CI: 1.03-1.26). S-ANT <10 was also associated with activities of daily living disability (OR 1.31; 95% CI: 1.13-1.51), instrumental activities of daily living disability (OR 1.85; 95% CI: 1.59-2.14), weaker hand grip (IRR 0.94; 95% CI: 0.92-0.96), and time to walk 2.5 m (IRR 1.23; 95% CI: 1.17-1.29). DISCUSSION ANT performance is not specific to CLD/cirrhosis but is associated with patient-reported outcomes and frailty in a nationally representative sample of elderly subjects with and without CLD.
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Affiliation(s)
- Elliot B. Tapper
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Brooke Kenney
- Center for Clinical Management Research, Veterans Affairs Ann Arbor Health System, Ann Arbor, Michigan, USA
| | - Samantha Nikirk
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Deborah A. Levine
- Division of General Medicine, Department of Internal Medicine and Cognitive Health Services Research Program, University of Michigan (U-M), Ann Arbor, Michigan, USA
| | - Akbar K. Waljee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Center for Clinical Management Research, Veterans Affairs Ann Arbor Health System, Ann Arbor, Michigan, USA
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Kochar B, Ufere NN, Ritchie CS, Lai JC. The 5Ms of Geriatrics in Gastroenterology: The Path to Creating Age-Friendly Care for Older Adults With Inflammatory Bowel Diseases and Cirrhosis. Clin Transl Gastroenterol 2022; 13:e00445. [PMID: 35080513 PMCID: PMC8806384 DOI: 10.14309/ctg.0000000000000445] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 10/20/2021] [Indexed: 12/22/2022] Open
Abstract
The number of Americans 65 years or older in 2060 will be more than double what it was in 2014. Approximately 40% of patients seen in gastroenterology (GI) and hepatology practices in the United States are 60 years or older. Adapting care delivery models, curating data on shifting risk-benefit decisions with geriatric syndromes, understanding appropriate assessments, and focusing on tailored implementation strategies are challenges that are actively confronting us as we provide care for a burgeoning population of older adults. Limited availability of geriatric specialists results in an onus of specialists caring for older adults, such as gastroenterologists, to innovate and develop tailored, comprehensive, and evidence-based care for adults in later life stages. In this article, we present the 5M framework from geriatrics to achieve age-friendly healthcare. The 5Ms are medications, mind, mobility, multicomplexity, and what matters most. We apply the 5M framework to 2 chronic conditions commonly encountered in clinical GI practice: inflammatory bowel diseases and cirrhosis. We highlight knowledge gaps and outline future directions to expand evidence-based care and advance the creation of age-friendly GI care.
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Affiliation(s)
- Bharati Kochar
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- The Mongan Institute, Boston, Massachusetts, USA
| | - Nneka N. Ufere
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Christine S. Ritchie
- Harvard Medical School, Boston, Massachusetts, USA
- The Mongan Institute, Boston, Massachusetts, USA
- Division of Palliative Care and Geriatric Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jennifer C. Lai
- Division of Gastroenterology and Hepatology, University of California San Francisco, San Francisco, California, USA
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Bloom PP, Tapper EB, Young VB, Lok AS. Microbiome therapeutics for hepatic encephalopathy. J Hepatol 2021; 75:1452-1464. [PMID: 34453966 PMCID: PMC10471317 DOI: 10.1016/j.jhep.2021.08.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/20/2021] [Accepted: 08/02/2021] [Indexed: 12/13/2022]
Abstract
Hepatic encephalopathy (HE) is a complication of cirrhosis characterised by neuropsychiatric and motor dysfunction. Microbiota-host interactions play an important role in HE pathogenesis. Therapies targeting microbial community composition and function have been explored for the treatment of HE. Prebiotics, probiotics and faecal microbiota transplant (FMT) have been used with the aim of increasing the abundance of potentially beneficial taxa, while antibiotics have been used to decrease the abundance of potentially harmful taxa. Other microbiome therapeutics, including postbiotics and absorbents, have been used to target microbial products. Microbiome-targeted therapies for HE have had some success, notably lactulose and rifaximin, with probiotics and FMT also showing promise. However, there remain several challenges to the effective application of microbiome therapeutics in HE, including the resilience of the microbiome to sustainable change and unpredictable clinical outcomes from microbiota alterations. Future work in this space should focus on rigorous trial design, microbiome therapy selection, and a personalised approach to HE.
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Affiliation(s)
- Patricia P Bloom
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, USA.
| | - Elliot B Tapper
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, USA
| | - Vincent B Young
- Department of Internal Medicine, Division of Infectious Disease, University of Michigan, USA; Department of Microbiology and Immunology, University of Michigan, USA
| | - Anna S Lok
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, USA
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A Trial of Ornithine Phenylacetate and the Arc of Ammonia's History in the Management of Overt Hepatic Encephalopathy. Clin Gastroenterol Hepatol 2021; 19:2493-2495. [PMID: 33157316 DOI: 10.1016/j.cgh.2020.11.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 11/01/2020] [Indexed: 02/07/2023]
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Kuang Y, Wu X, Lai H, Wang Z, Lei Q, Zhong W, Yang Y, Deng C, Zhou Z. Abnormal corpus callosum induced by overt hepatic encephalopathy impairs interhemispheric functional coordination in cirrhosis patients. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1579. [PMID: 34790785 PMCID: PMC8576733 DOI: 10.21037/atm-21-5109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/21/2021] [Indexed: 11/06/2022]
Abstract
Background Although overt hepatic encephalopathy (OHE) patients were shown to have bilaterally symmetrical structural and functional abnormalities in the whole brain, few studies have focused on the bilateral cerebral hemisphere commissural fibers and measured functional coordination between bilateral hemispheres. This study aimed to investigate the structural changes of the corpus callosum (CC) and interhemispheric functional coordination in patients with OHE and to test the hypothesis that abnormal CC induced by OHE impairs interhemispheric functional coordination in cirrhosis patients. Methods The microstructural integrity and the volumes of each subregion of the CC were analyzed by diffusion tensor imaging (DTI) and three-dimensional T1-weighted imaging. Voxel-mirrored homotopic connectivity (VMHC) was derived from resting-state functional magnetic resonance imaging (MRI). Results Compared with the healthy controls (HCs) and patients without hepatic encephalopathy (noHE), the OHE group showed decreased volumes in all subregions of the CC. In OHE patients, the decreased fractional anisotropy (FA) of CC-5 correlated with decreased VMHC in the middle occipital gyrus (MOG) and precuneus. The value of FA in CC-5 and the volumes of CC-3, CC-4, and CC-5 showed correlations with neuropsychological performance in patients with OHE. Conclusions These findings suggest that impairment of interhemispheric white matter pathways may disturb the functional connectivity associated with coordination and neurocognitive performance.
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Affiliation(s)
- Yangying Kuang
- Department of Radiology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaojia Wu
- Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hua Lai
- Department of Radiology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhigang Wang
- Department of Radiology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Qiang Lei
- Department of Radiology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Weijia Zhong
- Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ya Yang
- Department of Radiology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Chen Deng
- Department of Radiology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhiming Zhou
- Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Rahimi RS, Brown KA, Flamm SL, Brown RS. Overt Hepatic Encephalopathy: Current Pharmacologic Treatments and Improving Clinical Outcomes. Am J Med 2021; 134:1330-1338. [PMID: 34242619 DOI: 10.1016/j.amjmed.2021.06.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/11/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023]
Abstract
Overt hepatic encephalopathy is a generally reversible neurologic complication of cirrhosis. Overt hepatic encephalopathy has been associated with poor hospitalization- and mortality-related outcomes, which is important given increasing hepatic encephalopathy-related hospitalizations over time. The aim of this narrative review is to provide an overview of hospital- and mortality-related outcomes in patients with overt hepatic encephalopathy and the pharmacologic therapies that may improve these outcomes. Guideline-recommended prophylaxis with lactulose (first-line therapy) or secondary prophylaxis with rifaximin plus lactulose decreases hospital admissions and mortality rates. Rifaximin or lactulose treatment was beneficial for reducing the hospitalization rate in patients with hepatic encephalopathy compared with no treatment. Further, retrospective studies have shown that rifaximin with or without lactulose was effective for decreasing the number of hepatic encephalopathy episodes, hepatic encephalopathy-related hospitalizations, and duration of hospitalization. Ornithine phenylacetate, an ammonia-reducing agent currently in development, is also being investigated in hospitalized patients with hepatic encephalopathy. Overall, data support that prophylaxis for the prevention of hepatic encephalopathy recurrence improves outcomes in patients with cirrhosis and a history of hepatic encephalopathy.
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Affiliation(s)
- Robert S Rahimi
- Baylor Scott and White Hospital, Baylor University Medical Center, Dallas, Tex.
| | - Kimberly A Brown
- Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Mich
| | - Steven L Flamm
- Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Robert S Brown
- Weill Cornell Medicine, Center for Liver Disease, New York, NY
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