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Hepatic Encephalopathy: Clinical Challenges and Opportunities
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Hepatic Encephalopathy: Clinical Challenges and Opportunities

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Gastroenterology & Hepatopancreatobiliary Medicine".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 40318

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Lorenzo Ridola

E-Mail Website
Guest Editor
Department of Translational and Precision Medicine, "Sapienza" University of Rome, Latina, Italy
Interests: portal hypertension; cirrhosis; hepatic encephalopathy; sarcopenia; TIPS
Special Issues, Collections and Topics in MDPI journals
Prof. Oliviero Riggio

E-Mail Website
Guest Editor
Department of Translational and Precision Medicine, Sapienza University of Rome, Latina, Italy
Interests: hepatic encephalopathy; minimal hepatic encephalopathy; spontaneous portal-systemic shunts; transjugular intrahepatic portosystemic shunt; cirrhosis; portal hypertension; sarcopenia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hepatic encephalopathy (HE) is a complex neurological syndrome, characteristic of patients with liver disease, causing a wide and complex spectrum of nonspecific neurological and psychiatric manifestations, ranging from a subclinical entity, minimal or covert hepatic encephalopathy, to a deep form in which a complete alteration of consciousness can be observed: overt hepatic encephalopathy. Both minimal and overt hepatic encephalopathy have a high impact on patients, caregivers, and national health services, driving substantial consumption of economic resources. With this Special Issue, we hope to encourage submissions that discuss the current state-of-the-art, address ongoing knowledge gaps, and focus on ongoing controversies related to pathogenesis, diagnostic, and therapeutic management of hepatic encephalopathy.

Dr. Lorenzo Ridola
Prof. Oliviero Riggio
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Hepatic encephalopathy
  • Minimal hepatic encephalopathy
  • Sarcopenia
  • Spontaneous portal-systemic shunts
  • Transjugular intrahepatic portosystemic shunt
  • Portal hypertension
  • Cirrhosis

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 178 KiB  
Editorial
Hepatic Encephalopathy in the 21st Century: Still an Emerging Topic
by Lorenzo Ridola and Oliviero Riggio
J. Clin. Med. 2021, 10(2), 298; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10020298 - 15 Jan 2021
Cited by 3 | Viewed by 1664
Abstract
Why write about hepatic encephalopathy (HE) in the twenty-first century [...] Full article
(This article belongs to the Special Issue Hepatic Encephalopathy: Clinical Challenges and Opportunities)

Research

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18 pages, 1300 KiB  
Article
Patients with Minimal Hepatic Encephalopathy Show Altered Thermal Sensitivity and Autonomic Function
by Dalia Rega, Mika Aiko, Nicolás Peñaranda, Amparo Urios, Juan-José Gallego, Carla Giménez-Garzó, Franc Casanova, Alessandra Fiorillo, Andrea Cabrera-Pastor, Teresa San-Miguel, Cristina Ipiens, Desamparados Escudero-García, Joan Tosca, Cristina Montón, María-Pilar Ballester, José Ballester, Luis Aparicio, María-Pilar Ríos, Lucía Durbán, Amparo Mir, Elena Kosenko, Paula Cases, Vicente Felipo and Carmina Montoliuadd Show full author list remove Hide full author list
J. Clin. Med. 2021, 10(2), 239; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10020239 - 11 Jan 2021
Cited by 7 | Viewed by 2036
Abstract
Cirrhotic patients may experience alterations in the peripheral nervous system and in somatosensory perception. Impairment of the somatosensory system could contribute to cognitive and motor alterations characteristic of minimal hepatic encephalopathy (MHE), which affects up to 40% of cirrhotic patients. We assessed the [...] Read more.
Cirrhotic patients may experience alterations in the peripheral nervous system and in somatosensory perception. Impairment of the somatosensory system could contribute to cognitive and motor alterations characteristic of minimal hepatic encephalopathy (MHE), which affects up to 40% of cirrhotic patients. We assessed the relationship between MHE and alterations in thermal, vibration, and/or heat pain sensitivity in 58 cirrhotic patients (38 without and 20 with MHE according to Psychometric Hepatic Encephalopathy Score) and 39 controls. All participants underwent attention and coordination tests, a nerve conduction study, autonomic function testing, and evaluation of sensory thresholds (vibration, cooling, and heat pain detection) by electromyography and quantitative sensory testing. The detection thresholds for cold and heat pain on the foot were higher in patients with, than those without MHE. This hyposensitivity was correlated with attention deficits. Reaction times in the foot were longer in patients with, than without MHE. Patients with normal sural nerve amplitude showed altered thermal sensitivity and autonomic function, with stronger alterations in patients with, than in those without MHE. MHE patients show a general decrease in cognitive and sensory abilities. Small fibers of the autonomic nervous system and thermal sensitivity are altered early on in MHE, before large sensory fibers. Quantitative sensory testing could be used as a marker of MHE. Full article
(This article belongs to the Special Issue Hepatic Encephalopathy: Clinical Challenges and Opportunities)
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16 pages, 4712 KiB  
Article
A Look into Liver Mitochondrial Dysfunction as a Hallmark in Progression of Brain Energy Crisis and Development of Neurologic Symptoms in Hepatic Encephalopathy
by Elena Kosenko, Lyudmila Tikhonova, Gubidat Alilova and Carmina Montoliu
J. Clin. Med. 2020, 9(7), 2259; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9072259 - 16 Jul 2020
Cited by 5 | Viewed by 2469
Abstract
Background: The relationship between liver disease and neuropathology in hepatic encephalopathy is well known, but the genesis of encephalopathy in liver failure is yet to be elucidated. Conceptually, the main cause of hepatic encephalopathy is the accumulation of brain ammonia due to impaired [...] Read more.
Background: The relationship between liver disease and neuropathology in hepatic encephalopathy is well known, but the genesis of encephalopathy in liver failure is yet to be elucidated. Conceptually, the main cause of hepatic encephalopathy is the accumulation of brain ammonia due to impaired liver detoxification function or occurrence of portosystemic shunt. Yet, as well as taking up toxic ammonia, the liver also produces vital metabolites that ensure normal cerebral function. Given this, for insight into how perturbations in the metabolic capacity of the liver may be related to brain pathology, it is crucial to understand the extent of ammonia-related changes in the hepatic metabolism that provides respiratory fuel for the brain, a deficiency of which can give rise to encephalopathy. Methods: Hepatic encephalopathy was induced in starved rats by injection of ammonium acetate. Ammonia-induced toxicity was evaluated by plasma and freeze-clamped liver and brain energy metabolites, and mitochondrial, cytoplasmic, and microsomal gluconeogenic enzymes, including mitochondrial ketogenic enzymes. Parameters of oxidative phosphorylation were recorded polarographically with a Clark-type electrode, while other measures were determined with standard fluorometric enzymatic methods. Results: Progressive impairment of liver mitochondrial respiration in the initial stage of ammonia-induced hepatotoxicity and the subsequent energy crisis due to decreased ATP synthesis lead to cessation of gluconeogenesis and ketogenesis. Reduction in glucose and ketone body supply to the brain is a terminal event in liver toxicity, preceding the development of coma. Conclusions: Our study provides a framework to further explore the relationship between hepatic dysfunction and progression of brain energy crisis in hepatic encephalopathy. Full article
(This article belongs to the Special Issue Hepatic Encephalopathy: Clinical Challenges and Opportunities)
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Review

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18 pages, 1104 KiB  
Review
Minimal Hepatic Encephalopathy Affects Daily Life of Cirrhotic Patients: A Viewpoint on Clinical Consequences and Therapeutic Opportunities
by Jessica Faccioli, Silvia Nardelli, Stefania Gioia, Oliviero Riggio and Lorenzo Ridola
J. Clin. Med. 2022, 11(23), 7246; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11237246 - 06 Dec 2022
Cited by 5 | Viewed by 3667
Abstract
Minimal hepatic encephalopathy (MHE) is a frequent complication of hepatic encephalopathy (HE) and can affect up to 80% of patients with liver cirrhosis. It is characterized by the lack of obvious clinical signs and the presence of alterations detectable using psychometric or electrophysiological [...] Read more.
Minimal hepatic encephalopathy (MHE) is a frequent complication of hepatic encephalopathy (HE) and can affect up to 80% of patients with liver cirrhosis. It is characterized by the lack of obvious clinical signs and the presence of alterations detectable using psychometric or electrophysiological testing focused on attention, working memory, psychomotor speed and visuospatial ability. Ideally, each patient should be tested for this condition because, despite the absence of symptoms, it has severe repercussions on daily life activities. It may be responsible for an inability to drive, sleep disturbances, risk of falls and inability to work. Some studies have highlighted its prognostically unfavorable role on mortality and risk of “overt” HE (OHE). Finally, MHE severely affects the lives of patients and caregivers, altering their quality of life and their socioeconomic status. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics, such as rifaximin, probiotics and branched-chain amino acids, with promising results. For this reason, early diagnosis and intervention with appropriate measures is essential, with the aim of improving both performance on psychometric tests, as well as clinical aspects related to this condition. Full article
(This article belongs to the Special Issue Hepatic Encephalopathy: Clinical Challenges and Opportunities)
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24 pages, 530 KiB  
Review
Nutrition Assessment and Management in Patients with Cirrhosis and Cognitive Impairment: A Comprehensive Review of Literature
by Jessica Faccioli, Silvia Nardelli, Stefania Gioia, Oliviero Riggio and Lorenzo Ridola
J. Clin. Med. 2022, 11(10), 2842; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11102842 - 18 May 2022
Cited by 5 | Viewed by 4299
Abstract
Hepatic encephalopathy (HE) represents a common complication of liver cirrhosis. Protein-calorie malnutrition is frequently encountered in the cirrhotic patient and its most obvious clinical manifestation is sarcopenia. This condition represents a risk factor for HE occurrence because skeletal muscle acts as an alternative [...] Read more.
Hepatic encephalopathy (HE) represents a common complication of liver cirrhosis. Protein-calorie malnutrition is frequently encountered in the cirrhotic patient and its most obvious clinical manifestation is sarcopenia. This condition represents a risk factor for HE occurrence because skeletal muscle acts as an alternative site for ammonium detoxification. Preventive intervention through an adequate assessment of nutritional status should be carried out at early stages of the disease and in a multidisciplinary team using both non-instrumental methods (food diary, anthropometric measurements, blood chemistry tests) and instrumental methods (bioimpedance testing, DEXA, CT, indirect calorimetry, dynamometry). Dietary recommendations for patients with HE do not differ from those for cirrhotic patient without HE. Daily caloric intake in the non-obese patient should be 30–40 Kcal/Kg/day with a protein intake of 1–1.5 g/Kg/day, especially of vegetable origin, through 4–6 meals daily. In patients with HE, it is also essential to monitor electrolyte balance, supplementing any micronutrient deficiencies such as sodium and zinc, as well as vitamin deficiencies because they can cause neurological symptoms similar to those of HE. In light of the critical role of nutritional status, this aspect should not be underestimated and should be included in the diagnostic–therapeutic algorithm of patients with HE. Full article
(This article belongs to the Special Issue Hepatic Encephalopathy: Clinical Challenges and Opportunities)
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12 pages, 300 KiB  
Review
Ammonia and the Muscle: An Emerging Point of View on Hepatic Encephalopathy
by Simone Di Cola, Silvia Nardelli, Lorenzo Ridola, Stefania Gioia, Oliviero Riggio and Manuela Merli
J. Clin. Med. 2022, 11(3), 611; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11030611 - 26 Jan 2022
Cited by 14 | Viewed by 3131
Abstract
In the last years the link between the presence of muscular alterations and hepatic encephalopathy (HE), both minimal and overt, has been deeply studied. The pathophysiological background supporting the relationship between muscle depletion, and HE is characterized by an imbalance between the capacity [...] Read more.
In the last years the link between the presence of muscular alterations and hepatic encephalopathy (HE), both minimal and overt, has been deeply studied. The pathophysiological background supporting the relationship between muscle depletion, and HE is characterized by an imbalance between the capacity of muscle in ammonia metabolism and trafficking and the inability of the liver in removing ammonia through urea synthesis due to liver failure and/or the presence of porto-systemic shunts. This review will focus on the clinical burden, the physio pathological mechanisms understanding the liver muscle axis and principles of management of muscular alterations in cirrhosis. Full article
(This article belongs to the Special Issue Hepatic Encephalopathy: Clinical Challenges and Opportunities)
9 pages, 438 KiB  
Review
Cognitive Impairement in Non-Cirrhotic Portal Hypertension: Highlights on Physiopathology, Diagnosis and Management
by Stefania Gioia, Silvia Nardelli, Oliviero Riggio, Jessica Faccioli and Lorenzo Ridola
J. Clin. Med. 2022, 11(1), 101; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm11010101 - 25 Dec 2021
Cited by 6 | Viewed by 2589
Abstract
Hepatic encephalopathy (HE) is one of the most frequent complications of cirrhosis. Several studies and case reports have shown that cognitive impairment may also be a tangible complication of portal hypertension secondary to chronic portal vein thrombosis and to porto-sinusoidal vascular disease (PSVD). [...] Read more.
Hepatic encephalopathy (HE) is one of the most frequent complications of cirrhosis. Several studies and case reports have shown that cognitive impairment may also be a tangible complication of portal hypertension secondary to chronic portal vein thrombosis and to porto-sinusoidal vascular disease (PSVD). In these conditions, representing the main causes of non-cirrhotic portal hypertension (NCPH) in the Western world, both overt and minimal/covert HE occurs in a non-neglectable proportion of patients, even lower than in cirrhosis, and it is mainly sustained by the presence of large porto-systemic shunt. In these patients, the liver function is usually preserved or only mildly altered, and the development of porto-systemic shunt is either spontaneous or iatrogenically frequent; HE is an example of type-B HE. To date, in the absence of strong evidence and large cooperative studies, for the diagnosis and the management of HE in NCPH, the same approach used for HE occurring in cirrhosis is applied. The aim of this paper is to provide an overview of type B hepatic encephalopathy, focusing on its pathophysiology, diagnostic tools and management in patients affected by porto-sinusoidal vascular disease and chronic portal vein thrombosis. Full article
(This article belongs to the Special Issue Hepatic Encephalopathy: Clinical Challenges and Opportunities)
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10 pages, 673 KiB  
Review
Lights and Shadows in Hepatic Encephalopathy Diagnosis
by Piero Amodio and Sara Montagnese
J. Clin. Med. 2021, 10(2), 341; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10020341 - 18 Jan 2021
Cited by 5 | Viewed by 3689
Abstract
Hepatic encephalopathy (HE) is a form of brain dysfunction that is caused by liver insufficiency and/or portal-systemic shunting. The exact nature of HE is debated; as such, conflicting uses of the term “HE” may cause inconsistencies in its detection and management. This review [...] Read more.
Hepatic encephalopathy (HE) is a form of brain dysfunction that is caused by liver insufficiency and/or portal-systemic shunting. The exact nature of HE is debated; as such, conflicting uses of the term “HE” may cause inconsistencies in its detection and management. This review highlights the meaning of the term “HE” on the basis of its historical origins and current consensus. It also provides criteria for the diagnosis of the condition based on its phenotypes and risk factors for its occurrence. The procedure for differential diagnosis from other conditions which result in similar phenotypes is considered, together with precipitants and confounders. Finally, the current multidimensional approach for the correct clinical reporting of HE episodes is discussed. Full article
(This article belongs to the Special Issue Hepatic Encephalopathy: Clinical Challenges and Opportunities)
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12 pages, 269 KiB  
Review
Gut Microbiota Modulation and Fecal Transplantation: An Overview on Innovative Strategies for Hepatic Encephalopathy Treatment
by Ramzi Hassouneh and Jasmohan S. Bajaj
J. Clin. Med. 2021, 10(2), 330; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm10020330 - 18 Jan 2021
Cited by 33 | Viewed by 4045
Abstract
Hepatic encephalopathy (HE) is a major complication of cirrhosis, which is associated with gut microbial composition and functional alterations. Current treatments largely focus on gut microbiota using lactulose, rifaximin and other agents. However, despite these treatments, patients with HE have a high rate [...] Read more.
Hepatic encephalopathy (HE) is a major complication of cirrhosis, which is associated with gut microbial composition and functional alterations. Current treatments largely focus on gut microbiota using lactulose, rifaximin and other agents. However, despite these treatments, patients with HE have a high rate of readmission, morbidity and cognitive impairment. Fecal microbiota transplant (FMT) involves introduction of a donor microbiota into a recipient and is currently mainly used for recurrent C. difficile infection (rCDI). The role of FMT in cirrhosis and HE is evolving. There have been two randomized clinical trials (RCT) and several case reports/series in cirrhosis. Both RCTs were safety-focused phase 1 trials. One involved pre-FMT antibiotics and FMT enema versus standard of care, while the other involved 15 FMT capsules versus placebo without pre-FMT antibiotics. There was evidence of safety in both trials and the FMT group demonstrated reduction in hospitalizations compared to the non-FMT group. Changes in microbial function centered around short-chain fatty acids, bile acids and brain function showed improvement in the FMT groups. Long-term follow-up demonstrated continued safety and reduction in the antibiotic-resistance gene carriage. However, larger trials of FMT in HE are needed that can refine the dose, duration and route of FMT administration. Full article
(This article belongs to the Special Issue Hepatic Encephalopathy: Clinical Challenges and Opportunities)
13 pages, 1014 KiB  
Review
Shunt-Induced Hepatic Encephalopathy in TIPS: Current Approaches and Clinical Challenges
by Philipp Schindler, Hauke Heinzow, Jonel Trebicka and Moritz Wildgruber
J. Clin. Med. 2020, 9(11), 3784; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9113784 - 23 Nov 2020
Cited by 35 | Viewed by 9056
Abstract
Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment tool in decompensated liver cirrhosis that has been shown to prolong transplant-free survival. Hepatic encephalopathy (HE) is a frequent complication of decompensated cirrhosis, eventually induced and/or aggravated by TIPS, that remains a clinical challenge [...] Read more.
Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment tool in decompensated liver cirrhosis that has been shown to prolong transplant-free survival. Hepatic encephalopathy (HE) is a frequent complication of decompensated cirrhosis, eventually induced and/or aggravated by TIPS, that remains a clinical challenge especially in these patients. Therefore, patient selection for TIPS requires careful assessment of risk factors for HE. TIPS procedural parameters regarding stent size and invasive portosystemic pressure gradient measurements thereby have an important role. Endovascular shunt modification, in combination with a conservative medical approach, often results in a significant reduction of symptoms. This review summarizes HE molecular mechanisms and pathophysiology as well as diagnostic and therapeutic approaches targeting shunt-induced HE. Full article
(This article belongs to the Special Issue Hepatic Encephalopathy: Clinical Challenges and Opportunities)
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12 pages, 226 KiB  
Review
The Use of Administrative Data to Investigate the Population Burden of Hepatic Encephalopathy
by Patricia P. Bloom and Elliot B. Tapper
J. Clin. Med. 2020, 9(11), 3620; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9113620 - 10 Nov 2020
Cited by 7 | Viewed by 2201
Abstract
Hepatic encephalopathy (HE) is a devastating complication of cirrhosis with an increasing footprint in global public health. Although the condition is defined using a careful history and examination, we cannot accurately measure the true impact of HE relying on data collected exclusively from [...] Read more.
Hepatic encephalopathy (HE) is a devastating complication of cirrhosis with an increasing footprint in global public health. Although the condition is defined using a careful history and examination, we cannot accurately measure the true impact of HE relying on data collected exclusively from clinical studies. For this reason, administrative data sources are necessary to study the population burden of HE. Administrative data is generated with each health care encounter to account for health care resource utilization and is extracted into a dataset for the secondary purpose of research. In order to utilize such data for valid analysis, several pitfalls must be avoided—specifically, selecting the particular database capable of meeting the needs of the study’s aims, paying careful attention to the limits of each given database, and ensuring validity of case definition for HE specific to the dataset. In this review, we summarize the types of data available for and the results of administrative data studies of HE. Full article
(This article belongs to the Special Issue Hepatic Encephalopathy: Clinical Challenges and Opportunities)
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