Research progress in hepatic encephalopathy in recent 10 years: A Web of Science-based literature analysis

Abstract

OBJECTIVE:

To analyze international research trends in hepatic encephalopathy and examine the role of neuroelectrophysiology and neuroimaging in diagnosis of hepatic encephalopathy.

DATA RETRIEVAL:

We performed a bibliometric analysis of studies on hepatic encephalopathy published during 2002–2011 retrieved from Web of Science.

SELECTION CRITERIA:

Inclusion criteria: (1) peer-reviewed published articles on hepatic encephalopathy; (2) original article, review, meeting abstract, proceedings paper, book chapter, editorial material, news items, and (3) published during 2002–2011. Exclusion criteria: (1) articles that required manual searching or telephone access; (2) documents that were not published in the public domain; and (3) corrected papers from the total number of articles.

MAIN OUTCOME MEASURES:

(1) Annual publication output; (2) type of publication; (3) publication by research field; (4) publication by journal; (5) publication by author; (6) publication by institution; (7) publication by country; (8) publication by institution in China; (9) most-cited papers.

RESULTS:

A total of 3 233 papers regarding hepatic encephalopathy were retrieved during 2002–2011. The number of papers gradually increased over the 10-year study period and was highest in 2010. Most papers appeared in journals with a focus on gastroenterology and hepatology. Among the included journals, Hepatology published the greatest number of papers regarding hepatic encephalopathy, and the published studies were highly cited. Thus, Hepatology appears to represent a key journal publishing papers on hepatic encephalopathy. Regarding distribution by country for publications on hepatic encephalopathy indexed in Web of Science during 2002–2011, the United States published highest number of papers, with China ranked ninth. As per distribution by institute for publications, the University of Montreal in Canada published the highest number of papers (n = 111). Among the Chinese institutes, Zhejiang University in China was the most prolific institute with 15 papers.

CONCLUSION:

The present bibliometric analysis on hepatic encephalopathy provides an overview of research progress, as well as identifying the most active institutes and experts in this research field during 2002–2011. Research into hepatic encephalopathy has revealed changes in neural injury and regeneration in hepatic encephalopathy. Neuroelectrophysiological and neuroimaging examinations are important for determining clinical classifications and disease severity of hepatic encephalopathy, providing a foundation for further research.

Research Highlights

• (1)This paper reviews several theories about the pathological mechanisms underlying hepatic encephalopathy, including ammonia poisoning, manganese poisoning, plasma amino acids imbalance, and γ-aminobutyric acid.
• (2)The therapeutic regimen for hepatic encephalopathy should be designed based on the type of hepatic encephalopathy.
• (3)We examined global research trends in hepatic encephalopathy, analyzing annual publication output, types of publication, publication by research field, publication by journal, publication by author, publication by institution, publication by country, publication by institution in China, and most-cited papers of hepatic encephalopathy in Web of Science during 2002–2011.
• (4)We discuss the significance of neuroelectrophysiology and neuroimaging in the diagnosis of hepatic encephalopathy.

INTRODUCTION

Hepatic encephalopathy is a syndrome involving neuropsychiatric dysfunction due to a metabolic disturbance caused by severe hepatic damage and portosystemic venous shunting. This syndrome is clinically characterized by the onset of mental status changes ranging from subtle psychological abnormalities to profound coma. Distinctive electroencephalographic abnormalities and increased blood ammonia level are often the clearest manifestations of hepatic encephalopathy[1].

Pathogenesis and categorization of hepatic encephalopathy

Several theories have been proposed regarding the pathogenic mechanisms underlying hepatic encephalopathy, including ammonia poisoning, manganese poisoning, false neurotransmitters, imbalanced plasma amino acid levels, and γ-aminobutyric acid.

Ammonia poisoning theory

Ammonia, a metabolite of nitrogen compounds, is toxic in high concentrations. In patients with severe liver disease, abnormally high levels of ammonia have been proposed to cause central nervous system dysfunction via the following process[2]. First, five biochemical regions responsible for cerebral glucose metabolism become disturbed, leading to a reduction in adenosine triphosphate production and an eventual inability to maintain nervous system activity. Second, abnormal levels of excitatory and inhibitory neurotransmitters related to learning, memory, behavior and cerebral activation result in cerebral dysfunction. Third, cerebral ammonia activates the sodium pump in the neuronal membrane and competes with sodium ions, which leads to unbalance of intracellular and extracellular sodium ions and interferes neural impulse conduction. Fourth, cerebral ammonia stimulates cerebral limbic system and causes neuropsychiatric dysfunction.

Manganese poisoning theory

Manganese, a neurotoxic metal, is excreted by bile under normal circumstances. In severe liver diseases, manganese can accumulate in systematic circulation, entering the cerebrum via the blood-brain barrier.

In patients with hepatic encephalopathy, manganese accumulates in the peripheral blood and basal ganglia, presenting with abnormally high levels of activation in the globus pallidus, revealed by T1-weighted magnetic resonance imaging. This activation is related to the degree of liver damage[3]. Autopsy results revealed that the level of manganese in the basal ganglia in patients with hepatic encephalopathy is 2–7 times higher than in healthy controls. Some studies have reported that altered mitochondrial permeability is likely to be a key mechanism of manganese poisoning. In addition, manganese and ammonia are reported to exhibit synergistic effects in hepatic encephalopathy.

False neurotransmitter theory

Fischer et al[4] proposed the false neurotransmitter theory of hepatic encephalopathy in 1971. According to this theory, when the liver is damaged or collateral circulation occurs, amines will enter into the central nervous system via the systemic circulation. These amines function as “false neurotransmitters”, exhibiting a similar structure to neuromediators such as noradrenalin, and substituting normal nerve conduction mediators in the synapse. This inhibits the ascending activation system of the reticular formation in the brain stem, causing abnormal cerebral function and leading to disturbance of consciousness and even coma.

Amino acid unbalance theory

Glutamine synthetase primarily exists in astrocytes. In patients with severe liver disease, high blood ammonia levels may lead to accumulation of a large amount of γ-amino-glutamic acid in the astrocytes, resulting in cerebral edema and astrocyte swelling. This process may evoke neuronal dysfunction and reduced extracellular space, increasing intracellular accumulation of neurotoxic substance, finally leading to neuronal injury[5]. Aminoethylsulfonic acid exerts regulatory effects on nervous system function. Swollen astrocytes will consume aminoethylsulfonic acid and is therefore a pathological factor of ammonia toxicity and hepatic encephalopathy.

There is currently no uniform gold standard for hepatic encephalopathy treatment. Wang[6] proposed that, ideally, therapeutic regimens should be designed according to the types of hepatic encephalopathy (Table 1).

Table 1.

Types of hepatic encephalopathy

Neuroelectrophysiological and neuroimaging examinations and evaluation of hepatic encephalopathy

Hepatic encephalopathy patients often present with disturbances of consciousness, which can be helpful in diagnosing patients with mild hepatic encephalopathy. Currently-used testing methods include number connection test, trajectory tracking test, construction ability test, clock drawing test, digit symbol test, and the series dotting test. These methods are easy to implement, and the results are largely independent of patients’ education level. Simple intelligence scales are also used in the clinical examination of neuropsychiatric patients. Neuroelectrophysiological detection:

(1) Electroencephalography (EEG) examination: patients with hepatic encephalopathy present with abnormal EEG findings before the presence of symptoms, so EEG should be involved in initial examinations. Hepatic encephalopathy patients typically present with a slowed rhythm in EEG. These EEG changes are not specific to patients with hepatic encephalopathy, but they exhibit a strong correlation with the severity of disease focus and the clinical grading. (2) Evoked potential detection: examination of the P300 endogenous event-related evoked potential provides a valuable tool for diagnosis of hepatic encephalopathy. (3) Critical flicker frequency detection: this method is used to examine disorders of cerebral nerve conduction function. Critical flicker frequency can be used to diagnose mild hepatic encephalopathy. This simple method is reported to be sensitive and reliable, and can help to evaluate the severity of hepatic encephalopathy[7].

Neuroimaging examination: Cerebral edema can be detected by brain computed tomography (CT) and magnetic resonance imaging (MRI). Manganese deposition and γ-amino-glutamic acid effects lead to changes in astrocyte structure. Skull MRI examination can visualize brain atrophy in the frontal cortex. Typical findings in hepatic encephalopathy patients include enhanced T1-weighted signals in the globus pallidus and nucleocapsid internal capsule. Some studies have reported that T1-weighted signals in the white matter and outer pyramidal tract are enhanced with worsening liver function. Positron emission tomography is used to reflect abnormal biochemical and physiological processes in the brain, although imaging results depend on the tracers used.

DATA SOURCES AND METHODOLOGY

Based on literature regarding hepatic encephalopathy included in Web of Science during 2002–2011, a bibliometric analysis was performed to examine international research progress in hepatic encephalopathy over the last decade.

Data retrieval

We used bibliometric analyses to quantitatively and qualitatively investigate international research progress in studies of hepatic encephalopathy indexed in Web of Science during 2002–2011 using the key term hepatic encephalopathy. We conducted the search on October 20, 2012.

Inclusion criteria

We included published peer-reviewed articles on hepatic encephalopathy, including original research articles, review, meeting abstract, proceedings paper, book chapter, editorial material and news items, which were indexed in Web of Science.

Exclusion criteria

We excluded articles that required manual searching or telephone access, documents that were not published in the public domain, and corrected papers.

The outcomes of all articles regarding hepatic encephalopathy were assessed using the following criteria: (1) annual publication output; (2) type of publication; (3) research field; (4) journals; (5) authors; (6) institutions; (7) countries; (8) institutions in China; (9) most-cited papers.

RESULTS

Annual publication output regarding hepatic encephalopathy in Web of Science during 2002–2011

A total of 3 233 papers on hepatic encephalopathy published between 2002 and 2011 were retrieved from Web of Science. The number of relevant papers gradually increased over the 10-year study period. Of the years included, the greatest number of papers (n = 402, 12.4%) was published in 2010 (Figure 1).

Figure 1.

Annual output of publications about hepatic encephalopathy indexed in Web of Science during 2002–2011.

Publication types regarding hepatic encephalopathy indexed in Web of Science during 2002–2011.

Original research articles (n = 2 187, 67.6%) constituted the most common type of publication regarding hepatic encephalopathy indexed in Web of Science between 2002 and 2011 (Table 2). Other common types included meeting abstracts, proceedings papers, editorial material, letters, and book chapters.

Table 2.

Type of publications regarding hepatic encephalopathy indexed in Web of Science during 2002–2011

Distribution by research field in publications on hepatic encephalopathy indexed in Web of Science during 2002–2011 (Figure 2)

Figure 2.

Distribution by research field in publications regarding hepatic encephalopathy indexed in Web of Science during 2002–2011.

I: Gastroenterology and hepatology; II: neurosciences and neurology; III: general internal medicine; IV: surgery; V: biochemistry and molecular biology; VI: pharmacology and pharmacy; VII: transplantation; VIII: endocrinology and metabolism; IX: radiology, nuclear medicine and medical imaging; X: veterinary sciences.

We analyzed the research fields represented in publications regarding hepatic encephalopathy indexed in Web of Science during 2002–2011. The results revealed that 1 412 papers were in the field of gastroenterology and hepatology, followed by 636 papers in the field of neuroscience and neurology, 254 papers in the field of general internal medicine, and 232 papers in the field of biochemistry and molecular biology. Less than 200 papers were found in other research fields.

Distribution by journal for publications on hepatic encephalopathy indexed in Web of Science during 2002–2011 (Figure 3)

Figure 3.

Top 10 journals for publications on hepatic encephalopathy indexed in Web of Science from 2002–2011.

I: Hepatology; II: Journal of Hepatology; III: Metabolic Brain Disease; IV: Gastroenterology; V: American Journal of Gastroenterology; VI: Liver International; VII: Journal of Gastroenterology and Hepatology; VIII: Neurochemistry International; IX: Liver Transplantation; X: World Journal of Gastroenterology

Among the journals publishing papers on hepatic encephalopathy indexed in Web of Science during 2002–2011, Hepatology published 235 papers, accounting for 7.27% of the total, followed by the Journal of Hepatology (n = 172) and Metabolic Brain Disease (n = 134). Less than 100 papers were published in other journals.

Distribution by author for publications on hepatic encephalopathy indexed in Web of Science during 2002–2011 (Table 3)

Table 3.

Authors publishing papers on hepatic encephalopathy indexed in Web of Science during 2002–2011

Butterworth published 80 papers (2.47%) on hepatic encephalopathy, followed by Felipo (n = 74, 2.30%) and Haussinger (n = 74, 2.30%).

Butterworth's paper, “Neurobiology of ammonia”[8] was cited 236 times, followed by “Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes”[9] cited 151 times, and “Pathophysiology of hepatic encephalopathy: a new look at ammonia”[10] cited 141 times.

Felipo's paper, “Neurobiology of ammonia”[8] was cited 236 times, followed by “Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts”[11] cited 67 times, and “Value of the critical flicker frequency in patients with minimal hepatic encephalopathy”[12] cited 63 times.

Haussinger's paper, “Ammonia induces MK-801-sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes”[9] was cited 151 times, followed by “Critical flicker frequency for quantification of low-grade hepatic encephalopathy”[13] cited 141 times and “Pathogenetic mechanisms of hepatic encephalopathy”[14] cited 73 times.

Distribution of institutes publishing papers on hepatic encephalopathy indexed in Web of Science during 2002–2011 (Figure 4)

Figure 4.

Distribution of institutions publishing papers on hepatic encephalopathy indexed in Web of Science during 2002–2011.

I: University of Montreal; II: University of California system; III: Heinrich-Heine-University Düsseldorf; IV: UCL; V: Virginia Commonwealth University; VI: University of Padua; VII: Mayo; VIII: University of Miami; IX: The Sapienza University of Rome; X: University of Copenhagen.

Distribution of countries publishing papers on hepatic encephalopathy indexed in Web of Science during 2002–2011 (Figure 5)

Figure 5.

Distribution of countries publishing papers on hepatic encephalopathy indexed in Web of Science during 2002–2011.

I: USA; II: Spain; III: Germany; IV: England; V: Japan; VI: Italy; VII: Canada; VIII: India; IX: China; X: France.

Chinese institutes publishing papers on hepatic encephalopathy indexed in Web of Science during 2002–2011 (Table 4)

Table 4.

Distribution of Chinese institutes publishing papers on hepatic encephalopathy indexed in Web of Science during 2002–2011

Highly cited papers on hepatic encephalopathy indexed in Web of Science during 2002–2011

Within the 3 233 retrieved papers on hepatic encephalopathy indexed in Web of Science during 2002–2011, the paper “Hepatic encephalopathy-definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11^th World Congresses of Gastroenterology, Vienna, 1998” was the most cited, with 517 citations. Of the journals examined, Hepatology published the most papers on hepatic encephalopathy. Five other highly cited papers were also from Hepatology. Therefore, Hepatology appears to represent a key journal for publishing papers on hepatic encephalopathy (Table 5).

Table 5.

Ten top-cited papers on hepatic encephalopathy indexed in Web of Science during 2002–2011

DISCUSSION

The pathological mechanisms of hepatic encephalopathy involve severe hepatic damage or portosystemic venous shunting. Substances that can be effectively metabolized and play an important role in nerve functioning under normal circumstances are increased in brain tissue in hepatic encephalopathy patients, leading to various nervous system changes, which correspond with neurotransmitter system dysfunction and result in nervous system dysfunction.

The present bibliometric analysis on hepatic encephalopathy reported an overview of research progress, identifying outstanding institutes and experts in the research field. Neuroelectrophysiological and neuroimaging examinations have been used to determine clinical classification and disease severity of hepatic encephalopathy, providing helpful information for further scientific research on hepatic encephalopathy. Increasing understanding of the pathological mechanisms underlying hepatic encephalopathy via large-scale multi-center randomized clinical validation of various therapeutic measures will be important for developing improved therapeutic approaches.