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Correlation of ammonia and blood laboratory parameters with hepatic encephalopathy: A systematic review and meta-analysis
Correlation of blood ammonia and hepatic encephalopathy
Sepehrinezhad Ali Conceptualization Data curation Investigation Methodology Project administration Visualization Writing – original draft 1 2
Moghaddam Negin Ghiyasi Conceptualization Formal analysis Methodology Writing – original draft 1
Shayan Navidreza Conceptualization Data curation Methodology Writing – original draft 1
https://orcid.org/0000-0002-2242-9794
Sahab Negah Sajad Data curation Formal analysis Methodology Project administration Supervision Validation Writing – review & editing 1 2 3 *
1 Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
3 Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran
Starkel Peter Editor
Cliniques Universitaires Saint-Luc, BELGIUM
Competing Interests: The authors have declared that no competing interests exist

* E-mail: sahabnegahs@mums.ac.ir
3 9 2024
2024
19 9 e030789914 3 2024
12 7 2024
© 2024 Sepehrinezhad et al
2024
Sepehrinezhad et al
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Background and objectives

Emerging research suggests that hyperammonemia may enhance the probability of hepatic encephalopathy (HE), a condition associated with elevated levels of circulating ammonia in patients with cirrhosis. However, some studies indicate that blood ammonia levels may not consistently correlate with the severity of HE, highlighting the complex pathophysiology of this condition.

Methods

A systematic review and meta-analysis through PubMed, Scopus, Embase, Web of Science, and Virtual Health Library were conducted to address this complexity, analyzing and comparing published data on various laboratory parameters, including circulating ammonia, blood creatinine, albumin, sodium, and inflammation markers in cirrhotic patients, both with and without HE.

Results

This comprehensive review, which included 81 studies from five reputable databases until June 2024, revealed a significant increase in circulating ammonia levels in cirrhotic patients with HE, particularly those with overt HE. Notably, significant alterations were observed in the circulating creatinine, albumin, sodium, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα) in HE patients.

Conclusions

These findings suggest an association between ammonia and HE and underscore the importance of considering other blood parameters such as creatinine, albumin, sodium, and pro-inflammatory cytokines when devising new treatment strategies for HE.

The author(s) received no specific funding for this work. Data AvailabilityAll relevant data are within the manuscript and its Supporting Information files.
Data Availability

All relevant data are within the manuscript and its Supporting Information files.
==== Body
pmcIntroduction

Hepatic encephalopathy (HE) is the main complication of advanced liver disease and portosystemic shunt that is characterized by the development of the broad spectrum of neurological and neuropsychiatric disturbances from minimal changes in cognitive performances in covert HE (CHE) to gross disorientation and motor system abnormalities in overt HE (OHE) [1–3]. HE is associated with lower patient quality of life, increasing disabilities, being the primary cause of ER hospitalization, and showing a poor prognosis [4, 5]. In patients with cirrhosis, the prevalence of CHE ranges from 20% to 80%; nevertheless, 40% of these patients experienced OHE [6–8].

Although the majority of studies agree that ammonia and inflammation are key factors in the pathophysiology of HE, the specific underlying mechanisms of HE remain unclear [9, 10]. It has been demonstrated that cirrhotic individuals with HE, had elevated blood levels of ammonia, often referred to as hyperammonemia conditions [9, 11, 12]. This condition increased cerebral uptake of ammonia in HE patients [13–15]. Ammonia, a byproduct produced by gut microbes during the breakdown of nitrogen-containing compounds, is detoxified by intact hepatocytes through the production of urea under physiological conditions [16]. Numerous studies suggest that hyperammonemia may predispose patients with cirrhosis to HE, and it is associated with the severity of HE [17–22]. However, conflicting findings have emerged from multiple studies, suggesting that circulating ammonia may not be a suitable marker for evaluating HE in cirrhotic patients [23–25]. It has been proposed that systemic inflammation and ammonia might synergistically promote the progression of HE following liver diseases [25–29]. In contrast, a research team found that systemic inflammation alone did not correlate with the development of HE [30] or cognitive impairments [31] in cirrhotic patients, and anti-inflammatory therapy did not improve cognitive deficits in HE rats [32]. Several studies have also identified INR, white blood cells, hyponatremia, bilirubin, and blood creatinine as potential risk factors for HE [33–36]. Despite recent investigations, the relationship between these blood parameters and HE remains a topic of ongoing discussion. Therefore, we conducted a comprehensive review and meta-analysis to elucidate any potential correlations between circulating ammonia levels, inflammation, and several laboratory parameters with HE, integrating and examining all available results.

Methods

Data sources and search

We conducted a systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. The literature review and search of PubMed, Scopus, Embase, Web of Science, and Virtual Health Library (VHL) were used to find all original studies until June 2024. Three investigators used the following Medical Subject Headings (MESH) terms in this study: "hepatic encephalopathy", "hepatic coma", "portal systemic encephalopathy", "hepatocerebral encephalopathy", "portosystemic encephalopathy", "ammonia", "hyperammonemia", and "hyperammonemic". A combination of these terms was investigated using an advanced search in the aforementioned databases (S2 Table in S1 File).

Study selection, data extraction and quality assessment

All extracted papers were exported into an Excel file and classified according to some properties and parameters including title, authors, publication year, age, country, ammonia, albumin, platelets, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), creatinine, hemoglobin, prothrombin time (PT), International Normalized Ratio (INR), sodium, white blood cell, Model for End-stage Liver Disease (MELD) score, and Child-Pugh score. Before the quality assessment, exported papers underwent two rounds of screening. Three investigators reviewed each title and abstract in Step 1 to make sure they met the inclusion criteria. At the subsequent stages, all investigators carefully evaluate the full text of extracted studies according to the following criteria. Following strict quality control (appraisal check), all case-control and cross-sectional studies reporting cirrhosis patients (of any etiology) with HE was included in this analysis. The following criteria must be met by all included studies: I. Cirrhosis and HE were determined according to a valid and reliable diagnosis method; II. Patients should not have undergone liver transplantation during the study; III. The study reported mean and SD for quantitative parameters; IV. The study should report the average levels of ammonia in the cirrhosis group and HE, V. The levels of ammonia in case and control groups should be measured by the same and reliable method. Case reports, correspondence, review papers, in vitro studies, animal studies, randomized controlled trials or interventional studies, letters, books, conference papers, and editorials were not included in this study. The Joanna Briggs Institute (JBI) critical appraisal checklist for case-control studies was used to assess the risk of bias. Papers with a score of 5–10 were considered for meta-analysis as high-quality papers.

Data analysis

All analyses were conducted by the Review Manager (RevMan) software ver. 5 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). The standardized mean differences for ammonia and other parameters were calculated and a random-effects analysis model was applied. Moreover, heterogeneity between studies was assessed using I2 criterion (I2 ≥75% specified substantial heterogeneity). Furthermore, a p-value of less than 0.05 is used as a statistical significance cutoff. We also performed a subgroup analysis based on HE types (MHE, CHE, and OHE) and the level of circulatory ammonia.

Results

A total of 25121 papers were included in our literature review (Fig 1). Following the application of our intended criteria and full-text screening, we selected 81 high-quality papers for final analysis (Table 1 and S3 Table in S1 File).

10.1371/journal.pone.0307899.g001 Fig 1 PRISMA flow chart of the systematic review that represents our literature review process.

PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

10.1371/journal.pone.0307899.t001 Table 1 Characteristics of total included studies for the meta-analysis.

Index	Author	Year	Country	Journal	Reference	
1.	Tran et al.	2021	USA	Journal of Neuroimaging	[37]	
2.	Ampuero et al.	2020	Spain	Liver International	[38]	
3.	Tsai et al.	2019	Taiwan	Scientific reports	[39]	
4.	Nardelli et al.	2019	Italy	Hepatology	[40]	
5.	Zhang et al.	2018	Germany	Korean Journal of Radiology	[41]	
6.	Lu et al.	2018	China	NeuroReport	[42]	
7.	Cheng et al.	2018	China	Metabolic Brain Disease	[43]	
8.	Zheng et al.	2017	China	European Radiology	[19]	
9.	Zhang et al.	2017	Germany	Brain Imaging and Behavior	[11]	
10.	Zhou et al.	2016	China	Gastroenterology Research and Practice	[44]	
11.	Thomsen et al.	2016	UK	PLOS ONE	[45]	
12.	Schiff et al.	2016	China	Hepatology	[46]	
13.	Iwasa et al.	2016	Japan	Metabolic Brain Disease	[47]	
14.	Rodríguez et al.	2015	USA	Liver International	[48]	
15.	Jao et al.	2015	Taiwan	NeuroImage	[49]	
16.	Barbosa et al.	2015	Portugal	Acta Médica Portuguesa	[50]	
17.	Zheng et al.	2014	China	BioMed Research International	[51]	
18.	Zhang et al.	2014	China	European Journal of Radiology	[52]	
19.	Felipo et al.	2014	Spain	World Journal of Gastroenterology	[53]	
20.	Zhang et al.	2013	China	PLOS ONE	[54]	
21.	Luo et al.	2013	China	Clinics and Research in Hepatology and Gastroenterology	[55]	
22.	Felipo et al.	2013	Spain	Liver International	[56]	
23.	Michalska et al.	2013	Poland	Gastroenterology Review	[57]	
24.	Ni et al.	2012	China	PLOS ONE	[58]	
25.	Luo et al.	2012	China	Hepatology Research	[59]	
26.	Srivastava et al.	2011	India	Journal of Gastroenterology and Hepatology	[60]	
27.	Gad et al.	2011	Egypt	Arab Journal of Gastroenterology	[61]	
28.	Sharma et al.	2010	India	Saudi Journal of Gastroenterology	[62]	
29.	Goel et al.	2010	India	Liver International	[63]	
30.	Montoliu et al.	2009	Spain	Journal of Clinical Gastroenterology	[64]	
31.	Montoliu et al.	2007	Spain	Journal of Molecular Medicine	[65]	
32.	Kundra et al.	2005	India	Clinical Biochemistry	[20]	
33.	Nicolao et al.	2003	Italy	Journal of Hepatology	[66]	
34.	Romero-Gómez et al.	2001	Spain	American Journal of Gastroenterology	[67]	
35.	Testa R et al.	1989	Italy	Italian journal of neurological sciences	[68]	
36.	McCLAIN, et al.	1980	USA	Gut	[69]	
37.	Reichert et al.	2020	Germany	Digestive Diseases	[70]	
38.	Abid et al.	2020	Pakistan	Scientific reports	[71]	
39.	Zeng et al.	2019	China	Journal of Gastroenterology and Hepatology	[72]	
40.	 Yousif et al.	2019	Egypt	Internal and Emergency Medicine	[73]	
41.	Yoon et al.	2019	Korea	Scientific Reports	[74]	
42.	Tan et al.	2019	China	British Journal of Biomedical Science	[75]	
43.	Sato et al.	2019	Japan	Internal Medicine Journal	[76]	
44.	Metwally et al.	2019	Egypt	European Journal of Gastroenterology & Hepatology	[77]	
45.	Li et al.	2019	China	Neuroradiology	[78]	
46.	Wang et al.	2017	China	World Journal of Gastroenterology	[79]	
47.	Coskun et al.	2017	Turkey	Turkish Journal of Gastroenterology	[80]	
48.	Jeong et al.	2017	Korea	Journal of Korean Medical Science	[81]	
49.	Ruiz-Margáin et al.	2016	Mexico	World Journal of Gastroenterology	[82]	
50.	Lauridsen et al.	2016	USA	Clinical Gastroenterology and Hepatology	[83]	
51.	Chen et al.	2016	China	Scientific Reports	[84]	
52.	Tsai et al.	2015	Taiwan	PLOS One	[85]	
53.	Riggio et al.	2015	Italy	Clinical Gastroenterology and Hepatology	[86]	
54.	Wei Li et al.	2015	China	Hepatology International	[87]	
55.	Jindal et al.	2015	India	Digestive and Liver Disease	[88]	
56.	Patidar et al.	2014	USA	American Journal of Gastroenterology	[89]	
57.	Kircheis et al.	2014	Germany	Gastroenterology	[90]	
58.	Hassan et al.	2014	Egypt	Arab Journal of Gastroenterology	[91]	
59.	Cona et al.	2014	Italy	Clinical Neurophysiology	[92]	
60.	Zhang et al.*	2013	China	 American Journal of Gastroenterology	[93]	
61.	Merli et al.	2013	Italy	Metabolic Brain Disease	[94]	
62.	Li et al.	2013	China	World Journal of Gastroenterology	[95]	
63.	Sharma et al.	2012	India	Saudi Journal of Gastroenterology	[96]	
64.	Wunsch et al.	2011	Poland	Liver International.	[97]	
65.	Riggio et al.	2011	Italy	Clinical Gastroenterology and Hepatology	[98]	
66.	Duarte-Rojo et al.	2011	Mexico	Digestive Diseases and Sciences	[99]	
67.	Tan et al.	2009	Singapore	Singapore Medical Journal	[100]	
68.	Kircheis et al.	2009	Germany	Gastroenterology	[101]	
69.	Sugimoto et al.	2008	Japan	Official journal of the American College of Gastroenterology	[102]	
70.	Chakrabarti et al.	2002	Italy	Journal of Clinical Gastroenterology	[103]	
71.	Alvarez-Leal et al.	2001	Mexico	American Journal of Human Biology	[104]	
72.	Lee et al.	1999	Korea	 American Journal of Gastroenterology	[105]	
73.	Zheng et al.	2013	China	European Journal of Radiology	[106]	
74.	Tao et al.	2013	China	European Journal of Radiology	[107]	
75.	Iversen et al.	2014	Denmark	Frontiers in Neuroscience	[108]	
76.	Kooka et al.	2016	Japan	Hepatology Research	[109]	
77.	Garcia-Garcia et al.	2017	Spain	PLOS ONE	[110]	
78.	Formentin et al.	2019	Italy	Journal of Hepatology	[111]	
79.	Mangini et al.	2023	Italy	Digestive and Liver Disease	[112]	
80.	Kapoor et al.	2023	India	Turk J Gastroenterol	[113]	
81.	Fiorillo et al.	2023	Spain	International Journal of Molecular Sciences	[114]	

The studies included two groups of patients: a control group (cirrhosis patients without HE) and a case group (cirrhosis patients with HE). Sixty-three publications were suitable for determining the standardized mean difference in ammonia between HE (N = 1771) and control (N = 2558) groups (Fig 2). We compared the circulatory levels of ammonia in the HE groups—which included all HE types, including MHE, CHE, and OHE—to the control group in these analyses. The mean circulating ammonia in the cirrhosis with HE group was 127.676μg/dl compared to 92.503μg/dl in cirrhosis without HE individuals. There was high heterogeneity in this analysis; however, the forest plot of the included studies using random-effect analysis showed a significant increase in the mean difference of ammonia levels in the HE groups compared to the control (P < 0.00001; I2 = 90%; Fig 2).

10.1371/journal.pone.0307899.g002 Fig 2 Forest plot for estimating the association of circulatory ammonia and HE.

A random-effect model was used to compare the standardized mean difference of ammonia between groups. The below funnel plot represents potential publication bias in the study. HE: Hepatic encephalopathy.

Subgroup analysis was then used to compare the ammonia levels between the control group and several types of HE. To compare the ammonia levels between MHE (N = 874) and control (N = 1199) groups, twenty-nine studies were enrolled (Fig 3A). The mean circulating level of ammonia in the cirrhosis with MHE group was 125.19μg/dl compared to 106.482μg/dl in cirrhosis without HE individuals. The standardized mean difference of ammonia was significantly elevated in MHE group compared to cirrhosis-control (P < 0.0001; I2 = 91%; Fig 3A). Moreover, eight papers were included for analyzing ammonia levels between CHE (N = 263) and control (N = 559) groups. The mean circulating level of ammonia in the cirrhosis with CHE group was 95.15μg/dl compared to 85.94μg/dl in cirrhosis without HE individuals. The results showed that there was no statistical difference in ammonia levels between the groups (P = 0.27; I2 = 95%; Fig 3B). Twelve articles were subjected to another comparison of average ammonia levels between the control (N = 330) and OHE (N = 280) groups. The mean circulating level of ammonia in the cirrhosis with OHE group was 138.60μg/dl compared to 71.57μg/dl in cirrhosis without HE volunteers. Ammonia levels in the circulation were significantly higher in the OHE group (P < 0.00001; I2 = 83%; Fig 3C).

10.1371/journal.pone.0307899.g003 Fig 3 Forest plot for estimating the association of circulatory ammonia and type of HE.

A random-effect model was used to compare the standardized mean difference of ammonia between groups. Comparing average levels of ammonia between cirrhotic patients without HE and cirrhotic patients with minimal HE (a), cirrhotic patients with covert HE (b), and cirrhotic patients with overt HE (c). Funnel plots represent potential publication bias. HE: Hepatic encephalopathy.

Our analysis of 31 studies (2700 participants) revealed that patients with cirrhosis and HE had a mean creatinine level of 1.057mg/dl, significantly higher than the 0.939mg/dl observed in cirrhosis patients without HE. (P < 0.0001; I2 = 48%; Fig 4A). Fifty-three papers were used to compare the albumin levels between groups (4627 participants). The circulatory levels of albumin were significantly lower in cirrhotic patients with HE (mean = 3.19g/dl) in comparison to cirrhotic control (mean = 3.59g/dl) group (P < 0.00001; I2 = 85%; Fig 4B). Our meta-analysis of 22 studies (2683 participants) revealed significantly lower blood sodium levels in cirrhotic patients with HE (mean = 135.977 mEq/L) compared to cirrhotic controls without HE (mean = 137.69 mEq/L; P < 0.00001). Notably, low heterogeneity was observed across studies for this parameter (I2 = 64%; Fig 4C).

10.1371/journal.pone.0307899.g004 Fig 4 Forest plot for estimating the standardized mean difference of circulatory creatinine (a), albumin (b) and sodium (c) between control and HE groups. A random-effect model was used in the meta-analysis. Funnel plots represent potential publication bias.

On the other hand, in 12 enrolled papers (611 participants), blood interleukin-6 (IL-6) levels in cirrhotic patients with HE were higher than those in cirrhotic controls (P < 0.00001; I2 = 89%; Fig 5A). Furthermore, 5 studies were included to compare the circulating levels of tumor necrosis factor-alpha (TNFα) between both groups (313 participants). The average levels of TNFα were significantly increased in HE patients compared to control (P < 0.00001; I2 = 55%; Fig 5B).

10.1371/journal.pone.0307899.g005 Fig 5 Forest plot for estimating the standardized mean difference of IL-6 (a), and TNFα (b) between control and HE groups. Funnel plots represent potential publication bias.

Discussion

The pathophysiology of HE is not fully understood, and its prognosis is not very well in cirrhosis. Moreover, the association between elevated blood ammonia levels and the severity of HE remains controversial, despite reports suggesting these levels are a major predictor of hospitalization and mortality in individuals with advanced liver disease and liver failure [115–117]. This meta-analysis confirmed elevated levels of blood ammonia are associated with the development of HE in patients with cirrhosis. Surprisingly, the ammonia levels were raised in cirrhotic patients independent of the type of HE. However, this observation was more reliable in individuals with OHE as they showed lower heterogeneity. This could indicate that hyperammonemia mediated the progression of HE from subtle cognitive changes to severe personality changes and gross disorientation that has been found in patients with OHE [118, 119]. We must emphasize that our data confirmed the notion that patients with HE had significantly higher MELD score, Child-Pugh score, bilirubin, ALT, AST, and GGT (Supplementary results in S1 File). Due to poor prognosis associated with HE, we proceeded to our meta-analysis centered on multiple laboratory data to identify potential predictors for that. This study is the first systematic review and meta-analysis comparing levels of circulating ammonia, creatinine, albumin and sodium between cirrhotic patients with HE and cirrhotic volunteers without HE. Another intriguing observation is that patients with HE exhibited elevated average circulating creatinine levels. Studies have demonstrated a correlation between abnormal blood creatinine levels and the severity of HE, particularly in patients with hepatitis C [120]. The raised in blood creatinine is associated with kidney injury and mortality in cirrhotic patients [121]. Moreover, a retrospective study has demonstrated a correlation between higher circulating creatinine levels and hospital mortality in cirrhosis patients with HE [122]. The mechanism underlying kidney damage following cirrhosis is likely due to hemodynamic impairments. A series of these impairments, including portal hypertension, arterial vasodilation, ascites, hypotension, increased cardiac output, hypovolemia, activation of the renin-angiotensin-aldosterone system, and renal vasoconstriction, are considered to contribute to the development of kidney injury and renal dysfunction in the context of cirrhosis [123–125]. The meta-analysis also showed that cirrhotic patients with HE had decreased circulating albumin and sodium levels compared to individuals without HE. The results of multiple investigations showed that albumin infusion improved survival and decreased the mortality risk and progression of OHE in cirrhotic patients [126–128]. The purpose of albumin infusion in cirrhotic patients with HE is to promote plasma expansion, bind to toxic blood components, enhance antioxidant capacity, and have anti-inflammatory properties [129–132]. Consequently, hypoalbuminemia, which is induced by the depletion of hepatocyte mass, may function as a clinical indicator of hepatic encephalopathy (HE) and its severity in cirrhosis. In comparison to the control group, we noted a decrease of approximately 1.8 mEq/L in the average blood sodium levels in patients with HE. Notwithstanding, the blood sodium concentrations in both groups remained within the normal range of 135–145 mEq/L. It’s important to note that hyponatremia occurs when blood sodium levels fall below 135 mEq/L. In individuals with cirrhosis, hyponatremia is associated with increased morbidity and mortality as well as a higher grade of HE [133]. Additionally, cirrhotic patients who had blood sodium levels below 135 mEq/L were more likely to have HE [134]. In more than 75% of cirrhotic individuals with HE, hyponatremia has been seen, and more importantly, the reduction of blood sodium concentration was associated with the main consequences of cirrhosis, including ascites, coagulopathy, and spontaneous bacterial peritonitis [135]. Even when blood sodium reduction is within normal limits, its value should still be closely monitored in the circulation of patients with cirrhosis in terms of the potential occurrence of HE. The results of the current meta-analysis also revealed exacerbation of systemic inflammation in cirrhotic patients with HE, as evidenced by significantly elevated circulating levels of TNFα and IL-6. There is increasing evidence that in addition to ammonia, brain dysfunction following cirrhosis is also caused by systemic inflammatory response syndrome [136, 137]. Systemic inflammation is also associated with severity of MHE and progression to OHE [25, 64, 138]. Nevertheless, other research groups have demonstrated that cirrhosis does not necessarily lead to HE, and cognitive deficits are not solely due to inflammation [30, 31]. There is greater agreement among studies regarding the synergistic roles of inflammation and ammonia in the development of HE, and its severity in cirrhosis [31, 138–140]. This meta-analysis clearly demonstrated that a substantial enhancement of these two factors in cirrhotic individuals with HE in comparison to cirrhotic volunteers without HE. While several factors appear to contribute to the pathophysiology of, HE due to multifactorial nature of disease, rapid identification of blood diagnostic laboratory parameters that revealed in this study may enable physicians and researchers to stop the course of disease more quickly. The primary limitation of this study is the significant heterogeneity observed in several examined parameters. This heterogeneity primarily stems from methodological variations across the papers, including disparities in reported units that necessitated conversion, differences in sample sizes, and geographic locations.

Conclusion

This study has found a strong link between ammonia levels in the blood and HE in cirrhotic patients, particularly in OHE. Additionally, it is essential to closely monitor follow-up levels of creatinine, albumin, sodium, and systemic inflammation, as these may serve as significant prognostic indicators for hospital mortality and the progression of HE in cirrhosis patients. It is worth noting that because HE is a complex disease with multiple factors at play, relying solely on ammonia-scavenging strategies for treatment is not recommended. Instead, exploring novel approaches that target inflammation, creatinine, albumin, sodium, and ammonia levels in the bloodstream may be more beneficial.

Supporting information

S1 File (DOCX)

S1 Fig Forest plot for estimating the standardized mean difference of Child-Pugh, and MELD scores between control and HE groups.

(TIF)

S2 Fig Forest plot for estimating the standardized mean difference of circulatory PT and values of INR between control and HE groups.

(TIF)

S3 Fig Forest plot for estimating the standardized mean difference of circulatory total bilirubin between control and HE groups.

(TIF)

S4 Fig Forest plot for estimating the standardized mean difference of circulatory ALT, AST, and GGT between control and HE groups.

(TIF)

S5 Fig Forest plot for estimating the standardized mean difference of hemoglobin, platelets and white blood cells between control and HE groups.

(TIF)

10.1371/journal.pone.0307899.r001
Decision Letter 0
Starkel Peter Academic Editor
© 2024 Peter Starkel
2024
Peter Starkel
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version0
10 May 2024

PONE-D-24-09594Correlation of Ammonia and Blood Laboratory Parameters with Hepatic Encephalopathy: A Systematic Review and Meta-AnalysisPLOS ONE

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Additional Editor Comments:

In particular reviewer 2 raised serious concerns regarding several methodological aspects. Those concerns need to be thoroughly addressed and the required changes and adaptations need to be made to the manuscript. This likely requires additional work and potentially re-analysis of the data. All changes must be clearly highlighted in the paper and a complete and detailed point by point reply explaining how the criticism has been addressed needs to be provided if the authors opt for revision of their paper.

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #2: No

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Reviewer #1: Hepatic encephalopathy seen in liver cirrhosis is thought to involve multiple factors, with ammonia believed to play a central role. However, there are reports suggesting that the pathophysiology of hepatic encephalopathy cannot be accurately assessed based solely on blood ammonia levels. The authors conducted a meta-analysis of 79 studies, investigating not only the correlation between hepatic encephalopathy and blood ammonia levels in liver cirrhosis but also its association with creatinine, albumin, sodium, IL-6, and TNF-α concentrations. As a result, cases with hepatic encephalopathy showed significantly elevated levels of ammonia, creatinine, IL-6, and TNF-α, while albumin and sodium levels were significantly lower. Therefore, the authors concluded that relying solely on targeting ammonia in the treatment of hepatic encephalopathy might not be sufficient and suggested a new strategy involving addressing inflammation, creatinine, albumin, and sodium concentrations. This conclusion is supported by a comprehensive examination of numerous cases using appropriate methods. However, there are several points that warrant further discussion.

The authors also note significant variability in ammonia levels. One possible cause is the variation in ammonia reference values among studies. In multicenter studies involving ammonia levels, some use ratios to the upper limit of the reference value rather than raw data. It would be beneficial to address how this aspect is evaluated.

Blood ammonia levels are not necessarily an appropriate indicator for evaluating hepatic encephalopathy, partly because many of the examined ammonia values are from venous blood samples. Venous blood ammonia, being detoxified through the glutamine synthesis pathway in skeletal muscles, tends to be lower than arterial blood levels. However, since the ammonia entering the brain is transported by arterial blood, venous blood ammonia levels may not accurately reflect the concentration of ammonia flowing into the brain. This issue also warrants discussion in the analysis.

Reviewer #2: In this paper, Sepehrinezhad A and coll. attempted to synthetize the correlation of blood ammonia with hepatic encephalopathy in a meta-analysis. I have major concerns about the methodology of this paper, particularly regarding the literature search, the criteria for inclusion and exclusion of studies which are missing and the statistical analyses. Key search terms must be noted in the main text and must be combined within each database (not done), abstracts from liver congresses are usually screened (not done), literature search must be updated in April 2024 and some studies were not identified. In order to reduce risk of bias, strict criteria for inclusion and exclusion of studies must be clearly defined prior to the literature search. Also, aims of the study and endpoints are missing in the text. The selection of the studies for inclusion in the metaanalysis includes usually 4 processes which is mandatory to preserve: identification, screening, eligibility (missing) and inclusion (Fig 1). Regarding statistical analysis, I2 alone is not enough to assess heterogeneity between studies. Moreover, in cases of moderate or high heterogeneity, the methodological section of each study is usually re-reviewed to determine whether any discrepancy could be identified, and sensitivity analyses excluding the discrepant study is classically performed (not done). Therefore, because the methodology and statistical analyses were not complete and rigorous, I recommend rejecting this article.

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10.1371/journal.pone.0307899.r002
Author response to Decision Letter 0
Submission Version1
5 Jul 2024

To: 5th, July, 2024

To: PLOS ONE, Editor-in-Chief

Dear Editor-in-Chief

We would like to express our appreciation to the reviewer for his/her insightful comments, which have significantly helped us improve our manuscript. We have incorporated your feedback into our revisions, and we believe that your comments have helped to clarify and strengthen our paper. Please find our responses to your specific comments below (in blue), and note that the revised text in the manuscript is highlighted in blue for your convenience.

Reviewer #1:

Hepatic encephalopathy seen in liver cirrhosis is thought to involve multiple factors, with ammonia believed to play a central role. However, there are reports suggesting that the pathophysiology of hepatic encephalopathy cannot be accurately assessed based solely on blood ammonia levels. The authors conducted a meta-analysis of 79 studies, investigating not only the correlation between hepatic encephalopathy and blood ammonia levels in liver cirrhosis but also its association with creatinine, albumin, sodium, IL-6, and TNF-α concentrations. As a result, cases with hepatic encephalopathy showed significantly elevated levels of ammonia, creatinine, IL-6, and TNF-α, while albumin and sodium levels were significantly lower. Therefore, the authors concluded that relying solely on targeting ammonia in the treatment of hepatic encephalopathy might not be sufficient and suggested a new strategy involving addressing inflammation, creatinine, albumin, and sodium concentrations. This conclusion is supported by a comprehensive examination of numerous cases using appropriate methods. However, there are several points that warrant further discussion. The authors also note significant variability in ammonia levels. One possible cause is the variation in ammonia reference values among studies. In multicenter studies involving ammonia levels, some use ratios to the upper limit of the reference value rather than raw data. It would be beneficial to address how this aspect is evaluated. Blood ammonia levels are not necessarily an appropriate indicator for evaluating hepatic encephalopathy, partly because many of the examined ammonia values are from venous blood samples. Venous blood ammonia, being detoxified through the glutamine synthesis pathway in skeletal muscles, tends to be lower than arterial blood levels. However, since the ammonia entering the brain is transported by arterial blood, venous blood ammonia levels may not accurately reflect the concentration of ammonia flowing into the brain. This issue also warrants discussion in the analysis.

Our response: Thank you for your valuable comment. Based on various clinical studies, it has been observed that both venous and arterial ammonia levels have strong correlations with the severity of hepatic encephalopathy. Some studies even suggest a venous sample is adequate for measuring ammonia levels. Additionally, since arterial ammonia levels are higher than venous levels, it is believed that the venous level can accurately represent the level that may lead to brain injury, as arterial ammonia reaches the brain more quickly. Therefore, venous ammonia levels can be considered as reliable biomarkers. Thus, it appears that our systematic review and meta-analysis can overlook the kind of arterial and venous sampling used for ammonia measurement.

Mehmood, M. A., T. Waseem, F. Z. Ahmad, and M. A. Humayun. "Measuring partial pressure of ammonia in arterial or venous blood vs total ammonia levels in hepatic encephalopathy." J. Gastroenterol. Hepatol 2 (2013): 602.

Nicolao, Francesca, Cesare Efrati, Andrea Masini, Manuela Merli, Adolfo Francesco Attili, and Oliviero Riggio. "Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy." Journal of hepatology 38, no. 4 (2003): 441-446.

Ong JP, Aggarwal A, Krieger D, Easley KA, Karafa MT, Van Lente F, Arroliga AC, Mullen KD. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med. 2003 Feb 15;114(3):188-93. doi: 10.1016/s0002-9343(02)01477-8. PMID: 12637132.

K.N, Sricharan and Shifali Prabhaker. “Arterial vs Venous Ammonia Levels in Correlation with severity of Hepatic Encephalopathy.” International Journal of Contemporary Medical Research [IJCMR] (2019): n. pag.

Reviewer #2:

In this paper, Sepehrinezhad A and coll. attempted to synthetize the correlation of blood ammonia with hepatic encephalopathy in a meta-analysis. I have major concerns about the methodology of this paper, particularly regarding the literature search, the criteria for inclusion and exclusion of studies which are missing and the statistical analyses. Key search terms must be noted in the main text and must be combined within each database (not done), abstracts from liver congresses are usually screened (not done), literature search must be updated in April 2024 and some studies were not identified. In order to reduce risk of bias, strict criteria for inclusion and exclusion of studies must be clearly defined prior to the literature search. Also, aims of the study and endpoints are missing in the text. The selection of the studies for inclusion in the metaanalysis includes usually 4 processes which is mandatory to preserve: identification, screening, eligibility (missing) and inclusion (Fig 1). Regarding statistical analysis, I2 alone is not enough to assess heterogeneity between studies. Moreover, in cases of moderate or high heterogeneity, the methodological section of each study is usually re-reviewed to determine whether any discrepancy could be identified, and sensitivity analyses excluding the discrepant study is classically performed (not done). Therefore, because the methodology and statistical analyses were not complete and rigorous, I recommend rejecting this article.

Our response: I appreciate your attention to detail and thoughtful critique of the methodology used in this study. As you we have suggested, expanded our literature search to include publications up to June 2024 and have incorporated our key search terms into the main body of the revised manuscript. The primary keyword search pattern for each database is now available in Supplementary Table 2. For the following comment “abstracts from liver congresses are usually screened (not done)”, as we mentioned in the Prisma flowchart, we excluded abstracts from the conference because they didn’t have enough data for concluding as well as there weren’t inclusion criteria for the conference paper.

For the comment “In order to reduce risk of bias, strict criteria for inclusion and exclusion of studies must be clearly defined prior to the literature search”, I would like to confirm that we have implemented these measures. We established general exclusion criteria, which included non-English papers, abstracts, and reviews. Additionally, we only included studies that met the following specific criteria: i) studies that compared cirrhosis with hepatic encephalopathy, ii) the use of a valid evaluation method, iii) a valid and clear definition of cases, and iv) the measurement of outcomes using a reproducible and reliable method.

To further minimize the risk of bias, we conducted an appraisal utilizing the Joanna Briggs Institute (JBI) critical appraisal checklist for case-control studies. This approach shows that an appraisal checklist can effectively mitigate the risk of bias in studies with poor methodology.

In the comment, "The selection of the studies for inclusion in the meta-analysis involves four mandatory processes: identification, screening, eligibility (missing), and inclusion (Fig 1)," the eligibility of studies was assessed at three levels: general criteria, PICO criteria, and outcome measurements. For instance, we considered Population (i.e., cirrhosis and hepatic encephalopathy), Comparison (HE as the case and cirrhosis as the control), and Outcome (e.g., serum biomarkers). Given that our manuscript focused on evaluating observational studies, we intentionally refrained from providing a specific definition of intervention; instead, we exclusively included observational studies.

Regarding the comment, "I2 alone is not sufficient to assess heterogeneity between studies in statistical analysis. In cases of moderate or high heterogeneity, the methodological section of each study is usually re-reviewed to identify discrepancies, and sensitivity analyses excluding the discrepant study are typically performed (not done)," we precisely reviewed the methodology of each study and focused on the assessment methods, such as the evaluation of inflammatory markers using the Eliza method. Additionally, we only included similar studies in the sub-analysis that differed in one variable.

I believe the major comments on the methodology were due to the concise nature of this part. The manuscript's word limitation was the main challenge we encountered. Following the aforementioned details, we have provided a comprehensive description of the comments in the supplementary document.

Sincerely yours

Dr. Sajad Sahab Negah, PhD Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Pardis Campus, Azadi Square, Kalantari Blvd., Mashhad, Iran. Tel: +98-51-38002473; Email: sahabnegahs@mums.ac.ir

Attachment Submitted filename: Responses to reviewers.pdf

10.1371/journal.pone.0307899.r003
Decision Letter 1
Starkel Peter Academic Editor
© 2024 Peter Starkel
2024
Peter Starkel
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version1
15 Jul 2024

Correlation of Ammonia and Blood Laboratory Parameters with Hepatic Encephalopathy: A Systematic Review and Meta-Analysis

PONE-D-24-09594R1

Dear Dr. Sahab Negah,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Additional Editor Comments (optional):

Data have been updated and sufficient clarifications concerning the methods used have been provided.

Reviewers' comments:

10.1371/journal.pone.0307899.r004
Acceptance letter
Starkel Peter Academic Editor
© 2024 Peter Starkel
2024
Peter Starkel
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
23 Jul 2024

PONE-D-24-09594R1

PLOS ONE

Dear Dr. Sahab Negah,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

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on behalf of

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==== Refs
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