1. bookVolumen 76 (2022): Heft 1 (January 2022)
Zeitschriftendaten
License
Format
Zeitschrift
eISSN
1732-2693
Erstveröffentlichung
20 Dec 2021
Erscheinungsweise
1 Hefte pro Jahr
Sprachen
Englisch
access type Uneingeschränkter Zugang

S100 Beta Protein as a Marker of Hepatic Encephalopathy: A Breakthrough in Diagnostics or a False Trail? Review of the Literature.

Online veröffentlicht: 06 Apr 2022
Volumen & Heft: Volumen 76 (2022) - Heft 1 (January 2022)
Seitenbereich: 128 - 131
Eingereicht: 17 Aug 2021
Akzeptiert: 08 Feb 2022
Zeitschriftendaten
License
Format
Zeitschrift
eISSN
1732-2693
Erstveröffentlichung
20 Dec 2021
Erscheinungsweise
1 Hefte pro Jahr
Sprachen
Englisch
Abstract

Hepatic encephalopathy is a dysfunction of the central nervous system caused by chronic and acute liver disease. The dysfunction presents a wide spectrum of symptoms—from the undetectable in a standard clinical examination to hepatic coma—and could be caused by both chronic and acute liver diseases. For many years research has been conducted to find a marker that would allow for the accurate, quick, and possibly inexpensive detection of hepatic encephalopathy. Due to the pathogenesis of hepatic encephalopathy, researchers’ attention is focused on markers of damage to the central nervous system. One of the markers of astrocyte damage, known from research in neurology and neurosurgery, is the protein S100B. Published research results so far are inconclusive, but they allow us to look with optimism at the role of S100B as a marker of minimal hepatic encephalopathy (MHE).

Introduction

Hepatic encephalopathy (HE) is a complication of acute and chronic liver diseases as well as portal-systemic bypass surgery [1]. It is defined as a complex of psychological disorders related to the nervous and musculoskeletal systems. These disorders are potentially reversible. Hepatic encephalopathy is associated with several symptoms that have a significant impact on health-related quality of life [2]. These symptoms include the following: deterioration of cognitive functions, disturbed sleep-wake rhythm, muscle tremors, memory disorders, and an extended reaction time to stimuli.

According to the recommendations of the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) [1], the qualification of hepatic encephalopathy should include four factors. These are: the relationship with the underlying disease, the severity of clinical manifestation, the duration of the course, and the presence of triggering factors. Due to the relationship with the underlying disease, hepatic encephalopathy is divided into type A – in the course of acute hepatic failure; type B – in the course of the dominant portal-systemic bypass flow or leak; and type C – in the course of cirrhosis. The classification of encephalopathy according to the severity of clinical manifestation takes into account the West Haven (WHC) classification and the International Society for Hepatic Encephalopathy (ISHEN) classification. Minimal hepatic encephalopathy (MHE) is the most challenging for clinicians, due to the lack of overt symptoms. Depending on its duration, HE can be divided into episodic, recurrent, and chronic form. HE can also be divided on the basis of presence of triggering factors, such as gastrointestinal bleeding, infections, electrolyte disturbances, constipation, and overdose of diuretics. All four factors should be used to fully assess a patient with HE.

Due to the increasing clinical importance of HE, it has become very important to search for a biomarker that would allow easier identification of patients with hepatic encephalopathy, especially in its minimal form. The most commonly used biomarker of HE in clinical practice is ammonia. This is due to the participation of ammonia in the pathogenesis of hepatic encephalopathy (it causes damage to the blood-brain barrier, which enables the penetration of other toxins into the central nervous system [CNS], and is also converted into glutamine in astrocytes, which leads to astrocyte edema). Its availability in hospital laboratories is also a factor. However, the role of ammonia is limited. Elevated serum ammonia levels are also observed in patients with cirrhosis without encephalopathy [3], and no correlation between ammonia concentration and hepatic encephalopathy has been proven [4]. Ammonia level in serum is also influenced by the patient’s age, physical activity, and smoking [5]. The technical aspect of preparing the material for the study also poses significant difficulties. False neurotransmitters (phenylethanolamine, octopamine, synephrine) also seem to play important roles in the pathogenesis of HE. However, their determination is currently not possible in clinical practice.

The search for a biomarker that can accurately and easily identify patients with hepatic encephalopathy, including minimal encephalopathy, is ongoing. It would also be beneficial to correlate its level with the severity of the disease and its applicability to monitoring responses to therapy. As HE mainly concerns the nervous system, the search for the desired biomarker is related to the function of this system.

The pathomechanism of hepatic encephalopathy is not yet fully understood. It has been proven that it is characterized by damage to the blood-brain barrier, which increases the concentration of ammonia and false neurotransmitters in the brain. False neurotransmitters displace real neurotransmitters (dopamine, noradrenaline) from synaptic connections, causing neuronal dysfunction. The increase in the concentration of ammonia in the brain leads, in addition to the increased production of false neurotransmitters, to an increase in the concentration of glutamine and glutamate in neurons and astrocytes [6]. This results in an increase in the osmotic pressure and the inflow of water to these cells, and leads to their swelling. The relationship of hepatic encephalopathy with edema of astrocytes contributes to research on the possibility of using molecules previously used in neurological diagnostics to diagnose and monitor hepatic encephalopathy.

One of the markers of astrocyte damage, known from research in neurology and neurosurgery, is the protein S100B. The S100B protein belongs to the S100 family of proteins: small, acidic, calcium-ion-binding proteins that are found in many tissues of the body. They were first identified in high concentrations in the brain structures of various mammalian species in 1965 [7]. It has a dimeric structure, consisting of two subunits (alpha and beta). The S100B protein is found mainly in astroglia and Schwann cells [8], but is not only specific to the brain. It is produced in a smaller amount by adipose tissue, skin, and T lymphocytes [9]. Its concentration in the brain is by far the highest of any system. This protein is metabolized in the kidneys and excreted in the urine [10]. There were no differences in protein expression between ethnic groups, gender, or the daily cycle [11].

The serum concentration of S100B protein under normal conditions does not exceed 01 micg/l. The increase in its concentration is observed in the case of damage and activation of astrocytes. The kinetics of the increase in serum S100B protein levels in trauma-related brain injuries [12] and in ischemic strokes [13] have been most accurately investigated. Research has also been conducted on the use of S100B as a marker of epilepsy, schizophrenia, and Creutzfeldt-Jakob disease [14].

REVIEW OF THE LITERATURE

Studies on the use of the S100B protein level in EW are scarce. In 1999, Wiltfang et al. [15] investigated the level of S100B in 36 patients with portal-systemic encephalopathy confirmed by psychometric tests and clinical examination. The group consisted of patients with overt and latent HE. High specificity and sensitivity (56.5% and 100%, respectively) of the S100BP level in the detection of HE on the substrate of portal systemic leak were found. The study also showed the advantage of S100BP level determination over ammonia level in detecting this type of hepatic encephalopathy.

Vaquero et al. [16], using material from the US Acute Liver Failure Study serum bank, tested S100B protein levels in 54 random samples taken on days one and three of the study. The randomly selected patients were divided into groups according to the advancement of HE. S100B protein levels were elevated in all samples but did not correlate with the severity of encephalopathy and liver function.

In a study by Saleh et al. conducted in 2007 [17], 52 patients were divided into 3 groups: patients with liver cirrhosis without encephalopathy, patients with liver cirrhosis and hepatic encephalopathy, and healthy controls. A significant correlation was found between the level of S100B protein in patients with HE (stages I and II), compared to healthy and cirrhotic patients without HE. Based on the obtained results, the authors concluded that S100B may be a valuable marker signaling the initial stages of HE.

In a study published in the next year, Isobe-Harima et al. [18] investigated the levels of S100B in patients with fulminant hepatitis. Nine patients with fulminant hepatitis of various etiologies (HBV, drug-induced, and indeterminate) were included in the study. All patients presented symptoms of overt hepatic encephalopathy. A significantly higher level of S100B in HE patients has been proven, but its influence on prognosis has been noted.

Duarte Rojo et al. [19] analyzed the level of S100B in 61 patients (46 with cirrhosis and a 15-person control group) divided into 4 homogeneous groups: healthy, with cirrhosis without encephalopathy, with cirrhosis with overt hepatic encephalopathy and with cirrhosis of the liver with latent hepatic encephalopathy. The explicit HE was determined on the basis of WHC, while the latent HE was determined on the basis of the psychometric hepatic encephalopathy score (PHES) and Critical Flicker Frequency (CFF). S100B serum levels were found to be significantly higher in patients with cirrhosis than in healthy subjects and it was elevated in patients with HE. The obtained data confirmed the possibility of using the serum level of S100B as a marker of the initial stages of HE.

In turn, Strebel et al. [20] analyzed the studies of 30 patients divided into groups with overt and with minimal hepatic encephalopathy (based on PSE and CFF), assessing, among other things, S100B protein level before treatment initiation and after 6 days of ornithine aspartate (LOLA) therapy. Elevated S100B levels were observed in 63% of patients, 46% of MHE patients, and 80% of OHE patients, respectively. There was no correlation between the level of the protein tested and the severity of HE. There was also no change in the level of S100B after 6 days of LOLA therapy.

Studies on the use of the S100B protein level as a biomarker of hepatic encephalopathy were also conducted in children with acute childhood hepatic insufficiency (PALF). Toney et al. [21] analyzed data from a multicenter study conducted in the USA, which enrolled 82 children with PALF, finding a significant increase in the level of the S100B protein in the serum correlating with the presence of HE. The authors suggest that the level of S100B can be used as a biomarker in the assessment of the neurological status of PALF patients.

Qualification of hepatic encephalopathy; WHC - West Haven Classification, ISHEN - International Society for Hepatic Encephalopathy.

CONNECTION WITH THE UNDERLYING DISEASE DURATION PRESENCE OF TRIGGERING FACTORS WHC SEVERITY OF CLINICAL MANIFESTATION
ISHEN
type A acute liver failure episodic with triggering factors minimal covert
type B portosystemic bypass persistent I
without triggering factors II overt
type C hepatic cirrhosis recurrent III
IV

Literature review

Research Year Number of patients studied/control group Results
Wiltfang et al. [15] 1999 36/no control group S100B serum level has advantage over ammonia serum level in detecting portal-systemic encephalopathy
Vaquero et al. [16] 2003 54/no control group S100B serum level has no correlation with HE severity and liver function
Saleh et al. [17] 2007 43/9 S100B level has correlation with HE (stages I and II), compared to healthy and cirrhotic patients without HE
Isobe-Harima et al. [18] 2008 9/no control group S100B serum level is higher in HE patients
Duarte Rojo et al. [19] 2016 46/15 S100B serum levels are higher in patients with cirrhosis and HE than in healthy subjects
Toney et al. [21] 2019 82/no control group no correlation between serum S100B level and severity of HE
Strebel et al. [20] 2020 30/no control group serum S100B protein level correlated with the presence of HE
SUMMARY

The studies discussed here indicate that the assessment of the level of the S100B protein may be a promising marker in the diagnosis of hepatic encephalopathy. However, the results so far do not indicate the possibility of using the level of this protein to assess the effectiveness of therapy or to predict the course of the disease. In this respect, there is still a lack of multicenter studies in large groups of patients. Such studies would allow for final conclusions regarding the role and importance of the S100B protein level in the diagnosis and monitoring of ECT treatment.

Literature review

Research Year Number of patients studied/control group Results
Wiltfang et al. [15] 1999 36/no control group S100B serum level has advantage over ammonia serum level in detecting portal-systemic encephalopathy
Vaquero et al. [16] 2003 54/no control group S100B serum level has no correlation with HE severity and liver function
Saleh et al. [17] 2007 43/9 S100B level has correlation with HE (stages I and II), compared to healthy and cirrhotic patients without HE
Isobe-Harima et al. [18] 2008 9/no control group S100B serum level is higher in HE patients
Duarte Rojo et al. [19] 2016 46/15 S100B serum levels are higher in patients with cirrhosis and HE than in healthy subjects
Toney et al. [21] 2019 82/no control group no correlation between serum S100B level and severity of HE
Strebel et al. [20] 2020 30/no control group serum S100B protein level correlated with the presence of HE

Qualification of hepatic encephalopathy; WHC - West Haven Classification, ISHEN - International Society for Hepatic Encephalopathy.

CONNECTION WITH THE UNDERLYING DISEASE DURATION PRESENCE OF TRIGGERING FACTORS WHC SEVERITY OF CLINICAL MANIFESTATION
ISHEN
type A acute liver failure episodic with triggering factors minimal covert
type B portosystemic bypass persistent I
without triggering factors II overt
type C hepatic cirrhosis recurrent III
IV

Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014; 60: 715–735. VilstrupH AmodioP BajajJ CordobaJ FerenciP MullenKD WeissenbornK WongP Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver Hepatology 2014 60 715 735 10.1002/hep.27210 Search in Google Scholar

Schomerus H, Hamster W. Quality of life in cirrhotics with minimal hepatic encephalopathy. Metab Brain Dis. 2001; 16: 37–41. SchomerusH HamsterW Quality of life in cirrhotics with minimal hepatic encephalopathy Metab Brain Dis 2001 16 37 41 10.1023/A:1011610427843 Search in Google Scholar

Ong JP, Aggarwal A, Krieger D, 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; 114: 188–193. OngJP AggarwalA KriegerD AggarwalA KriegerD EasleyKA KarafaMT Van LenteF ArroligaAC MullenKD Correlation between ammonia levels and the severity of hepatic encephalopathy Am J Med 2003 114 188 193 10.1016/S0002-9343(02)01477-8 Search in Google Scholar

Qureshi MO, Khokhar N, Shafqat F. Ammonia levels and the severity of hepatic encephalopathy. J Coll Physicians Surg Pak. 2014; 24: 160–163. QureshiMO KhokharN ShafqatF Ammonia levels and the severity of hepatic encephalopathy J Coll Physicians Surg Pak 2014 24 160 163 Search in Google Scholar

Romero-Gómez M. Pharmacotherapy of hepatic encephalopathy in cirrhosis. Expert Opin Pharmacother. 2010; 11: 1317–1327. Romero-GómezM Pharmacotherapy of hepatic encephalopathy in cirrhosis Expert Opin Pharmacother 2010 11 1317 1327 10.1517/14656561003724721 Search in Google Scholar

Jones EA. Ammonia, the GABA neurotransmitter system, and hepatic encephalopathy. Metab Brain Dis. 2002; 17: 275–281. JonesEA Ammonia, the GABA neurotransmitter system, and hepatic encephalopathy Metab Brain Dis 2002 17 275 281 10.1023/A:1021949616422 Search in Google Scholar

Moore BW. A soluble protein characteristic of the nervous system. Biochem Biophys Res Commun. 1965; 19: 739–744. MooreBW A soluble protein characteristic of the nervous system Biochem Biophys Res Commun 1965 19 739 744 10.1016/0006-291X(65)90320-7 Search in Google Scholar

Böttiger BW, Möbes S, Glätzer R, Bauer H, Gries A, Bärtsch P, Motsch J, Martin E. Astroglial protein S-100 is an early and sensitive marker of hypoxic brain damage and outcome after cardiac arrest in humans. Circulation. 2001; 103: 2694–2698. BöttigerBW MöbesS GlätzerR BauerH GriesA BärtschP MotschJ MartinE Astroglial protein S-100 is an early and sensitive marker of hypoxic brain damage and outcome after cardiac arrest in humans Circulation 2001 103 2694 2698 10.1161/01.CIR.103.22.2694 Search in Google Scholar

Allampati S, Duarte-Rojo A, Thacker LR, Patidar KR, White MB, Klair JS, John B, Heuman DM, Wade JB, Flud C. Diagnosis of minimal hepatic encephalopathy using Stroop EncephalApp: A multicenter US-based, norm-based study. Am J Gastroenterol. 2016; 111: 78–86. AllampatiS Duarte-RojoA ThackerLR PatidarKR WhiteMB KlairJS JohnB HeumanDM WadeJB FludC Diagnosis of minimal hepatic encephalopathy using Stroop EncephalApp: A multicenter US-based, norm-based study Am J Gastroenterol 2016 111 78 86 10.1038/ajg.2015.37726644276 Search in Google Scholar

Sen J, Belli A. S100B in neuropathologic states: The CRP of the brain? J Neurosci Res. 2007; 85: 1373–1380. SenJ BelliA S100B in neuropathologic states: The CRP of the brain? J Neurosci Res 2007 85 1373 1380 10.1002/jnr.2121117348038 Search in Google Scholar

Ikeda Y, Umemura K. Analysis of reference values of serum S100B concentrations of Japanese adults. Rinsho Byori. 2005; 53: 395–399. IkedaY UmemuraK Analysis of reference values of serum S100B concentrations of Japanese adults Rinsho Byori 2005 53 395 399 Search in Google Scholar

Undén J, Ingebrigtsen T, Romner B. Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and consensus-based update. BMC Med. 2013; 11: 50. UndénJ IngebrigtsenT RomnerB Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and consensus-based update BMC Med 2013 11 50 10.1186/1741-7015-11-50362184223432764 Search in Google Scholar

Foerch C, Singer OC, Neumann-Haefelin T, du Mesnil de Rochemont R, Steinmetz H, Sitzer M. Evaluation of serum S100B as a surrogate marker for long-term outcome and infarct volume in acute middle cerebral artery infarction. Arch Neurol. 2005; 62: 1130. FoerchC SingerOC Neumann-HaefelinT du Mesnil de RochemontR SteinmetzH SitzerM Evaluation of serum S100B as a surrogate marker for long-term outcome and infarct volume in acute middle cerebral artery infarction Arch Neurol 2005 62 1130 10.1001/archneur.62.7.113016009772 Search in Google Scholar

Otto M, Wiltfang J, Schutz E, Zerr I, Otto A, Pfahlberg A, Gefeller O, Uhr M, Giese A, Weber T, Kretzschmar HA, Poser S. Diagnosis of Creutzfeldt-Jakob disease by measurement of S100 protein in serum: Prospective case-control study. BMJ. 1998; 316: 577–582. OttoM WiltfangJ SchutzE ZerrI OttoA PfahlbergA GefellerO UhrM GieseA WeberT KretzschmarHA PoserS Diagnosis of Creutzfeldt-Jakob disease by measurement of S100 protein in serum: Prospective case-control study BMJ 1998 316 577 582 10.1136/bmj.316.7131.577284599518907 Search in Google Scholar

Wiltfang J, Nolte W, Otto M, Wildberg J, Bahn E, Figulla HR, Pralle L, Hartmann H, Rüther E, Ramadori G. Elevated serum levels of astroglial S100beta in patients with liver cirrhosis indicate early and subclinical portal-systemic encephalopathy. Metab Brain Dis. 1999; 14: 239–251. WiltfangJ NolteW OttoM WildbergJ BahnE FigullaHR PralleL HartmannH RütherE RamadoriG Elevated serum levels of astroglial S100beta in patients with liver cirrhosis indicate early and subclinical portal-systemic encephalopathy Metab Brain Dis 1999 14 239 251 10.1023/A:1020785009005 Search in Google Scholar

Vaquero J, Jordano Q, Lee WM, Blei AT. Serum protein S-100b in acute liver failure: Results of the US Acute Liver Failure Study group. Liver Transplant. 2003; 9: ajlts50172. VaqueroJ JordanoQ LeeWM BleiAT Serum protein S-100b in acute liver failure: Results of the US Acute Liver Failure Study group Liver Transplant 2003 9 ajlts50172 10.1053/jlts.2003.5017212884207 Search in Google Scholar

Saleh A, Kamel L, Ghali A, Ismail A, El Khayat H. Serum levels of astroglial S100-beta and neuron-specific enolase in hepatic encephalopathy patients. East Mediterr Heal J. 2007; 13: 1114–1123. SalehA KamelL GhaliA IsmailA El KhayatH Serum levels of astroglial S100-beta and neuron-specific enolase in hepatic encephalopathy patients East Mediterr Heal J 2007 13 1114 1123 10.26719/2007.13.5.111418290405 Search in Google Scholar

Isobe-Harima Y, Terai S, Segawa M, Uchida K, Yamasaki T, Sakaida I. Serum S100b (astrocyte-specific protein) is a useful marker of hepatic encephalopathy in patients with fulminant hepatitis. Liver Int. 2008; 28: 146–147. Isobe-HarimaY TeraiS SegawaM UchidaK YamasakiT SakaidaI Serum S100b (astrocyte-specific protein) is a useful marker of hepatic encephalopathy in patients with fulminant hepatitis Liver Int 2008 28 146 147 10.1111/j.1478-3231.2007.01604.x18173564 Search in Google Scholar

Duarte-Rojo A, Ruiz-Margáin A, Macias-Rodriguez RU, Cubero FJ, Estradas-Trujillo J, Muñoz-Fuentes RM, Torre A. Clinical scenarios for the use of S100β as a marker of hepatic encephalopathy. World J Gastroenterol. 2016; 22: 4397. Duarte-RojoA Ruiz-MargáinA Macias-RodriguezRU CuberoFJ Estradas-TrujilloJ Muñoz-FuentesRM TorreA Clinical scenarios for the use of S100β as a marker of hepatic encephalopathy World J Gastroenterol 2016 22 4397 10.3748/wjg.v22.i17.4397485369827158209 Search in Google Scholar

Strebel H, Haller B, Sohn M, Schepp W, Gundling F. Role of brain biomarkers S-100-beta and neuron-specific enolase for detection and follow-up of hepatic encephalopathy in cirrhosis before, during and after treatment with L-ornithine-L-aspartate. GE - Port J Gastroenterol. 2020; 27: 391–403. StrebelH HallerB SohnM ScheppW GundlingF Role of brain biomarkers S-100-beta and neuron-specific enolase for detection and follow-up of hepatic encephalopathy in cirrhosis before, during and after treatment with L-ornithine-L-aspartate GE - Port J Gastroenterol 2020 27 391 403 10.1159/000507225767034733251288 Search in Google Scholar

Toney NA, Bell MJ, Belle SH, Hardison RM, Rodriguez-Baez N, Loomes KM, Vodovotz Y, Zamora R, Squires RS, et al. Hepatic encephalopathy in children with acute liver failure: Utility of serum neuromarkers. J Pediatr Gastroenterol Nutr. 2019; 69: 108–115. ToneyNA BellMJ BelleSH HardisonRM Rodriguez-BaezN LoomesKM VodovotzY ZamoraR SquiresRS Hepatic encephalopathy in children with acute liver failure: Utility of serum neuromarkers J Pediatr Gastroenterol Nutr 2019 69 108 115 10.1097/MPG.0000000000002351659105731058776 Search in Google Scholar

Empfohlene Artikel von Trend MD

Planen Sie Ihre Fernkonferenz mit Scienceendo