Covert hepatic encephalopathy: a neglected topic—a narrative review

Covert hepatic encephalopathy (CHE) is a form of cerebral dysfunction that affects 30–40% of patients with liver cirrhosis as a grave sequel of disease progression. Although being a silent condition, yet; CHE has been reported as seriously predictive for the development of overt hepatic encephalopathy. Covert hepatic encephalopathy is said to conclude grades (0 and 1) hepatic encephalopathy in West Heaven grading of hepatic encephalopathy, hence; inferring to discrete deficits in attention, cognition, and motor control, strongly associated with poorer quality of pri‑ vate and social aspects of the patients’ life. Clinical recognition of cases of CHE is such a tedious task that unluckily devoid of discernment. Worthwhile; the battery of neuropsychometric tests widely known as the only tool to iden‑ tify CHE can give abnormal results without specifying the cause of brain dysfunction Therefore, dedicated history‑ taking and clinical evaluation of liver cirrhosis patients are still the cornerstones that should unify other diagnostic tools to identify those patients at risk of developing overt hepatic encephalopathy. Diagnosis of CHE is challenging and often neglected in clinical practice, so the aim of this review is to improve our approach to CHE and begin a uni‑ fied effort for the advancement of CHE through studying easy, fast, and reliable psychometric diagnostic tests to meet our clinical needs.


Definition and nomenclature
Hepatic encephalopathy (HE) is defined as brain dysfunction caused by liver insufficiency and or portosystemic shunting (PSS) [1].It is a common and wide spectrum of neuropsychiatric complications of acute and chronic liver diseases, ranging from subclinical manifestations to coma.Hepatic encephalopathy occurs along a spectrum that can be broadly divided into CHE and overt HE (OHE) [2,3].Minimal HE (MHE) is a clinically undetectable cognitive disturbance closely associated with loss of quality of life.Early detection and treatment improve the patients' daily life and prevent HE-related hospital admissions [4].Covert hepatic encephalopathy includes patients with minimal and grade I encephalopathy by West-Haven Criteria."Sub-clinical", "latent", and "minimal" are now replaced by the term covert which is more accurate and applicable [5].Overt hepatic encephalopathy (OHE) is characterized by personality changes, progressive disorientation in time and space, acute confusional state, stupor, and coma.Based on its time course, OHE can be divided into episodic, recurrent, or persistent.Episodic HE is generally triggered by one or more precipitant factors that should be found and treated.Unlike MHE, clinical examination and decision are crucial for OHE diagnosis, and West Haven criteria are widely used to assess the severity of neurological dysfunction [6].

Epidemiology, clinical, and economic importance
From the epidemiological perspective, it has become clear that HE is probably the most frequent cirrhosis complication, leading to hospitalizations and repeated readmissions with poor outcomes [3].It is challenging to quantify precise incidence and prevalence measures for HE because of differences in causes, diagnostic tools, and disease severity [7].
The healthcare, societal, and economic burden of HE is considerable.It contributes greatly to increasing the rate of inpatient admissions and re-hospitalization (0.33% in the United States of America (USA) in all patients' admissions), so it reduces the quality of life with increased morbidity and mortality [9].

Classification
The currently recommended classification of HE is based on the type, the severity of the disease manifestation (grade), the time course, and the precipitating factors (when identified).The presence of PSS should also be recorded [10].Hepatic encephalopathy should be qualified as type A in patients with acute liver failure, type B in those with PSS without significant liver disease, and type C in those with cirrhosis with or without PSS shunt [1].
In terms of severity, HE is classified as covert (minimal or no signs/symptoms but abnormalities on neuropsychological and/or neurophysiological tests) or overt (grades II or over according to the West Haven criteria).The Glasgow coma scale should be added to patients with grades III-IV West Haven criteria.In terms of its time course, OHE should be qualified as recurrent if 2 or more attacks occur within 6 months and persistent if the patient does not return to the baseline in between bouts [10,11].

Pathogenesis and pathophysiology of HE
Hepatic encephalopathy is a neuropsychiatric abnormality seen in patients with liver disorders after the exclusion of other known brain diseases.Hyperammonemia is the principal factor responsible for brain abnormalities in HE [12].Several mechanisms that explain the influence of ammonia on the central nervous system (CNS) have been proposed such as.

Ammonia and blood-brain barrier
Ammonia is a toxin responsible for the occurrence of HE via a direct effect on the metabolism and functions of the CNS and influencing the passage of several molecules across the blood-brain barrier, as transport of branched-chain amino acids (AA), and aromatic amino acids.Disturbances of AA transport affect the catecholamine synthesis as serotonin and dopamine in the brain and the formation of "false neurotransmitters" as octopamine and phenylethylamine, resulting in impaired GABA-ergic, serotonergic, and glutamatergic neurotransmission [13].

Neurotransmission in hepatic encephalopathy
In HE with chronic liver disease, there is an imbalance between excitatory and inhibitory neurotransmission.The upper hand of inhibition is due to reduced expression of glutamate (Glu) receptors, resulting in decreased glutamatergic tone.Also, inactivation of glutamate transporter GLT-1.γ-aminobutyric acid (GABA) is another factor increasing inhibitory neurotransmission through several mechanisms as increased levels of endogenous benzodiazepines, increased availability of GABA at GABA-A receptors due to increased synaptic release of the amino acid, direct interaction of elevated concentration of ammonia with the GABAA-benzodiazepine receptor complex [14].

Hyperammonemia and neurosteroids
Hyperammonemia may additionally be responsible for the overproduction of neurosteroids.In experimental studies adding ammonia to the culture of astrocytes, increases pregnenolone level, which is a neurosteroid that stimulates mitochondrial peripheral-type benzodiazepine receptors in the brain of patients with HE [15].

Hyperammonemia and oxidative stress
According to oxidative stress induced by ammonia is a main pathogenic factor in the HE of acute liver failure (ALF) and causes a whole cascade of events leading to astrocyte swelling and brain edema.However, HE occurs in chronic liver dysfunction and is not accompanied by cerebral edema [16].

Hyperammonemia and neuroinflammation
The neuro-inflammation is an important factor determining the occurrence and severity of neuropsychological dysfunction in mild HE caused by ammonia, that is, more prominent in more severe inflammation.A prominent increase of TNF-α and IL-6 proinflammatory cytokines in patients with mild HE was noticed.Alvarez et al. study on the astrocyte cultures reported that proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and IF-γ and ammonia induce disruption of the mitochondria permeability and may be a major factor in the pathogenesis of HE [17].

Ammonia and brain energy metabolism
A major cause of HE may be due to abnormal interactions between neurons and astrocytes and impairment of brain energy metabolism.Ammonia affects the transport of nitric oxide precursors such as arginine and ornithine through the blood-brain barrier and also affects the transport of energy substrates for the brain such as creatine, and glucose [18].

Neurotoxic effects of manganese
Accumulation of toxins in the brain, including manganese, which is deposited in the basal ganglia might be the cause of increased signals on T1-images in magnetic resonance imaging.Abnormalities of manganese and other minerals homeostasis may be responsible for the cognitive impairment associated with liver cirrhosis [19].

The gut-liver-brain axis and the role of the microbiome in HE
Studies have documented that the intestinal microbiome is closely associated with emotional and cognitive-behavioral functions.The gut-liver-brain axis full treatment concept can be used to manage behavioral and cognitive and behavioral disorders in HE [20].Gutmicrobiota and their metabolites communicate with the CNS by enhancing the activity of the vagus nerve and by modulating endocrine and immune pathways, which in turn exert an impact on motor, cognitive, and nervous system development [21].
In severe hepatic disease and portal shunt disease, the homeostasis of intestinal microbiota is affected.Gut-origin substances are delivered through the vagus nerve the immune, and the humoral pathway to the brain.The leaky gut due to chronic intestinal inflammation promotes gut-microbiota metabolite and bacterial translocation into the systemic circulation leading to systemic inflammation and body metabolic disorders.
Additionally, the brain microenvironment loses stability, followed by blood-brain barrier dysfunction.Moreover, several factors disturb the CNS function, such as changes in neurotransmitters, brain structure, and other substance concentrations, resulting in cognitive impairments in HE [22].

Disease-related mental dysfunction and role of comorbidities
Mild cognitive dysfunction as in covert or minimal hepatic encephalopathy can be present in different metabolic disturbances, many neurological diseases, and even with old age [23].There is an overlap regarding the domains of cognitive functions affected by the different conditions and comorbidities.Especially executive function, attention, and processing speed are declined, irrespective of the underlying disorder.Although renal dysfunction, diabetes mellitus, and Wernicke's encephalopathy show alterations in motor function, these are less pronounced than in patients with HE [23].

Impact of HE on neurological outcome following liver transplantation
Neurological complications are a common problem after liver transplantation, affecting about 13-47% of transplant recipients.These complications could arise as a consequence of prior HE, but multiple factors may influence neurological function in these patients.The role of immunosuppressive medications, anoxic intraoperative complications, comorbidities, and deficiencies of many neuroactive agents, such as thiamine, should be considered [24].
Evidence supports the post-transplant persistence of cognitive impairment or radiologic changes in patients exhibiting MHE before.In a prospective study, 14 patients with CHE underwent a liver transplant and were evaluated for visuomotor function, Improvement of visuoconstructive and visuomotor skills was observed in some patients after the liver transplant, however, worsening was observed in others.Also, there was no significant improvement in post-transplant visuomotor and visuoconstructive skills compared with pretreatment performance, with 50% of patients deteriorating in performance.In addition, the mean post-transplant results for the 14 patients with CHE were significantly less than age-matched healthy individuals [24].

Diagnosis of CHE
Accurate diagnosis of CHE is one of the challenges, due to the time and psychological competence needed, the expense, and the copy-right restrictions of the psychometric tests suggested by the Working Group of Hepatic Encephalopathy, the majority of cirrhotic patients are not routinely tested [25].Before HE can be diagnosed, other brain disorders or causes of encephalopathy must be ruled out.Patients with CHE exhibit minor neurocognitive abnormalities that include cognitive and attention deficiencies that influence disinhibition, decreased working memory, and visuomotor coordination.This is a challenging hurdle to overcome.Specific outcomes from psychometric tests can be used to establish that a patient did not have additional cognitive deficiency after motor coordination and response inhibition (which are important for operating a motor vehicle) [26].These attention deficits affect a patient's ability to orient and perform executive functions and impair learning and working memory [27].It is possible to do traditional paper-andpencil or computerized tests with accuracy when using data from psychometric or neurophysiological examinations [28] (Fig. 1).

Neuropsychological assessment of MHE
The diagnosis of MHE is complicated by the lack of standard and dependable individual tests that are suitable for clinical practice [29].Neurophysiological and psychometric tests are recommended to diagnose MHE grounded on the recent guidelines by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL).The psychometric hepatic encephalopathy score (PHES) and repeatable battery for the assessment of neuropsychological status (RBANS) are the two most considerably used paper-and-pencil psychometric tests Fig. 1 Diagram for CHE testing [28] for MHE diagnosis [30].The PHES is presently recommended internationally as the gold standard for the diagnosis of MHE [11].
It was specifically designed for the diagnosis of MHE and is composed of the following five tests number connect test (NCT)-A, NCT-B, serial dotting test, line tracing test, and digit symbol test.It evaluates motor speed, motor accuracy, concentration, attention, visual perception, visual construction, and memory, which are related to the utmost of the neuropsychological impairments of MHE [30].
The repeatable battery for the assessment of neuropsychological status (RBANS) has been used as an indispensable test for the PHES and has been recommended for the diagnosis of MHE by the International Society for the Study of Hepatic Encephalopathy and Nitrogen Metabolism [31].It assesses anterograde memory, working memory, cognitive processing speed, language, and visuospatial function, which are cognitive domains not told in HE [30].While the PHES and RBANS have been validated in clinical studies, they frequently bear a significant quantum of time to administer and, thus, cannot be fleetly and accessibly performed to diagnose MHE in clinical practice [32].
Several recent studies have indicated that psychometric tests can be computerized for simplification and administered in the clinic within many twinkles.Several computer-backed psychometric tests are available for screening MHE in cases with cirrhosis, including the checkup test, Cognitive Drug Research (CDR) assessment battery, inhibitory control test (ICT), EncephalApp Stroop App, and critical flicker frequency (CFF) [30].These tests have been verified to be rapid-fire, simple, and dependable styles for webbing MHE [33].The advances from paper and pencil to computer-aided versions of psychometric tests may not only help hepatologists to screen cases for MHE but, eventually, also support early treatment of MHE, perfecting the quality of life and reducing the threat of progression to OHE [30].Also, auditory P300 and their response times were useful for securing cases with MHE [34] (Table 1).

Management and emergency therapies of CHE
The AASLD/EASL guidelines do not recommend specific treatment for all patients with CHE, as there are no universally, and no consensus-accepted detection tools.In addition, CHE encompasses heterogeneous conditions.Covert HE requires some kind of quantification ranging from time disorientation to coma and agitation, for which different management options are recommended [35].
The recommended treatment of CHE is derived from patients with episodic HE with the absence of clinical signs (Table 1).Many options for treatment were based on different types of pathogenesis of HE.These include N-methyl-D-aspartate antagonist, N-acetylcysteine, flumazenil, anti-inflammatory (cyclo-oxygenase inhibitors), and bromocriptine.However, all have been abandoned due to lack of efficacy and side effects.The target of therapy of CHE is directed against the circulating level of ammonia and other gut-derived toxins.The gut microbiota plays an important role in the production of ammonia and other toxins resulting in oxidative stress/ inflammation [36] (Table 2).

Non-absorbable disaccharides
Lactulose or lactitol are synthetic non-absorbable disaccharides that are extensively used in the management of OHE.Lactulose is fermented in the colon into acetic and lactic acid resulting in acidification of intestinal contents and conversion of ammonia (NH 3 ) to ammonium (NH 4+ ) [37].In a randomized open-label trial, lactulose therapy of 30-60 ml/day was compared to no treatment in patients with cirrhosis and MHE compared to the untreated group.There was a significant decrease in the number of psychometric tests in the group treated with Paper-and-pencil test PHES [30] Psychomotor speed, visual perception, visuospatial function, visuomotor ability, and attention 20 RBANS [31] Psychomotor speed, anterograde memory, and working memory 30 Computer-aided test Scan test [30] Working memory, alertness, and attention 15 CDR assessment battery [30] Response time, memory, and recognition 15 ICT [30] Response inhibition, working memory, vigilance, and attention 15 EncephalApp Stroop App [30] Psychomotor speed and cognitive alertness 10 FF [30] Visual discrimination and general arousal 10 lactulose (P < 0.0001).Treatment also demonstrated a significant improvement in the health-related quality of life (HRQoL) vs those who did not receive lactulose[6.81vs 0.17 (95% CI, 5.24-8.37)and (95% CI, − 0.29 to 0.63), respectively; P < 0.001] [38].

Antibiotics
In minimal/covert HE, rifixamine is the only systematically studied antibiotic.Rifaximine showed improvement in cognition, inflammation, and quality driving simulator performance but cost analysis does not favor its use at the current time [39].
l-ornithine-l-aspartate l-ornithine-l-aspartate reduces the ammonia levels by urea cycle activity and upregulating glutamine synthetase.l-ornithine and l-aspartate are metabolized to form glutamate, which combined with ammonia results in the formation of glutamine.Therefore, LOLA lowers the level of ammonia by enhancing the metabolism of ammonia to glutamine [40].

Fecal microbiota transplant (FMT)
The promising treatment for refractory OHE is fecal microbiota transplant.The gut bacteria play an important role in the pathophysiology of HE and reverse the intestinal dysbiosis [34].

Nutrition and probiotics
Nutritional therapy is modulating the nitrogen metabolism in HE.Historically, restriction of dietary protein was advised to reduce the production of intestinal ammonia.However, this may worsen HE and lead to sarcopenia.Thus, it was recommended by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism that 1.2-1.5 g/kg of protein be given in small meals distributed throughout the day with a late-night snack of complex carbohydrates [41].
Supplementation with BCAA is an alternative If patients are unable to maintain dietary protein intake.Vitamin and electrolyte deficiencies can be associated with a wide range of neuropsychiatric symptoms [42].Zinc supplementation showed a potential improvement in psychometric tests [43].Probiotics play an important role in the treatment of HE by decreasing the production, absorption of ammonia and counts of pathogen bacteria, intestinal mucosal acidification, decreased endotoxin levels, alterations in permeability of the gut, and changes in the production of short-chain fatty acids [44].

Liver transplantation
Liver transplantation is not always an available option but remains the most effective treatment available for cirrhosis and HE.Permanent cognitive impairment from pre-transplant HE may persist even after liver transplantation [45].

Legal ramifications for physicians who diagnose and treat patients with hepatic encephalopathy
In 2011, Cohen and Colleagues 9 evaluated the legal ramifications for physicians treating patients with HE who drive, they examined the motor vehicle code of each state and the requirement for physician reporting of potentially impaired patients with covert or overt HE.They also searched for lawsuits against physicians related to MVAs involving patients with HE [46].

Recommendations for physicians dealing with patients with CHE and OHE
Recognize that both CHE and OHE impair the ability to drive or operate machinery.
Know and abide by your state-specific reporting laws for impairment.
Know the legal ramifications of reporting and not reporting impairment in your state.
Recognize that CHE has no clinical manifestations and requires neurocognitive testing for diagnosis.In the absence of validated diagnostic criteria for practitioners, physicians have no medical legal responsibility to perform diagnostic tests for CHE.
Mandatory and permissive reporting does not violate physician-patient confidentiality statutes or the protected health information statutes of the Health Insurance Portability and Accountability Act of 1996 (HIPPA).
To date, no publications describe lawsuits against physicians caring for cirrhotic patients with either CHE or OHE.
Inform patients with CHE or OHE about the risks of driving or operating machinery.
Recommend a formal, professional driving assessment by the Department of Transportation for patients with CHE or OHE.
Recognize that only the state has the authority to determine who can or cannot drive [47].

Future prospects
The management of HE has evolved over the last 10 years with the addition of rifaximin into current treatment guidelines.More studies are needed to ascertain the pathophysiology that will to new options in the treatment of HE.More studies are needed to discover the role of gut microbiota in the pathogenesis of HE.Liver support systems such as the Molecular Adsorbent Recirculating System and Prometheus device may act by removing circulating toxins that accumulate in the blood due to liver dysfunction.

Summary
Hepatic encephalopathy is an important contributor to morbidity in patients with advanced liver disease.It significantly affects the quality of life of patients and relatives.The identification of MHE necessitates specialized testing, which is frequently challenging to do due to existing clinical needs.However, with further study opportunities, MHE diagnosis and therapy can enhance patient safety and quality of life (QOL).Early recognition of and hence avoiding the precipitating factors of HE in addition to the combination of treatment with rifaximin and lactulose remain the mainstay of treatment.Future studies are needed to identify novel pathogenesis and targets for future options of treatments with the hope of translating this into real benefits for patients with HE.

Table 1
Diagnostic and screening tests of MHE

Table 2
Treatment options for hepatic encephalopathy