Breakfast improves cognitive function in cirrhotic patients with cognitive impairment anoxia refers to

Next section abstract

Background: cognitive disturbances are relatively common in patients with liver disease. High protein load precipitates hepatic encephalopathy

In cirrhotic patients. Minimal hepatic encephalopathy (MHE) is a prevalent neurocognitive complication of cirrhosis.

Objective: because the influence of nutritional factors on the progression of cognitive impairment has not been explored in depth, this

Study aimed to investigate the effect on cognition of acute metabolic changes induced by breakfast consumption.

Design: twenty-one subjects (10 women) with child A cirrhosis and 21 age- and sex-matched healthy controls were enrolled.


And controls were divided into 2 groups: those receiving a breakfast of 500 kcal and 21 g protein and those receiving no breakfast.Anoxia refers to

Serum ammonia concentrations and cognitive functions were studied (mindstreams; neurotrax, fresh meadows, NY) before and 2

H after breakfast. A mixed model was used to analyze the data.

Results: at baseline, cirrhotic patients had significantly lower total scores and significantly lower subscores ( P 85 μg/dl) scored significantly lower for attention than did patients with normal serum ammonia concentrations ( P 0.003). After 2 h, MHE patients and controls responded differently to breakfast consumption with regard to attention and

Executive functions ( P 0.003 and P 0.04, respectively). Although patients’ scores improved after breakfast consumption, despite an increase in serum ammonia,

Healthy controls who continued to fast performed better.Anoxia refers to

Conclusions: chronic hyperammonemia may negatively affect attention. Eating breakfast improves attention and executive functions of patients

With MHE. Prolonged periods of starvation may be partly responsible for these changes. This trial was registered at clinicaltrials.Gov

As NCT01083446.

Previous section next section INTRODUCTION

Cognitive disturbances are relatively common in patients with liver disease, and they may vary widely from minimal neurological

Changes detectable only by specific tests to deep coma ( 1). Cirrhosis is the most frequent liver disease that causes hepatic encephalopathy. Minimal hepatic encephalopathy (MHE) is

One of the prevalent neuro-cognitive complications of cirrhosis that is diagnosed in up to 80% of cirrhotic patients ( 2).Anoxia refers to MHE is characterized mainly by a subtle impairment of neurocognitive status and is not readily detectable by standard tests

For mental status or neurological examinations. The condition was shown to predict the eventual development of overt hepatic

Encephalopathy ( 3) and to impair daily functioning ( 4). Drivers with MHE were recently shown as being more likely to be involved in motor vehicle crashes and violations ( 5). For the most part, the changes in cognitive functions are attributed to an increase in blood ammonia concentrations and/or

Other intestinal neurotoxins and neurotransmitters of the benzodiazepine/γ-aminobutyric acid system ( 1). Encephalopathy, especially in its mild forms, may have a fluctuating nature, depending on changes in blood ammonia or neurotoxin

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Concentrations. Different factors, among them a high protein load, were shown to precipitate the induction of hepatic encephalopathy

( 1).

We hypothesized that, due to an acute increase in blood ammonia concentrations, breakfast may have an effect on cognitive

Functions of patients with child A cirrhosis with and without concurrent impaired neurocognitive functions.

Previous section next section SUBJECTS AND METHODS

The study population included 21 subjects (10 women) with child A cirrhosis who were being followed in our liver outpatient

Clinic and 21 age- and sex-matched healthy controls.

Inclusion criteria for the cirrhotic patients were as follows: age ≥18 y, diagnosis of child A cirrhosis with a mayo end-stage

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Liver disease score of 10, diagnosis of liver cirrhosis by liver biopsy (stage IV) and/or a fibroscan score ≥12 kpa or a

Fibrotest score ≥0.74, or imaging evidence (eg, computerized tomography or magnetic resonance). Exclusion criteria were a

History of grade II or greater hepatic encephalopathy; a diagnosis of dementia, parkinson’s disease, or schizophrenia; use

Of sedatives, tranquilizers, or antipsychotic medication during and/or 2 wk before enrolling in the study; current use of

Lactulose or neomycin; and use of alcohol or illicit drugs during and/or 6 mo before study entry. Study patient characteristics

Are given in table 1. The effect of breakfast on cognitive functions was studied in the cirrhotic patients and healthy controls after an overnight

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Fast. All the subjects were admitted to the unit of clinical nutrition at 0800–0900, venous blood was drawn for determination

Of ammonia concentrations, and each subject completed a computerized test (neurotrax, fresh meadows, NY) for assessing performance

Across an array of cognitive domains, including memory, executive functions, visual spatial perception, verbal functions,

Attention, information processing speed, and motor skills. Each subject was then randomly assigned to eating a breakfast meal

(30% of daily calories and 21 g of protein) or to fasting. Two hours later, all subjects repeated the tests, and venous blood

Was drawn again for measuring ammonia concentrations.

All participants completed a battery of tests (mindstreams; neurotrax) designed to detect mild impairment in their primary

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Cognition of language. The computerized assessment system has been described in detail elsewhere ( 6). Briefly, it consists of commercial software installed in a computer and serves as a basis for interactive cognitive tests

That produce data on accuracy and reaction time (millisecond timescale). Once tests are run on the local computer, data are

Automatically uploaded to a central server that calculates outcome variables from raw single-trial data, normalizes data,

And generates a report of the findings. The cognitive domains assessed by the computerized battery include memory (verbal

And nonverbal), executive function, visual spatial skills, verbal function, attention, information processing, and motor skills

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( 6). The tests that compose the battery have been shown to detect cognitive impairment in the elderly in multiple cognitive

Domains ( 7). All responses are made by clicking the computer mouse or by means of a number pad. Patients are familiarized with these

Devices and undergo practice sessions before the individual tests so that they will correctly provide the kind of responses

Required for each test. They are administered in the same fixed order for all participants. Outcome variables vary according

To the test. To minimize differences in age and levels of education and to permit the averaging of performances across different

Types of outcome variables (eg, accuracy, reaction time), each outcome variable is normalized according to stratifications

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Of age and education. Normalization for the current study was based on the 1569 cognitively healthy participants of the mindstreams

Normative database. Normalized subsets of the various outcome variables were averaged to produce 7 summarized scores as follows,

Each indexing a different putative cognitive domain: the 7 scores serve as the primary dependent variables for the analysis.

A global cognitive score is computed as the average of these index scores and serves as a secondary dependent measure. Institutional

Review board approval from the tel aviv sourasky medical center (tel aviv, israel) was obtained to conduct this study.

The relative change between tests was calculated for each subtotal score as the difference between test grades divided by

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The grade in the first test ( t 2 − t 1/ t 1). The same procedure was performed for ammonia concentrations. All test results at baseline were compared between patients

And controls by the t test for independent samples. An analysis of variance was performed with repeated measures by using the mixed model, which

Was applied to the relative change in each test and compared patients to their healthy matched controls and to the 2 treatment

Groups (breakfast, nonbreakfast), taking into account the ammonia concentration at baseline (below or above 85 μg/dl). Pearson’s

Correlation coefficient was used to assess the correlation between ammonia concentrations and the neurotrax results at baseline.

All statistical analyses were performed by using the SAS for windows version 9.1.3 (SAS institute, cary, NC).Anoxia refers to

Previous section next section RESULTS

A total of 21 subjects with MHE (age range 31–83 y, 10 women) and 21 age- and sex-matched healthy controls were recruited

Into the study after they signed informed consent forms. Patient characteristics are described in table 1. At baseline, blood ammonia concentrations were significantly higher in the patient group compared with the control group

(71.8 ± 49.0 compared with 45.8 ± 16.4 μg/dl, P 85 μg/dl at baseline. After 2 h, mean ammonia concentrations increased

In cirrhotic patients who ate and decreased in those who continued to fast (56.7 ± 28.9 to 87.2 ± 47.4 compared with 85.5

± 60.1 to 79.4 ± 61.3 μg/dl, respectively). Ammonia concentrations increased 85 μg/dl in 5 cirrhotic patients who ate breakfast

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And stayed above normal in another patient. In the patients who continued to fast, in one patient ammonia blood concentration

Increased 85 μg/dl whereas in 3 others blood ammonia concentrations decreased to 85 μg/dl) compared

With those with ammonia concentrations within the normal range.

Previous section next section DISCUSSION

Our results indicate that patients with child A cirrhosis and MHE may improve their attention and executive functions by eating

Breakfast even with an increase in ammonia concentrations. By using the mixed model, we learned that patients responded differently

To breakfast than did healthy individuals. Yet patients with abnormally high ammonia concentrations scored lower for attention

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At baseline. This may indicate factors other than hyperammonemia; for example, higher glucose utilization may be of importance.

Improvement in cognitive functions after eating breakfast had also previously been shown in other situations, eg, among elementary

School children ( 8) and elderly subjects ( 9), and had been attributed to the increase in glucose concentrations.

Actually, protein-calorie malnutrition is highly prevalent in all clinical stages of liver disease ( 10). Sufficient caloric and adequate protein intake therefore are crucial for affected individuals. The influence of nutritional

Factors on the progression of liver cirrhosis and hepatic encephalopathy has been extensively investigated ( 11).Anoxia refers to for example, precipitation of hepatic encephalopathy by a high protein load is a well-established phenomenon ( 1). The influence of prolonged starvation or protein supplementation on cognitive function of patients with MHE, on the other

Hand, is less clear.

A number of earlier studies had shown that cirrhotic patients seem to handle substrates differently from the healthy control

Subjects. When 8 patients with cirrhosis were measured in a respiratory chamber, the measured respiratory quotient was significantly

Lower during the morning preprandial period (0900–1200), reflecting a higher oxidation rate of fat to carbohydrate that is

Compatible with a more catabolic state ( 12). A similar metabolic pattern was also shown by owen et al ( 13).Anoxia refers to after an overnight fast, the hepatic glucose production in patients with cirrhosis diminished as a result of low-rate glycogenolysis

Whereas hepatic gluconeogenesis and ketogenesis increased. Owen et al ( 13) concluded that this pattern of hepatic metabolism mimics that seen in healthy subjects after more advanced stages of starvation.

The calculated caloric equivalents of substrates in the bloodstream, which could potentially be oxidized by peripheral tissues,

Were significantly lower in cirrhotic patients compared with healthy controls, both after an overnight and after a 3-d fast.

On the basis of the above findings, it was suggested that a late evening snack of carbohydrate be recommended ( 14) or that an oral branched-chain amino-acid–enriched nutrient mixture be given to these patients ( 15).Anoxia refers to finally, weissenberg et al ( 16) observed that deficits in memory and attention in patients with cirrhosis were accompanied by a decrease of cerebral glucose

Utilization in the cingulated gyrus, the dorsolateral prefrontal cortex, and the parietal cortex on the basis of 2-deoxy-2[F-18]fluoro- d-glucose positron emission tomography studies. The brain is the main organ consumer of glucose in the body during regular

Metabolism and switches to usage of ketone bodies only after a few days of starvation. All of these findings taken together

Serve to explain why prolonged starvation may affect the cognitive functions of cirrhotic patients and why eating breakfast

May improve the cognitive functions most probably by increasing glucose utilization.Anoxia refers to

We propose that our cirrhotic patient group may be considered as having MHE. None of the members of this group had any signs

Of encephalopathy on the day of the exams, and their results at baseline ( table 2) indicate that they scored lower in all the tests compared with age- and sex-matched healthy controls. In addition, 4 of

The 7 variables as well as the global score were significantly lower in our patient group compared with normal controls.

Two of the 7 subcategories of the cognitive scores of our cirrhotic patients—attention and executive functions, both of which

Are related to everyday activities, including driving skills—improved after eating. As such and based on the difference in

Metabolic handling of substrates, we reason that eating breakfast may also improve driving skills that were recently observed

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To be impaired in patients with MHE ( 5, 17). This may also affect fatigue, which was also recently reported in these patients ( 18). Thus, on the basis of our study, we can conclude that a regular breakfast that supplies 25% of daily calories and 21 g

Of protein may improve cognitive functions.

Ammonia was suggested to play a central role in the pathogenesis of hepatic encephalopathy due to a direct neurotoxic effect

And brain swelling causing hypoxia ( 19). We studied the effect of acute hyperammonemia in our patients after they had eaten breakfast. We expected that changes

In blood ammonia concentrations would be correlated with deterioration in the neuro-cognitive scores, but this was not the

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Case. The acute increase in blood ammonia concentrations after breakfast seems not to affect their cognitive functions, which

Improved in spite of an increase in blood ammonia concentrations 85 μg/dl. On the other hand, the baseline attention level

Was significantly lower in the patients with fasting hyperammonemia ( P 0.003). This may indicate that breakfast (glucose consumption?) may override the effects of hyperammonemia. Similar results

Were observed by others in the past and were reportedly related to a difference in the brain uptake of ammonia, which is increased

In hepatic encephalopathy independently of blood ammonia concentrations ( 20). Differences in cerebral microcirculation and blood-brain abnormalities may also contribute to the lack of correlation.Anoxia refers to

In the studies that did suggest some correlation, the relation was nonlinear, especially for the lower grades of encephalopathy

( 21). Our results indicate that eating breakfast has a beneficial effect that masks any deterioration due to a further increase

In ammonia concentrations. This may shed some light on the role of ammonia in the pathogenesis of hepatic encephalopathy ( 21).

In conclusion, we have shown that eating a regular breakfast improves the attention and executive functions of patients with

Cognitive impairment consistent with MHE. On the basis of the metabolic characteristics of these patients and the recent publications

On high rates of accidents, traffic violations, and fatigue among patients with MHE, we believe that prolonged periods of

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Starvation may be partly responsible for these outcomes and suggest that patients with MHE be encouraged to diligently incorporate

Breakfast into their daily routine.