Clinical manifestations

Presentation and course

Hepatic encephalopathy has a wide spectrum of clinical manifestations, which comprise neurologic, psychiatric, and musculoskeletal symptoms. The presentation in each patient varies and depends on the severity graded with the West Haven criteria (shown above in the classification section). Patients with minimal hepatic encephalopathy have imperceptible symptoms in a clinical setting. Their attention, work memory, psychomotor speed, or visuospatial ability are decreased, and psychometric testing is needed for diagnosis and detection.

In hepatic encephalopathy grade I of the West Haven criteria, often the first symptom is a disruption in their sleep-wake cycles. Other presentations may include personality changes (disinhibition, irritability, or apathy), altered handwriting, issues with coordination, or a mild alteration of the level of consciousness. In this grade, the patient’s family or close friends may be the ones who notice these symptoms. It may also be detected during a medical examination if the doctor is familiar with the patient and their baseline status.

In the overt hepatic encephalopathy, grade II of the West Haven criteria, the earlier symptoms worsen and show up as clear cognitive impairments, such as losing track of time, changing personality and behavior, difficulty remembering things, slurred speech, or a shortened attention span. Dyspraxia, dyskinesia, or ataxia are possible displays, but the hallmark finding is asterixis (flapping tremor). Asterixis is a negative myoclonus that results in a loss of postural tone rather than a true tremor. Although it is visible in other muscles of the body, wrist hyperextension with arms outstretched is a common test for it. The diencephalic motor centers, which control the tone of paired agonist and antagonist muscles, are the source of the problem. It is not pathognomonic; asterixis can be found in other conditions, such as uremic encephalopathy.

On the other hand, patients in hepatic encephalopathy grade III of the West Haven criteria exhibit an alteration of consciousness with somnolence or semi-stupor, disorientation, confusion, or an altered response to stimuli. Hyperreflexia, clonus, and rigidity can be seen.

Finally, hepatic encephalopathy grade IV of the West Haven criteria includes a comatose state that does not respond to painful stimuli.

Some extrapyramidal symptoms that can occur from cirrhosis-related parkinsonism in people with persistent hepatic encephalopathy include bradykinesia, masked facial expressions, rigidity, delayed speech, and parkinsonian tremor. The most frequent clinical manifestation of chronic hepatic encephalopathy or advanced neurologic damage in hepatic encephalopathy is parkinson-like dementia.

Prognosis and complications

Hospitalization due to hepatic encephalopathy is a significant cause of hospital costs, both direct and indirect. Patients’ quality of life is negatively impacted, and caregivers are burdened. Hepatic encephalopathy is associated with a poor prognosis in terms of survival and overt hepatic encephalopathy repeated events.

The onset of hepatic encephalopathy (together with ascites and variceal bleeding) establishes the progression of liver disease from compensated cirrhosis to decompensated cirrhosis. Decompensated cirrhosis, regardless of the cause of decompensation, is the main factor in the poor prognosis in the natural history of liver disease. Therefore, the presence of hepatic encephalopathy has essential prognostic value. Since 1973, the Child-Turcotte-Pugh classification has been part of the basic staging scale to determine the progress of liver disease and its prognosis. Both covert and overt hepatic encephalopathy have been shown to have worse clinical outcomes, with reduced global survival as the main result, but also more frequent hospitalizations, increased falls, or increased motor vehicle accidents. It has also been demonstrated that the existence of hepatic encephalopathy before liver transplantation affects the prognosis.

There may be different outcomes and risks depending on the cause of liver disease, such as alcohol, viral hepatitis, metabolic-associated fatty liver disease, etc. However, in most studies, the cause of liver disease is not a factor that can predict the risk of overt hepatic encephalopathy (05).

In covert hepatic encephalopathy, even though intelligence and communication skills are usually preserved, the distortion in attention, focus, and predisposition to fatigue results in learning impairment and loss of working memory. The impact on quality of life is observed in the detriment of sleep, self-care, eating, home management, mobility and driving, social interaction, or emotional behavior. Also, these patients have a higher chance of developing overt hepatic encephalopathy, which carries greater prognostic significance. In addition, it is associated with an increased risk of death and liver transplantation, independent of the model for end-stage liver disease (MELD) score.

In overt hepatic encephalopathy, the implications for survival have been well-established for more than 30 years. Already in the 1990s, it was seen that the first episode of hepatic encephalopathy, as an independent factor, determined a clear decrease in survival: cumulative survival in 1 year was about 50%, and 25% in 3 years. Also, the duration of the acute episode has been observed to worsen the survival rates, marking the cut-off point at 48 hours, regardless of MELD score or hepatic encephalopathy grade.

In other situations, such as in the colocation of a transjugular intrahepatic portosystemic shunt, the incidence of hepatic encephalopathy increases, as does mortality when hepatic encephalopathy is established. Also, as mentioned earlier, hospitalization because of hepatic encephalopathy increases mortality regardless of the cause that triggered it.

Risk factors for poor prognosis during hepatic encephalopathy have been identified: male gender, hyponatremia, acid-base disturbances (pH less than 7.3 or greater than 7.55), worse renal function, increased bilirubin or potassium, decreased prothrombin activity, or serum albumin levels.

Improvement in outcomes has been demonstrated with the conventional therapies, lactulose and rifaximin, which are associated with a reduction in the risk of new episodes and duration of hospitalization.

Clinical vignette

A 58-year-old man with liver cirrhosis due to alcohol consumption was decompensated with ascites and treated with diuretics. He had active ethanol consumption. He was admitted to the emergency department after being found disoriented and with disjointed speech on the street.

Examination revealed signs of chronic liver disease, including ascites, edema in the lower extremities, and flapping. Neurologically, he was sleepy and disoriented in space and time. He had mild dysarthria, with the rest of the neurologic examination normal or incomplete due to a lack of cooperation.

A general analysis was performed with ethanol in the blood, and an infection work-up included paracentesis that showed ascitic fluid with more than 250 polymorphonuclear cells. Head CT showed no acute intracranial pathology.

The diagnoses reached were spontaneous bacterial peritonitis, hepatic encephalopathy, ascites decompensation, and alcohol use disorder. He started antibiotics as well as laxatives (lactulose), diuretic adjustment, and alcohol withdrawal treatment. The hepatic encephalopathy had a complete progressive resolution in 5 days.

Biological basis

Etiology and pathogenesis

Ammonia is essential to the pathophysiology of hepatic encephalopathy. The pathogenic basis in hepatic encephalopathy is the lack of detoxification of toxic products in the liver and their arrival in the brain. It depends on the origin type of hepatic encephalopathy, as explained previously in the classification. So, this lack of detoxification may be due to acute liver failure, a sick liver (cirrhosis), or a natural or artificial shunt.

Several products are involved in this toxicity, such as drugs, food metabolites, gamma-aminobutyric acid (GABA), short-chain fatty acids, mercaptans, neurosteroids, or manganese. However, the most studied product, with more correlation, is ammonia. Being a multifactorial pathophysiology, the fact that ammonia is metabolized in the muscles, kidneys, and brain explains that even with high levels of ammonia in the blood, hepatic encephalopathy is not always triggered; on the contrary, even with low levels, it can occur.

At the cerebral level, the brain does not detoxify by the urea cycle like the liver but by glutaminase, one of the most important stimulant neurotransmitters, increasing glutamine levels and decreasing glutamate levels. Although more extensive and complex, unknown pathophysiology is involved, like the production of GABA activation, neurotransmitter competition, cerebral inflammation, direct toxic injury, or cerebrovascular disorders.

The other factor to explore is the role of the gut, its content, and metabolism. The microbiota, quantity and quality, its interaction with the food, and the derived substances that may have additional neurotoxic effects are the leading precursors of hepatic encephalopathy. As an explanation for increased levels of ammonia, mercaptans or benzodiazepine-like substances have been extensively studied and are the main target of treatment.

Ammonia. Levels of ammonemia are primarily maintained in 35 to 50 micromolar range because of the liver urea cycle and also, via glutamine synthetase and glutaminase, in the brain, muscle, and kidney. Pernicious effects of ammonia include cellular swelling, oxidative stress, mitochondrial dysfunction, disruption of cellular bioenergetics, inflammation or changes in pH, and alterations in membrane potential.

Findings have demonstrated that glutamine deamination can produce hyperammonemia and encephalopathy even in the absence of bacteria. Phosphate-activated glutaminase hydrolyzes glutamine, which then catalyzes the production of ammonia. Patients with cirrhosis had roughly 4-fold greater duodenal phosphate-activated glutaminase activity. Genetic factors may play a part in the development of overt hepatic encephalopathy. These factors include differences in the K-glutaminase gene promoter area or microsatellites that change phosphate-activated glutaminase activity.

Inflammation and oxidative stress. The liver possesses a capital role in the immune response and inflammation as the first barrier to splanchnic blood recognition and metabolism, plus the degradation of pro-inflammatory factors. Cirrhosis, like liver inflammation, leads to immune dysregulation, systemic inflammation, impaired blood-brain barrier permeability, and, consequently, neuroinflammation.

Bile acids. Bile acids may be elevated in liver disease due to disrupted enterohepatic circulation, and their deposit on neuronal tissue worsens neuroinflammation. Hepatocytes produce bile acids, which are a metabolic byproduct of cholesterol breakdown.

Metals. Manganese and zinc are both described as being associated with hepatic encephalopathy. Zinc is a cofactor for the antioxidant enzyme superoxide dismutase, and its deficiency is described in these patients. On the other hand, manganese is a well-described neurotoxin related to end-stage liver disease. It has a major implication because of cerebral deposits, thus neurotoxicity. It is excreted into the bile, and in the absence of elimination, it accumulates and deposits in the CNS. The basal ganglia are the main deposit spot, specifically the globus pallidus. Cellular pathophysiology stands out as a susceptibility in astrocytes and a sequester in the mitochondria, leading to cellular stress. It also acts on glutamate transport and the loss of postsynaptic dopamine-D2 binding. Extrapyramidal symptoms with motor disturbances and neuropsychiatric and cognitive disabilities, similar to Parkinson disease, are the prototypical clinical presentation in this situation.

Hyponatremia. Patients with cirrhosis frequently collect water instead of excreting diuretic waste because of disruptions in the usual regulation of water-electrolyte balance in renal function. This event originates from dilutional hyponatremia, which is involved in osmotic effects. There is a linear risk relationship between low plasma sodium concentrations and risk for hepatic encephalopathy.

Neuropathophysiology. The archetype of neuropathophysiology in cirrhosis is beyond ammonia--it is the blood-brain barrier. The barrier separates blood and brain, and characteristics in a healthy individual’s composition, metabolism, and immunity differ. Therefore, CSF characteristics between healthy individuals and cirrhotic patients vary. Even among cirrhotic patients, those with hepatic encephalopathy manifest significantly different fluid compositions than those without hepatic encephalopathy.

Besides the blood-brain barrier, increased brain water is observed. Hyperammonemia leads to the accumulation of intracellular glutamine and lactate, which provoke astrocyte water swelling. Astrocyte dysfunction impacts metabolism and neurotransmission, worsening lactate homeostasis and depleting neuronal energy supply.

Novel evidence has been reported on neuronal cell death, which was thought not to occur due to the characteristic reversibility of hepatic encephalopathy. However, permanent brain injury may lead to neurodegeneration, as astrocyte senescence cell death is a result of neurotoxicity.

The glymphatic system may also be changed to eliminate different substances, and patients have been said to have higher levels of neurosteroids, which change the way GABA receptors work.

Gut liver axis and microbiome. The other key point, and most important therapeutic target, is the gut microbiota. Its complexity makes it distinctive due to numerous interrelated factors, including structural or histological changes, immunity, systemic inflammation, permeability, or switching to a higher pathogenic flora versus a lower autochthonous strain. Multiple toxic elements, among them ammonia or methionine, are produced and absorbed.

This ends up being a cycle that feeds itself: greater alteration of the flora causes greater impact on immunity and inflammation, impairment of mucosa barrier and permeability, increased bacterial translocation, and again, higher pathogenic flora.

Malnutrition. Patients with cirrhosis typically have increased energy expenditure and impaired digestion and malabsorption. Additionally, malnutrition usually results in inadequate dietary intake. These elements yield a nearly universal, persistent disease: sarcopenia.

Sarcopenia is an independent prognostic factor for survival and a risk factor in and of itself for hepatic encephalopathy. Muscle tissue has the capacity to remove circulating ammonia; on the contrary, muscle catabolism produces glutamine, which ends up generating more ammonia.

Comorbidities. Various coexisting conditions are associated with hepatic encephalopathy and this group of patients. Alcohol abuse often appears in these patients as a direct neurotoxin and an important cause of structural brain damage, which may require a difficult diagnosis and prognosis. Metabolic-associated fatty liver disease, even in noncirrhotic stages, is associated with lower brain volume, more aggravated neuroinflammation, and hyperammonemia. Hepatitis C has various neuropsychiatric symptoms due to neuroinflammation, like HIV. It has been shown that the hepatitis C virus also replicates in endothelial cells, astroglia, and microglia. Hepatic encephalopathy prevalence is greater in diabetes, obesity, or aging, and concomitant medications may aggravate it.

Epidemiology

Hepatic encephalopathy is the first and most common liver decompensation, regardless of the etiological cause. The degree of underlying liver insufficiency and portosystemic shunting is associated with the incidence and prevalence of hepatic encephalopathy. The reported incidence and prevalence rates may be affected by the fact that many tools are available to detect hepatic encephalopathy, and its clinical manifestations may not be obvious.

The major economic burdens of cirrhosis are hospitalizations, multiple readmissions, and health care costs in general. Nearly 25% of readmissions in cirrhosis are related to hepatic encephalopathy.

The prevalence and cumulative incidence of hepatic encephalopathy, on account of its wide variety of clinical presentations and the lack of accurate diagnosis, are difficult to assert precisely. The incidence of hepatic encephalopathy is estimated at 11.6 per 100 person-years. When cirrhosis is diagnosed, the prevalence of overt hepatic encephalopathy is 10% to 14%, 16% to 21% in cases of decompensated cirrhosis, and 10% to 50% in patients with transjugular intrahepatic portosystemic shunt. Minimal hepatic encephalopathy is estimated in the range of 20% to 80% in patients with cirrhosis. The risk of developing the first overt hepatic encephalopathy episode is 25% in 5 years, depending on other risk factors and precipitating factors explained above. Patients with a previous episode have about a 42% risk of recurrence per year, and those with recurrent episodes have a 46% risk in 6 months. The median survival for patients with cirrhosis and following hepatic encephalopathy is shortened to 2 years--1 year if patients are more than 65 years old.

Prevention

General nutritional recommendations should be initiated for all patients regarding a sufficient food intake, estimated at 30 to 40 Kcal/kg body weight, a consumption of 1 g/kg body weight of protein, and a nighttime snack to avoid muscle tissue catabolism and sarcopenia.

The most common scenario in prevention is established after the first episode of hepatic encephalopathy. The use of nonabsorbable disaccharides (lactulose and lactitol) is the first-line pharmacological prevention. Maintaining the right bowel motility and avoiding constipation are the main goals. The misuse of lactulose also triggers hepatic encephalopathy and has been described as an important cause of recurrence in the context of hydroelectrolytic imbalance. As another form of prevention, mannitol or nonabsorbable disaccharides can be given to cirrhotic patients who have upper gastrointestinal bleeding. This lowers the risk of overt hepatic encephalopathy.

On the other hand, any measure to prevent liver disease progression may be considered primary prophylaxis for hepatic encephalopathy, such as stopping alcohol consumption, treating virus-related liver disease, treating metabolic syndrome or iron overload, and more.

Differential diagnosis

Confusing conditions

The two possible presentations of hepatic encephalopathy should be considered: overt hepatic encephalopathy and covert hepatic encephalopathy. The first one, because of the more noticeable neuropsychiatric symptoms, is often a differential diagnosis between more acute entities, such as intoxications, withdrawal, or metabolic disorders. Regarding covert hepatic encephalopathy, because of its mild, practically imperceptible presentation, differential diagnosis is carried out among more chronic and latent diseases. The most important differential diagnosis is summarized in the next two tables, divided into overt hepatic encephalopathy and covert hepatic encephalopathy (12).

Diagnostic workup

The diagnosis of hepatic encephalopathy is divided into two clinical situations: overt hepatic encephalopathy and covert hepatic encephalopathy. The clinical manifestations in overt hepatic encephalopathy make its diagnosis less challenging than covert hepatic encephalopathy. In overt hepatic encephalopathy, the first and most common manifestation or sign, which clearly differentiates it from covert hepatic encephalopathy, is its asterixis. Asterixis is not specific for overt hepatic encephalopathy and can appear in hypercarbia and uremia. The rest of the manifestations of hepatic encephalopathy are variable depending on grade and are explained in the Clinical manifestations section of this article.

Overt hepatic encephalopathy is diagnosed clinically with the West Haven criteria and is associated, practically always, with a precipitating factor. The most common ones are constipation, infection, acute kidney injury, gastrointestinal bleeding, electrolyte imbalances, or any form of liver injury (hepatocellular carcinoma or alcoholic injury, for instance). It might be necessary to do more tests, analysis, and imaging on the first episode to rule out other neurologic conditions, such as stroke, other focal cerebral lesions, or other metabolic encephalopathies. After the initial differential diagnosis approach, the most important diagnostic investigation is centered on identifying the precipitating factor. It is important to rule out any infectious focus and carry out an infectious work-up even in the absence of infectious signs and symptoms in every patient. Cerebral imaging is not often necessary, but it should be carried out in cases of unusual clinical presentation, localizing signs, abrupt symptoms, or absence of therapeutic response.

Assessing liver disease staging is important to guide the type of hepatic encephalopathy. In the Child-Turcotte-Pugh A stage, toxic elements such as ammonia are less likely to be the precipitant cause, and large portosystemic shunts should be strongly considered.

There are no established analytical tools to assess the diagnosis of hepatic encephalopathy. Ammonia levels have been largely looked into, and European Association for the Study of the Liver-AASLD guidelines are not yet positioned on this issue. A recommendation to evaluate ammonia levels for every patient with delirium or encephalopathy and liver disease has been published. Normal blood ammonia levels have a negative predictive value, so normal levels may rule out the diagnosis of hepatic encephalopathy. There are limitations to testing ammonia levels. Patients without liver disease or hepatic encephalopathy can display hyperammonemia, and hyperammonemia may remain elevated after clinical hepatic encephalopathy resolution. Advanced hepatic encephalopathy in patients with cirrhosis is associated with relatively low ammonia levels. So, the best evidence for ammonia testing is observed in patients with acute liver failure and its severity, as well as the associated risk of developing intracranial hypertension and cerebral edema.

With regard to covert hepatic encephalopathy, unlike overt hepatic encephalopathy, the mixture of mild clinical symptoms and the absence of a diagnostic gold standard make it hard to detect. There are no blood biomarkers or characteristic imaging findings, and the lack of clear clinical manifestations on examination means that caregivers play an important role in detecting the slightest behavior changes. The results of psychometric or neuropsychological tests and scores play a further crucial role. These tests are hardly used in clinical practice because of a lack of operability and standardization, so their utility remains mainly for research purposes. The most important ones are listed here:

In summary, paraclinical diagnosis embraces those tests that do not give a proper diagnosis but give support to it, especially on initial presentation. Within this could be measurements of plasma ammonia levels, an electroencephalogram, and a cerebral MRI. An electroencephalogram typically displays a slowing of basic rhythmic activity with triphasic waves and anterior-predominant abnormalities. Cerebral imaging is mostly useful to rule out other disease processes. In addition, it can provide structural and functional information. Brain size with volumetric MRI, spectroscopy with oxygenation measurement, PET studies, or diffusion are examples of the variety of radiology tools. The main limitation is the lack of consensus, which remains in the trial field.

Management

General measures

Finding and treating any triggering factors is the main objective in the management of hepatic encephalopathy. First, the cause of the underlying liver disease should be investigated, and steps should be taken to stop it from getting worse, such as quitting drinking. It is important to rule out and treat infections (such as spontaneous bacterial peritonitis), renal failure, gastrointestinal bleeding, electrolyte imbalance (eg, due to diuretics), and drugs that affect the central nervous system. On the other hand, it is important to recognize, address, and prevent any triggers for hepatic encephalopathy episodes in the future (14).

Specific therapies

Nonabsorbable disaccharides. The objective is to use nonabsorbable disaccharides to decrease the quantity of bacterial load, nitrogen, and toxins absorbed from the intestine. Lactulose is generally the first line of treatment. It is prescribed at a starting dose of 25 mL every 12 hours until at least two soft bowel movements are generated daily. Dose reduction should be performed as required, with titration to a level that maintains two to three bowel movements per day. According to a meta-analysis comprising 38 trials involving 1828 patients, patients receiving nonabsorbable disaccharide treatment have a lower risk of hepatic encephalopathy (RR = 0.63; 95% CI = 0.5-0.74) and mortality (RR = 0.36; 95% CI = 0.14-0.94) when compared to patients receiving placebo or no intervention (07).

Rifaximin. For treating hepatic encephalopathy, several studies have been done that compare rifaximin with placebo, other antibiotics, nonabsorbable disaccharides, and different doses. These studies demonstrated rifaximin’s superior or comparable effects to the compared drugs with good tolerability. After the second hepatic encephalopathy episode, rifaximin is usually added to nonabsorbable disaccharides. Research has demonstrated that in individuals with a history of recurrent hepatic encephalopathy, rifaximin dramatically lowers the risk of hepatic encephalopathy recurrence and hepatic encephalopathy-related admissions. Rifaximin is administered orally at a dose of 400 mg three times daily or 550 mg twice daily.

Probiotics. Probiotics have been shown to positively affect patients’ hepatic encephalopathy, including cytokine level reduction. Even so, its function might be more significant when combined with other treatments, like antibiotics. Most of the research has assessed VSL3’s applicability. Probiotic therapy has yielded encouraging outcomes in the early stages, but there have not been enough data to suggest that individuals with hepatic encephalopathy have improved cognitively. A Cochrane review evaluating 21 studies concluded that probiotics appear to have no beneficial effect on hepatic encephalopathy compared to placebo (04). On the other hand, there is still uncertainty over whether using probiotics is linked to changes in the microbiome’s composition that could promote an improvement of normal flora.

Branched-chain amino acids. According to an updated meta-analysis of eight randomized, controlled trials, oral branched-chain amino acids-enriched formulations improve the symptoms of episodic hepatic encephalopathy, whether it be overt hepatic encephalopathy or minimal hepatic encephalopathy (06). Intravenous branched-chain amino acids did not affect the episodic hepatic encephalopathy type.

L-ornithine L-aspartate. The urea cycle is the most significant method of ammonia elimination that doesn’t include energy consumption, and in cirrhotic patients, most of the ammonia is removed from the muscle. L-ornithine-L-aspartate is an amino acid complex that stimulates both muscle protein synthesis and the urea cycle. L-ornithine-L-aspartate was better at improving mental status, lowering hyperammonemia, and making psychometric tests better in two double-blind, randomized trials for treating hepatic encephalopathy type C (08). As a result, L-ornithine-L-aspartate is only advised as an extra or alternative treatment for patients with hepatic encephalopathy who do not react to standard treatment modalities. It is not regarded as a first-line treatment for hepatic encephalopathy.

Obliteration of spontaneous portosystemic shunts. In stable cirrhotic patients with a MELD score lower than 11, obliteration of accessible portosystemic shunts in those who have recurrent or persistent hepatic encephalopathy (despite receiving appropriate medical treatment) may be explored (05). Nonetheless, this technique carries some risks, such as the potential for problems related to the procedure and aggravation of portal hypertension. For shunt embolization, patient selection is, therefore, essential.

Emerging therapies

Ornithine phenylacetate. An ammonia scavenger called ornithine phenylacetate works by increasing the activity of glutamine synthetase in skeletal muscles and hepatocytes and bringing back to normal the activity of intestinal glutaminase. A randomized controlled trial revealed that ornithine phenylacetate was safe and able to decrease serum ammonia levels in patients with cirrhosis and hepatic encephalopathy, but no significant difference in time to clinical improvement was found between patients given ornithine phenylacetate versus placebo.

Polyethylene glycol. The HELP trial and other trials investigated the off-label use of polyethylene glycol (PEG)-3350 electrolyte solution for treating overt hepatic encephalopathy. Patients enrolled in the polyethylene glycol arm, the majority of whom had previously received lactulose, showed a noteworthy improvement in hepatic encephalopathy grades as compared to lactulose, along with a faster resolution of hepatic encephalopathy (11).

Benzodiazepine antagonists. Flumazenil is not frequently used. It temporarily enhances mental status in overt hepatic encephalopathy without enhancing survival or recovery. A Cochrane review evaluating 14 studies revealed low-quality evidence suggesting a short-term beneficial effect of flumazenil on hepatic encephalopathy in patients with cirrhosis. To assess the possible advantages and disadvantages of flumazenil in cirrhotic patients with hepatic encephalopathy, randomized clinical trials are required.

Fecal microbiota transplantation. In patients with cirrhosis, fecal microbiota transplantation from healthy donors improves gut dysbiosis, but it is not routinely recommended as a treatment option. According to studies, fecal microbiota transplantation can alleviate inflammation, lower ammonia levels, and modify the gut microbiome. Two randomized clinical trials with either enema or capsules have shown improvements in dysbiosis and safety and encouraging trends toward bettering clinical outcomes. Extensive research is being conducted to evaluate additional safety and effectiveness.

Liver transplantation. Hepatic encephalopathy is associated with a lower quality of life and is a sign of poor survival. Because it is not considered in the MELD score, its significance in ranking patients for liver transplantation priority is challenging. Referrals for evaluation to a hepatology transplant center are necessary for patients with hepatic encephalopathy. Furthermore, transplantation will be extremely beneficial for patients with the uncommon variety of hepatic encephalopathy known as hepatic myelopathy, which is characterized by significant motor abnormalities.

Special considerations

Pregnancy

Up to 20% of liver dysfunction in pregnancy is due to liver diseases unique to the pregnant state, which are divided according to the association with or without preeclampsia. The most serious entity associated with hepatic encephalopathy is the acute fatty liver of pregnancy. It is a sudden, catastrophic illness that occurs almost exclusively in the third trimester. It causes acute liver failure with fatty infiltration of the hepatocytes, followed by hepatic encephalopathy and coagulopathy. Postpartum hemorrhage would be the most frequent complication, and hepatic encephalopathy and platelet-to-white blood cell ratio are important prognostic indicators for mortality.

Encephalopathy is treated in the standard way, and early diagnosis and immediate delivery are essential for both fetal and maternal survival.

Anesthesia

Sedatives, such as benzodiazepines and opioids, increase the risk of both overt and covert hepatic encephalopathy, so they should be avoided. The risk depends on drug dosage and liver function (high risk on Child-Turcotte-Pugh C). They can trigger hepatic encephalopathy up to 6 hours later.

Sedation used in digestive endoscopy usually includes the use of midazolam. In patients with liver cirrhosis, the risk has been definite, with doses greater than 3 mg as a cutoff point. On the contrary, compared to midazolam, propofol has been demonstrated to have a higher safety and effectiveness profile, a quicker recovery period, and no significant cognitive side effects.

To preserve the airway, intubation should be considered for all patients with a Glasgow scale score less than 8 and West Haven criteria grade III or IV. Short-acting medications, like dexmedetomidine or propofol, should be utilized for sedation in critical care. Dexmedetomidine has been linked to preserving cognitive abilities and shortening the need for mechanical ventilation in patients in intensive care (09; 10).

Many anesthetic drugs can affect hepatic blood flow, distribution, metabolism, and elimination. Therefore, specific indications for these patients are not discussed in this article but are important to keep in mind.