The common symptoms of HE are related to mental activities (feeling slow, confusion, lethargy, slurred speech, difficulty drawing objects, changes in handwriting), changes in sleep patterns, slip-ups with memory, and mood issues such as feeling depressed and not wanting to eat. Difficulties in driving may also be noticed by the patient or family/friends. Problems with balance and coordination are frequent and may result in falls.

The presence of nonspecific neuropsychiatric signs and symptoms is the hallmark of HE [5, 16]. MHE is regarded as a preclinical stage of OHE in SONIC and is comprised of deficits in multiple domains including attention, vigilance, response inhibition, and executive function [11, 17, 18]. Over recent years, CHE has received more attention given its propensity to degenerate into OHE. The difficulty with CHE is that it is difficult to diagnose clinically even for an astute physician, given its characteristic cognitive profile [16, 19, 20]. Driving skills are known to be impaired in CHE patients hence, exposing the driver as well as others to danger [21–23]. Studies have demonstrated that patients with CHE have impaired quality of life as well as working capability [24–27]. Furthermore, not only does CHE predict the subsequent onset of OHE [14, 28, 29] but it is also associated with poor prognosis and is an independent predictor of survival [30]. The appearance of asterixis or disorientation as per consensus heralds the onset of OHE [5]. However, asterixis (flapping tremor) which reflects negative myoclonus is not seen in HE alone as it can be elicited in other metabolic conditions such as uremia and carbon dioxide narcosis [31]. Sleep–wake cycle disturbances (insomnia, hypersomnia, and excessive day time sleepiness) due to disturbance in the circadian rhythm are common even in early stages of HE and may precede other neuropsychiatric disturbances [32, 33]. With the progression of HE from covert to overt stages, more advanced neuro-psychiatric signs and symptoms emerge. These may include progressive disorientation, behavioral issues including confusion, irritability, apathy, disinhibition, depression, agitation, increased sleepiness, and finally stupor leading to coma [34, 35].

An initial thorough history and physical examination should be performed with specific questions directed to both the patient as well as the caregiver to assess for the presence of any cognitive or mental status changes. In the case of CHE, the caregiver may be better able to answer some of the questions about changes in sleep patterns, behavior, mood, and driving errors. The provider should pose direct questions about disturbances in cognition such as impairment in working memory, decrease in attention span, difficulty in driving leading to accidents, and/or problems working with machines potentially leading to work impairment. On examination, initially assess the general level of alertness and orientation. A detailed neurological examination may reveal upper motor neuron signs (hypertonia, brisk reflexes, positive Babinski sign) in many HE patients but maybe absent in coma. Extrapyramidal dysfunction manifested as expression-less masked facies, slowness of movements/speech, parkinsonian-like tremors, and dyskinesic movements can be observed [31]. In addition to examination findings due to other manifestations of cirrhosis, distinct and focal transient neurological deficits including hemiplegia have been reported with no evidence of abnormalities seen on brain imaging or cerebrospinal fluid analysis [36]. Seizures including those leading to status epilepticus are rare but are reported in patients with HE [37, 38] as are rapidly progressive Parkinsonian-like symptoms which have been shown in a study done using SPECT imaging to be related to disturbances at the pre- and postsynaptic level in the striatal region involved in dopaminergic neurotransmission. These symptoms are not responsive to ammonia lowering strategies and have been reported in around 4.2 % of patients [39]. A dramatic but rare pattern of spinal cord involvement in some patients with HE (wherein the mental status changes may be minimal) related to liver disease and PSS is characterized by progressive spastic lower limb weakness and termed as hepatic myelopathy (HM). MRI of spine is often normal in HM with no reported motor involvement of upper limbs. Hepatic myelopathy can predate OHE in some case. There are approximately 90 cases reported in literature since the first description in 1949 [40]. These motor manifestations of HM do not respond to usual ammonia lowering strategies but early liver transplantation (LT) does lead to better neurological outcomes hence, making a case for MELD exception for patients with HM [41].

Patients with underlying portal hypertension can have HE triggered by infections, bleeding in the GI tract (upper or lower GI), effects from medications (excessive use of pain medications and sleeping pills or lack of adherence to ammonia lowering regimens), dehydration, electrolyte disturbances (particularly low sodium and potassium levels), being constipated, and/or changes in diet.

The precipitation of HE may be secondary to multiple causes including infection, electrolyte abnormalities, medication nonadherence, gastrointestinal bleeding, excessive diuretic use, and constipation. In a US-based study lactulose nonadherence was the most common precipitating event after the first OHE episode [42] but infections are typically thought to be the most common cause of episodic OHE implicated in 56 % of cases [43] with electrolyte disorders more commonly implicated in recurrent cases [44–47]. The most common infectious triggers of OHE are SBP and urinary tract infections.

When approaching the patient with OHE, the clinician should ask focused questions to assess for other precipitants such as prescription/nonprescription drug usage (sedative medications like benzodiazepines, narcotics, recreational drugs), alcohol usage, reasons for being dehydrated (over-diuresis, GI losses), and history of procedures (iatrogenic/spontaneous shunts, recent large-volume paracentesis). However, it is not always possible to find a clear precipitant as reported in one study in which for 12 % patients no precipitant was found [46].

Overt hepatic encephalopathy has nonspecific neuropsychiatric manifestations but in the right clinical setting, the diagnosis remains straight forward. A number of other entities which can result in acute confusional states or delirium include metabolic causes (diabetes related: hypoglycemia or hyperglycemia, diabetic ketoacidosis, nonketotic hyperosmolar state), electrolyte abnormalities (hyponatremia or hypernatremia, hypokalemia, hypercalcemia), pulmonary issues (hypoxic or hypercarbic states), renal-mediated (uremia), toxin-related (acute alcohol intoxication, Wernicke’s or Korsakoff syndromes, and delirium tremens), medications and illicit drugs (inappropriate use or over dosage of either prescription or over-the-counter medications, drugs of abuse like sedative-hypnotics, opiates, antihistamines, hallucinogens, heroine, cannabis, atypical alcohols) infectious (sepsis and meningo-encephalitic syndromes, severe systemic infections) CNS-related (cerebrovascular accidents including subdural hematomas, brain tumors, traumatic brain injuries, convulsive or nonconvulsive seizures, and dementing or psychiatric illnesses). In the end, any severe medical and physical stress (leading to organ failure or inflammation) can lead to altered mentation. Hyponatremia (serum sodium levels <130 mEq/l) is an independent risk factor for development of OHE and may be a target for preventive intervention [48]. Diabetes mellitus in patients with hepatitis C-related cirrhosis has been shown to be a risk factor for development of HE at earlier stages of liver decompensation. Patients with liver cirrhosis and renal dysfunction are also at an elevated risk of developing HE irrespective of the severity of the underlying liver disease [49].

Individual cases can follow different patterns of disease progression within the category of type C HE. And it appears that the pathogenesis of OHE and CHE is likely to be similar and the differences occur among levels of severity and stages of liver disease. Studies into the pathophysiology of HE and CHE have focused on the accumulation of toxins in the bloodstream and brains of patients with chronic liver disease. Ammonia is only a single component of this multifactorial disease and synergistic action of ammonia with other toxins may play a role in changing the metabolism of amino acid neurotransmitters and increasing the permeability of blood–brain barrier to these neurotransmitters. Ultimately, this leads to shifting of the balance towards the inhibitory gamma-aminobutyric acid (GABA) neurotransmission with suppression of the excitatory neurotransmitters like glutamate and catecholamine. The presence of the chronic neuro-inflammation, sepsis, oxidative stress, hyponatremia, and perturbations of gut flora could have a larger role in development of HE as well [50–53]. Although the mechanism by which ammonia cause brain dysfunction are not fully elucidated but there is some evidence of the association of ammonia with MHE [54]. The main source of ammonia in the body seems to be the gut microbiota, although animal model studies suggest alternative sources [55]. Glutamate is found mainly in the enterocytes of the small bowel and to a lesser extent in the colon and glutaminase from these multiple sources produces ammonia by metabolizing glutamine into glutamate and ammonia [56]. Ammonia is typically metabolized in the liver to urea, a water-soluble molecule that can be excreted by the kidneys. The diseased liver is not able to process the ammonia at normal capacity. It has been demonstrated that in patients with acute liver failure (ALF) brain and muscle cells get more involved in ammonia metabolism [57]. Studies have shown that after insertion of a portacaval shunt in rats there is increased expression of an intestinal glutaminase in rat enterocytes leading to increased ammonia levels, which may explain the increased risk of HE among patients who have undergone this procedure [58]. In the endoplasmic reticulum of brain astrocytes (only cells to metabolize ammonia in brain) glutamine synthetase produces equimolar ratios of ammonia and glutamine [57, 59]. Hence, with the advancing liver failure the intracellular levels of glutamine increase. As glutamine is an osmotic agent this increase is believed to be one of the putative reasons in the development of low-grade cerebral edema in patients with MHE or OHE [60].

The role of inflammation with or without hyperammonemia in the pathogenesis of HE is being recognized clearly more [61]. In patients with cirrhosis, inflammatory processes result mainly from infections but also from other causes like GI bleeding, obesity, and alterations in the intestinal flora. In a recent study by Merli et al., addressing the association between bacterial infections and cognitive dysfunction in cirrhotic (n = 150) vs. noncirrhotic patients (n = 81) found that neurocognitive changes were significantly increased in the cirrhotic group as compared to the noncirrhotics (90 % vs. 39 %) after the diagnoses of sepsis [62]. There were lowered scores on cognitive testing in patients with cirrhosis with systemic inflammatory response syndrome (SIRS) and induced hyperammonemia only when they also had increased levels of the inflammatory cytokines (tumor necrosis factor (TNF), interleukins (IL)-1 and IL-6) implying that hyperammonia only causes alterations in cognition in presence of neuro-inflammation and not alone [51]. This has been demonstrated in animal model studies as well where in administration of lipopolysaccharide in the liver damaged rats resulted in brain edema leading to altered consciousness but not in healthy rats [63]. Again, various other studies have demonstrated that the serum levels of various inflammatory cytokines (TNF-alfa, IL-6, and IL-18) in cirrhotic patients are associated with presence and severity of both OHE and CHE [64, 65]. In the end, it appears that infections promote the development of HE and cerebral edema in patients with ALF with inflammatory cytokines synergizing with hyper-ammonemia to produce cerebral edema [66, 67].

While there are multiple tests available which help in establishing the diagnosis of HE including simple blood tests, electroencephalography (EEG) which measures brain electrical activity, brain CT or MRI scans, the diagnosis of OHE is ultimately made by physician based on examination and historical findings and no single test by itself establishes the diagnosis of OHE. The diagnosis of MHE, which cannot be detected simply on examination or questioning requires specialized paper and pencil or computerized tests for testing the thinking ability of the patient. The physician depending upon the circumstances may do none, one, some, or all of these tests.

The diagnosis of OHE requires clinical evaluation and exclusion of other etiologies as noted above with judicious use of additional testing depending on circumstances and the severity of mental status changes [68]. Laboratory testing should include basic metabolic panel (for renal function, hypokalemia, or hyponatremia), liver function tests, coagulation panel, CBC (for leukocytosis and platelet counts), urine analysis, ascitic fluid analysis to rule out SBP, culturing of blood, urine, ascitic fluid, and serum alphafetoprotein levels in the appropriate setting. The measurement of serum ammonia routinely in CLD patients suspected to have HE is not helpful as a high blood level of ammonia by itself does not provide any extra diagnostic or prognostic value [69]. However, in a case of OHE if the serum ammonia level is normal then the diagnosis of OHE should be reconsidered. Adding complexly to the utility of ammonia levels is that not only can other nonhepatic causes result in elevations of ammonia (such as medications) but problems with preservation and processing samples may also lead to difficulty with accurately determining ammonia levels. A study done in an emergency department (ED) setting to see whether elevated blood ammonia levels coincide with HE (additionally established by the WHC and the critical flicker frequency) found that ammonia blood levels do not reliably detect HE. The use of ammonia as sole indicator for HE in the ED may result in frequent errors in diagnosis [70]. Brain imaging (CT or MRI scans) do not contribute significantly to diagnosis or prognosis but should be considered in the appropriate clinical setting keeping in view the fact this subgroup of patients are at increased risk of intracranial bleeding [71].

It is important to address the potential trigger of the HE. Hence, actively seeking and treating the infections, correcting the electrolyte disturbances, avoiding medications causing excessive sleepiness, avoiding constipation by taking medications, and making appropriate dietary changes are the foundations of treatment.

While a majority of patients with episodic OHE may need to be hospitalized, the grade and severity of HE often determines the level of care, with patients who are not able to safely protect their airways preferably being managed in the intensive care unit. Since the majority (up to 90 %) of OHE episodes do have a precipitating trigger as outlined above [96], actively seeking and treating these precipitants is of paramount importance and may in itself result in resolution of the OHE episode. The main objectives of drug treatment in OHE are to reduce ammonia production and absorption. Thus a two-pronged approach is used.

You should keep on eating several small meals at regular intervals in a day and a late snack before going to bed at nighttime. This late snack should consist of complex carbohydrates such as whole-grain breads, starchy vegetables, and proteins.

Malnutrition is an under recognized problem in patients with HE and the presence of severe protein calorie malnutrition can exacerbate the manifestations of HE in turn. It is know that muscles have a role in clearing ammonia, hence loss of muscle mass may further exacerbate the manifestations of HE [59, 128]. Per se malnutrition may be an independent risk factor for survival in cirrhotic patients [129]. All patients with HE should get a formal evaluation of nutritional status with the involvement of dieticians, nutrition experts, or special teams. While as hand-grip dynamometer has a good sensitivity and specificity for providing information on depletion of body cell mass with its associated effect on survival in males but it cannot be held true for females [130, 131]. The best method of providing nutrition is orally however, alternative routes like nasogastric tubes and parenteral may be used in patients with higher levels of HE who are either not able to cooperate or able to maintain adequate oral intake. Avoidance of fasting state, along with small frequent meals and a late night snack has been shown to be beneficial in a recent systematic analysis [132]. The energy intake should be maintained at 35–40 kcal/kg/day of ideal body weight with a protein intake of 1.2–1.5 g/kg/day and these recommendation have been incorporated in the recent evidence-based guidelines by ISHEN [133]. The source of the dietary protein should be richer in vegetable and dairy proteins rather than meat based proteins. In patients not able to tolerate proteins, use of oral BCAA supplementation should be considered [134]. There is some overlap of signs and symptoms in both HE and Wernicke’s encephalopathy (WE), also patients with cirrhosis (alcohol and nonalcohol related) may be deficient in water-soluble vitamins including thiamine. Hence, oral vitamin supplements may be considered in HE patients as vitamins are safe and cheap. In case of WE, parenteral thiamine supplementation prior to giving a glucose load is important. Correcting of electrolyte abnormalities in particularly, low sodium and potassium levels that are risk factors for development of HE is pertinent [48, 135]. However, extreme caution needs to be exercised while correcting low sodium levels, which should be done slowly as rapid corrections can lead to central pontine myelinolysis, which is a devastating condition.