1) How should varices be monitored?

2) Who needs monitoring for varices?

3) How can the development and progression of EVs be prevented?

4) Who needs treatment to prevent initial esophageal variceal bleeding?

5) What is the proper management for preventing initial esophageal variceal bleeding?

6) How can acute esophageal variceal bleeding be diagnosed?

7) What is the appropriate pharmacological treatment for acute esophageal variceal bleeding?

8) What is the proper endoscopic treatment for acute esophageal variceal bleeding?

9) What are the options for rescue treatment when endoscopic treatment of acute variceal bleeding fails?

10) What is the primary treatment to prevent EVs from rebleeding?

11) What are the options for rescue treatment when primary treatment to prevent EVs from rebleeding fails?

12) Who needs treatment to prevent gastric variceal bleeding?

13) What is the proper treatment to prevent gastric variceal bleeding?

14) What is the proper treatment of acute gastric variceal bleeding?

15) What is the primary treatment to prevent gastric varices from rebleeding?

16) How should portal hypertensive gastropathy be classified?

17) How should portal hypertensive gastropathy be managed?

1) How should HE be diagnosed and classified?

2) How should overt HE be defined and diagnosed?

3) What are the precipitating factors of overt HE?

4) What differential diagnoses should be considered in diagnosing overt HE?

5) Is the measurement of serum ammonia helpful in diagnosing overt HE?

6) Is radiologic image evaluation of the central nervous system helpful in diagnosing overt HE?

7) What neurophysiological or neuropsychological tests are clinically necessary to diagnose overt HE?

8) How should the acute phase of overt HE be treated, and how should recurrence be prevented?

9) Are branched chain amino acids helpful in treating and preventing overt HE?

10) Is L-ornithine-L-aspartate (LOLA) helpful in treating and preventing overt HE?

11) Is proper education helpful in preventing the recurrence of and readmission for HE?

12) How should covert HE be defined and diagnosed?

13) What is the clinical significance of covert HE?

14) How should covert HE be treated?

15) How should the quality of life of HE patients be assessed? Does treating HE improve patient quality of life?

Given the high prevalence of varices and poor prognosis with variceal bleeding, monitoring varices is important in patients with liver cirrhosis. Therefore, upon first diagnosis with liver cirrhosis, endoscopy should be performed to look for varices and assess the risk of bleeding. Diagnosis of liver cirrhosis is not difficult in patients with decompensated liver cirrhosis accompanied by ascites or variceal bleeding, but a liver biopsy is needed to diagnose patients with compensated cirrhosis who have no clinical symptoms or signs. However, liver biopsy is an invasive procedure with a risk of serious complications [16]. Furthermore, doubt has been cast on the accuracy of liver biopsy because of the risk of sampling errors [17,18] and intra- and interobserver variability [18,19].

Liver cirrhosis can disappear with appropriate treatment of the underlying liver disease [20,21], though portal hypertension can accompany the severe stage of fibrosis (F3) [22,23]. Various practice guidelines recommend surveillance for hepatocellular carcinoma in patients with liver fibrosis, even before the development of cirrhosis [24,25]. Therefore, the alternative term compensated advanced chronic liver disease (cACLD) has been proposed for patients with severe fibrosis (F3) and compensated liver cirrhosis to better reflect that the spectrum of severe fibrosis and cirrhosis is a continuum in asymptomatic patients and that distinguishing between these two conditions is often clinically impossible [26]. A liver stiffness value, measured by transient elastography, of <10 kPa can rule out cACLD, and a value between 10 and 15 kPa is suggestive of cACLD but needs further tests for confirmation. A value >15 kPa is highly suggestive of cACLD [26]. Endoscopic surveillance of all patients with cACLD can cause problems, such as an increase in medical costs due to an increase in unnecessary tests. Therefore, noninvasive screening tests have been proposed for patients with EVs, especially those whose EVs have a high risk of bleeding, to reduce unnecessary endoscopic surveillance. The Baveno VI criteria suggest that endoscopic surveillance can be avoided in cACLD patients with a liver stiffness <20 kPa and a platelet count >150×10⁹/L because they are at very low risk for varices that need to be treated [26]. Augustin et al. [27] expanded the Baveno VI criteria to say that endoscopic surveillance can be avoided in cACLD patients with liver stiffness <25 kPa and a platelet count >110×10⁹/L. However, considering that noninvasive screening for varices that need to be treated is not particularly reliable [28,29] and endoscopy is more easily accessed in Korea than in Western countries, we do not deem screening by noninvasive test to be useful in Korea.

The incidence of EV development in cirrhotic patients without varices is 5–9% at 1 year and 14–17% at 2 years [6,7]. Small EVs progress to large varices at the rate of 12% after 1 year and 25% after 2 years [7]. Therefore, endoscopic surveillance should be performed more frequently in patients with small EVs than in those without EVs. In addition, because the type of underlying liver disease (e.g., alcoholic cirrhosis) and liver function (e.g., decompensated cirrhosis) are risk factors for the progression of EVs, they should be taken into account when determining the surveillance interval. Endoscopic surveillance should be performed at 2–3-year intervals in patients with compensated liver cirrhosis and at 1–2-year intervals in those with decompensated liver cirrhosis [30,31].

EVs can be classified as large or small according to their size, with a breakpoint at 5 mm in diameter [32], or they can be classified as F1 (linearly dilated, small and straight varices), F2 (beady varices, tortuous and occupying less than one third of the esophageal lumen), or F3(nodular varices, large and occupying more than one third of the esophageal lumen) [33]. However, because the F2 and F3 classifications are fairly subjective and prophylactic treatment is recommended both for F2 and F3, F1 is usually classified as small, and F2 and F3 are classified together as large.

In cirrhotic patients with small EVs, the risk of bleeding is low (3% at 2 years and 8% at 4 years) and remains low in patients whose varices remain small at the follow-up endoscopy, though it increases significantly when the varices become large. An increase in Child-Pugh score during follow-up appears to be a significant predictor of enlarged varices and thus an increase in bleeding risk [46]. The prevention of first bleeding in patients with small EVs depends on their risk of bleeding. Patients with small varices with red color signs on endoscopy or decompensated cirrhosis have an increased risk of bleeding and should consider using NSBBs [26,47].

In patients with upper gastrointestinal bleeding, variceal bleeding caused by portal hypertension can be suspected if the patients show jaundice, ascites, HE, splenomegaly, collateral circulation of the abdominal vessels, lower extremity edema, or spider angiomas. A definite diagnosis can be established by endoscopic examination. If blood clots or white nipples appear on the surface of the varices, or if blood is found in the stomach without a potential bleeding focus other than EVs, acute EV bleeding can be diagnosed [45].

Acute EV bleeding is a medical emergency requiring intensive care. It is essential to protect the circulatory and respiratory status of the patient regardless of the cause of bleeding. Volume resuscitation via adequate fluid therapy and a packed red blood cell (PRBC) transfusion should be initiated to restore and maintain hemodynamic stability. A recent RCT showed that bleeding-related mortality (5% vs. 9%, P=0.02) and the incidence of serious adverse events (12% vs. 18%, P=0.01) were significantly decreased in the “restrictive” PRBC transfusion group (initiating PRBC transfusion at a hemoglobin threshold of 7 g/dL and maintaining it at 7–9 g/dL) compared with the “liberal” PRBC transfusion group [83]. Improved survival in the restrictive transfusion group might be associated with lower rates of hemostasis failure and serious adverse events. In patients with acute EV bleeding, adequate fluid therapy/PRBC transfusion should be performed while considering age, cardiovascular disease, presence or absence of ongoing bleeding, and hemodynamic status. Excessive fluid therapy/PRBC transfusion may increase the portal pressure and aggravate bleeding from the varices, so that should be taken into account [84]. Regarding correction of coagulopathy, clinical studies of recombinant factor VIIa have not shown a clear benefit, and therefore the routine use of fresh frozen plasma or recombinant factor VIIa is not recommended [85,86]. Although the efficacy of platelet transfusion in patients with acute EV bleeding has not been proven because of a lack of clinical studies, it can be considered in patients with severe thrombocytopenia.

Cirrhotic patients presenting with acute gastrointestinal bleeding have a high risk of developing bacterial infections, therefore initiation of prophylactic antibiotic treatment at the time of admission is necessary. Meta-analyses of RCTs have shown that the use of antibiotic prophylaxis reduces the risk of infections, recurrent bleeding, and bleeding-related death [87,88]. A recent meta-analysis demonstrated that prophylactic antibiotic treatment was associated with a decrease in bleeding-related mortality (RR, 0.79; 95% CI, 0.63–0.98), mortality from bacterial infections (RR, 0.43; 95% CI, 0.19–0.97), development of bacterial infections (RR, 0.35; 95% CI, 0.26–0.47), and rebleeding (RR, 0.53; 95% CI, 0.38–0.74) [88]. However, another recent retrospective study questioned the usefulness of the routine antibiotic prophylaxis in cirrhotic patients experiencing acute variceal bleeding because of a very low incidence of bacterial infections (2%) and mortality (0.4%) in Child-Pugh class A patients with acute variceal bleeding, even in the absence of prophylactic antibiotic treatment [89]. No prospective study has evaluated the usefulness of antibiotic prophylaxis, and therefore the routine use of prophylactic antibiotics is recommended for all cirrhotic patients presenting with variceal bleeding, regardless of their Child-Pugh class. In a previous RCT comparing intravenous ceftriaxone (1 g every 24 hours) and oral norfloxacin (400 mg every 12 hours) for the prophylaxis of bacterial infection in cirrhotic patients with gastrointestinal bleeding, the incidence of proven or possible infections (11% vs. 33%, P=0.003), proven infections (11% vs. 26%, P=0.03), and spontaneous bacterial peritonitis or bacteremia (2% vs. 12%, P=0.03) was significantly lower in the ceftriaxone group [90]. However, controversy remains about whether those results are applicable to general cirrhotic patients because that was study conducted in Spain among patients with advanced cirrhosis, and most of the Gram-negative bacilli detected in the patients receiving oral norfloxacin were norfloxacin-resistant strains. Therefore, it is necessary to select appropriate antibiotics based on local antimicrobial susceptibility patterns. Generally, short-term (maximum 7 days) antibiotic prophylaxis with intravenous ceftriaxone (1 g every 24 hours) is recommended in patients with acute variceal bleeding.

Vasoactive agents, such as vasopressin, terlipressin, somatostatin, and octreotide, are effective in supporting hemostasis in patients with acute variceal bleeding by decreasing portal pressure. In a meta-analysis, the use of vasoactive agents in patients with acute variceal bleeding was significantly associated with a reduction in 7-day mortality (RR, 0.74; 95% CI, 0.57–0.95) and an increase in the hemostasis rate (RR, 1.21; 95% CI, 1.13–1.30) [91]. In patients with suspected variceal bleeding, vasoactive agents should be initiated as soon as possible, together with prophylactic antibiotics, before the diagnostic endoscopy. Vasopressin reduces portal pressure by inducing systemic and splanchnic vasoconstriction, but it is not now recommended for patients with acute variceal bleeding because of the significant side effects, such as an increase in peripheral vascular resistance and reduction in cardiac output and coronary blood flow. Although terlipressin, a synthetic analogue of vasopressin, is the only drug proven to reduce bleeding-related mortality (RR, 0.66; 95% CI, 0.49–0.88) [92], its side effects, such as hyponatremia and myocardial ischemia due to coronary artery vasoconstriction, should be considered [93,94]. A recent meta-analysis [91] and a Korean multicenter RCT [11] comparing three vasoactive agents (terlipressin, somatostatin, and octreotide) found no significant differences among them regarding the hemostasis rate and survival time. In patients with acute variceal bleeding, it is recommended that one of the vasoactive agents should be started as soon as possible (Table 2) and continued for 3–5 days [26,47].

If acute variceal bleeding is suspected, endoscopy should be performed as soon as possible to confirm the hemorrhagic focus and hemostasis. Endoscopic hemostasis should be done when acute EV hemorrhage is confirmed by endoscopy. EVL is the endoscopic treatment of choice for patients with acute bleeding from EVs. Endoscopic injection sclerotherapy (EIS) is no longer recommended as standard treatment for acute EV bleeding because of its higher incidence of treatment failure, bleeding-related mortality, and adverse events compared with EVL [95-99]. In a meta-analysis comparing EVL and EIS in patients with acute EV bleeding, bleeding-related mortality did not differ significantly (RR, 0.95; 95% CI, 0.77–1.17), but the risk of rebleeding was reduced (RR, 0.68; 95% CI, 0.57–0.81) and the rate of variceal eradication was increased (RR, 1.06; 95% CI, 1.01–1.12) in patients undergoing EVL compared with EIS [100]. Most practice guidelines recommend endoscopy within 12 hours after presentation with suspected variceal bleeding, but that recommendation lacks evidence. A previous Taiwanese retrospective study reported that delayed endoscopy (>15 hours after admission) was an independent risk factor of inhospital mortality (odds ratio [OR], 3.67; 95% CI, 1.27–10.39) [101]. In addition, a prospective observational study of 101 patients with acute EV bleeding showed that the 6-week rebleeding rate (18.9% vs. 38.9%, P=0.028) and mortality (27% vs. 52.8%, P=0.031) were significantly lowered in patients undergoing early endoscopy (≤12 hours) compared with those undergoing delayed endoscopy (>12 hours) [102]. However, because those studies were performed without randomization, several confounders that can delay the endoscopy, such as hemodynamic instability, might have influenced the results. Therefore, until the results of large RCTs are reported, endoscopy should be performed as soon as possible in patients with suspected acute EV bleeding. However, the specific timing should be determined by the hemodynamic status of individual patients and the experience and medical resources of the institution.

Once endoscopy and EVL have been performed, early placement of a transjugular intrahepatic portosystemic shunt (TIPS) can be considered in carefully selected patients at high risk for rebleeding. Early TIPS placement reduced the rates of treatment failure and bleeding-related mortality in an RCT [103] of patients with a HVPG >20 mmHg and in an RCT [104] of patients with Child-Pugh class C cirrhosis (score of 10–13) or Child-Pugh class B cirrhosis with active bleeding on endoscopy despite intravenous administration of a vasoactive agent. However, because these two trials excluded patients with Child-Pugh class A cirrhosis, Child-Pugh class B cirrhosis without active bleeding during endoscopy, ChildPugh class C with a score of 14–15, patients >75 years, HCC beyond the Milan criteria, or a creatinine level greater than 3 mg/dL, it should be considered that those study results apply to only a very small portion of patients with acute variceal bleeding. Notably, a recent prospective observational study showed that the 1-year rebleeding risk was significantly decreased (3% vs. 49%, P<0.001), but 1-year survival did not differ between patients with and without a TIPS (66.8±9.4% vs. 74.2±7.8%, P=0.78) [105]. Further studies are needed to evaluate the beneficial effect of early TIPS placement.

Recently, the efficacy of applying hemostatic powder via endoscopy within 2 hours of admission was evaluated in 86 randomized patients with acute variceal bleeding [106]. Cirrhotic patients with acute variceal bleeding received standard medical treatment and were randomized to receive either immediate endoscopy with hemostatic powder application within 2 hours of admission followed by early elective endoscopy the next day (that is, within 12–24 hours of admission) for definitive treatment (EVL for EV bleeding or endoscopic variceal obturation [EVO] for gastric variceal bleeding; study group) or early elective endoscopy only (control group). Improved rates of hemostasis and survival time in the study group suggested the therapeutic potential of endoscopic application of hemostatic powder, an easy procedure requiring minimal expertise.

Failure to control acute EV bleeding is defined as death or the need to change therapy (defined by one of the following criteria) within 5 days of an acute bleeding episode [107].

- Fresh hematemesis of ≥100 mL of fresh blood ≥2 hours after the start of a specific pharmacological treatment or therapeutic endoscopy

- Development of hypovolemic shock

- 3 g drop in hemoglobin (9% drop in hematocrit) within 24 hours without transfusion

TIPS placement is considered the best rescue treatment for patients with inadequate bleeding control despite combined pharmacological and endoscopic therapy [108]. A prospective observational study to evaluate the efficacy of TIPS in 58 patients who failed to achieve hemostasis after EIS and pharmacological treatment reported that the TIPS achieved control of the bleeding in 52 patients (90%), and 1-year and 3-year survival rates were 51.7% and 40.2%, respectively [108]. Balloon tamponade is still used as a bridge therapy and provides hemostasis in 80–90% of patients, but the rebleeding rate after deflation is as high as approximately 50% [109,110]. Moreover, because it is associated with a high rate of serious complications, such as esophageal ulceration, esophageal rupture, and aspiration pneumonia, balloon tamponade should not exceed 24 hours [111]. In a small RCT, a self-expandable, esophageal covered metal stent was tested as an alternative to balloon tamponade in patients in whom pharmacological and endoscopic treatment failed to control bleeding [112]. Although survival in the esophageal stent group was not improved compared with the balloon tamponade group, bleeding control was higher (85% vs. 47%, P=0.037), and serious adverse events were lower (15% vs. 47%, P=0.077) in the esophageal stent group [112]. This stent can be placed endoscopically without radiological guidance, and it can stay in place for up to 2 weeks. However, because only 28 patients were included in that study, further study is warranted.

EV rebleeding is defined as recurrent bleeding after an absence of bleeding for at least 5 days following recovery from acute EV bleeding [107]. An average of 60% of patients with acute EV bleeding experience rebleeding within 1–2 years, and the mortality rate from rebleeding is 33%. Therefore, appropriate treatment to prevent rebleeding is necessary [15,48].

The diagnosis of EV rebleeding is the same as the diagnosis of acute EV bleeding. Clinically significant rebleeding can be suspected in a patient who has recurrent melena or hematemesis with 1) hospitalization or the need for a transfusion, 2) a decrease in hemoglobin of more than 3 g /dL, or 3) death within 6 weeks [107].

NSBBs and EVL are the most common methods used to prevent EV rebleeding. NSBBs, which reduce portal pressure, have been reported to be more effective than placebo at preventing rebleeding in several RCTs [113-115]. The combination of an NSBBs plus ISMN could improve portal pressure reduction [116], but it could also increase the incidence of side effects such as headache and dizziness [117]. EVL is the endoscopic treatment of choice for the prevention of EV rebleeding. EVL should be repeated every 2–8 weeks until variceal eradication is achieved. Periodic endoscopic follow-up is needed to detect the recurrence of varices even after achievement of variceal eradication. Several systematic reviews and meta-analyses comparing EVL alone to NSBBs alone demonstrated no difference in the rebleeding rate [51,118,119], but the overall mortality rate during follow-up was significant higher with EVL alone (RR, 1.25; 95% CI, 1.01–1.55) [51] or not different [119]. In a long-term follow-up study, the rebleeding rate was higher (30% vs. 64%, P=0.001) but the survival time was longer (30% vs. 49%, P=0.013) in patients treated with the combination of an NSBBs plus ISMN [120].

Several RCTs and meta-analyses comparing the combination of EVL plus NSBBs to EVL alone or NSBBs alone showed that the combination therapy had lower overall rebleeding and variceal rebleeding [121-124]. Therefore, the combination of EVL plus an NSBBs has been suggested as the primary treatment for preventing EV rebleeding. A recent meta-analysis demonstrated that the rebleeding rate decreased (RR, 0.44; 95% CI, 0.28–0.69) and the mortality rate during follow-up tended to decrease with the combination of EVL plus a NSBBs (RR, 0.58; 95% CI, 0.33–1.03) compared with EVL alone. However, although the overall rebleeding rate tended to decrease (RR, 0.76; 95% CI, 0.58–1.00), the mortality rate during follow-up did not differ between the combination of EVL plus NSBBs and NSBBs alone [125]. These results suggest the importance of NSBBs in preventing EV bleeding.

RCTs comparing carvedilol to EVL (36.4% vs. 35.5%, P=0.857) and carvedilol to the combination of nadolol plus ISMN (51% vs. 43%, P=0.46) did not show any significant difference in rebleeding rate, and the side effects of carvedilol were less than those with the combination of nadolol plus ISMN (1.6% vs. 28.3%, P<0.0001) [126,127]. Therefore, the use of carvedilol to prevent EV rebleeding can be considered, but no studies have compared the combination of EVL plus carvedilol with the combination of EVL plus an NSBBs, which is currently considered to be the primary treatment to prevent rebleeding. Further studies using carvedilol to prevent EV rebleeding are required.

In a meta-analysis of studies about preventing variceal rebleeding by using NSBBs to reduce portal pressure, the risk of variceal rebleeding was significantly reduced (OR, 0.17; 95% CI, 0.09–0.33; P=0.0001) when the HVPG was decreased to the target level (reduction in HVPG of ≥20% or to ≤12 mmHg) compared with the non-responding group [128]. A recent RCT comparing HVPGbased medical therapy with TIPS placement to reduce variceal rebleeding showed lower incidence of rebleeding within 2 years (26% vs. 7%, P=0.002) in the TIPS group, but there was no significant difference in mortality during follow-up between the two groups, and the incidence of HE was lower (8% vs. 18%, P=0.05) in the HVPG-based medical therapy group [129]. Considering that a TIPS is a limited treatment method, HVPG-based medical therapy is a useful way to prevent rebleeding if HVPG measurement is possible. However, because HVPG measurement is invasive, it is not widely practiced in many hospitals.

An RCT comparing TIPS placement with a combination of EVL plus an NSBBs to prevent variceal rebleeding found a lower variceal rebleeding rate in the TIPS group (0% vs. 29%, P=0.001), but the incidence of HE within 1 year in that group was higher (35% vs. 14%, P=0.035). There was no difference in the follow-up mortality rate (32% vs. 26%, P=0.418) between the two groups [130]. Therefore, the use of TIPS is not recommended as a primary treatment for the prevention of variceal rebleeding, and it should instead be considered a rescue therapy for patients with primary treatment failure [131]. In addition, liver transplantation is considered a rescue therapy for patients with recurrent variceal rebleeding because it exhibits good long-term results [132,133].

Gastric varices are enlarged submucosal veins of the stomach that cause critical upper gastrointestinal bleeding. GVs occur in approximately 20% of patients with portal hypertension, and the bleeding rate in 2 years is known to be 25% [134]. The incidence of gastric varices is lower than that of EVs, but their rebleeding rate and mortality rate are higher because they cause severe bleeding [134-136].

Gastric varices are classified as gastroesophageal varices (GOV) or isolated gastric varices (IGV) depending on their location and relation to any EVs (Fig. 1). GOVs are classified by whether they extend along the lesser curvature (GOV1) or the gastric fundus (GOV2). IGV are classified as varices located in the fundus (IGV1) and those in any other region, i.e., stomach or duodenum (IGV2) [134]. The incidence of GOV1s is about 74%.

The risk factors for gastric variceal bleeding are location (IGV1>GOV2>GOV1), variceal size, redness, and severe liver dysfunction [26,47,93,137-139].

To prevent bleeding from GOV1s, follow the guidelines for the prevention of EV bleeding. In a Korean study of 85 patients with GOV1s, the GOV1s also disappeared when EVs were eliminated by EVL (64.7%) [140]. For GOV2s and IGV1s, EVO, balloon-occluded retrograde transvenous obliteration (BRTO), and vascular plug-assisted retrograde transvenous obliteration (PARTO) can be considered to prevent bleeding [141,142]. NSBBs are non-invasive and can be used because they can reduce other side effects in patients with cirrhosis.

One randomized study reported the prevention of first gastric variceal bleeding. It enrolled 89 patients with GOV2s or IGV1s larger than 10 mm [141]. The effects of EVO (cyanoacrylate), an NSBB, and simple observation were compared. For the prevention of gastric variceal bleeding, EVO (10%) was superior to an NSBB (38%) and simple observation (53%) [141]. The survival rate of the EVO group (93%) was higher than that of the simple observation group (73%), but it did not differ from that of the NSBB group (83%). In a meta-analysis of patients with a high risk of gastric variceal bleeding, BRTO was effective in preventing gastric variceal bleeding (clinical success rate, 97.3%) [142]. In a recent study of 73 patients, PARTO was found to be a safe procedure without serious side effects that effectively prevented gastric variceal bleeding (Fig. 2) [143,144].

Although the incidence of portal hypertensive gastropathy bleeding in cirrhosis is not high, some patients experience poor quality of life due to chronic bleeding and the associated iron-deficiency anemia and repeated transfusions [196,197]. Portal hypertensive gastropathy is diagnosed when gastric mucosal changes cause a snake-skin appearance or mosaic pattern on endoscopy in patients with portal hypertension [198-200]. When gastric mucosal changes alone are found, it is diagnosed as a mild form. When red or dark brown viscous changes are found along with changes in the gastric mucosa, it is considered to be severe (Fig. 4) [30]. Severe portal hypertensive gastropathy causes more chronic bleeding than the mild form [201].

Portal hypertensive gastropathy is associated with portal hypertension and causes gastric mucosal changes in the stomach and body, and 30% of patients with gastric antral vascular ectasia (watermelon stomach) also have portal hypertension. It is unclear whether portal hypertension is involved in the development of gastric antral vascular ectasia. Gastric antral vascular ectasia causes dilated vessels with fibrin thrombi and fibromuscular hyperplasia of the lamina propria [202].

In chronic bleeding caused by portal hypertensive gastropathy, the goal of treatment is lowering the portal pressure with NSBBs, vasoconstrictors, or a TIPS [203,204]. In cases with active bleeding, endoscopic treatment with argon plasma coagulation can be used. In addition, iron supplementation is recommended [205].

HE presents with a wide range of clinical patterns, from minimal HE (MHE), in which cognitive impairment cannot be identified without a cognitive function test, to OHE, which is easily detected based solely on symptoms and does not require a cognitive function test. As HE progresses, symptoms such as personality changes, indifference, anxiety, and irritability appear and can reduce sleep quality and quality of life [214]. In some patients, increased muscle tension, hyperreactivity, and the Babinski reflex are present, and they are rarely accompanied by seizures [215,216]. The flapping tremor, a phenomenon in which hand tremors are caused by incongruity in the tension of various muscles resulting from hyperextension of the wrist as the fingers are spread apart, is a common symptom in the early and middle phases of OHE.

The severity of HE is classified using the West-Haven criteria and the Glasgow Coma Scale [207], with the former used as the basic diagnostic criteria. However, due to their large number of subjective factors, the West-Haven criteria suffer from significant interobserver deviation, which makes it difficult to diagnose the first stage (grade 1) of HE in a clinical setting. Therefore, MHE and stage 1 HE are classified as CHE (Table 3) [217]. The International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) defines the onset of disorientation or flapping tremor as the start of OHE [218].

HE requires differentiation from underlying brain diseases, such as cerebral hemorrhage and edema, that can accompany cognitive dysfunction. It should also be differentiated from substance abuse, alcoholism, hyponatremia, and psychiatric illnesses. In chronic alcoholics in particular, it can be difficult to differentiate HE from other alcohol-related neurological diseases. For example, Korsakoff syndrome, which is caused by a thiamine deficiency induced by long-term drinking, is characterized by symptoms such as anterograde amnesia and decreased word memory [219], and Wernicke’s encephalopathy is marked by eye movement paralysis, gaze-induced nystagmus, and gait disturbances, in addition to memory lapses [220]. Delirium caused by withdrawal from alcohol also needs to be differentiated from HE. Delirium that results from alcohol withdrawal is characterized by an increased heart rate, cold sweats, loud shouting, and a harsh and repetitive tremor [221]. A differential diagnosis is required for acute hyponatremia, hypoglycemia, and metabolic alkalosis because each can present with symptoms similar to those of HE [222]. The differential diagnosis for hyponatremia requires particular caution because its symptoms are very similar to those of HE, and hyponatremia itself can lead to HE [223]. Subdural hematoma can also present with symptoms similar to those of HE and should be carefully differentiated. Cases of subdural hematoma are commonly accompanied by other neurological symptoms, such as hemiplegia. Encephalitis often presents with symptoms such as headache, fever, vomiting, and stiff neck, but a differential diagnosis is required because those symptoms are not always clear and can be accompanied by sleepiness, drowsiness, and unconsciousness. In cases of dementia, the symptoms appear relatively gradually in most cases, whereas alcohol-related dementia often includes violent tendencies caused by frontal lobe damage, as well as the inability to remember recent events [224].

OHE can be diagnosed based solely on clinical symptoms, but other diseases that can cause cognitive dysfunction should still be ruled out. Brain CT and brain magnetic resonance imaging (MRI) are helpful for differentiating neuropsychological abnormalities caused by underlying brain diseases, such as intracranial hemorrhage [225]. Because the risk of cerebral hemorrhage is about five times higher in patients with liver cirrhosis than in healthy people, brain CT or MRI should be performed if a brain lesion is suspected [226]. Brain MRI, in particular, is helpful for diagnosing HE, in which brain edema is associated with nonspecific symptoms such as headache and vomiting, when acute liver failure is suspected [225]. On T1-weighted MRI, an increased signal in the basal ganglia is commonly observed, but those changes lack the sensitivity and specificity required to diagnose HE [227].

If the diagnosis of HE is difficult, neurophysiological or neuropsychological tests can also be performed. In HE, a characteristic, slow triphasic wave is observed during electroencephalography (EEG) [228]. This slow triphasic wave is an overall periodic waveform in the bilateral frontal lobes that demonstrates bilateral synchronization and is often accompanied by slow background activity; it is usually seen in phase 2 or 3 HE and disappears in comatose patients [225,229]. Once a slow triphasic wave has developed, the clinical outcome is reportedly very poor [230]. In recent studies, the decrease in EEG amplitude in patients with OHE was associated with the severity of HE [231].

The brainstem auditory-evoked-potential test is sensitive for the diagnosis of CHE [226,227,232]. Patients with liver cirrhosis accompanied by CHE exhibit conduction time delays (I–V latency) from the auditory nerve to the midbrain and conduction time delays (III–V latency) from the pontine to the midbrain on the brain auditory-evoked-potential test. It is also known that the risk of developing OHE is increased when abnormal findings are observed on the brain auditory-evoked-potentials test [227]. However, in a study using the cortical auditory-evoked-potential test, the N200 latency was increased in patients with HE [233]. Therefore, the diagnosis of HE cannot be made using EEG alone; further research is required to determine the usefulness of evoked-potential EEG in the diagnosis and prognosis of HE.

The venous blood ammonia level is not proportional to the degree of HE and has no association with its prognosis [234]. The metabolism of ammonia is greatly influenced by various organs, such as the kidneys, muscles, brain, and bowel, as well as the liver [235]. However, repeated measurements of ammonia concentrations can help to determine a treatment’s effects [235,236]. If patients with suspected OHE have normal ammonia concentrations, attention should be paid to the differential diagnosis to look for other diseases [234]. There are various methods of measuring ammonia concentrations, such as those involving the venous or arterial blood or plasma. Because the normal range varies depending on the specific measurement method, a suitable reference value should be used. Although the partial pressure of ammonia gas in arterial blood is thought to be closely related to both the neurophysiological test results and the ammonia concentration in the blood–brain barrier in patients with HE, additional studies are needed to determine the clinical usefulness of that value [237]. Regarding other serum markers, some studies have reported increases in the serum S100β concentration that were proportional to the cognitive function test results in HE patients [238].

The goals of treatment are as follows: 1) prevention of secondary damage caused by decreased consciousness and normalization of the patient’s state of consciousness, 2) elimination of social and economic restrictions by preventing recurrence, and 3) improvement of patient prognosis and quality of life. Therefore, appropriate supportive care should be provided to prevent secondary damage (e.g., fall-related injuries or aspiration pneumonia) from an altered consciousness. Furthermore, the precipitating factors should be identified and managed appropriately as soon as possible, and treatments should be initiated using medications that can decrease or eliminate the production of ammonia, the major pathogenic material.

The precipitating factor can be identified in 80–90% of patients with HE [239]. In many cases, HE can be improved simply by eliminating the precipitating factor; therefore, identifying and promptly managing the precipitating factors is required [240]. The currently known precipitating factors of HE and the corresponding diagnostic tests and treatments are shown in Table 4. According to reports from patients in the Republic of Korea [241,242], gastrointestinal bleeding, infection, dehydration by paracentesis, and constipation were the major precipitating factors.

Among patients with OHE, 50–70% will experience a recurrence within 1-year, so secondary prevention for OHE should be started after the first event. As the first-line therapy, nonabsorbable disaccharides (lactulose [278,279], lactutol [280]) should be used. A dose of 30–60 mL of lactulose, allowing 2–3 stools per day, in patients who recovered from acute episodes of OHE significantly reduced the recurrence of OHE (19.6%) compared with the control group (46.8%) [278]. In cases of lactulose/lactitol intolerance, rifaximin can be used as single therapy (400 mg tid or 550 mg bid) [281]. According to a case-control study that included decompensated liver cirrhosis patients, a median 2 years of rifaximin therapy significantly lowered the recurrence of OHE compared with the control group (31.5% vs. 47%, P=0.034) [281].

A prospective RCT by Bass et al. [282] found that 6-months of rifaximin therapy significantly lowered the recurrence of OHE compared with the placebo group (hazard ratio [HR], 0.42; 95% CI, 0.28–0.64); about 91% of that study population used lactulose concomitantly. Non-absorbable disaccharide and rifaximin combination therapy can reduce the recurrence of OHE more than each single therapy [240,282], and it is therefore recommended for recurrent OHE. These medical treatments can effectively prevent OHE recurrence and improve the survival times of patients with OHE [281,283]. Long-term treatment with rifaximin raised concerns about the risk of Clostridium difficile (C. difficile) infection, but recent studies found that C. difficile infection was not increased by rifaximin treatment compared with the control group [283-285].

Long-term oral BCAA treatment is recommended for patients whose oral diet is insufficient because it can improve symptoms and reduce the recurrence of OHE [266,286]. In a meta-analysis of 16 RCTs, oral BCAA reduced the recurrence of OHE (HR, 0.73; 95% CI, 0.61–0.88), but the overall survival time did not differ between the two groups [266].

LOLA can reduce the recurrence of HE. In an RCT including 150 patients, oral LOLA (6 g three times per day) for 6 months significantly reduced the recurrence of OHE (HR, 0.39; 95% CI, 0.17–0.87) [287]. Nonetheless, recent meta-analyses have shown that oral LOLA was not more effective than lactulose or rifaximin for OHE prevention [287,288].

In patients with intractable ascites, intravenous albumin infusion can prevent OHE. A recent prospective RCT showed that long-term intravenous albumin (40 g per week) infusion significantly lowered the risk of grade 3 or 4 OHE (HR, 0.48; 95% CI, 0.37–0.63) and improved overall survival times (HR, 0.62; 95% CI, 0.40–0.95) [269].

A structured educational intervention has been reported to improve patient adherence to prophylactic therapy and reduce readmission with OHE [289]. According to an RCT of 39 patients with a history of OHE, a 15-minute educational session reduced the risk of OHE-related hospitalization (HR, 0.14; 95% CI, 0.02–0.77) [269]. The education of patients and caregivers should include 1) the effects and potential side effects (e.g., diarrhea) of the prescribed medication (lactulose, rifaximin, and so on), 2) the importance of adherence, 3) early symptoms and signs of recurring OHE, and 4) actions to be taken if a recurrence begins [209].

Nutritional deficits and subsequent sarcopenia are known to increase complications, including HE [290,291], and lower the overall survival times of cirrhotic patients [292-294]. Therefore, adequate assessment and intervention for nutritional status are recommended. Because most decompensated cirrhotic patients are malnourished, daily energy intake should be 35–40 kcal/kg, and protein intake should be 1.2–1.5 g/kg. Long-term protein restriction should be avoided because it can induce protein catabolism, hepatic dysfunction, and sarcopenia [295].

To take in enough energy, small frequent meals (4–6 times per day including a night snack) improve the long-term prognosis for liver cirrhosis patients while preventing sarcopenia [296], but the direct effect that small meals and a night snack has on OHE prevention has not been fully established.

Exercise can improve the long-term outcomes of cirrhotic patients [297,298]. In particular, cirrhotic patients usually have decreased skeletal muscle volume [291] because hyperammonemia hinders the synthesis of skeletal muscles [299,300]. An adequate exercise program can prevent muscle loss [301], enhance effective ammonia metabolism, and prevent OHE recurrence. However, exercise can temporarily increase the portal pressure in OHE patients [297,298], and it could increase the risk of a fall or fracture in malnourished patients. Therefore, adequate nutritional support should precede exercise therapy (Fig. 5).

CHE is regarded as the preclinical stage of OHE, and it includes West-Haven criteria grade 1 and MHE, which is the mildest form of HE [210]. It is difficult to diagnose CHE it because it can be diagnosed only by psychometric or neurophysiologic examination and is without definite clinical manifestations, such as disorientation or asterixis. Furthermore, it is difficult to clinically distinguish MHE and grade 1 HE. Therefore, MHE and grade 1 HE from the West-Haven criteria are often defined as a single syndrome called CHE. Because the concept of CHE was initiated by ISHEN in 2011, most previous studies have been done on MHE; little research has been done on CHE, including West-Haven criteria grade 1 HE [210].

The prevalence of MHE is 22–78% of patients with liver cirrhosis, although the rate can differ depending on the diagnostic method [226,302-308]. The prevalence of MHE is related to prior episodes of OHE, age, severity of liver disease, and the presence of EVs [309]. In a study using the psychometric HE score (PHES) in a single institution in Korea, MHE was seen in 25.6% of patients with cirrhosis, including 20.2% of those in Child-Pugh A, 42.9% in Child-Pugh B, and 60% in Child-Pugh C [310].

Patients with CHE have impaired cognitive functions such as attention, executive functions, visuospatial perception, psychomotor speed, and reaction times [311]. Those impaired cognitive functions interfere with daily functioning, such as social interactions, alertness, emotional behavior, sleep, home management, and recreation, and lower the quality of life [214,304,312].

Patients with CHE are at risk of falls and fractures [313,314], and their poor cognitive performance increases the risk that they will lose their jobs [315]. Therefore, CHE increases the burden on both individual patients and society. CHE is regarded as the preclinical stage of OHE because of the increased risk of progression to OHE [226,302], and CHE is associated with worsened survival times [316,317]. However, it is difficult to distinguish whether the shortened survival is caused by CHE or hepatic dysfunction.

To diagnose CHE, the patient must have 1) a disease that can lead to CHE, such as liver cirrhosis or a portosystemic shunt, 2) no other neurological disease, 3) no neurological manifestation such as disorientation or asterixis, and 4) abnormal cognitive or neurophysiologic functioning.

HRQoL is measured using self-administered, standardized questionnaires in which patients report their health status. The questionnaires are classified as generic and disease-specific [363]. Because generic questionnaires provide an overview of HRQoL, usually taking into account the physical, mental, and social aspects of a patient’s health status, generic questionnaires have the advantage of depicting the relative impacts of different diseases. However, generic questionnaires have the disadvantage of insensitivity to clinically important changes. Thus, generic questionnaires are often combined with disease-specific questionnaires. The most widely used generic questionnaires for measuring HRQoL are the SIP, Nottingham Health Profile (NHP), and Medical Outcomes Study Short Form-36 (SF-36) [364]. The SIP consists of 136 items that measure 12 domains. It requires several minutes to complete, and patients with cognitive dysfunctions sometimes fail to complete it [365]. The NHP measures distress and is useful in patients with moderate or severe disability, but it is not very sensitive to mild disability [366]. The SF-36 is applicable to a wide range of patients, from those with a severe disability to the general population. The SF-36 is easy to complete and has high sensitivity, which makes it the best and most widely used scale in clinical practice. It contains 36 questions that are split into eight domains and provides a physical component summary (PCS) and a mental component summary (MCS) (Supplementary Table 1) [367].

Disease-specific questionnaires have been developed for a variety of chronic diseases, such as renal failure, heart failure, liver cirrhosis, diabetes, and osteoarticular diseases, that greatly affect the HRQoL of patients. Liver-disease-specific questionnaires include the Chronic Liver Disease Questionnaire (CLDQ), Liver Disease Quality of Life (LDQOL), Short Form Liver Disease Quality of Life (SF-LDQOL), and Liver Disease Symptom Index 2.0 (LDSI). The CLDQ comprises 29 questions split into six domains, with domain scores and an overall score presented as 1–7 scales. Higher scores on the CLDQ represent better HRQoL. The CLDQ is short, easily applicable, and correlates with the severity of liver disease [368]. The LDQOL uses the SF-36 and adds 12 liver-specific scales comprising 75 questions. All scales are scored from 0–100, with higher scores representing better HRQoL [369]. The SF-LDQOL uses the SF-36 and adds 36 Likert questionnaires; it is also scored from 1–100 [370]. The LDSI uses 18 items to measure the impact and severity of a patient’s liver disease on daily activities in nine areas (Supplementary Table 2) [371].

Although there is a large consensus about the direct and profound effect that HE has on HRQoL, most studies have focused on MHE [208,372,373]. A small study about the HRQoL of patients with and without HE compared 18 patients experiencing OHE with 57 patients without a previous episode. Patients with a previous episode of OHE had significantly low SF-36 PCS and MCS scores. However, patients with MHE were affected in only one domain, physical functioning, of the SF-36 [374]. One study of 160 cirrhotic patients undergoing liver transplantation found that patients with MHE or OHE had a lower MCS than patients without HE [357].

Cognitive impairment of patients with HE mainly affects areas that require multiple and complicated functions, such as attention, visuospatial abilities, psychomotor speed, balance, and coordination, rather than language or general intellect. In other words, patients can perform daily activities such as wearing clothes or using the toilet, but their overall planning or cognitive function and exercise performance might suffer [318]. Because driving a vehicle requires comprehensive performance and a strategic way of thinking, patients with MHE require attention while driving [375-378]. Cirrhotic patients engaged in professions that required sustained attention and motor coordination are more severely affected by MHE than those with jobs that require mainly verbal abilities. In an outpatient cohort with cirrhosis, up to 60% of blue collar workers lost their jobs, versus only 20% of white collar workers [236].

A disruption of normal sleep-wake patterns is another early sign of HE [379], and regular sleep is a key indicator of perceived health status. Sleep disturbances are included as relevant items in the assessment of HRQoL in the NHP questionnaire, and sleep disturbances in patients with HE negatively affect HRQoL [380]. Patients with MHE report a decrease in the quality of their sleep and in their physical and mental HRQoL [214,381].

Psychological status and a patient’s mood can affect the course of a disease and treatment response, and depression affects social functioning, physical abilities, and health status [382]. Cirrhotic patients suffer not only from liver disease itself, but also from decreased quality of life in the form of poor work performance and an increased risk of accidents. Therefore, there is a need for extensive social attention and research on public social support systems and economic support for cirrhotic patients.

Although many studies have aimed at improving HE, relatively few studies have aimed at a significant improvement in the HRQoL of patients with HE [383]. Prasad et al. [304] first investigated the effect of treatment-related improvements in cognitive function on HRQoL. Patients with MHE treated with lactulose for 3 months showed a significant improvement in their HRQoL on several SIP subscores, particularly in emotional behavior, mobility, sleep/rest, and recreation and pastimes. In an 8-week study of rifaximin therapy in patients with MHE, the patients showed significantly improved scores in both neuro-psychometric performance and the SIP [305]. Another study reported that rifaximin therapy to prevent a recurrence in patients with HE favorably affected HRQoL as measured by CLDQ scores [384]. Treating OHE patients with oral LOLA [385] and MHE patients with acetyl-L-carnitine [354] also improved HRQoL. However, a 60-day course of probiotic yogurt supplementation had no significant effects on HRQoL in 25 patients with cirrhosis [346].

To date, insufficient studies have been done to establish an association between improved HRQoL and treatments for OHE and MHE. Considering that 10% or more of cirrhotic patients have HE, and 50% of cirrhotic patients with MHE who have not been treated can progress to OHE within 4–24 months [386], it is necessary to change the paradigm of treatment to improve the HRQoL of patients.