Revision and update on clinical practice guideline for liver cirrhosis



# Introduction
Liver cirrhosis (LC) is a disease with a high rate of prevalence and one of the most common causes of mortality in the Republic of Korea (hereafter "Korea"). In Korea, the main etiologies of LC have been found to be chronic hepatitis B (CHB), alcohol, and chronic hepatitis C (CHC).
In patients with complications such as ascites, variceal bleeding, and encephalopathy, the 5-year survival rates were 32%, 21%, and 40%, respectively, reflecting the poor (moderate-quality evidence), and C (low-quality evidence).
The strength of recommendation has been classified into 2 categories: strong and weak [fig_ref] 1: What are the precipitating factors of hepatic encephalopathy? -Precipitating factors of hepatic... [/fig_ref] 

## 1-3. pathological diagnosis of liver cirrhosis
The gold standard for confirming the diagnosis of LC is liver biopsy, but it is invasive and susceptible to a sampling error and inter-observer discrepancy. Therefore, liver biopsy has not been widely used in clinical practice. Liver biopsy can be carried out selectively for evaluating activity of the underlying disease and fibrosis. Particularly, when cirrhosis is diagnosed by clinical findings and imaging studies, but not compatible with laboratory data, a liver biopsy is especially helpful for diagnosing LC. 11

## 1-4. others
The serum markers for liver fibrosis directly or indirectly reflect extracellular matrix metabolism. However, their clinical utility in the diagnosis of LC has not been verified. [bib_ref] Noninvasive measures of liver fibrosis, Rockey [/bib_ref] FibroScan has been introduced to measure liver elasticity noninvasively and is an objective diagnostic tool for the diagnosis of LC. However, there is no exact guideline on how to apply it clinically, and there is some variation in its diagnostic accuracy for the diagnosis of LC. Therefore, the practical use of FibroScan is limited.

## 2-1. chronic hepatitis b
Antiviral therapy that regulates inflammation via the inhibition of viral proliferation is recommended for improving liver fibrosis. [bib_ref] Histological outcome during long-term lamivudine therapy, Dienstag [/bib_ref] [bib_ref] Long-term use of entecavir in nucleoside-naive Japanese patients with chronic hepatitis B..., Yokosuka [/bib_ref] [bib_ref] Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis..., Marcellin [/bib_ref] [bib_ref] Efficacy and safety of entecavir in patients with chronic hepatitis B and..., Schiff [/bib_ref] [bib_ref] Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up..., Hadziyannis [/bib_ref] [bib_ref] Analogs and fibrosis regression in hepatitis B, Bourliere [/bib_ref] There were no significant differences in the degree of improvement in fibrosis according to antiviral drugs. [bib_ref] A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B, Chang [/bib_ref] [bib_ref] Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B, Lai [/bib_ref] [bib_ref] Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B, Marcellin [/bib_ref] As liver fibrosis progresses, the rate of improvement by antiviral treatment increases. [bib_ref] Efficacy and safety of entecavir in patients with chronic hepatitis B and..., Schiff [/bib_ref] 

## 2-3. alcohol
Abstinence is the most important treatment of alcoholic liver disease. [bib_ref] Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and..., Veldt [/bib_ref] Abstinence not only improves fibrosis in hepatic tissue but also reduces portal pressure and inhibits progression to LC. Ultimately, the survival rate of patients in all stages of alcoholic liver disease increases following abstinence, with improvements being observed in up to 66% of patients. [bib_ref] Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and..., Veldt [/bib_ref] Sustained drinking increases the risk of variceal bleeding by portal hypertension and is closely related with mortality.
In severe alcoholic hepatitis, steroid and pentoxifylline therapy have been recommended by several studies. However, the effect of these drugs on fibrosis has not been confirmed; therefore, these medications are not recommended in the treatment of fibrosis as anti-fibrotic therapy.

## 2-4. nonalcoholic fatty liver
Treatment of nonalcoholic fatty liver comprises improving insulin resistance, removing risk factors of metabolic syndrome, lifestyle modifications, drug therapy, and operative treatment. [bib_ref] Effects of weight loss on nonalcoholic fatty liver disease, Rafiq [/bib_ref] [bib_ref] Effect of body weight and lifestyle changes on long-term course of nonalcoholic..., Kim [/bib_ref] [bib_ref] Independent effects of physical activity in patients with nonalcoholic fatty liver disease, St George [/bib_ref] [bib_ref] Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without..., Johnson [/bib_ref] [bib_ref] Pharmacological interventions for nonalcoholic fatty liver disease in adults and in children:..., Socha [/bib_ref] [bib_ref] A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis, Belfort [/bib_ref] [bib_ref] Randomized, placebo-controlledtrial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis, Aithal [/bib_ref] [bib_ref] Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand..., Neuschwander-Tetri [/bib_ref] [bib_ref] Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis, Sanyal [/bib_ref] [bib_ref] A pilot study of vitamin E versus vitamin E and pioglitazone for..., Sanyal [/bib_ref] [bib_ref] Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic..., Harrison [/bib_ref] [bib_ref] Safety of oral intake of vitamin E, Bendich [/bib_ref] [bib_ref] Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality, Miller Er 3rd [/bib_ref] [bib_ref] Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial, Lindor [/bib_ref] [bib_ref] High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebocontrolled trial, Leuschner [/bib_ref] [bib_ref] Metformin in non-alcoholic steatohepatitis, Marchesini [/bib_ref] [bib_ref] Lactic acidosis in patients with diabetes treated with metformin, Misbin [/bib_ref] Weight loss appears to help in liver steatosis as well as relieves hepatic inflammation and fibrosis. [bib_ref] Effects of weight loss on nonalcoholic fatty liver disease, Rafiq [/bib_ref] [bib_ref] Effect of body weight and lifestyle changes on long-term course of nonalcoholic..., Kim [/bib_ref] [bib_ref] Independent effects of physical activity in patients with nonalcoholic fatty liver disease, St George [/bib_ref] [bib_ref] Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without..., Johnson [/bib_ref] Therefore, the first choice of therapy in nonalcoholic fatty liver disease is weight loss through diet therapy and lifestyle

## 2-5. primary biliary cirrhosis
Ursodeoxycholic acid has been proven to improve primary biliary cirrhosis and is the only drug recognized for its treatment. [bib_ref] Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response..., Pares [/bib_ref] [bib_ref] A multicenter, controlled trial of ursodiol for the treatment of primary biliary..., Poupon [/bib_ref] [bib_ref] Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study..., Poupon [/bib_ref] [bib_ref] Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary..., Poupon [/bib_ref] Ursodeoxycholic acid reduces serum bilirubin levels, which is an important prognostic factor, and delays the progression and deterioration of fibrosis [bib_ref] Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study..., Poupon [/bib_ref] [bib_ref] Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary..., Poupon [/bib_ref] 13-15 mg/kg/day is the most effective dose in terms of biological effect and cost-effectiveness. Improvements of liver function tests appear within 6-9 months of therapy in more than 90% of patients. [bib_ref] Effect of cholestyramine on bile acid pattern and synthesis during administration of..., Rust [/bib_ref] Ursodeoxycholic acid treatment is not known to improve fatigue, itching, bone diseases, or autoimmune reactions associated with primary biliary cirrhosis. [bib_ref] Effect of cholestyramine on bile acid pattern and synthesis during administration of..., Rust [/bib_ref] 

## Variceal bleeding
Esophageal variceal bleeding is found in approximately 40% of patients with Child-Pugh A class LC, and in approximately 80% of patients with Child-Pugh C class LC. [bib_ref] Platelet count/spleen diameter ratio for the noninvasive diagnosis of esophageal varices: results..., Giannini [/bib_ref] The risk of variceal bleeding depends on the size of varices, red color sign, and the Child-Pugh classification.
Variceal bleeding due to portal hypertension can be prevented when the value of hepatic venous pressure gradient is lower than 12 mmHg or when it is decreased to lower than 20% of the baseline measurement. [bib_ref] Variceal bleeding: pharmacological therapy, Bosch [/bib_ref] 

## 3-1. diagnosis
It is recommended that all patients undergo endoscopy

## 3-2. acute esophageal variceal bleeding

## 3-2-1. definition and diagnosis
Acute variceal bleeding is defined as hematemesis within last 24 hours of presentation, and/or ongoing melena, with the last melenic stool within last 24 hours before the hospital visit in a known or suspected case of portal hypertension.

## 3-2-2. treatment
The first line of therapy includes vasoconstrictors such as terlipressin and somatostatin. [bib_ref] Somatostatin and analogues in portal hypertension, Abraldes [/bib_ref] Antibiotics are recommended for patients admitted in the hospital. [bib_ref] Management of varices and variceal hemorrhage in cirrhosis, Garcia-Tsao [/bib_ref] Antibiotic therapy is recommended for 5-7 days to prevent sepsis and rebleeding following endoscopy [fig_ref] Table 2: Drugs for acute esophageal variceal bleeding [/fig_ref]. [bib_ref] Antibiotic prophylaxis for the prevention ofbacterial infections in cirrhotic patients with gastrointestinal..., Bernard [/bib_ref] Medication and endoscopic therapy are recommended in patients with acute variceal bleeding for the first time. [bib_ref] Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a..., Banares [/bib_ref] If active bleeding is present, banding of the culprit vessel or that just below the ooze should be performed endoscopically. Nonselective beta-blockers do not lower the incidence of bleeding in patients with small esophageal varices. [bib_ref] Pharmacological treatment of portal hypertension: an evidence-based approach, D&apos;amico [/bib_ref] However, patients with a high risk of bleeding (Child-Pugh class B/C or endoscopic red color sign), are considered for nonselective beta-blocker therapy.The dose of nonselective beta-blockers is adjusted for a reduction in the resting heart rate by 25%, to 55 beats/minute, or until the occurrence of side effects. In Koreans, the mean adjusted dose of propranolol is 160 mg/day. [bib_ref] Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop..., De Franchis [/bib_ref] with lesser side effects as compared with EVL. However, additional research is needed before they can be routinely used. [bib_ref] Management of varices and variceal hemorrhage in cirrhosis, Garcia-Tsao [/bib_ref] [bib_ref] Randomized controlled trial of carvedilol versus variceal band ligation for the prevention..., Tripathi [/bib_ref] Combination therapy with EVL and nonselective beta-blockers for the prevention of first bleeding has shown no differences as compared with monotherapy. [bib_ref] Endoscopic variceal ligation plus propranolol versus endoscopic variceal ligation alone in primary..., Sarin [/bib_ref] 

## 3-4. prevention of variceal rebleeding

## 3-4-1. definition and diagnosis
Variceal rebleeding is defined as bleeding after 5 days of recovery from acute variceal bleeding.It is diagnosed similar to acute variceal bleeding.

## 3-4-2. prevention
Nonselective beta-blockers alone or combination therapy with isosorbide mononitrate are known to be effective in the prevention of rebleeding. [bib_ref] Isosorbide mononitrate and propranolol compared with propranolol alone for the prevention of..., Gournay [/bib_ref] EVL shows better outcomes than endoscopic injection sclerotherapy in endoscopic therapy for prevention of rebleeding. [bib_ref] Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding. A..., Laine [/bib_ref] Rebleeding has been reported in 32% of patients after EVL. Combination therapy of EVL and nonselective beta-blockers has been shown to have better outcomes than EVL alone. [bib_ref] Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for..., Lo [/bib_ref] [bib_ref] Variceal ligation plus nadolol compared with ligation for prophylaxis of variceal rebleeding:..., De La Pena [/bib_ref] TIPS shows a significantly low rebleeding rate as compared with endoscopic therapy. However, it shows a significantly high incidence of hepatic encephalopathy. TIPS is not recommended as a first-line therapy for esophageal variceal bleeding and is recommended only as a rescue therapy when combination therapy fails.Liver transplantation should be considered for patients who meet indications for liver transplantation. [bib_ref] Salvage therapies for refractory variceal hemorrhage, Henderson [/bib_ref] [bib_ref] Current management of portal hypertension, Wright [/bib_ref] If the hepatic venous pressure gradient is reduced to less than 12 mmHg or to more than 20% reduction in baseline levels by medical therapy, the incidence rate of rebleeding is low (10%). [bib_ref] Prevention of variceal rebleeding, Thalheimer [/bib_ref] In such cases, further endoscopic therapy may not be required.

## 3-5. gastric varices

## 3-5-1. definition and diagnosis
Gastric varices are enlarged submucosal veins of the stomach that cause critical upper gastrointestinal bleeding.
Gastric varices occur in approximately 20% of patients with portal hypertension, and the bleeding rate in 2 years is known to be 25%. [bib_ref] Prevalence, classification and natural history of gastric varices: a long-term follow-up study..., Sarin [/bib_ref] Diagnosis is performed by endoscopy.
Endoscopic ultrasound can also be helpful. [bib_ref] Prevalence of paraesophageal varices and gastric varices in patients achieving variceal obliteration..., Lo [/bib_ref] 3 and any other regions, i.e., stomach or duodenum (IGV2). [bib_ref] Prevalence, classification and natural history of gastric varices: a long-term follow-up study..., Sarin [/bib_ref] 

## 3-5-3. treatment and prevention
EVL is recommended for the treatment of GOV1.
Endoscopic variceal obturation (EVO) can be an alternative. [bib_ref] Gastric variceal ligation: a new technique, Shiha [/bib_ref] 

## Ascites
Ascites is the most common complication in LC, occurring in 60% of the patients with compensated LC within 10 years. [bib_ref] Compensated cirrhosis: natural history and prognostic factors, Gines [/bib_ref] Ascites appears in 2/3 of the patients who required admission due to LC, [bib_ref] The change of the etiology, complications and cause of death of the..., Han [/bib_ref] and 60% of the patients requiring paracentesis is because of LC. [bib_ref] Etiologic and laboratory analyses of ascites in patients who underwent diagnostic paracentesis, Hwangbo [/bib_ref] 

## 4-1. diagnosis
Abdominal ultrasound can diagnose ascites with only 100 mL. [bib_ref] Review article: Management of ascites and associated complications in patients with cirrhosis, Kuiper [/bib_ref] Ascites is classified by the amount of fluid as follows: Furthermore, paracentesis should be performed in cirrhotic patients with fever, abdominal pain, bleeding, encephalopathy, hypotension, or kidney dysfunction to assess for spontaneous bacterial peritonitis (SBP), since 10-27% of the patients with ascites have SBP. [bib_ref] Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International..., Rimola [/bib_ref] The main purpose of paracentesis is to discriminate the cause of ascites. Therefore, screening tests should include total cell count and differential, albumin, and total protein. Blood cell count is the most useful test for diagnosing SBP. For differential diagnosis of ascites, a serum-ascites albumin gradient can be calculated. If the serum-ascites albumin gradient is is greater than of equal to 1.1 g/dL, ascites is ascribed to portal hypertension with an accuracy of 97%.

## 4-2. treatment
Although controversial, 118 a low salt diet is considered effective for controlling ascites and shortening hospitalization.
Less than 5 g/day of salt (sodium for 2 g, 88 mEq) is recommended. When plasma sodium is lower than 120-125 mEq/L, water intake should be restricted to 1-1.5 L/day.

## 4-2-1. medications
If severe ascites is present, diuretic therapy should be used for negative sodium balance.When peripheral edema is present, the rate of weight loss should be no greater than 1 kg/day. For patients without edema, 0.5 kg/day of weight loss is ideal.If there is no weight loss even with 5 g/day of salt intake, the diet and diuretic dose should be evaluated by examining the amount of urinary sodium excretion per day. [bib_ref] Management of adult patients with ascites due to cirrhosis: an update, Runyon [/bib_ref] Patients with low salt intake should not excrete more than 78 mEq of urinal sodium in 24 hours. In such patients, if urinary sodium excretion is more than 78 mEq, low salt intake is judged not to be followed. When the excretion is less than 78 mEq, the diuretic is considered to be inadequate and the dose needs to be increased. Spot urine Na/K ratio of more than 1 represents 24 hours urine sodium excretion more than 78 mEq. [bib_ref] Detection of diuretic-resistace or diuretic-sensitivity by the spot urine Na/K ratio in..., Stiehm [/bib_ref] It is important to check the weight loss, vital sign, changes in consciousness level, and the level of plasma sodium, potassium, and creatinine during diuretic administration.
When plasma sodium is more than 126 mEq/L, diuretics can be used without the restriction of water intake. However, when plasma sodium is less than 125 mEq/L, the physician should consider cessation or reduction in the dose of the diuretic and restriction of water intake. If plasma sodium is less than 120 mEq/L, the diuretic and water intake should be stopped and a plasma expander such as albumin should be administered. If plasma sodium is less than 125 mEq/L with kidney dysfunction, the diuretic should be stopped and a plasma expander should be administered. [bib_ref] Guidelines on the management of ascites in cirrhosis, Moore [/bib_ref] If plasma potassium is less than 3.5 mEq/L, the dose of loop diuretic should be reduced or stopped. If plasma potassium is more than 5.5 mEq/L, the dose of aldosterone antagonist should be reduced. And if plasma potassium is more than 6.0 mEq/L, the aldosterone antagonist should be ceased.

## 4-2-2. therapeutic paracentesis (reference to intractable ascites section)
Therapeutic paracentesis is an effective treatment for tension-type ascites, because it relieves the symptoms more quickly than diuretics and shortens hospitalization [fig_ref] Table 3: Treatment of ascites depending on the grade Grade 1, a small amount... [/fig_ref]. with refractory ascites die within 6 months and the median survival period is also less than 1 year, they should be considered for liver transplantation. [bib_ref] Persistent ascites and low serum sodium identify patients with cirrhosis and low..., Heuman [/bib_ref] 

## 4-3-2. hyponatremia
The diagnostic criterion for hyponatremia is less than 130 mEq/L.A hypervolemic state can be corrected to normal by a negative water balance. Eventually, dilutional hyponatremia can be improved. [bib_ref] Ascites, hepatorenal syndrome and spontaneous bacterial peritonitis in patients with portal hypertension, Kim [/bib_ref] Restriction of water intake can prevent a decrease in the serum sodium level.Hypertonic sodium injection can worsen ascites and edema. [bib_ref] Pathogenesis and treatment of dilutional hyponatremia in cirrhosis, Cardenas [/bib_ref] Plasma expanders can be useful in the treatment of hyponatremia.Vaptan, [bib_ref] Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management, Gines [/bib_ref]. New International Ascites Club's diagnostic criteria of hepatorenal syndrome 1) Cirrhosis with ascites 2) Serum creatinine >133 mmol/L (1.5 mg/dL) 3) No improvement of serum creatinine (decrease to a level of 133 mmol/L) after at least 2 days with diuretic withdrawal and volume expansion with albumin; the recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day 4) Absence of shock 5) No current or recent treatment with nephrotoxic drugs 6) Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria (>50 red blood cells/high-power field), and/or abnormal renal ultrasound.
solute-free water. This agent can be used in the treatment of hyponatremia caused by inappropriate antidiuretic hormone secretion, heart failure, or liver cirrhosis. In the United States and Europe, tolvaptan and conivaptan are approved for the treatment of severe hyponatremia (<125 mEq/L).

## 4-4. hepatorenal syndrome

## 4-4-1. definition and diagnosis
Renal failure in LC occurs in 2 forms. First, type 1 hepatorenal syndrome is a rapid progressive acute renal dysfunction which occurs due to the strong contraction of the renal vasculature. Type 2 hepatorenal syndrome is a relatively slow process with a rather moderate renal dysfunction. The most important mechanism involved in the occurrence of hepatorenal syndrome is decreased effective blood volume due to the dilation of the splanchnic and peripheral circulation. This situation activates the sympathetic nervous system as well as the renin-angiotensin system and causes functional renal disorder. [bib_ref] Circulatory function and hepatorenal syndrome in cirrhosis, Ruiz-Del-Arbol [/bib_ref] [bib_ref] Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial..., Ruiz-Del-Arbol [/bib_ref] [bib_ref] Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current..., Arroyo [/bib_ref] In 1994, the International Ascites Club announced the diagnostic criteria for hepatorenal syndrome; in 2007, they revised these criteria to providing clearer diagnostic methods and including infectious diseases . After administration of terlipressin, hepatic venous pressure gradient is known to decrease while the renal blood flow increases. [bib_ref] Effects of terlipressin on systemic, hepatic and renal hemodynamics in patients with..., Narahara [/bib_ref] [bib_ref] Acute hemodynamic effects of octreotide and terlipressin in patients with cirrhosis: a..., Baik [/bib_ref] Therefore, it can also be used for treatment in patients with secondary renal insufficiency due to variceal bleeding. [bib_ref] Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results..., Ortega [/bib_ref] [bib_ref] Renal failure in cirrhotic patients: role of terlipressin in clinical approach to..., Alessandria [/bib_ref] [bib_ref] Long-term outcome of patients treated with terlipressin for types 1 and 2..., Testro [/bib_ref] Although TIPS [bib_ref] Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type..., Wong [/bib_ref] [bib_ref] Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and..., Guevara [/bib_ref] [bib_ref] Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with..., Brensing [/bib_ref] reduces the serum creatinine levels in most patients with hepatorenal syndrome, the effect is slower than the combined use of terlipressin and albumin.
In a group that used molecular adsorbent recirculating system [bib_ref] Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a..., Mitzner [/bib_ref] imaging study such as a CT should be performed (A1), and additional examinations such as those for total protein, LDH, glucose, or gram staining can be performed. (B1) -If the patient has a history of SBP, gastrointestinal bleeding, or protein in ascites less than 1.5 g/dL, although there is no gastrointestinal bleeding, prophylactic antibiotics should be considered because the chance of SBP is high. (B1)

## 4-4-3. prevention
Hepatorenal syndrome can be prevented by inhibiting the decrease of plasma volume. Diuretics and lactulose should be used carefully to prevent excessive fluid loss. [bib_ref] Midodrine versus albumin in the prevention of paracentesisinduced circulatory dysfunction in cirrhotics:..., Singh [/bib_ref] [bib_ref] Noradrenaline and albumin in paracentesis-induced circulatory dysfunction in cirrhosis: a randomized pilot..., Singh [/bib_ref] [bib_ref] Randomized trial comparing albumin and saline in the prevention of paracentesis-induced circulatory..., Sola-Vera [/bib_ref] [bib_ref] Terlipressin versus albumin in paracentesis-induced circulatory dysfunction in cirrhosis: a randomized study, Singh [/bib_ref] In patients with SBP, the use of albumin and antibiotics reduce the incidence of hepatorenal syndrome. [bib_ref] Effect of intravenous albumin on renal impairment and mortality in patients with..., Sort [/bib_ref] [bib_ref] Restricted use of albumin for spontaneous bacterial peritonitis, Sigal [/bib_ref] The use of oral norfloxacin has been shown to reduce the occurrence of hepatorenal syndrome and increase 3-month survival rates in patients with low serum protein (<1.5 g/dL) or renal insufficiency (creatinine 1.2 mg/dL, or blood urea nitrogen 25 mg/dL, or serum Na 130 mEq/L). [bib_ref] Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival..., Fernandez [/bib_ref] 

## Hepatic encephalopathy

## 5-1. definition
Hepatic encephalopathy is a neuropsychiatric syndrome that follows liver dysfunction. Patients with hepatic encephalopathy can show various neurological illnesses [fig_ref] Table 7: West-Haven criteria for hepatic encephalopathy183 MHE, minimal hepatic encephalopathy [/fig_ref]. [bib_ref] Practice Parameters Committee of the American College of Gastroenterology. Hepatic Encephalopathy, Blei [/bib_ref] Venous levels of ammonia are not helpful because they are not proportional to the severity of hepatic encephalopathy and some patients with sever hepatic encephalopathy have normal venous ammonia levels. [bib_ref] Studies of the blood ammonia in liver disease. Its diagnostic, prognostic, and..., Stahl [/bib_ref] Brain MRI is considered better than brain CT in the diagnosis of brain edema accompanying hepatic failure, but this is not true for hepatic encephalopathy. Brain CT is useful when differentiating between organic causes of neuropsychiatric disorders such as intracranial hemorrhage. [bib_ref] Manganese and chronic hepatic encephalopathy, Krieger [/bib_ref] 

## 5-3. treatment
The goal of treatment is to prevent secondary damage caused by decreased consciousness, normalize the patient's state of consciousness, prevent recurrence, and to improve the prognosis and quality of life by eliminating the social and economic restrictions caused by hepatic encephalopathy.
The precipitating factor can be identified in more than 80% of patients with hepatic encephalopathy. [bib_ref] An analysis of the causes and prevention of hepatic coma, Fessel [/bib_ref] The currently known precipitating factors of hepatic encephalopathy and the corresponding tests and treatments are shown in

## 5-3-2. liver transplantation
Liver transplantation is indicated in patients with severe hepatic encephalopathy, who do not respond to the above treatments. Patient with acute liver failure who shows hepatic encephalopathy are also considered for liver transplantation because of the poor prognosis. [bib_ref] Hepatic encephalopathy as a predictor of survival in patients with end-stage liver..., Stewart [/bib_ref] 

## 5-3-3. prevention of relapse
Because the recurrence rate of hepatic encephalopathy is 50-70%, [bib_ref] Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose..., Sharma [/bib_ref] [bib_ref] Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients, Bajaj [/bib_ref] [bib_ref] Rifaximin treatment in hepatic encephalopathy, Bass [/bib_ref] therapy for the prevention of recurrence should be considered. Lactulose 189 or rifaximin [bib_ref] Rifaximin treatment in hepatic encephalopathy, Bass [/bib_ref] have been used for the prevention of recurrence.

## 5-4. minimal hepatic encephalopathy

## 5-4-1. definition and diagnosis
Minimal hepatic encephalopathy is a mild form of hepatic encephalopathy that is defined as a cognitive dysfunction presenting a abnormal psychometric tests without clinical

## 5-4-2. treatment
Cognition and health-related quality of life improve significantly in the treatment group compared to placebo group. [bib_ref] Lactulose improves cognitive functions and health-related quality of life in patients with..., Prasad [/bib_ref] It has been reported that microviral agents (e.g., probiotics, synbiotics, etc.) improve minimal encephalopathy by changing intestinal normal flora and suppressing the production of ammonia. [bib_ref] Probiotic yogurt for the treatment of minimal hepatic encephalopathy, Bajaj [/bib_ref] Even though reports are displayed that LOLA [bib_ref] Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy:..., Kircheis [/bib_ref] and acetyl L-carnitine 205 improved minimal encephalopathy, there is no evidence regarding its effectiveness.
[fig] 1: Diagnosis of LC LC is a pathologically defined disease, and is clinically classified as compensated and decompensated LC. Decompensated LC includes cases with ascites, variceal bleeding, hepatic encephalopathy, or jaundice. Image studies for diagnosing LC are CT, abdominal ultrasound, and MRI. Typical findings of these images are nodular liver surface, splenomegaly, and the presence of intra-abdominal collateral vessels, which mean increasing portal venous pressure. Although there are not established criteria for the diagnosis of compensated LC, imaging studies may be helpful for the diagnosis of LC b y integrating laboratory findings such as albumin, bilirubin, or prothrombin time and platelet values. [/fig]
[table] Table 2: Drugs for acute esophageal variceal bleeding [/table]
[table] Table 3: Treatment of ascites depending on the grade Grade 1, a small amount of ascites detected in the ultrasound test; Grade 2, ascites of the amount which distends abdomen symmetrically; Grade 3, ascites of the large volume which distends abdomen; , major treatment; , recommended. [/table]
[table] Table 4: Definition and diagnosis of refractory ascites [/table]
[table] Table 6: Classification of hepatic encephalopathy180 [/table]
[table] Table 7: West-Haven criteria for hepatic encephalopathy183 MHE, minimal hepatic encephalopathy.such as cognition and orientation disorders. Hepatic encephalopathy is classified into 3 groups according to the causative liver disease(Table 6). 180,1815-2. DiagnosisHepatic encephalopathy is generally accompanied by advanced liver disease; therefore, muscle weakness, jaundice, ascites, palmar erythema, edema, spider telangiectasias, and fetor hepaticus can be noted on physical examination.Clinicians should check for gastrointestinal hemorrhage, uremia, use of anti-psychotics or diuretics, protein hyperingestion, infection, constipation, dehydration, electrolyte imbalance, etc. 182 Common symptoms include concentration disorders, sleep disorders, and movement disorders, including lethargy or coma. The severity of hepatic encephalopathy can be evaluated using the West Haven criteria [/table]
[table] Table 8: Precipitating factors, tests, and treatment of hepatic encephalopathy The primary treatment of hepatic encephalopathy is nonabsorbable disaccharides such as lactulose (-galactosidofructose) or lactitiol (-galctoside sorbitol). These treatments lead to the recovery of 70-90% of patients with hepatic encephalopathy. Although nonabsorbable disaccharides have been reported to have no significant effect on hepatic encephalopathy, 187 randomized controlled studies have indicated a positive effect of lactulose in the treatment and prevention of hepatic encephalopathy. 188,189 Enema with nonabsorbable disaccharides can be used until the consciousness is recovered. After consciousness is restored, nonabsorbable disaccharides (15-45 mL, orally 2-4 times/day) should be recommended for loose stool defecation 2-3 times a day.Antibiotics such as neomycin, metronidazole, and rifaximin that are not absorbed by the intestine, affect urea-producing bacteria and reduce the generation of ammonia, thereby improving hepatic encephalopathy. [/table]