Clinical Practice Guidelines for the Cirrhosis of Liver 2017 Development Committee

Transcription

1 1 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r FOREWORD Cirrhosis of the liver is very common in Myanmar as the consequence to chronic hepatitis B, C and alcoholic liver disease. It imposes a huge socio-economic burden on the government and health care system. There are recent developments in the management of cirrhosis of the liver and it is entirely essential to educate the health care providers with the update management. As Myanmar GI and Liver Society, Myanmar Medical Association has been diligently trying to conduct continuing medical education programs throughout the country at different levels various clinical practice guidelines for important diseases are developed for the last 10 years. Therefore, Myanmar GI and Liver Society with the participation of all members developed the first Myanmar GI and Liver Society Clinical Practice Guidelines for the Cirrhosis of Liver It is expected that this guidelines will be very helpful for the health care providers at different levels. It is also realized that this guidelines will need to be revised periodically whenever necessary. Myanmar GI and Liver Society would like to express sincere thanks to those who contributed to the development of this guidelines. Professor Khin Maung Win Professor Kyaw Soe Tun Founder President and Senior Patron President Myanmar GI and Liver Society Myanmar GI and Liver Society Myanmar Medical Association Myanmar Medical Association Chief Scientist Clinical Practice Guidelines for the Cirrhosis of Liver 2017 Development Committee November 2017

2 2 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r Clinical Practice Guidelines for the Cirrhosis of Liver 2017 Myanmar GI & Liver Society (MGLS) Myanmar Medical Association (MMA) Table of Contents 1. Introduction 2. Diagnosis of liver cirrhosis 3. Monitoring the risks for complications of liver cirrhosis 4. Treatment of liver cirrhosis 4.1 Nutritional therapy Protein Intake Branched Chain Amino Acids (BCAA) Late Evening Snacks 4.2 Anti-viral therapy Hepatitis B-related cirrhosis Hepatitis C-related cirrhosis 4.3 Anti-fibrotic therapy 4.4 Therapy for non-viral liver cirrhosis Therapy for alcohol-related liver cirrhosis Therapy for NAFLD (Non-Alcoholic Fatty Liver Disease) 5. Management of complications of cirrhosis of liver 5.1 GI Bleeding and portal hypertension 5.2 Ascites 5.3 Spontaneous Bacterial Peritonitis (SBP) 5.4 Hepato-renal syndrome 5.5 Hyponatremia 5.6 Hepatic Encephalopathy

3 3 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r EC Members of Myanmar GI and Liver Society (MGLS) Myanmar Medical Association (MMA) ( ) Prof. U Myo Thwe Prof. Brigadier General Than Sein (Rtd) Prof. U Kyaw Hla Prof. U Khin Maung Win Prof. U Thein Saw Prof. Daw Than Than Swe Prof. Daw Tin Tin May Prof. U Win Myint Prof. U Han Win Prof. U Tun Oo Prof. Win Naing PATRONS President Prof. Lt. Col. Kyaw Soe Tun Vice President (1) - Prof. Daw Nwe Ni Vice President (2) - Prof. Naomi Khaing Than Hlaing GI Society President - Prof. U Thein Myint Vice President (1) - Prof. Daw Than Than Aye Vice President (2) - Associate Professor Daw Khin San Aye Vice President (3) - Associate Professor U Than Tun Oo Liver Society President - Prof. Daw Naomi Khaing Than Hlaing Vice President (1) - Prof. Win Win Swe Vice President (2) - Associate Professor Daw Thandar Tun General Secretary - Prof. Lt. Col. Aye Min Soe Joint Secretary (1) - Associate Professor Daw Tin Moe Wai Joint Secretary (2) - Major Thet Aung Zaw Myint Academic Committee Academic secretary (1) - Prof. U Myint Maung Academic secretary (2) - Prof. Moe Myint Aung Academic secretary (3) - Associate Professor U Naing Naing Tun Treasurer - Capt. Yan Naung Win Joint Treasurer - Capt. Kyaw Ko Ko Aung

4 4 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r AASLD ALT AST CBC CrCl CTP DAA DCV EASL ESRD FDA GFR HBsAg HBV HCC INR MELD PCR RAV RBC RBV RGT RVR SVR12 (or 24) TSH ABBREVIATIONS - American Association for the Study of Liver Diseases - alanine aminotransferase - aspartate aminotransferase - complete blood cell (eg, complete blood cell count) - creatinine clearance - Child Turcotte Pugh - direct-acting antiviral - Daclatasvir - European Association for the Study of the Liver - end-stage renal disease - Food and Drug Administration - glomerular filtration rate - hepatitis B virus surface antigen - hepatitis B virus - hepatocellular carcinoma - international normalized ratio - model for end-stage liver disease - Polymerase Chain Reaction - resistance-associated variant - red blood cell (eg, red blood cell count) - ribavirin - response-guided therapy - rapid virologic response - sustained virologic response at 12 weeks (or at 24 weeks) - thyroid-stimulating hormone

5 5 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r INTRODUCTION In Myanmar, the major causes of cirrhosis include chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcoholism, and non-alcoholic steatohepatitis. HCV infection and nonalcoholic steatohepatitis are the causes that are primarily responsible for the growing burden of cirrhosis in health care. A diagnosis of compensated cirrhosis is associated with a risk of death that is 4.7 times as high as the risk in the general population, and decompensated cirrhosis is associated with a risk that is 9.7 times as high. The average life expectancy of a patient with compensated cirrhosis is 10 to 13 years, and the average life expectancy may be as low as 2 years if there is decompensation. [1] Among patients with alcoholic cirrhosis, 65% of the patients who abstain from drinking alcohol are alive at 3 years, as compared with 0% who continue drinking alcohol. [2] This guideline covers diagnosis, monitoring, and treatment of patients with cirrhosis of liver. It aims to provide proper and systematic identification and diagnosis of cirrhosis. It recommends methods to assess the severity of cirrhosis and gives advice on monitoring people with cirrhosis to detect and manage complications early, and referral criteria for tertiary care. The aim of this guidelines is to provide the information to the Healthcare professionals caring for people with cirrhosis Doctors Health Assistants and Nurses

6 6 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r DIAGNOSIS OF LIVER CIRRHOSIS 2.1 High-risk people for cirrhosis of liver The following people have the high risk for liver cirrhosis and the diagnosis of liver cirrhosis should be done periodically depending upon the clinical status of the patient. HBV-infected persons HCV-infected persons Misuse alcohol and alcohol-related liver diseases Obese (BMI > 30 kg/m 2 ), NAFLD and advanced liver fibrosis Type 2 DM (NICE guideline Cirrhosis in over 16s, published: 6 July 2016) 2.2 Investigations to diagnose liver cirrhosis Liver biopsy Liver biopsy was the gold standard for the diagnosis of liver cirrhosis. However, because of the sampling errors, invasive nature and the possibility of fatal complications, it is not recommended for the diagnosis of liver cirrhosis in Myanmar. [Liver fibrosis: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) Received: 30 August 2008 / Accepted: 30 October 2008] Ultrasound Scan (USG) Abdominal ultrasound (USG) is a simple imaging technique for almost all the cases of chronic liver disease. An ultrasound evaluation of the liver fibrosis stage of chronic liver disease has been performed by assessing various US factors such as the liver size, the bluntness of the liver edge, the coarseness of the liver parenchyma, nodularity of the liver surface, or splenomegaly. Although ultrasonographic data proved reliable in differentiating cirrhosis from milder stages of fibrosis, diagnostic value has not been definitely clarified, as documented by the wide range of sensitivity and specificity. [Liver fibrosis: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) Received: 30 August 2008 / Accepted: 30 October 2008] Conventional ultrasound cannot be used for the diagnosis of hepatic fibrosis. The diagnosis of early cirrhosis should be confirmed by additional studies such as Contrast-enhanced Ultrasound, CT, MRI, Contrast-enhanced MRI, Diffusion-weighted magnetic resonance imaging (DWMRI) and Magnetic resonance spectroscopy (MRS). (Asian-Pacific Association for the Study of the Liver (APASL) consensus guidelines on invasive and non-invasive assessment of hepatic fibrosis: a 2016 update)

7 7 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r In Myanmar, for the diagnosis of the liver cirrhosis, it is recommended to perform ultrasonography and if USG findings are not conclusive, to proceed CT scan examination Transient Elastography (FibroScan) FibroScan (Transient Elastography- TE or Liver Stiffness Measurement) is a test based on the physics of transient elastography to assess liver fibrosis. It is a non-invasive test and no adverse effects have been reported. Fibroscan takes less than 5 minutes to perform and produces immediate, operator-independent results expressed in kilo pascals (kpa). In general, if kpa are more than 10, it is regarded as being in the range of cirrhosis of the liver and Metavir Staging (F1 to F4) is done according to the underlying etiology. Metavir Stages F3 and F4 are regarded as cirrhosis of the liver. [Liver fibrosis: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) Received: 30 August 2008 / Accepted: 30 October 2008] TE is a fast, simple, and safe procedure available in Yangon and Mandalay. Its main limitation is the impossibility of obtaining results in case of ascites or morbid obesity and its limited applicability in case of obesity and limited operator experience. Correct interpretation of TE results in clinical practice must consider the following parameters: IQR/ median value (<30%), Serum aminotransferases levels (<5 x ULN), BMI (use XL probe above 30 kg/m 2 or if skin-to-capsule distance is >25 mm), Absence of extra-hepatic cholestasis Absence of right heart failure, or other causes of congestive liver Absence of ongoing excessive alcohol intake Fasting 3-4 hours LS (Liver Stiffness) measurement should be interpreted with caution among patients with elevated ALT, and should not be used in patients with very high ALT levels (>10 x ULN). TE can be considered the non-invasive standard for the measurement of LS. TE is well validated in viral hepatitis with performance equivalent in hepatitis B and C and in HIV-HCV coinfection. TE is less well validated in NAFLD and in other chronic liver diseases. TE performs better for detection of cirrhosis than for detection of significant fibrosis. TE is a reliable method for the diagnosis of cirrhosis in patients with chronic liver diseases that generally performs better at ruling out than ruling in cirrhosis (with negative predictive value higher than 90%). (EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis Journal of Hepatology 2015 vol. 63) Previously, in chronic HCV, patients with values above the high cut-off value (Significant Fibrosis Metavir F2, FibroScan kpa) would be prioritized for treatment as they have a high

8 8 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r probability (94%) of having F4 cirrhosis. However, currently with the availability of the potent DAAs, it is recommended to treat all patients with the chronic HCV infection. (WHO Guidelines for the screening, care and treatment of persons with chronic hepatitis C infection, April 2016) In chronic HBV, high cut-off with high specificity is used to diagnose persons with fibrosis and a low cut-off with high sensitivity to rule out the presence of a particular stage of fibrosis. But FibroScan uses a single cut-off (Significant Fibrosis Metavir F2, FibroScan kpa). (WHO Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection, March 2015) Amongst all the machines for the measurement of liver stiffness, the FibroScan machines produced by Echosens company are the recognized by the EASL and APASL as the standard and reference machines. Liver fibrosis can be staged using 1-dimensional ultrasound TE (FibroScan, Echosens, Paris, France), which measures the velocity of a low-frequency (50 Hz) elastic shear wave propagating through the liver. (EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis Journal of Hepatology 2015 vol. 63) [Liver fibrosis: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) Received: 30 August 2008 / Accepted: 30 October 2008] APRI (AST to Platelet Ratio Index) In resource-limited circumstances, APRI is proposed as a simple and non-invasive predictor in the evaluation of liver fibrosis status. It is readily available because AST and Platelets count are part of the routing tests in managing chronic liver disease. It is easy to compute without the use of complicated formula. APRI was originally derived in a group of patients with chronic HCV infection. Its usefulness in other forms of chronic liver diseases remains uncertain. [Liver fibrosis: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) Received: 30 August 2008 / Accepted: 30 October 2008] APRI Formula = [(AST / ULN AST) x 100] / Platelets (10 9 /L) - APRI > 1 = Cirrhosis of Liver ~ F4 - APRI = Severe Fibrosis ~ F3 - APRI 0.7 = Significant Fibrosis ~ F2-F3 Based on 2011 meta-analysis in Hepatology by Lin et. al: [3] - Significant fibrosis: APRI threshold of 0.7 was 77% sensitive and 72% specific. - Severe fibrosis: APRI threshold of 1.0 was 61% sensitive and 64% specific. - Cirrhosis: APRI threshold of 1.0 was 76% sensitive and 72% specific - WHO APRI >2 is regarded as cirrhosis (high cut-off point)

9 9 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r Recommendations 1. Liver biopsy is generally not recommended for the diagnosis of liver cirrhosis in Myanmar. 2. Conventional ultrasound cannot be used for the diagnosis of hepatic fibrosis or early cirrhosis. 3. Fibroscan is recommended as the preferred non-invasive test to rule out/ assess for the presence of cirrhosis. 4. APRI is an alternative test for detection of cirrhosis in resource-limited settings. 3. MONITORING THE RISKS FOR COMPLICATIONS OF LIVER CIRRHOSIS 3.1 Hepatocellular Carcinoma (HCC) People with cirrhosis are at high risk of developing HCC with an annual cancer risk of between 1% and 6% depending on the etiology of liver disease. Regular surveillance for people with cirrhosis, using ultrasound with serum AFP testing at 3 to 12 months intervals, endeavours to detect a tumour at an early stage when potentially curative treatment can be offered. (NICE guideline Cirrhosis in over 16s, published: 6 July 2016) Liver ultrasound and serum AFP every 6 months are the de facto standard for screening, although some experts discourage the use of AFP because of its low sensitivity of early stage disease. In clinical practice, the sensitivity of liver ultrasound alone for detecting early stage HCC in cirrhotic patients was found to be as low as 32% although most studies report better performance. [4] The combination of biannual ultrasound and AFP testing increases the sensitivity of early stage of HCC detection to 63.4%. Recent studies suggest that trends of variations in AFP levels are also predictive of HCC development. [5] [6] The AASLD suggests surveillance using ultrasound (USG), with or without alpha- fetoprotein (AFP), every 6 months. (AASLD guidelines for the treatment of hepatocellular carcinoma, December 2016) Alpha-fetoprotein (AFP) is not recommended by APASL as a confirmatory test in small HCC. The cut-off value of AFP should be set at 200 ng/ml for surveillance programs when used in combination with USG. (Asia Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update) Surveillance of HCC should be performed by experienced personnel in all at-risk populations using abdominal ultrasound every 6 months. (EASL EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma, December 2011) However, according to Myanmar real-life experience, AFP is a useful diagnostic tool for the surveillance of HCC in high-risk patients. For patients who do not have advanced fibrosis (i.e. those with Metavir stage F0-F2), recommended follow-up is once a year. Surveillance for hepatocellular carcinoma, AFP (Alpha Feto Protein) with 6-monthly ultrasound examination is recommended for patients with advanced fibrosis (i.e. Metavir stage F3 or F4) who achieve an SVR.

10 10 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r (2017 Myanmar GI and Liver Society, Clinical Practice Guidelines for the Treatment of Chronic Hepatitis C) 3.2 Oesophageal varices Variceal bleeding occurs in 25-40% of patients with cirrhosis and each bleeding episode is associated with 10-30% mortality rate. Consequently, prevention of variceal bleeding is an important goal in management of patients with cirrhosis. Therefore, it is important that people with cirrhosis at risk for variceal bleeding should be identified as early as possible. (NICE guideline Cirrhosis in over 16s, published: 6 July 2016) Gastro-oesophageal Varices are present in approximately 50% of patients with cirrhosis, but this depends on the clinical stage. In patients with compensated cirrhosis, Gastro-oesophageal Varices are present in 30%-40%, whereas they can be present in up to 85% of patients with decompensated cirrhosis. [7] [8] (Portal Hypertensive Bleeding in Cirrhosis: Risk Stratification, Diagnosis, and Management: 2016 Practice Guidance by the American Association for the Study of Liver Diseases - AASLD) VH occurs at a rate of around 10%-15% per year and depends on the severity of liver disease, size of varices, and presence of red wale marks (areas of thinning of the variceal wall). (Portal Hypertensive Bleeding in Cirrhosis: Risk Stratification, Diagnosis, and Management: 2016 Practice Guidance by the American Association for the Study of Liver Diseases - AASLD) [9] [10] The American College of Gastroenterology (ACG) and American Association for the Study of Liver Diseases (AASLD) have published guidelines recommending that all people with cirrhosis should be screened for the presence of varices using Oesophago-Gastro-Duodenoscopy (OGDS). Patients with an LS <20 kpa and platelet count >150,000/mm 3 have a very low probability (<5%) of having high-risk varices, and OGDS can be circumvented. (Garcia-Tsao, Guadalupe, et al. "Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American association for the study of liver diseases." Hepatology (2017): ) Patients in whom there are no varices should have an endoscopic surveillance every 2 years. The frequency of endoscopic surveillance depends on the severity of liver disease. In decompensated patients, screening should be done more frequently. Patients with compensated cirrhosis and small varices ( 5 mm) at initial endoscopy should undergo endoscopic surveillance at 1-year intervals. (Portal Hypertensive Bleeding in Cirrhosis: Risk Stratification, Diagnosis, and Management: 2016 Practice Guidance by the American Association for the Study of Liver Diseases - AASLD)

11 11 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r Ascites Ascites is the most common complication of cirrhosis and ~60% of patients with compensated cirrhosis develop within 10 years during the course of the disease. Development of ascites is associated with poor prognosis and impaired quality of life in patients with cirrhosis. Ascites should be diagnosed by clinical examination and ultrasound. (EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis Journal of Hepatology 2010) 3.4 Spontaneous Bacterial Peritonitis (SBP) SBP is very common bacterial infection in patients with cirrhosis and ascites. When first described, its mortality exceeded 90% but it has been reduced to approximately 20% with early diagnosis and treatment. SBP is bacterial infection of ascites, without an evident intra-abdominal, surgically treatable source of infection. Ascitic polymorphonuclear leukocyte (PMN) 250/mm 3 and bacteria in the ascitic culture without an evident intra-abdominal infection is diagnostic. Diagnostic paracentesis should be performed in all patients with new onset grade 2 or 3 ascites and in all patients hospitalized for worsening of ascites or any complications of ascites particularly to detect SBP. (EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis Journal of Hepatology 2010) 3.5 Heapto-renal syndrome (HRS) HRS can be defined as the occurrence of renal failure in a patient with advanced liver disease in the absence of an identifiable cause of renal failure. HRS should be diagnosed by demonstrating significant increase in serum creatinine and excluding other known causes of renal failure for therapeutic purposes, HRS is usually diagnosed only when serum creatinine increases to > 133 µmol/l (1.5 mg/dl). Repeated measurement of serum creatinine over time, particularly in hospitalized patients is helpful in early identification of HRS. (EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis Journal of Hepatology 2010) With the introduction of effective treatments, HRS is no longer a terminal condition. Therefore, it is of paramount importance that early and accurate diagnosis should be made, so as to implement treatment to improve the outcome for these patients. 3.6 Hepatic encephalopathy (HE) HE is the brain dysfunction caused by liver insufficiency and/or PSS (porto-systemic shunt). It manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from sub-clinical alternation to coma. The prevalence of HE at the time of diagnosis of cirrhosis is 10-14% in general,

12 12 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r % in those with decompensated cirrhosis and 10-50% in patients with TIPS (Trans-jugular Intrahepatic Porto-systemic Shunt). The diagnosis of HE is based on clinical examination and clinical decision. (Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases Journal of Hepatology 2014 vol. 61) Recommendations 1. Surveillance for HCC (Hepatocellular Carcinoma) by ultrasound with serum AFP test should be done Annually for patients with Metavir score F0-F2 3 to 6-monthly for patients with Metavir score F3-F4 and advanced cirrhosis 2. Endoscopic surveillance for oesophageal varices should be done in all patients diagnosed with liver cirrhosis. Patients with compensated cirrhosis without varices on screening endoscopy should have endoscopy repeated every 2 years (with ongoing liver injury or associated conditions, such as obesity and alcohol use) or every 3 years (if liver injury is quiescent, e.g., after viral elimination, alcohol abstinence). Patients with compensated cirrhosis with small varices on screening endoscopy should have endoscopy repeated every year (with ongoing liver injury) or every 2 years (if liver injury is quiescent, e.g., after viral elimination, alcohol abstinence). Patients with compensated cirrhosis without varices or with small varices who develop decompensation should have a repeat endoscopy when this occurs. Patients in whom varices are found should be treated and followed up as indicated. 3. Patients with liver cirrhosis should be examined to clinically detect the presence of ascites in every follow-up visits and confirmed by ultrasound. 4. All patients with new onset grade 2 or 3 ascites and all patients hospitalized for worsening of ascites or any complications of ascites should be screened to detect SBP (Spontaneous Bacterial Peritonitis) by paracentesis. 5. Periodic measurement of serum creatinine should be done to detect HRS and repeated measurement of serum creatinine over time, particularly in hospitalized patients is helpful in early identification of HRS. 6. History taking and clinical examination should be done in all patients with advanced cirrhosis to detect the occurrence of hepatic encephalopathy (HE).

13 13 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r TREATMENT OF LIVER CIRRHOSIS 4.1 Nutritional Therapy Protein Intake Malnutrition occurs in 20-60% of patients with cirrhosis and current guidelines recommends daily protein intake of g/kg of dry body weight. High protein diets are welltolerated and are associated with sustained improvement in mental status whereas restriction of protein intake does not have any beneficial effects in patients with acute hepatic encephalopathy. [11] Patients with cirrhosis frequently have either global malnutrition or alteration in specific aspects of nutritional status, such as micro-nutrients deficiency due to multiple mechanisms, including poor nutritional intake, poor absorption and increased losses. Malnutrition is present in almost every patients with alcoholic cirrhosis and is frequent in most other types of cirrhosis. One of the most common deficiencies involves zinc. Therefore supplementing patients with zinc is often helpful in many types of cirrhosis. [12] In general, oral nutritional supplements are recommended. If patients are not able to maintain adequate oral intake, tube feeding is recommended (even when oesophageal varices are present). Parenteral nutrition is safe and improves metal state in patients with cirrhosis and severe HE. [13] [14] Recommendation Recommends g of protein per kg body weight. [1 tical (kyat-thar) = 16 g)] [E.g. 70 kg man requires 105 g or 6 tical (kyat thar) of protein daily] High protein diets are well-tolerated and are associated with sustained improvement in mental status. Restriction of protein intake does not have any beneficial effect in acute hepatic encephalopathy Branched Chain Amino Acids (LIVACT Granules) The Branched Chain Amino Acids Valine, Leucine and Isoleucine are three of nine essential amino acids that are not synthesized by our body and therefore must be obtained from diet. Oral Branched Chain Amino Acids are recommended for cirrhotic patients because it relieves hypoalbuminemia and hepatic encephalopathy and improves quality of life and increases the muscle mass. [15] Perioperative supplementation with BCAA-enriched nutrient mixture reduces the morbidity associated with post-operative complications, preserves albumin level and shortens the duration of hospitalization of patients undergoing liver resection for HCC. It is also associated with

14 14 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r reduced incidence of HCC in patients with CTP A cirrhosis and in patients with BMI of 25 kg/m 2 or higher. [15] An updated meta-analysis of eight randomized controlled trials (RCTs) indicated that oral BCAA-enriched formulations improve the manifestations of episodic HE whether OHE or MHE. There is no effect of IV BCAA on the episodic bout of HE. Oral Branched Chain Amino Acids-enriched formulations improve the manifestation of episodic HE. Oral Branched Chain Amino Acids can be used as an alternative or additional agent to treat patients non-responsive to conventional therapy for HE. [Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases Journal of Hepatology 2014 vol. 61 (EASL and AASLD)] Recommendation Recommended dose of Branched Chain Amino Acids (containing Leucine, Isoleucine and Valine) is 12 gram/day (LIVACT Granules 3 packs/day) Oral Branched Chain Amino Acids are recommended o to relieve hypoalbuminemia and hepatic encephalopathy o to improve the quality of life o to reduce incidence of HCC in mild chronic liver diseases o to increase the muscle mass Late Evening Snacks Because of a hypermetabolic state, overnight fasting contributes to muscle depletion in patients with cirrhosis. Late evening meals may improve nitrogen balance without exacerbating HE. Randomized trials involving patients with cirrhosis who received two cans of high-protein nutritional supplements (474 ml/can) (200 kcal) nightly showed that nocturnal supplementation resulting in sustained increase in total body protein. [11] Small meals or liquid nutritional supplements evenly distributed throughout the day and a late-night snack should be offered. [Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases Journal of Hepatology 2014 vol. 61 (EASL and AASLD) Recommendation Late evening snack of 200 kcal such as a rice bowl or liquid nutrient is recommended o to improve nocturnal fasting o improve nutritional status increasing body protein content and o to diminish fat and protein oxidation

15 15 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r Anti-viral Therapy Anti-viral Therapy for HBV-related cirrhosis Nucleoside/tide analogues are recommended to be taken for life because they enhance SVR and HBeAg seroconversion, relieve liver fibrosis, improve patient prognosis and prevent the development of HCC. [16] Patients with decompensated cirrhosis should be immediately treated with a NA with high barrier to resistance, irrespective of the level of HBV replication, and should be assessed for liver transplantation. PegIFNα is contraindicated in patients with decompensated cirrhosis. (EASL 2017 Clinical Guidelines on the Management of chronic HBV infection) Recommendation Nucleoside analogues (Tenofovir or Entacavir) are recommended to be taken for life because o they enhance HBeAg seroconversion, o relieve liver fibrosis o improve patient prognosis and o prevent the development of HCC Entacavir should be avoided in the patients who previously received lamivudine. Peg IFNα is contraindicated in patients with decompensated cirrhosis Anti-viral Therapy for HCV-related cirrhosis Liver fibrosis is gradually relieved when SVR is attained in HCV-related cirrhosis. Pegylated Interferon is not recommended. All-oral Direct-acting antivirals (DAAs) regimens should be used because of the high SVR rates exceeding 90% and absence of serious adverse reactions. SVR will provide significant reversion of the fibrosis and prevention of HCC. [15] Patients with decompensated cirrhosis (CTP B and CTP C up to 12 points) without concomitant co-morbidities that could impact their survival should be treated urgently. Patients with decompensated cirrhosis without HCC can be treated prior to liver transplantation. Treatment should be initiated as soon as possible in order to complete a full treatment course before transplantation and assess the effect of viral clearance on liver function because significant improvement in liver function may lead to deferring liver transplant in selected cases. (EASL Recommendations on Treatment of Hepatitis C 2016)

16 16 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r Recommendation All-oral Direct-acting antivirals (DAAs) regimens should be used because of the high SVR rates that provide significant reversion of the fibrosis and prevention of HCC. The treatment regimens should be chosen according to 2017 Myanmar GI and Liver Society Guidelines for the treatment of the Chronic Hepatitis C Infection. Pegylated Interferon is not recommended. 4.3 Anti-fibrotic therapy No therapy has confirmed efficacy. Ursodeoxycholic acid (UDCA) stabilizes serum ALT levels in HCV-related liver cirrhosis. [15] [17] The clinical use of statins is promising and should be evaluated in further phase 3 studies. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) can be safely started and continued in patients with cirrhosis. Routine monitoring of the alanine aminotransferase level in patients who use statins is no longer recommended. [11] Recommendation No proven anti-fibrotic therapy. The use of statins in cirrhosis of liver needs further studies. 4.4 Therapy for Non-viral liver cirrhosis Therapy for alcohol-related liver cirrhosis Abstinence is recommended for such patients because long-lasting abstinence improves their prognosis. [17] 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. [18] Therapy for NAFLD (Non-Alcoholic Fatty Liver Disease)-related liver cirrhosis NAFLD is an emerging etiological factor for the development of cirrhosis of the liver. If not properly treated, the situation can progress to NASH and cirrhosis of liver and even HCC. However there is no drug which has the proven efficacy for the NAFLD. Treatment of non-alcoholic fatty liver comprises improving insulin resistance, removing risk factors of metabolic syndrome, lifestyle modifications, and operative treatment. Weight loss appears to help in reduction of liver steatosis as well as relieves hepatic inflammation and fibrosis. [18]

17 17 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r Recommendation Long-term abstinence of alcohol drinking is recommended to improve prognosis in patients with alcohol-related liver cirrhosis. NAFLD should be controlled to prevent further progression into NASH and cirrhosis of liver No drug with proven efficacy is available for NAFLD-associated liver cirrhosis Weight reduction and life style modifications are recommended.

18 18 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r MANAGEMENT OF COMPLICATIONS OF LIVER CIRRHOSIS 5.1 GI BLEEDING AND PORTAL HYPERTENSION Diagnosis HVPG (Hepatic Venous Pressure Gradient) measurement is the gold-standard method to assess the presence of clinically significant portal hypertension (CSPH), defined as an HVPG 10mm Hg. CSPH can be identified by noninvasive tests: LS (Liver Stiffness) > kpa, alone or combined with platelet count and spleen size. The presence of portosystemic collaterals on imaging is sufficient to diagnose CSPH. Patients with gastro-oesophageal varices on endoscopy have, by definition, CSPH. (Garcia-Tsao, Guadalupe, et al. "Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American association for the study of liver diseases." Hepatology (2017): ) Non-invasive tests cannot replace Hepatic Venous Pressure Gradient (HVPG) for a detailed portal hypertension evaluation and upper GI endoscopy for detecting varices. However, in settings where HVPG is not available, Transient Elastography (TE) could be considered to stratify the risk of clinically significant portal hypertension. (EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis Journal of Hepatology 2015 vol. 63) It is recommended that all patients undergo endoscopy when they are first diagnosed with liver cirrhosis in order to evaluate the presence of esophageal varices and the risk of bleeding which is the most dangerous complication of liver cirrhosis which can have fatal outcomes. Compensated liver cirrhosis should be considered for endoscopy every 2 to 3 years. Decompensated liver cirrhosis should have endoscopy every 1 to 2 years in order to evaluate the occurrence and progression of varices. [19] Management of GI bleeding and Portal Hypertension If there are no varices, non-selective beta-blockers (NSBB) are not recommended to prevent their development. If varices are small and have not bled, nonselective beta-blockers should be used for the prevention of first variceal hemorrhage. If varices are medium/large but have not bled, nonselective beta-blockers or EVL may be recommended for the prevention of first variceal hemorrhage. Low doses of carvedilol have been shown to lower the frequency of variceal bleeding with lesser side effects as compared with EVL. Repeated EVL is recommended until the disappearance of esophageal varices. (Garcia-Tsao, Guadalupe, et al. "Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American association for the study of liver diseases." Hepatology (2017): )

19 19 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r Prophylaxis Beta-blockers are useful for primary prophylaxis of esophageal variceal bleeding. Propranolol is proposed for management of portal hypertensive gastropathy because it is effective in relieving portal hypertensive gastropathy. It is to be noted that beta-blockers may have negative effects in those patients with CTP B or C. The combination of endoscopic therapy and betablockers is proposed for secondary prophylaxis of esophageal variceal bleeding as it decreases rebleeding and mortality. [15] Either traditional NSBBs (propranolol), carvedilol, or EVL is recommended for the prevention of first VH (primary prophylaxis) in patients with medium or large varices. Choice of treatment should be based on patient preference and characteristics. Patients on NSBBs or carvedilol for primary prophylaxis do not require monitoring with serial EGD. Combination therapy NSBB plus EVL is not recommended in this setting. (Garcia-Tsao, Guadalupe, et al. "Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American association for the study of liver diseases." Hepatology (2017): ) Stop beta-blockers under these conditions: [11] Refractory ascites Systolic blood pressure <100 mm Hg Mean arterial pressure <82 mm Hg Serum sodium level <120 mmol/liter Acute kidney injury Hepatorenal syndrome Spontaneous bacterial peritonitis Sepsis Severe alcoholic hepatitis Poor follow-up or non-adherence to regimen Gastric varices (GV) are present in around 20% of patients with cirrhosis. Sarin s classification is the most commonly used for risk stratification and management of GV. GOV type 1 (GOV1) are EV extending below the cardia into the lesser curvature and are the most common (75% of GV). GOV type 2 (GOV2) are those extending into the fundus. Isolated GV type 1 (IGV1) are located in the fundus (IGV1). GOV2 and IGV1 are commonly referred to as cardiofundal varices. Isolated GV type 2 (IGV2) are located elsewhere in the stomach, but are extremely infrequent in patients with cirrhosis.

20 20 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r The main factors associated with a higher risk of bleeding are localization (IGV1>GOV2>GOV1), large size, presence of red spots, and severity of liver dysfunction. For prevention of first variceal haemorrhage from GOV2 or IGV1, NSBBs can be used, although the data are not as strong as for EV. Prevention of first bleeding from GOV1 varices may follow the recommendations for EV. Neither TIPS nor BRTO (Balloon-occluded Retrograde Transvenous Obliteration) are recommended to prevent first hemorrhage in patients with fundal varices that have not bled. (Garcia-Tsao, Guadalupe, et al. "Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American association for the study of liver diseases." Hepatology (2017): ) Recommendation Diagnosis All cirrhotic patients should undergo endoscopy to evaluate the occurrence and progression of varices o Every 2-3 years endoscopy for patients with compensated liver cirrhosis and o Every 1-2 years endoscopy for patients with decompensated liver cirrhosis Treatment o If there are no varices, nonselective beta-blockers (Carvedilol) are not recommended. o If varices are small and have not bled, nonselective beta-blockers (Carvedilol) should be used for the prevention of first variceal hemorrhage. o If varices are medium/large but have not bled, EVL may be recommended for the prevention of first variceal hemorrhage Prophylaxis o Non-selective beta-blockers (Carvedilol) are useful for primary prophylaxis of esophageal variceal bleeding. o The combination of endoscopic therapy and beta-blockers is proposed for secondary prophylaxis of esophageal variceal bleeding as it decreases rebleeding and mortality. o Propranolol is proposed for management of portal hypertensive gastropathy because it is effective in relieving portal hypertensive gastropathy.

21 21 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r ASCITES Diagnosis Grade 1 ascites is mild and only detectable by ultrasound. Grade 2 ascites is evident by moderate symmetrical distension of abdomen and confirmed by inspection, physical examination and paracentesis. Grade 3 ascites is large and gross with marked abdominal distension. Neutrophil count and culture of ascitic fluid (by inoculation into blood culture bottles at the bedside) should be performed to exclude bacterial peritonitis. (EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis Journal of Hepatology 2010) If serum-ascites albumin gradient is greater than or equal to 1.1 g/dl, it indicates ascites by portal hypertension. [21] Treatment Grade 1 or Mild ascites Bed rest is NOT recommended for the treatment of ascites. A low salt diet is considered effective for controlling ascites and shortening hospitalization. Grade 2 or Moderate ascites Moderate restriction of salt intake is an important component of the management of ascites. Fluid restriction is not necessary unless serum sodium is less than 125 mmol/l. It is recommended by EASL to start spironolactone at 100 mg/day and increasing stepwise every 7 days (in 100 mg steps) to a maximum of 400 mg/day if given alone. However, our real life experience indicated that spironolactone should not be given more than 150 mg in Myanmar patients. In refractory cases of ascites, referral to specialist centre is recommended. The doses of both oral diuretics can be increased simultaneously every 3 to 5 days (maintaining the spironolactone 100 mg : furosemide 40 mg ratio) if weight loss and natriuresis are inadequate. In general, this ratio maintains normokalemia. Usual maximum doses are 400 mg per day of spironolactone and 160 mg per day of furosemide. (AASLD Management of Adult Patients with Ascites due to Cirrhosis: Update 2012) In patients with severe oedema there is no need to slow down the rate of daily weight loss. [22] Once the oedema has resolved but ascites persists, then the rate of weight loss should not exceed 0.5 kg/day. [23]

22 22 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r Grade 3 or Massive ascites Large-volume paracentesis (LVP) is the first-line therapy in patients with large ascites. LVP should be performed together with the administration of albumin (one bottle of 50 ml albumin for 1 litre of ascitic fluid removed) to prevent circulatory dysfunction after LVP. In patients undergoing LVP of greater than 5 L of ascites, the use of plasma expanders other than albumin is not recommended because they are less effective in the prevention of postparacentesis circulatory dysfunction. After LVP, patients should receive the minimum dose of diuretics necessary to prevent the re-accumulation of ascites. LVP in Myanmar more than 2 litres may not be feasible because of the prohibitively expensive albumin infusions (1 litre paracentesis must be done with one bottle of 50 ml albumin). The goal of long-term treatment is to maintain patients free of ascites with the minimum dose of diuretics. Thus, once the ascites has largely resolved, the dose of diuretics should be reduced and discontinued later, whenever possible. All diuretics should be discontinued if there is severe hyponatremia (serum sodium concentration <120mmol/L) progressive renal failure worsening hepatic encephalopathy, or incapacitating muscle cramps (particularly spironolactone) (EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis Journal of Hepatology 2010) Starting with both drugs (spironolactone and furosemide) appears to be the preferred approach in achieving rapid natriuresis and maintaining normokalaemia. Furosemide should be stopped if there is severe hypokalemia (<3 mmol/l). Spironolactone should be stopped if patients develop severe hyperkalemia (serum potassium >6 mmol/l) Contraindicated drugs in patients with ascites NSAIDs ACEI ARB Aminoglycosides (AASLD Management of Adult Patients with Ascites due to Cirrhosis: Update 2012) Contrast media should be used with caution and the use of general preventive measures of renal impairment is recommended. (EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis Journal of Hepatology 2010) Refractory ascites

23 23 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r Refractory ascites is defined as fluid overload that is not controlled despite restriction of sodium intake and the maximum dose of diuretics, and recurs rapidly after paracentesis. Diuretic-resistant ascites - Being not responsive to sodium limit and diuretic, ascites is not controlled, and recurs early Diuretic-intractable ascites - Since sufficient amount of diuretic cannot be given for its complication, ascites is not controlled, and recurs early [19] Treatment o Serial therapeutic paracentesis are a treatment option o Referral for liver transplantation should be expedited if the patient is otherwise a candidate for transplantation (AASLD Management of Adult Patients with Ascites due to Cirrhosis: Update 2012) Recommendation Diagnosis o Grade 1 - mild and only detectable by ultrasound o Grade 2 - evident by moderate symmetrical distension of abdomen and confirmed by inspection, physical examination and paracentesis o Grade 3 - large and gross with marked abdominal distension. Treatment o Grade 1 Bed rest is not recommended and low salt diet (no added salt / salt-free) is advised. No treatment is required. o Grade 2 Use of diuretics and dietary restriction of sodium. o Grade 3 Use of diuretics and Large Volume Paracentesis (LVP) followed by Dietary restriction of sodium Refractory Ascites o Serial therapeutic paracentesis are a treatment option o Referral for liver transplantation should be expedited if the patient is otherwise a candidate for transplantation 5.3 SPONTANEOUS BACTERIAL PERITONITIS (SBP) Diagnosis SBP is a very common bacterial infection in patients with cirrhosis and ascites ( % in outpatients and ~10% in hospitalized patients). When first described, its mortality exceeded 90% but it has been reduced to approximately 20% with early diagnosis and treatment. The diagnosis of SBP is reached with a cutoff neutrophil count of 250/mm 3. When culture is positive

24 24 P a g e C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e c i r r h o s i s o f l i v e r (40% of cases), the most common pathogens include Gram-negative bacteria (GNB), usually Escherichia coli and Gram-positive cocci. Patients with SBP may have one of the following; local symptoms and/or signs of peritonitis: abdominal pain, abdominal tenderness, vomiting, diarrhea, ileus signs of systemic inflammation: hyper or hypothermia, chills, altered white blood cell count, tachycardia, and/or tachypnea; worsening of liver function; hepatic encephalopathy; Shock; renal failure; and gastrointestinal bleeding However, it is important to point out that SBP may be asymptomatic, particularly in outpatients Treatment Patients with SBP in a community-acquired setting in the absence of recent Β-lactam antibiotic exposure should receive empiric antibiotic therapy, e.g., an intravenous third-generation cephalosporin, preferably cefotaxime 2 g every 8 hours. Patients with SBP in a nosocomial setting and/or in the presence of recent Β-lactam antibiotic exposure should receive empiric antibiotic therapy based on local susceptibility testing of bacteria in patients with cirrhosis. Patients with ascitic fluid PMN counts less than 250 cells/mm 3 (0.25 x 10 9 /L) and signs or symptoms of infection (temperature >100 F or abdominal pain or tenderness) should also receive empiric antibiotic therapy, e.g., intravenous cefotaxime 2 g every 8 hours, while awaiting results of cultures. (AASLD Management of Adult Patients with Ascites due to Cirrhosis: Update 2012) Prophylaxis for SBP In patients with gastrointestinal bleeding and severe liver disease, ceftriaxone (for 7 days) is the prophylactic antibiotic of choice. In patients with less severe liver disease, oral norfloxacin or an alternative oral quinolone is recommended to prevent the development of SBP. Patients who have survived an episode of spontaneous bacterial peritonitis should receive long-term prophylaxis with daily norfloxacin. (EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis Journal of Hepatology 2010)