Management of Cirrhosis: New Guidelines

Educational Objectives

The goal of this program is to improve management of cirrhosis. After hearing and assimilating this program, the clinician will be better able to:

1. Identify patients with portal hypertension.
2. Select medications for treatment of ascites.
3. Recognize signs and symptoms of hepatorenal syndrome.

Summary

Cirrhosis: >1 million persons in the United States have cirrhosis; prevalence is increasing; liver disease is one of the top 10 causes of mortality in certain populations, primarily because of an increased incidence of nonalcoholic fatty liver disease (NAFLD); hepatitis C virus (HCV)-associated cirrhosis is curable and rates are decreasing; end-stage liver disease is causing increasing numbers of hospital admissions; mortality has increased because the transplantation system is overloaded with new cases; etiology — HCV accounts for ≈25% of cases of cirrhosis, NAFLD accounts for ≈20%, and alcohol accounts for ≈20%; HBV accounts for 15% of cases nationwide; local prevalence depends on location; other causes, eg, autoimmune, Wilson disease, and α-1 antitrypsin deficiency account for a small proportion

Diagnosis: blood tests and liver elastography (FibroScan) indicate the extent of fibrosis; in decompensated cirrhosis, patients exhibit, eg, jaundice, ascites, edema, weight loss; compensated cirrhosis is more difficult to diagnose; patients may have elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) with NAFLD, HCV, or alcohol use disorder; certain physical findings increase the probability of liver disease by 30% to 40%; caput medusa is uncommon but indicative of cirrhosis; consists of abdominal veins radiating from the umbilicus; gynecomastia in men is a good marker for cirrhosis (when not drug-induced); spider angiomas increase the probability of cirrhosis by ≈30% in patients with abnormal liver enzymes; patients with ∼3 or 4 spider angiomas on the upper chest and neck are very likely to have cirrhosis; to differentiate spider angiomas from actinic keratosis or sun damage, press on the center of the lesion; spider angiomas disappear with pressure and fill in from the center outward when released; swollen abdomen and icterus are more obvious signs of cirrhosis

Imaging: specific but not sensitive; a nodular contour may be seen on computed tomography (CT) and ultrasonography (US); the left lobe of the liver enlarges, and the right lobe shrinks; the enlarged left lobe may be palpable as an epigastric mass, and the shrunken right lobe may not be palpable under the costal margin; enlarged spleen is indicative of cirrhosis; these findings may be absent in patients with cirrhosis, or there may be mild fatty infiltration

Diagnostic tests: the fibrosis 4 (FIB-4) score should be calculated based on the patient’s age, AST, ALT, and platelet count; the specificity and sensitivity for cirrhosis are acceptable; elastography should be obtained in cases of positive scores; patients may additionally be tested for cirrhosis with fibrotest and fibrosure; useful for extremes (fibrosis and no cirrhosis) but the tests are not useful for distinguishing, eg, F2 from F1; proprietary tests use combinations of markers of fibrosis, eg, metalloproteinases, hyaluronic acid; useful if elastography is not available

Elastography: higher scores indicate greater degrees of fibrosis; fibrosis is at F3 level and the 3-yr risk for decompensation is <1% if the score is <10; patients are on the cusp of fibrosis but have a good prognosis; a score of 10 to 15 suggests advanced cirrhosis; scores >15 are very suggestive of advanced cirrhosis; the report provides the F score and indicates, eg, early or advanced cirrhosis; higher scores indicate a higher risk for decompensation; patients with NAFLD typically have scores of 4 to 6 or F0 to F1; more advanced disease may be present at F2

Compensation and liver disease: compensation is more important than the stage of disease; patients with compensated liver disease have no ascites, elevated international normalized ratio (INR) or jaundice, and no variceal bleeding; a decompensating event changes the prognosis; a study followed patients with HCV and no decompensation at baseline (ie, normal INR and albumin); those who remained compensated had a 10-yr survival rate of 80%; decompensation, eg, jaundice, ascites, bleeding, markedly decreased the survival rate; markers (eg, bilirubin and albumin) may be checked every 6 mo for patients with compensated cirrhosis to detect a trend toward decompensation before ascites develop; be mindful that patients are often frightened of the diagnosis of cirrhosis and may assume the condition is fatal; discussing compensation and preventing decompensation with patients is recommended

Portal hypertension: increased resistance from scar tissue in the liver increases pressure in blood vessels; increased nitric oxide causes dilation of the gut vasculature (ie, splanchnic vasodilation); blood from the gut flows through the portal vein to the liver; there is increased resistance and increased flow, which further increases the pressure

Impact on the kidneys: the effective circulating volume is lower because of portal vasodilation; the kidneys recognize this decreased volume and reabsorb sodium and water; the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system are activated, leading to renal vasoconstriction and sodium and water retention, which creates edema; ascites results when fluid leaks out of the vasculature of the gut and out of the liver because of high pressure; this fluid overload further increases the pressure

Impact on the heart: with increased fluid, the heart initially increases cardiac output (patients may develop a flow murmur) as part of the overall neurohumoral activation (RAAS) through increased cardiac contractility; overloading of the heart may cause cardiac dysfunction in late cirrhosis

Therapy: arresting the process (ie, curing HCV, ceasing consumption of alcohol) may resolve ascites and jaundice (cirrhosis becomes compensated); medications may be used to decrease portal pressure; β-blockers — β-1-specific drugs reduce sympathetic outflow and decrease the hyperdynamic state; nonselective β-blockers (β-1 and β-2 activity) take advantage of the β-2 activity to stop vasodilation, lowering flow, reducing pressure, reducing cardiac output, reducing systemic vascular resistance, and increasing splanchnic vascular resistance; α-blockers — resistance in the liver is caused by tissue scarring and vasoconstriction (myofibroblasts surround the vessels); carvedilol blocks the α component, which reduces vasoconstriction; carvedilol acts on β-1, β-2, and α, which may prevent progression of cirrhosis

Chronic inflammatory state: likely results from the impaired barrier function caused by high pressures; patients also have dysbiosis and systemic leakage of bacteria and endotoxins (lymph nodes contain endotoxin); the chronic inflammatory state contributes to portal hypertension; data are limited for the use of inflammatory blockers; bacterial translocation into the lymph nodes creates pathogen-associated molecular patterns and liver damage-associated patterns from the innate immune system; activation of the innate immune system creates systemic inflammation; systemic inflammation causes splanchnic vasodilation, which may be a result of bacteria-associated endotoxin and nitric oxide production; energy production in the gut and liver are altered, leading to mitochondrial dysfunction that creates further liver damage; when combined with tissue damage from the immune system, multiorgan system failure may occur

Portal pressure measurement: a catheter is inserted through the inferior vena cava to the hepatic vein; the wedge pressure and free pressure are used to obtain the hepatic venous pressure; this test is invasive and only performed in clinical studies or during a transjugular intrahepatic portosystemic shunt (TIPS) procedure; instead, markers are used to determine the likelihood of high pressure, which is associated with decompensation

Liver stiffness measurement (LSM): clinically significant portal hypertension may be measured noninvasively; LSM <15 fibroscan and a normal platelet count (≥150,000/mcL) rules out deleterious portal hypertension and avoids unnecessary upper endoscopies; an LSM >25 rules in clinically significant portal hypertension; patent with LSM scores of 20 to 25 and platelets <150 have a 50% to 60% chance of having clinically significant portal hypertension

Treatment recommendations: lowering portal pressures to improve outcomes is the goal of treatment; the prior Baveno group recommendation was to avoid β-blockers unless patients have varices; the new recommendation is to use nonselective β-blockers to prevent decompensation; carvedilol is preferred because it provides α blockade, is well tolerated, and portal pressure is reduced more than with β-blockers; the PREDESCI trial found the cumulative incidence of decompensation or death was lower (hazard ratio 0.5) with nonselective β-blockers; nonselective β-blockers may be titrated according to heart rate and blood pressure; the primary benefit of carvedilol is prevention of ascites; patients may be kept on nadolol and propranolol

Ascites: usually the first sign of decompensation; seen on US or CT; with the first sign of decompensation, 5-yr survival drops to ≈30% and 2-yr mortality is 50%; referral to a transplant center to start the listing process should be considered; paracentesis should be performed in all hospitalized patients to assess for spontaneous bacterial peritonitis (SBP); platelet or fresh frozen plasma transfusion is not needed, even with an elevated INR and low platelets; the risk for hemoperitoneum with an INR of, eg, 1.8 is <1 in 1000; the highest risk is for an abdominal wall hematoma, which is easily resolved; however, patients with acute kidney injury (AKI) have decreased platelet function which may increase the risk for bleeding; paracentesis may rule out causes other than cirrhosis for ascites

Paracentesis studies: the most important tests on ascitic fluid are albumin, total protein, and cell count; excess fluid may be used for cultures; the cell count indicates SBP before cultures are completed; total protein and the serum ascites-albumin gradient (SAAG) are analyzed to make a diagnosis of cirrhosis; most individuals with cirrhosis have a SAAG >1.1 (albumin is low in ascitic fluid, which is transudate from high pressure); a high protein level with a low SAAG indicates infection or malignancy (eg, ovarian cancer, metastatic gastric cancer with peritoneal carcinomatosis); a high SAAG and high total protein indicates cardiac ascites; SAAG has 97% accuracy; special circumstances — bilirubin should be checked in patients with recent biliary surgery to look for bile leaks; amylase should be checked in cases of severe pancreatitis

Treatment recommendations for ascites: sodium should be restricted to ≤2 g/day; fluid restriction is not necessary unless the patient is severely hyponatremic; diuretic therapy with spironolactone (≤400 mg) or furosemide (Lasix; ≤160 mg) at a 100:40 ratio is recommended; spironolactone is a long-acting daily drug (dividing the dose is not necessary); the effect is not seen for 3 days; furosemide may be given 1 to 2 times/day; painful gynecomastia is a potential adverse effect of spironolactone, which may necessitate switching to eplerenone or amiloride; therapeutic paracentesis may be performed in cases of persistent ascites; ≤8 L of fluid should be removed to avoid inducing AKI; albumin should be replaced if ≥5 L was removed

TIPS for refractory ascites: used for patients with persistent ascites despite maximum-dose diuretics or AKI with increasing doses; patients must meet specific health criteria to qualify, because right-heart overload may occur; all patients should be assessed with echocardiography and measurement of pulmonary pressures; the major adverse effect is encephalopathy from shunting of blood

Liver transplantation: any patient with ascites should be considered for transplantation; contraindications include active substance abuse, homelessness, and nonadherence; alternatives — peritineovenous shunts; home drainage is associated with a high risk for infection

Tylenol: patients with compensated cirrhosis may take ≤2g/day

Other medications: nonsteroidal anti-inflammatory drugs (NSAIDs) block prostacyclins, which preserve glomerular filtration rate (GFR) in the setting of liver vasoconstriction; creatinine levels should be monitored when using ACE inhibitors and ARBs; β-blockers may be harmful in cases of severe refractory ascites

Hepatorenal syndrome: renal dysfunction induced by splanchnic vasodilation, RAAS activation, and sympathetic activation; vasoconstriction of the kidney causes renal ischemia; creatinine should be 0.5 to 0.7 mg/dL (because patients with have low muscle mass); consider changing doses in patients with higher creatinine levels and a low GFR; hypovolemia (prerenal) may be ruled out by discontinuing diuretics and providing colloid (eg, albumin); assessment for infection is recommended because SBP may induce hepatorenal syndrome; paracentesis may be performed; diuretics should be stopped; therapies — data are limited for albumin, midodrine, and octreotide; norepinephrine may be effective, but must be given in the intensive care unit; liver transplantation is an option; terlipressin has been effective, with fewer side effects than vasopressin; researchers with the CONFIRM trial found better hepatorenal reversal but no improvement in survival and increased respiratory failure

Readings

Aday AW, Mayo MJ, Elliott A, Rockey DC. The beneficial effect of beta-blockers in patients with cirrhosis, portal hypertension and ascites. Am J Med Sci. 2016;351(2):169-176. doi:10.1016/j.amjms.2015.11.018. View Article; Ahn J, Attia Z, Rattan P, et al. Development of the AI-cirrhosis-ECG score: An Electrocardiogram-based deep learning model in cirrhosis. The American Journal of Gastroenterology. 2022; 117 (3): 424-432. doi: 10.14309/ajg.0000000000001617. View Article; Asrani S, Hall L, Reddy V, et al. Comorbid chronic diseases and survival in compensated and decompensated cirrhosis: A population-based study. The American Journal of Gastroenterology. 2022; 117 (12): 2009-2016. doi: 10.14309/ajg.0000000000001909. View Article; Hernaez R, Hamilton JP. Unexplained ascites. Clin Liver Dis (Hoboken). 2016;7(3):53-56. Published 2016 Mar 29. doi:10.1002/cld.537. View Article; Gupta A, Rana R, Agarwal S, et al. Assessing the risk of further decompensation and survival in patients with cirrhosis with variceal bleeding as their first decompensation event. The American Journal of Gastroenterology. 9900; Publish Ahead of Print doi: 10.14309/ajg.0000000000002018. View Article; Jindal A, Bhardwaj A, Kumar G, et al. Clinical Decompensation and outcomes in patients with compensated cirrhosis and a hepatic venous pressure gradient ≥20 mm Hg. The American Journal of Gastroenterology. 2020; 115 (10): 1624-1633. doi: 10.14309/ajg.0000000000000653. View Article; Kim SG, Kim TY, Sohn JH, et al. A randomized, multi-center, open-label study to evaluate the efficacy of carvedilol vs. propranolol to reduce portal pressure in patients with liver cirrhosis. American Journal of Gastroenterology. 2016; 111 (11): 1582-1590. doi: 10.1038/ajg.2016.327. View Article; Ozaki K, Matsui O, Kobayashi S, Minami T, Kitao A, Gabata T. Morphometric changes in liver cirrhosis: aetiological differences correlated with progression. Br J Radiol. 2016;89(1059):20150896. doi:10.1259/bjr.20150896. View Article; Shukla R, Kramer J, Cao Y, et al. Risk and predictors of variceal bleeding in cirrhosis patients receiving primary prophylaxis with non-selective beta-blockers. American Journal of Gastroenterology. 2016; 111 (12): 1778-1787. doi: 10.1038/ajg.2016.440. View Article; Smith A, Baumgartner K, Bositis C. Cirrhosis: diagnosis and management. Am Fam Physician. 2019;100(12):759-770. View Article; Tsujimoto T, Kajio H. Veeregowda, Sahana, Krishnamurthy, Jayakumar, Krishnaswamy, Bhuvana, Narayana, Sarala. Spironolactone-induced unilateral gynecomastia. Int. j. appl. basic med. res.. 2018;8(1):45-47. doi:10.4103/ijabmr.IJABMR_399_16. View Article; Wong F, Pappas SC, Curry MP, et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. N Engl J Med. 2021;384(9):818-828. doi:10.1056/NEJMoa2008290. View Article.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Lowe’s lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Lowe was recorded at Controversies in Internal Medicine, held May 2-6, 2022, on Hilton Head Island, SC, and presented by Boston University School of Medicine. For more information on upcoming CME activities from the Boston University School of Medicine, please visit cme.bu.edu. Audio Digest thanks the speakers and sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.50 CE contact hours.

Lecture ID:

FP710601

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.