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Clinical Review & Education JAMA | Review Diagnosis and Management of Cirrhosis and Its Complications A Review Elliot B. Tapper, MD; Neehar D. Parikh, MD, MS...

Clinical Review & Education JAMA | Review Diagnosis and Management of Cirrhosis and Its Complications A Review Elliot B. Tapper, MD; Neehar D. Parikh, MD, MS Multimedia IMPORTANCE Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021, the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9 per 100 000 people. OBSERVATIONS The most common causes of cirrhosis in the US, which can overlap, include alcohol use disorder (approximately 45% of all cases of cirrhosis), nonalcoholic fatty liver disease (26%), and hepatitis C (41%). Patients with cirrhosis experience symptoms including muscle cramps (approximately 64% prevalence), pruritus (39%), poor-quality sleep (63%), and sexual dysfunction (53%). Cirrhosis can be diagnosed by liver biopsy but may also be diagnosed noninvasively. Elastography, a noninvasive assessment of liver stiffness measured in kilopascals, can typically confirm cirrhosis at levels of 15 kPa or greater. Approximately 40% of people with cirrhosis are diagnosed when they present with complications such as hepatic encephalopathy or ascites. The median survival time following onset of hepatic encephalopathy and ascites is 0.92 and 1.1 years, respectively. Among people with ascites, the annual incidence of spontaneous bacterial peritonitis is 11% and of hepatorenal syndrome is 8%; the latter is associated with a median survival of less than 2 weeks. Approximately 1% to 4% of patients with cirrhosis develop hepatocellular carcinoma each year, which is associated with a 5-year survival of approximately 20%. In a 3-year randomized clinical trial of 201 patients with portal hypertension, nonselective β-blockers (carvedilol or propranolol) reduced the risk of decompensation or death compared with placebo (16% vs 27%). Compared with sequential initiation, combination aldosterone antagonist and loop diuretics were more likely to resolve ascites (76% vs 56%) with lower rates of hyperkalemia (4% vs 18%). In meta-analyses of randomized trials, lactulose was associated with reduced mortality relative to placebo (8.5% vs 14%) in randomized trials involving 705 patients and reduced risk of recurrent overt hepatic encephalopathy (25.5% vs 46.8%) in randomized trials involving 1415 patients. In a randomized clinical trial of 300 patients, terlipressin improved the rate of reversal of hepatorenal syndrome from 39% to 18%. Trials addressing symptoms of cirrhosis have demonstrated efficacy for hydroxyzine in improving sleep dysfunction, pickle brine and Author Affiliations: Division of taurine for reducing muscle cramps, and tadalafil for improving sexual dysfunction in men. Gastroenterology and Hepatology, University of Michigan, Ann Arbor. CONCLUSIONS AND RELEVANCE Approximately 2.2 million US adults have cirrhosis. Many Corresponding Author: Elliot B. symptoms, such as muscle cramps, poor-quality sleep, pruritus, and sexual dysfunction, are Tapper, MD, Division of common and treatable. First-line therapies include carvedilol or propranolol to prevent Gastroenterology and Hepatology, variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists University of Michigan, 3912 Taubman, 1500 E Medical Center Dr, and loop diuretics for ascites, and terlipressin for hepatorenal syndrome. Ann Arbor, MI 48109 (etapper@ umich.edu). JAMA. 2023;329(18):1589-1602. doi:10.1001/jama.2023.5997 Section Editor: Mary McGrae McDermott, MD, Deputy Editor. C irrhosis affects approximately 2.2 million adults in the US1 Outcomes for patients with cirrhosis can be improved with and is associated with mortality rates of 21.9 per 100 000 evidence-based therapies directed toward both the etiology of people.2,3 Cirrhosis is defined as the fibrotic replacement cirrhosis6-12 and its complications.13-21 Recent innovations include of liver tissue that can result from any chronic liver disease. Most noninvasive risk stratification of cirrhosis22,23 as well as interven- prevalent cases of cirrhosis are caused by alcohol use disorder (ap- tions that improve survival by preventing or reducing the compli- proximately 45% of all cirrhosis cases), hepatitis C (41%), and non- cations of cirrhosis.24 Such complications include variceal hemor- alcoholic fatty liver disease (26%), with many patients having rhage, ascites, and hepatic encephalopathy. People with cirrhosis overlapping causes.4 However, hepatitis C is now curable with direct- have reduced quality of life.25 Poor quality of life is associated with acting antivirals and most newly diagnosed cirrhosis is due to non- many common symptoms26 such as muscle cramps,27,28 poor- alcoholic fatty liver disease (NAFLD) (accounting for 61.8% of inci- quality sleep,29 pruritus,30,31 and sexual dysfunction,32,33 which can dent cases) and alcohol use disorder (accounting for 20.0%).5 be improved with therapy. jama.com (Reprinted) JAMA May 9, 2023 Volume 329, Number 18 1589 © 2023 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Biblioteca Nacional de Salud y Seguridad Social User on 06/01/2023  Clinical Review & Education Review Diagnosis and Management of Cirrhosis and Its Complications men.35-37 Between 2010 and 2021, age-adjusted mortality from cir- Box. Common Questions on the Management and Complications rhosis increased from 14.9 to 21.9 per 100 000 people.2,3 Cirrhosis of Cirrhosis mortality increased from 1.1 to 3.3 per 100 000 people aged 25 to Does my patient need a liver biopsy to diagnose cirrhosis? 34 years from 2010 to 20203 due to increases in alcohol-related liver No. Cirrhosis can be accurately diagnosed using sequential disease.2 The epidemiology of cirrhosis and its complications are de- noninvasive testing such as the fibrosis-4 index followed by a liver scribed further in Table 1.24,34,36,38-56 stiffness measurement obtained by elastography (eg, vibration- controlled transient elastography or magnetic resonance Pathophysiology of Cirrhosis elastography). Because liver stiffness measurements are also Chronic inflammatory liver injury causes activation of hepatic myo- prognostic, they can be used, for example, to determine which patients need endoscopy to screen for esophageal varices. fibroblasts and macrophages, which increase collagen accumula- tion (fibrosis) in the extracellular matrix. This process disrupts the What is the most common cause of cirrhosis? Most prevalent cases of cirrhosis in the US are caused by alcohol connection between hepatocytes and sinusoids where blood flows, use disorder, nonalcoholic fatty liver disease (NAFLD), and leads to formation of nodules of fibrosis, and impedes portal inflow hepatitis C infection. Most incident cases of cirrhosis are caused resulting in portal venous hypertension. Chronic liver injury results by NAFLD; however, there is also an increase in alcohol-related in increased vasoconstrictor signaling (such as endothelin-1) and cirrhosis, particularly among young people. decreased production of vasodilators (such as nitric oxide), further What can be done to improve survival among patients with restricting sinusoidal flow. Inflammatory injury from alcohol or ste- compensated cirrhosis? atosis also increases vascular resistance. In both NAFLD and alcohol- Survival for patients with cirrhosis is improved with control of related liver disease, heritable factors in lipid metabolism have been their underlying chronic liver disease (eg, alcohol use disorder, viral hepatitis, NAFLD). Beyond that, screening for liver cancer associated with progression of liver disease.57 In addition, chronic with biannual ultrasound and α-fetoprotein is associated with liver injury causes hepatocyte loss and reduces the liver’s capacity higher rates of curative treatment when cancer is detected. for metabolic activity including protein synthesis, detoxification, nu- When patients develop portal hypertension, nonselective trient storage, and bilirubin clearance. Proteins synthesized by the β-blockers (particularly carvedilol or propranolol) are associated liver include albumin, hormones (eg, thrombopoietin [responsible with lower rates of decompensation or death. for platelet production]), and hemostatic factors (procoagulants and anticoagulants).58 The multisystem impact of these processes is de- picted in Figure 1. This review summarizes the current evidence regarding the di- Over time, patients may progress from compensated cirrhosis agnosis and management of cirrhosis and its complications (Box). without clinical manifestations to decompensated cirrhosis with variceal hemorrhage, ascites, or hepatic encephalopathy. Portal hy- pertension, defined as a pressure gradient between the hepatic and portal vein of 10 mm Hg or greater, promotes development of vari- Methods ces (collateral vessels that shunt portal blood to systemic veins and We searched PubMed (January 1, 2000, to March 10, 2023) for sys- often result in dilated esophagogastric channels prone to hemor- tematic reviews, meta-analyses, randomized clinical trials (RCTs), and rhage). Disrupted portal flow causes decreased cardiac return and relevant guidelines. We prioritized recent RCTs of higher quality decreased central blood volume, leading to increased plasma renin based on rigor of study design, sample size, and length of follow- activity, increased renal-tubular affinity for sodium, peripheral vol- up. Of 8887 articles retrieved, 115 were included, consisting of 9 prac- ume expansion, and kidney vasoconstriction, predisposing pa- tice guidelines, 3 consensus statements, 25 RCTs, 17 meta- tients to ascites, hyponatremia, and kidney injury, particularly in analyses, 7 systematic reviews (without meta-analysis), and 54 the setting of volume depletion, infection, or hemorrhage. Increas- observational cohort studies. ing portal pressure induces ascites from hepatic sinusoids. In- creased sinusoidal pressure causes increased lymph production, which extravasates into the peritoneum when lymphatic drainage capacity is exceeded. Gut-derived toxins, such as ammonia and Discussion bacterial products that induce systemic inflammation, cause he- Epidemiology patic encephalopathy. Hepatic encephalopathy can develop at low The causes of cirrhosis vary by context and many overlap. In a study ammonia levels in the context of infection.59 While the mecha- of 68 673 patients from a national sample of patients in the Veter- nisms are incompletely characterized, the presence of hepatic fi- ans Administration (2020-2021), the causes of cirrhosis were hepa- brosis and hepatic injury from inflammation contribute to the ge- titis C (24.0%), alcohol related (27.9%), hepatitis C and alcohol re- netic and epigenetic aberrations that lead to the development of lated (17.4%), NAFLD related (25.9%), and due to other conditions hepatocellular carcinoma. (3.7%).4 Patients diagnosed with cirrhosis typically have a mean age of 59.5 to 62.4 years.34,35 Patients with NAFLD cirrhosis often Diagnosing Cirrhosis present at a mean age of 67 years.34 However, cirrhosis is now more Medical history and physical examination can identify patients with common among younger patients. The incidence of cirrhosis by age or at risk for cirrhosis. Patients with cirrhosis frequently experience 35 years was 46.9 per 100 000 people among those born during muscle cramps (64% prevalence) and pruritus (39%),26 poor- or after 1980 compared with 32.6 per 100 000 born between 1945 quality sleep (63%),60 and sexual dysfunction (53%).61 Risk fac- and 1960.36 A total of 54% to 60% of cirrhosis cases occur among tors, such as diabetes or alcohol use, and symptoms, such as muscle 1590 JAMA May 9, 2023 Volume 329, Number 18 (Reprinted) jama.com © 2023 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Biblioteca Nacional de Salud y Seguridad Social User on 06/01/2023  Diagnosis and Management of Cirrhosis and Its Complications Review Clinical Review & Education Table 1. Epidemiology of Cirrhosis and Its Complications in the US Condition Prevalence/incidence Mortality Hospitalization rates Cirrhosis Prevalence, 840-1058/100 00034,36 56 989 in 2020a 56.4-125.7 of every 100 000 hospitalizations involve cirrhosis38,39 25.8% 30-d readmission rate40 Hepatic encephalopathy 40% 5-y risk overall among patients with Median survival, 0.95 y and 2.5 y for those HE presents in 10.1% of cirrhosis (HE) cirrhosis aged ≥65 y or 40) body mass index (calculated as weight in kilograms di- age, alanine aminotransferase, aspartate aminotransferase, platelet vided by height in meters squared). However, cost and access limit count) is a widely accepted risk-stratification tool that, for people with widespread use of magnetic resonance elastography. Liver inflam- either NAFLD or alcohol-related liver disease, classifies scores as low mation (ie, alanine aminotransferase >120 IU/L68) and central ve- (2.67). Age increases the nous congestion from heart failure can also increase liver stiffness, FIB-4; for patients older than 65 years, the lower risk threshold is 2.0 generating false-positives from elastography. jama.com (Reprinted) JAMA May 9, 2023 Volume 329, Number 18 1591 © 2023 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Biblioteca Nacional de Salud y Seguridad Social User on 06/01/2023  Clinical Review & Education Review Diagnosis and Management of Cirrhosis and Its Complications Figure 1. Impact of Portal Hypertension and Hepatic Insufficiency on Cirrhosis Pathophysiology Cross section of cirrhotic liver lobule Chronic inflammatory liver injury (eg, alcohol use disorder, hepatitis C, or nonalcoholic fatty liver disease) H E PATO C Y T ES Hepatocyte death Fibrosis accumulation CIRRHOTIC LIVER Reduced metabolic activity including Formation of nodules protein synthesis, detoxification, Portal flow blockage leading nutrient storage, and bilirubin clearance to portal hypertension Systemic effects of cirrhosis Hepatocyte Fibrosis death accumulation Disrupted portal flow Development of varices CENTRAL and variceal hemorrhage VEIN Decreased cardiac return H E PAT I C and decreased central ARTERY blood volume Increased plasma SINUSO renin activity ID Vasoconst Portal riction Peripheral volume expansion hypertension Chronic inflammatory liver injury Hyponatremia Increased vasoconstrictor P O RTA L Kidney vasoconstriction signaling via endothelin-1 VEIN and injury Decreased vasodilator production Restriction of sinusoidal flow Gut-barrier disruption Enteric bacteria release leading to inflammation BILE Increased DUCT Ascites lymph production Hepatic dysfunction Increased lymph production Extravasation of lymph Increased nitric oxide levels into the peritoneum (ascites) Increased vasodilatory neurotransmitters Hepatic fibrogenesis and Increased ammonia levels chronic inflammatory injury ! can lead to the development Hepatic encephalopathy (HE) of hepatocellular carcinoma Cirrhosis leads to intrahepatic resistance, which causes portal hypertension and, portosystemic shunting, resulting in the multisystem complications of cirrhosis, at later stages, hepatic insufficiency, which disrupts the liver’s normal metabolic eg, hepatic encephalopathy, sarcopenia, ascites, and kidney injury. functions. Together these features cause gut-barrier disruption and Diagnosis of Portal Hypertension All patients with varices have CSPH. Because portal pressures are Portal pressures can be estimated using a transjugular catheter to not routinely measured, it is recommended to screen for varices in pa- determine the hepatic venous pressure gradient, a measure of the tients with cirrhosis every year if decompensated or every 2 to 3 years pressure gradient across the liver. Clinically significant portal hyper- if compensated (2 years if the patient is actively drinking alcohol or tension (CSPH) is defined as a gradient of 10 mm Hg or greater (nor- chronic liver disease is uncontrolled, eg, untreated hepatitis B or C or mal 40 Magnetic resonance ascites, hepatic encephalopathy, and transient elastography (VCTE) elastography (MRE) variceal hemorrhage. It is important to evaluate for the presence of Suggestive results: High LSM (≥15 kPa on VCTE or ≥5 kPa on MRE) cirrhosis in people with risk factors or any diagnosed chronic liver disease. While physical examination findings Confirm diagnosis of cirrhosis with FIB-4 and LSM results may be suggestive, it is recommended to stratify risk for all Highest degree of certainty: Requires further confirmation: Cirrhosis is unlikely: using the FIB-4 followed by FIB-4 score ≥2.67 and high LSM FIB-4 score 2.67 and low LSM elastography for at-risk patients. After identifying patients with cirrhosis, optimal care may involve referral to a hepatologist, liver cancer Consider liver biopsyb Noncirrhotic screening, and consideration of endoscopy for varices screening Stage 4 fibrosis and/or initiation of nonselective β-blockers. BMI indicates Initiate evidence-based care body mass index. a Terry nails identified by white Screen for varices with endoscopy Screen for liver cancer Refer to Treat underlying liver disease discoloration, absent lunula, and or defer if VCTE result is 150 x 109/L and α-fetoprotein dark pink tips. obesity and alcohol use disorder b Biopsy is of highest value when the diagnosis of the underlying liver Initiate nonselective β-blockers Refer for transplant evaluation if patient disease is unclear or noninvasive (eg, carvedilol) if varices are found develops ascites, hepatic encephalopathy, tests yield indeterminate or Consider nonselective β-blockers variceal bleeding, or liver cancer discordant results. The role of if VCTE result is >25 kPa biopsy is also based on patient preference and clinical context. Up to one-third of patients with spontaneous bacterial peritonitis below healthy control performance on the 5-test paper-pencil bat- do not have fever or pain. Therefore, diagnostic paracentesis is rec- tery called the Psychometric Hepatic Encephalopathy Score. This ommended for all hospitalized patients with cirrhosis and ascites.53,76 battery can be replaced by some bedside measures42 including the Hepatorenal syndrome is defined as kidney injury in the presence Animal Naming Test (in a prospective cohort of 327 patients, 5 reflects poor sleep).78 behavior, and gait disturbance. The criterion-standard diagnostic An algorithm based on age, sex, and self-reported loss of balance, for covert hepatic encephalopathy is greater than or equal to 4 SDs irritability/impatience, anorexia, and disinterest in physical activity jama.com (Reprinted) JAMA May 9, 2023 Volume 329, Number 18 1593 © 2023 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Biblioteca Nacional de Salud y Seguridad Social User on 06/01/2023  Clinical Review & Education Review Diagnosis and Management of Cirrhosis and Its Complications Figure 3. Natural History of Cirrhosis, Its Complications, and Modifiable Factors Biomarkers and complications associated with increased risk of decompensation and death Low risk Indeterminate High risk Variceal bleeding Platelet count ≥150 x 109/L 110-149 x 109/L