Lesson 5. Evaluation and Prognosis of Persons with Cirrhosis

Overview

In an estimated 20 to 30% of persons with hepatitis C virus (HCV) infection, persistent liver inflammation leads to fibrosis and eventual development of cirrhosis.[1,2,3] Advanced fibrosis and cirrhosis—at their early stages—are not usually clinically apparent or symptomatic.[4] As individuals develop more extensive hepatic fibrosis, physiologic complications can develop, such as increased pressure within the portal system, disruption in bilirubin metabolism, and reduced production of coagulation factors and other proteins.[5,6] This lesson discusses the clinical considerations that come with the care of a person with HCV-related cirrhosis.

Defining Compensated and Decompensated Cirrhosis

Once it has been established that an individual has cirrhosis, it is very important to determine whether they have compensated or decompensated cirrhosis.[7] Persons with compensated cirrhosis often do not have signs or symptoms related to their cirrhosis, although they may have evidence of portal hypertension, such as esophageal or gastric varices.[8,9,10] In contrast, persons with decompensated cirrhosis often have symptomatic complications related to cirrhosis, including those related to hepatic insufficiency (jaundice or hepatic encephalopathy) and those related to portal hypertension (ascites or variceal hemorrhage).[11] Some experts have proposed a 4-stage cirrhosis classification system to risk-stratify individuals according to the presence of ascites, esophageal varices, and variceal bleeding to differentiate and stage compensated and decompensated disease, although the Child-Turcotte-Pugh score (discussed later in this lesson) is more widely used (Figure 1).[12,13]

Importance of Distinguishing Compensated versus Decompensated Cirrhosis

Prognosis and survival are markedly better in persons with compensated cirrhosis than in those with decompensated cirrhosis (Figure 2).[14,15] In addition, the presence of decompensated cirrhosis can have major implications regarding management and prevention of cirrhosis-related complications, as well as the potential need for a referral for liver transplantation evaluation.[16] In general, any person with decompensated cirrhosis should receive evaluation and medical care from a hepatologist or liver diseases specialist.[7]

Once an individual is diagnosed with cirrhosis, there are key elements of the history, physical examination, and laboratory studies that need to be addressed and monitored.

Medical History

• Alcohol Use: Detailed quantitative information should be obtained from the patient regarding current and past alcohol use. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) offers resources for clinicians on how to take an appropriate alcohol history (NIAAA Screen and Assess) and how to conduct a brief intervention (NIAAA Conduct a Brief Intervention). Excessive alcohol use (greater than 40 grams per day in women and greater than 60 grams per day in men) in patients with chronic HCV infection has been associated with accelerated fibrosis progression.[17] In addition, for those individuals with chronic HCV and more advanced liver disease, ongoing alcohol use will impact their eligibility for liver transplantation.
• Injection Drug Use: Recent or active injection drug use should be addressed through the application of harm reduction principles. A person with chronic HCV and cirrhosis who continues to use injection drugs remains at risk for acquiring other bloodborne viruses, such as HIV and hepatitis B virus (HBV), and they can become reinfected with HCV after obtaining a sustained virologic response with treatment. For persons with decompensated cirrhosis, ongoing illicit drug use may impact consideration for liver transplantation.
• Medication Use: For individuals with cirrhosis, medication use, including all nonprescription drugs and prescription drugs, should be carefully reviewed. Persons with cirrhosis should be counseled to limit potentially hepatotoxic drugs. LiverTox, a comprehensive database developed by the National Institutes of Health (NIH), is an excellent online resource for clinicians to query the potential hepatotoxicity of medications. Of note, LiverTox does not provide detailed discussion on how medications are likely to impact persons with more advanced liver disease; for this inquiry, reviewing the drug package insert may be the best route. Commonly used medications, such as aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), are associated with an increased risk of gastrointestinal bleeding in persons with cirrhosis and should be avoided. It is important to identify any medication that may lead to nephrotoxicity in a person with decompensated cirrhosis, since this may cause them to develop hepatorenal syndrome.
• Comorbid Medical Conditions: A thorough medical history should be documented, including those diseases that might impact the progression of liver disease, such as HIV, hepatitis B, diabetes, obesity, and metabolic-associated steatotic liver disease (MASLD)—formerly referred to as nonalcoholic fatty liver disease or (NAFLD). These conditions can accelerate liver disease progression and all have enhanced importance in persons with chronic HCV infection and cirrhosis.
• Review of Symptoms: In patients with cirrhosis, it is critical to inquire about symptoms that would suggest complications of advanced liver disease, including abdominal girth swelling or tightness, lower extremity edema, jaundice, hematemesis or melena, and any signs of confusion or daytime somnolence.
• Psychiatric History: Chronic HCV infection may be associated with depression, and coexistent depression may lead to poorer survival.[18] Therefore, it is important to elicit a comprehensive mental health history.

Physical Examination

• Body Mass Index (BMI): Height, weight, and the calculated body mass index (BMI) should be documented. Persons who are overweight (BMI greater than or equal to 25 kg/m²) or obese (BMI greater than or equal to 30 kg/m²) are at risk for MASLD.[19,20] In persons with chronic HCV infection, MASLD may contribute to and accelerate the development of cirrhosis.[21,22]
• General Inspection: Muscle wasting suggests advanced liver disease. Scleral icterus can usually be detected if the serum bilirubin level is greater than 3.0 mg/dL. Identifying jaundice is an important factor in determining if a person has decompensated liver disease. Lower extremity edema can be an early sign of decompensated disease.
• Peripheral Stigmata of Advanced Liver Disease: Spider angiomata, also known as spider nevi or spider telangiectasias, represent anomalous dilatation of cutaneous blood vessels and are among the earliest physical examination signs of cirrhosis. Spider angiomata are most commonly seen on the anterior chest, neck, face, and upper thorax.[23] Palmar erythema, gynecomastia, and testicular atrophy can also be seen in advanced liver disease, and, like spider angiomata, are a reflection of impaired estrogen clearance. It is important to note that the absence of these findings is not sufficient to rule out cirrhosis.[23]
• Abdominal Examination: Examination of the abdomen may help determine the size of the liver and the presence of splenic enlargement, but the accuracy of physical examination in assessing organ size is limited.[8] The most useful physical examination findings to confirm ascites are the presence of a fluid wave and shifting dullness. The presence of flank dullness is highly sensitive and may be helpful in excluding clinically significant ascites.[24] For more detailed information about ascites, see the lesson Diagnosis and Management of Ascites.
• Mental Status Assessment: A brief general assessment of patient mental status is appropriate at each visit. For persons with suspected altered or impaired mental status, a formal assessment for hepatic encephalopathy should be performed. The mental status assessment for hepatic encephalopathy is addressed in detail in the lesson Diagnosis and Management of Hepatic Encephalopathy.

Child-Turcotte-Pugh Score (CTP)

The Child-Turcotte classification system was developed in 1964 to risk-stratify patients undergoing shunt surgery for portal decompression.[25] In 1972, Pugh modified the Child-Turcotte system, and it became known as the Child-Turcotte-Pugh (CTP) score.[26] The CTP has been shown to predict survival and other clinical outcomes in persons with cirrhosis and portal hypertension.[14,27] Because it is simple and does not require complicated calculation, clinicians have widely used this tool to assess the risk of mortality in cirrhotic patients.[28] It is also the primary modality by which we distinguish between compensated versus decompensated liver disease.

• Calculation: The CTP scoring system incorporates two clinical parameters (encephalopathy and ascites) and three laboratory values (bilirubin, albumin, and prothrombin time) (Figure 3). Based on the sum of the points from these five parameters, the person is categorized into one of three CTP classes: A, B, or C. The CTP Calculator automatically computes the CTP score based on the data entered.
• Limitations: The CTP score has several limitations. First, the score has limited discriminatory capacity and does not adequately account for the degree of abnormal lab results.[28,29] For example, a person with a serum bilirubin of 20 mg/dL would be assigned the same number of points as a person with a serum bilirubin of 3.5 mg/dL even though an extremely high serum bilirubin has poorer prognostic impact.[29] Second, the CTP score gives equal weight to each of the five variables, which has been questioned by some experts.[28,29] Third, the two clinical parameters—ascites and encephalopathy—are vulnerable to subjective interpretation. Fourth, some important prognostic factors, including serum sodium, serum creatinine, and variceal hemorrhage, are not included in the CTP scoring system.[28,29]
• Clinical Use: The CTP score is still widely used in the clinic and hospital setting as a simple prognostic tool. Studies involving persons with cirrhosis have shown that CTP scores can estimate survival at 3 months, as well as 1- to 2-year survival (Figure 4).[14,30] For persons with cirrhosis, most experts recommend assessing the CTP score at each clinical visit. The CTP score was previously used as a major criterion for liver transplantation evaluation, but it is no longer widely used for this purpose.[16]

Model for End-stage Liver Disease (MELD)

The Model for End-Stage Liver Disease (MELD) score was originally developed to predict the survival of persons with advanced liver disease who underwent an elective transjugular intrahepatic portosystemic shunt (TIPS) procedure.[31] Investigators then studied the MELD scoring system in other individuals with cirrhosis and found it to be a good predictor of mortality in persons who did not have TIPS placed; with the MELD score, the higher the score, the higher the 90-day mortality (and lower the 90-day survival) (Figure 5).[30,32,33] The MELD score was adopted in 2002 by the United Network for Organ Sharing (UNOS) to prioritize allocation of deceased donor organs for liver transplantation.[34] The MELD score has undergone several iterations, with the most recent version being the MELD 3.0.[35]

MELD 3.0

The MELD 3.0 version, which also incorporates sex (male or female) and albumin level, affords more accurate mortality prediction, in general, than the prior version, MELDNa.[35] With MELD 3.0, similar to prior versions of MELD, the higher the score, the lower the 90-day survival.[30] For example, a person with a MELD 3.0 score less than or equal to 15 has a predicted 3-month survival of 98%, whereas an individual with a MELD score of 30 has a predicted 3-month survival of only 73%.[35]

• Calculation of MELD 3.0 Score: The MELD 3.0 score, which estimates the survival probability of a patient with end-stage liver disease, is based on sex (male or female) and several commonly obtained laboratory tests, including serum bilirubin, serum creatinine, and international normalized ratio (INR), serum sodium, and serum albumin.[35] The MELD 3.0 Calculator will compute the MELD 3.0 score based on the variable entered.
• Limitations: The MELD 3.0 score can be influenced by the method in which serum creatinine and INR are measured across laboratories.[28,29,35] When compared with the CTP scoring system, the MELD 3.0 score has an advantage in its use of objective data, and it can distinguish disease severity along a continuous spectrum.[35] Earlier versions of the MELD scoring system have been reported to have a misclassification rate of up to 10 to 20%.[28]
• Clinical Use: The MELD 3.0 score should be calculated on any person with cirrhosis or advanced liver disease at each clinic visit. Individuals with cirrhosis and a MELD 3.0 score of 15 or greater should be referred for a liver transplantation evaluation.[16,35]

Definition and Natural History

Cirrhosis is considered to be compensated in the asymptomatic patient with or without gastroesophageal varices. Child-Turcotte-Pugh scores of these individuals are generally in class A (6 or less). Persons with compensated cirrhosis are not jaundiced and have not yet developed ascites, variceal bleeding, or hepatic encephalopathy.[14,36] Cirrhosis can remain compensated for many years.[36] The transition from compensated to decompensated cirrhosis occurs at a rate of approximately 5 to 7% per year overall, including among patients with untreated chronic HCV.[14,37] The median survival of persons with compensated cirrhosis is approximately 9 to 12 years.[14]

Surveillance for Hepatocellular Carcinoma

The development of cirrhosis is the single most important risk factor for developing hepatocellular carcinoma (HCC).[38,39] Accordingly, all persons with cirrhosis (compensated or decompensated) should undergo surveillance for HCC with hepatic ultrasound, with or without serum alpha-fetoprotein (AFP), every 6 months.[9,16] For patients with chronic HCV infection and cirrhosis, surveillance for HCC should continue after treatment for HCV, even if the individual obtained a sustained virologic response.[40] Some experts also recommend surveillance for HCC in persons with chronic HCV infection and Metavir stage F3 (stage before cirrhosis), although the data in support of screening in this subpopulation are limited.[41,42]

Screening for Gastroesophageal Varices

Among persons with cirrhosis, gastroesophageal varices develop at a rate of approximately 8% per year, and varices often develop initially without causing any symptoms or bleeding.[36] All patients with cirrhosis should undergo screening for gastroesophageal varices with transient elastography as a method for risk stratifications or an upper endoscopy to identify those individuals who may benefit from taking a nonselective beta-blocker for prophylaxis.[6,9,43] The subsequent assessment and management is based on the findings at endoscopy and is discussed in detail in Module 3, in the lesson Screening for Varices and Prevention of Bleeding.

Treatment of HCV in Patients with Compensated Cirrhosis

The major goal of managing patients with HCV and compensated cirrhosis is to treat the HCV infection.[44,45] Treatment of HCV in patients with compensated cirrhosis using direct-acting antiviral (DAA) medications has been associated with sustained virologic response (SVR) rates of 90% or better.[46,47,48,49] Patients with HCV-related cirrhosis who undergo treatment and achieve a cure have a dramatically decreased 10-year risk of all-cause mortality (hazard ratio [HR] = 0.26), liver-related mortality or transplantation (HR = 0.06), hepatocellular carcinoma (HR = 0.19), and hepatic decompensation (HR = 0.07).[45] For a more detailed discussion of this topic, see the lesson Treatment of HCV in Persons with Cirrhosis.

Definition and Natural History

Decompensated cirrhosis is defined by a calculated CTP score of 7 to 15 (CTP Class B or C) and is often accompanied by the development of jaundice, ascites, variceal hemorrhage, and/or hepatic encephalopathy.[14] The survival of persons with decompensated liver disease is significantly lower than in those with compensated disease. A MELD score should be calculated for all persons with decompensated cirrhosis to better estimate the survival probability and to determine eligibility for transplantation. Evaluation for transplantation should be considered once a person is diagnosed with decompensated cirrhosis or has a MELD score of 15 or greater.[16]

Treatment of HCV in Patients with Decompensated Cirrhosis

Treatment of HCV in persons with decompensated cirrhosis has become possible with all-oral DAA therapy. Moderately high rates of sustained virologic response rates have been demonstrated with DAA therapy in persons with decompensated cirrhosis.[50,51,52,53] Treatment of HCV in persons with decompensated cirrhosis should be managed either by a hepatologist or with the very close involvement of a hepatologist. For individuals with chronic HCV and decompensated cirrhosis who are liver transplantation candidates, successful treatment of HCV with DAA therapy has occurred before and after transplantation.[54,55,56] Given the complexity of these situations, decisions regarding the approach to HCV treatment and optimal timing of HCV treatment (before or after the transplant) should be made by the liver transplantation team.

Ascites

Ascites is the pathologic accumulation of fluid in the peritoneal cavity and a manifestation of portal hypertension in cirrhosis. It is the most common and often the first complication of cirrhosis for many individuals, with approximately 5-10% of individuals with compensated cirrhosis developing ascites per year.[57] The development of ascites results in a significant drop in survival by 50% due to other life-threatening complications, such as hepatorenal syndrome or infections, that may ensue.[57] Although treatment of ascites does not result in enhanced survival, it does improve the individual’s quality of life and decreases the risk of developing spontaneous bacterial peritonitis (SBP). This topic is addressed in greater detail in the lesson Diagnosis and Management of Ascites.

Spontaneous Bacterial Peritonitis (SBP)

Among persons with cirrhosis and ascites, SBP is the most common infectious complication, accounting for 27% of bacterial infections in hospitalized patients.[57,58] The recurrence rate of SBP after an initial episode is very high (approximately 70%) without prophylaxis. Persons who survive an initial episode of SBP should receive antibiotic prophylaxis. This topic is addressed in greater detail in the lesson Recognition and Management of Spontaneous Bacterial Peritonitis.

Variceal Hemorrhage

The rate of bleeding with known varices is estimated to be 10 to 30% per year, depending on the size of the varices and underlying severity of liver disease.[9] The mortality rate from each episode of variceal hemorrhage is approximately 15%.[59,60] Acute variceal bleeding is a medical emergency and requires control of bleeding and prevention of complications.[60] The risk of rebleeding within 1 year of the initial bleed is approximately 60%.[61] Thus, it is extremely important that persons who survive an initial variceal hemorrhage start prophylactic therapy to prevent future bleeds.[60] Recommendations regarding primary prophylaxis, secondary prophylaxis, and management of variceal bleeding are discussed in greater detail in the lesson Screening for Varices and Prevention of Bleeding.

Hepatic Encephalopathy

Hepatic encephalopathy is thought to result from a buildup of toxic compounds generated by gut bacteria.[62] In a normal liver, these compounds are transported through the portal vein to the liver and metabolized and excreted immediately. In persons with cirrhosis, however, these toxins are not metabolized properly. Individuals who develop hepatic encephalopathy may have subtle symptoms, and the onset is often insidious. Hepatic encephalopathy represents a continuum from minimal to overt and can be episodic or persistent. This topic is addressed in greater detail in the lesson Diagnosis and Management of Hepatic Encephalopathy.

Hepatorenal Syndrome

Hepatorenal syndrome is defined as renal failure in a person with cirrhosis in the absence of intrinsic renal disease.[63] The pathophysiology of hepatorenal syndrome is not completely understood, but it is thought to occur secondary to underfilling of the arterial circulation because of arterial vasodilation in the splanchnic circulation.[64] This causes sodium and water retention, with renal vasoconstriction, which results in decreased renal blood flow and urinary output. Some experts have noted that use of beta-blockers in persons with decompensated cirrhosis may increase the risk of hepatorenal syndrome, and many experts recommend discontinuing or avoiding the use of beta-blockers in persons with cirrhosis who have developed hepatorenal syndrome.[65,66,67] Hepatorenal syndrome has historically been divided into 2 types: type 1 and type 2.[63,64,68,69] These terms have since been replaced by the terms hepatorenal syndrome acute injury and hepatorenal syndrome chronic kidney disease, respectively.[64,70]

• Persons with decompensated cirrhosis have complications related to cirrhosis (e.g., jaundice, ascites, variceal hemorrhage, and/or hepatic encephalopathy.
• Most individuals with chronic HCV infection will have a normal physical examination, but those with advanced liver disease may have findings that suggest cirrhosis.
• The CTP scoring system is based on five parameters (serum bilirubin, serum albumin, prothrombin time, severity of ascites, and grade of encephalopathy); it is easy to calculate and provides valuable prognostic information.
• The MELD score provides accurate short-term prognostic information and should be calculated on any person with cirrhosis. Individuals with a MELD score greater than or equal to 15 or decompensated cirrhosis, should be considered for a liver transplantation evaluation.
• Management of persons with chronic HCV infection and compensated cirrhosis should include treatment of the HCV infection.
• Decompensated cirrhosis is defined by a CTP score of 7 or greater and is often accompanied by the development of jaundice, ascites, variceal hemorrhage, or hepatic encephalopathy.
• Survival is poor in persons with decompensated cirrhosis, and they should be considered for liver transplantation.