Cirrhosis

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Practice Essentials

Cirrhosis is defined histologically as a diffuse hepatic process characterized by fibrosis and conversion of the normal liver architecture into structurally abnormal nodules. The progression of liver injury to cirrhosis may occur over several weeks to years.

Most patients with cirrhosis are well compensated. They have no or minimal symptoms and—with the modification of risk factors—may have a reasonably good life expectancy. Compensated cirrhotic patients may or may not progress to a state of decompensated cirrhosis. In this condition, patients experience complications that stem from decreased hepatic synthetic function, portal hypertension, or decreased detoxification capabilities of the liver. Signs and symptoms of decompensated cirrhosis include jaundice, variceal bleeding, ascites, hepatorenal syndrome (HRS), and hepatic encephalopathy. In addition, patients with cirrhosis are at increased risk of developing malignancies (eg, hepatocellular carcinoma (HCC), cholangiocarcinoma[1] ) and infections.[2]

Patients with compensated cirrhosis have a near 70% likelihood of survival 10 years after diagnosis. In contrast, patients with decompensated cirrhosis have only a 9% likelihood of survival 10 years after diagnosis.[3] Patients should be referred for consideration for liver transplantation after the first signs of hepatic decompensation appear.

Relatively recent practice guidelines highlight the importance of making an early diagnosis of clinically significant portal hypertension (CSPH). Patients with compensated cirrhosis may or may not have CSPH. However, by definition, patients with decompensated cirrhosis have CSPH. Early initiation of beta-blocker therapy may help to reduce the risk of progressive CSPH and resultant decompensation. Clinicians now have access to multiple noninvasive liver disease assessments (NILDAs) that can assist them as they attempt to determine whether or not their patients with chronic liver disease have CSPH.

Overview

The term cirrhosis was first introduced by Laennec in 1826. There is debate whether the term was derived from the Greek term skleros meaning “hard” or kirrhos meaning “tawny."

Cirrhosis represents the final common histologic pathway for a wide variety of chronic liver diseases. This condition is defined histologically as a diffuse hepatic process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules. The progression of liver injury to cirrhosis may occur over weeks to decades.

An in-depth discussion of hepatic fibrosis is beyond the scope of this article. Briefly, for many years, hepatic fibrosis and cirrhosis were thought to be irreversible processes. It is now recognized that successful treatment of the underlying cause of a patient’s liver disease has the potential to induce fibrinolysis and regression of fibrosis.[4, 5]

The initial step in fibrogenesis is likely the stimulation of immune cells within the liver by an insult—whether toxic, metabolic, or caused by viral infection. Damage to liver cells may also lead to hepatocyte apoptosis and the release of damage-associated molecular patterns (DAMPs).[6] Inflammatory mediators (eg, transforming growth factor beta [TGF-β], platelet-derived growth factor [PDGF], epidermal growth factor [EGF]) and DAMPs in turn stimulate the differentiation of hepatic stellate cells into myofibroblasts.[7]

Activated myofibrolasts have proliferative, fibrogenic, and contractile properties. They can produce collagen, fibronectin, and proteoglycans that can deposit into surrounding liver tissue. The accumulation of so-called extracellular matrix in the space of Disse can result in the capillarization of hepatic sinusoids, subsequently leading to the development of portal hypertension.[8] Contraction of the hepatic sinusoids by myofibroblasts can also contribute to portal hypertension.

Finally, the death of hepatocytes can cause “early parenchymal extinction” and the replacement of hepatocytes by fibrous septa. There remains a potential for both the resorption of septa and hepatocyte regeneration. On the other hand, there is also the potential for ongoing parenchymal extinction, with the destruction of normal liver architecture and the replacement of dying hepatocytes with fibrous tissue.[4, 5]

Multiple scoring systems exist to assess the degree of hepatic fibrosis and cirrhosis.[9] For the purposes of this article, the METAVIR system (META-analysis of histological data in VIRal hepatitis) is used[10] :

A patient’s knowledge of their degree of hepatic fibrosis (as judged by liver biopsy or by noninvasive testing) can produce an enormous psychological burden. Many patients assume that the detection of F4 or “stage 4” fibrosis on liver biopsy or noninvasive testing is a death sentence, often drawing a parallel between their stage 4 hepatic fibrosis and stage 4 cancers in which an oncology patient might very well have a very poor prognosis. It is incumbent upon healthcare practitioners (HCPs) to counsel their patients as to the true prognosis of having advanced hepatic fibrosis. This also gives the patient the opportunity to modify risk factors that contribute to and/or could accelerate the progression of hepatic fibrosis.

In the author’s opinion, a discussion about hepatic fibrosis can be structured as a “call to action,” which provides an opportunity for the HCP to encourage patients to do the following:

HCPs also have the opportunity to:

Epidemiology

Chronic liver disease is common around the world and in the United States. It is believed to affect more than 1.5 billion people worldwide[16] and leads to more than 2 million deaths each year.[17]

More than 40% of of US adults are affected by some type of chronic liver disease, of which the most common causes include the following[18] :

Other causes of chronic liver disease and cirrhosis include the following conditions:

Many patients with chronic liver disease are asymptomatic and will not experience progressive liver disease. Even cirrhosis develops, these individuals may not go on to decompensate and die from cirrhosis. Still, progressive liver disease leads to the annual death of more than 55,000 Americans from decompensated cirrhosis or HCC.[18, 19]

In previous years, the hepatitis C epidemic was responsible for the greatest proportion of US patients undergoing liver transplantation. In the current decade, the demand for organs is fueled by a dramatic increase in the number of patients presenting with advanced alcohol-associated liver disease (ALD) and MASH-induced cirrhosis.

In 2022, 9527 liver transplants were performed in the United States. The following were the most common diagnoses in 9001 adult liver transplant recipients in 2022[20] :

The challenge to clinicians caring for patients with cirrhosis is how to implement the strategies that maximize patients' chances for remaining well-compensated and minimize their risk for liver decompensation.

Diagnosis of Cirrhosis: Introduction

Two of the primary tasks of the HCP caring for patients with chronic liver disease are to:

Unfortunately, the perfect diagnostic test does not exist. Some studies are better equipped to rule out advanced hepatic fibrosis in patients who are at low risk for developing cirrhosis (eg, patients in a diabetes clinic). Other tests are better suited to ruling in advanced hepatic fibrosis in patient cohorts that are at high risk (eg, patients with abnormal aspartate transaminase [AST] and alanine transaminase [ALT] measurements, a mildly elevated serum bilirubin, and splenomegaly on an abdominal imaging study).

The American Association for the Study of Liver Diseases (AASLD) classifies hepatic fibrosis as follows[21] :

The finding of F2 or F3 fibrosis can identify patients at significant risk for developing cirrhosis, as well as those at risk for premature death.[22] The finding of cirrhosis can identify individuals at the highest risk of developing liver decompensation, HCC, or liver-related mortality.

In some patients, the diagnosis of cirrhosis is straightforward. For example, the presence of ascites on physical examination and a nodular-appearing liver on an abdominal imaging study makes a diagnosis of cirrhosis extremely likely. In other patients, it can be very challenging to determine whether or not a patient has advanced fibrosis or cirrhosis. Not uncommonly, a combination of tests is necessary to accurately assess liver disease severity.

The next section reviews traditional assessments for cirrhosis, as well as more recent advances in the use of noninvasive testing.

Traditional Assessments for Cirrhosis

Physical examination

Since the time of Hippocrates, astute physicians have attempted to make a diagnosis of cirrhosis on the basis of patients’ symptoms and signs. However, fatigue—patients’ most common complaint—is perhaps the least specific complaint in all of medicine. Other symptoms, often in those with more advanced disease, are equally nonspecific: anorexia, weight loss, muscle wasting, and dyspnea on exertion.

Physical examination findings (eg, hepatomegaly, splenomegaly) also have a notoriously low specificity and sensitivity for cirrhosis.

Nonspecific cutaneous manifestations of cirrhosis include:

Patients with more advanced disease might exhibit jaundice or signs of ascites or hepatic encephalopathy. The presence of ascites is suggested by physical examination findings that include:

Hepatic encephalopathy is suggested by:

Commonly available blood tests

For many years, clinicians have utilized commonly available blood tests to help determine whether a patient has cirrhosis or not. These are not particularly accurate as isolated tests, but—when used in combination with other blood tests or with imaging studies—can aid in identifying patients with cirrhosis (see the next section below, under “Noninvasive Liver Disease Assessments”).

Liver biopsy

Liver biopsy is the classic gold standard by which other liver fibrosis assessments are judged. Still, in many cases, liver biopsy is inaccurate in the assessement of fibrosis. In one study that used laparoscopic visualization of the liver as a gold standard, liver biopsy did not correctly lead to a diagnosis of cirrhosis in 32% of patients.[24] Furthermore, liver biopsy is complicated by clinically significant bleeding in approximately 1 in 500 biopsies.[25] These factors have justified the search for safe and accurate alternatives to liver biopsy for estimating hepatic fibrosis.

Radiologic studies

Conventional ultrasonography, computerized tomography (CT) scanning, and magnetic resonance imaging (MRI) have been used for decades to investigate liver disease. Unfortunately, the sensitivity and specificity for detecting cirrhosis with these imaging modalities are disappointingly low, as noted in Table 1, below.[26]

Table 1. Accuracy of Radiologic Studies in the Diagnosis of Cirrhosi.s[26]



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Noninvasive Liver Disease Assessments

Overview of NILDAs

The advent of NILDAs over the past decade has revolutionized the ability of clinicians to accurately assess liver fibrosis. NILDAs have a major impact on the ways that HCPs care for both noncirrhotic and cirrhotic patients.

Multiple ways exist for the use of NILDAs to assist HCPs with their management of patients with liver disease, as outlined below.

NILDAs can provide the HCP with a sense of whether or not an underlying chronic liver disease is present in a patient who presents with abnormal liver chemistries of unknown origin.

NILDAs may permit clinicians to follow their patients with chronic liver disease (eg, MASLD, ALD, hepatitis B, hereditary hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) over time to determine whether or not there is progression of hepatic fibrosis.

In patients with suspected MASLD:

NILDAs can assist clinicians attempting to determine whether or not their patients have advanced fibrosis or cirrhosis.

In patients with well compensated cirrhosis, NILDAs can help determine whether or not the patient has CSPH.

Blood-based NILDAs

Blood-based NILDAs are very good at determining whether or not an individual patient has advanced hepatic fibrosis. They are well-validated in disease states like MASLD and hepatitis C. However, their accuracy in patients with ALD, primary biliary cholangitis, and primary sclerosing cholangitis is less clear.

Complex biomarkers

There are a number of complex, proprietary tests that have been assessed in patients with chronic liver disease, particularly patients with MASLD and hepatitis C. They rely upon markers of collagen synthesis and degradation.[27] Some of the complex blood-based NILDAs and their component blood tests are noted in Table 2, below.

Table 2. Complex Biomarkers and Their Components.



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However, the utility of these tests may be limited due to potential inaccuracies in individuals at the extremes of age and in those with comorbid conditions (eg, systemic inflammation, hemolysis, active alcohol use).

Simple, nonproprietary models

The so-called simple, blood-based NILDAs utilize commonly available blood tests that are routinely performed to estimate fibrosis in patients with chronic liver disease. See Table 3, below.

Table 3. Simple Formulae for Estimating Hepatic Fibrosis.



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At this time, the AASLD recommends the use of the simple tests (eg, FIB-4) over complex biomarkers for the detection of advanced fibrosis.[27] Advocates of the use of FIB-4 use as a screening tool cite its high negative predictive value for advanced fibrosis (> 90%), as well as the widespread availability and the low cost of the basic blood tests that are required to permit a FIB-4 calculation. However, note that FIB-4 is a less than perfect tool for diagnosing advanced fibrosis, with a positive predictive value of only 66-72.5%, depending on where on where the cutoff values are set for the test.[28, 29, 30]

The AASLD supports screening for clinically significant fibrosis (ie, ≥ F2) in a number of patient cohorts such as those with[31] :

The FIB-4 score is the primary screening tool recommended to assess patients with MASLD risk factors. The FIB-4 should be calculated every 1-2 years in those with diabetes or at least two metabolic risk factors (eg, obesity, hypertension), or every 2-3 years in patients without diabetes and less than fewer than two metabolic risk factors.[31] As noted by the European Association for the Study of Liver Diseases (EASL), noninvasive fibrosis tests are better at ruling out advanced fibrosis—as opposed to diagnosing advanced fibrosis—in low-prevalence populations.[32] Typically, the finding of a FIB-4 score of at least 1.3, particularly in patients with MASLD and ALD, should prompt referral to radiology, gastroenterology, or hepatology for the performance of a liver stiffness measurement (LSM) by transient elastography.[31, 32]

Imaging-based NILDAs

Imaging-based NILDAs play a critical role in the assessment of fibrosis in patients with chronic liver disease, offering clinicians an LSM that correlates well with a patient’s degree of hepatic fibrosis. Although imaging-based NILDAs are believed to be more accurate than blood-based NILDAs,[21] they should not be used as standalone tests.

Imaging-based NILDAs include:

The accuracy of the studies in assessing fibrosis can be variably affected by a postprandial state, obesity, hepatic steatosis, liver inflammation, infiltrative tumors, ascites, and congestive heart failure. Direct patients to not consume food for at least 3 hours prior to their elastography examination.

Area under the receiver operating characteristic curves (AUROCs) are often used to assess the accuracy of a given diagnostic test—in this case, the accuracy of tests at ruling in or ruling out advanced fibrosis. MRE performs better than VCTE and ARFI, particularly in the assessment of fibrosis in MASLD. Here, MRE has an AUROC of 0.93,[21] as compared to an AUROC of 0.83 with VCTE in the diagnosis of advanced fibrosis and an AUROC of 0.93 in the diagnosis of cirrhosis in MASLD patients.[33] SWE appears to have a similar accuracy.[34]

In more recent years, VCTE has been available in most US hepatology practices. Shear wave-based tests are available at many radiology units. MRE offers the most accurate assessments of hepatic fibrosis, but test expense and low availability limit its widespread adoption.

Making a Diagnosis of Cirrhosis

Clinicians can make a diagnosis of cirrhosis in their patients by combining data obtained from:

Use of NILDAs is evolving. A proposed algorithm for investigating patients with possible cirrhosis recommends performing an FIB-4 calculation.[35] If the FIB-4 score is ≥ 1.3 (or ≥ 2.0 in patients older than 65 years):

Another more complicated schema for investigating fibrosis can be found in figure 1 of the following AASLD guideline: Sterling RK, Duarte-Rojo A, Patel K, et al. AASLD Practice guideline on imaging-based noninvasive liver disease assessment of hepatic fibrosis and steatosis. Hepatology. 2025 Feb 1;81(2):672-724. PMID: 38489518.[21] A simplified version is shown in figure 2 of the same guideline.

Baveno VI Consensus Workshop criteria

The organizers of the Baveno VI Consensus Workshop in 2015 came to slightly different conclusions.[36]

Criteria to suspect compensated cirrhosis

Criteria to confirm compensated cirrhosis

In this author’s opinion, technologies such as VCTE and MRE are not 100% reliable. VCTE in particular can be plagued by considerable inter-operator variability; it can also be inaccurate in patients with obesity and MASH.[37] No single diagnostic finding should “clinch” a diagnosis of cirrhosis. Conversely, it is not critical that a patient undergo NILDA testing if there is a clear-cut diagnosis of cirrhosis based upon traditional testing.

HCPs should use good clinical judgment when all data are not in agreement. In a hypothetical example, a patient with MASLD who has a relatively low LSM on VCTE might have a concurrent liver biopsy that shows severe steatohepatitis and stage 3 fibrosis. This hypothetical patient should be classified as having advanced fibrosis. In another example, a MASLD patient might have a relatively low LSM on MRE and a nodular liver with signs of portal hypertension on CT scan. This hypothetical patient should be assigned a diagnosis of cirrhosis in spite of the low LSM.

The Spectrum of Cirrhosis

Overview

Most patients with a clinical, radiologic, or histologic diagnosis of cirrhosis are well-compensated. Compensated cirrhosis is defined by what is absent:

The transition from a compensated to a decompensated state may take several years or even decades. The precipitant for such a transition could be ongoing exposure to a toxin (eg, alcohol), the chronic lipotoxicity that is seen in MASH, or ongoing liver inflammation experienced by a patient with poorly controlled autoimmune hepatitis.

In other circumstances, patients can experience acute decompensation that occurs over the course of hours. The precipitant could be a single dramatic event (eg, infection with COVID-19 or influenza, or the performance of a major abdominal operation). Or, it might be unknown.

D’Amico and colleagues classified this transition as follows, with a steady increase in the risk of death across these stages[3] :

The progression from compensated to decompensated disease is typically marked by worsening of portal hypertension.

Making an early diagnosis of CSPH is important. Patients with compensated cirrhosis may or may not have CSPH. However, by definition, patients with decompensated cirrhosis have CSPH. Early institution of beta blocker therapy may help to reduce the risk of progressive CSPH and resultant decompensation. (See below.)

Routine patient monitoring

Patients with cirrhosis should undergo routine follow-up monitoring of their complete blood cell (CBC) count, renal and liver chemistries, and INR. This author's policy is to monitor stable, compensated patients 3-4 times per year. An ultrasound and alpha-fetoprotein (AFP) blood test should be obtained twice per year.

Assessing the severity and prognosis of cirrhosis

For many years, the prognostic tool most commonly used in patients with cirrhosis was the Child-Turcotte-Pugh (CTP) system, which was first introduced in 1964 as a means of predicting the operative mortality associated with portocaval shunt surgery. Pugh et al revised the system in 1973 and substituted albumin for the less-specific variable of nutritional status.[38] Subsequent revisions used the INR in lieu of the prothrombin time (PT). Most patients with Child class A and some patients with Child class B are compensated. The majority of patients with Child class B and all patients with Child class C are decompensated. In fact, the median survival of patients with Child class C status is about 1 year. See Table 4, below.

Table 4. Child-Turcotte-Pugh Scoring System for Cirrhosis.



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Since 2002, US liver transplant programs have used the Model for End-Stage Liver Disease (MELD) and the Pediatric End-Stage Liver Disease (PELD) scoring systems to assess the relative severity of patients' liver disease. Patients may receive a MELD or PELD score of 6-40 points.

In 2023, the Organ Procurement and Transplantation Network (OPTN) adopted the current scoring system for use in indviduals over age 12 years—the so-called MELD 3.0 score. The MELD 3.0 formula uses traditional variables, including levels of bilirubin, creatinine, sodium, and INR. It also adds new variables, including albumin level and patient sex. The latter was incoroporated to account for the fact the women typically have a lower serum creatinine level than men with the same degree of renal dysfunction.[39] Click here for a link to the OPTN MELD calculator.

The PELD system uses a formula that employs the candidate’s age and levels of albumin, total bilirubin, INR, and creatinine, as well as the Centers for Disease Control and Prevention (CDC) height or weight Z-score.[40]

In years past, The 3-month mortality associated with patients' MELD scores in years past is shown in Table 5, below.[41]

Table 5. Model for End-Stage Liver Disease (MELD) Score and 3-Month Mortality.[41]



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Managing the Patient With Compensated Cirrhosis

The focus of HCPs should be on efforts to prevent liver decompensation and maximize liver transplant-free survival. Some strategies are outlined below.

Treatment of the underlying disease state

Specific medical therapies may be applied to many liver diseases to diminish symptoms and to prevent or forestall the development of cirrhosis. In some cases, medical therapy—particularly in MASH, autoimmune hepatitis, hepatitis B, and hepatitis C—may lead to regression of hepatic fibrosis. Examples of these disease states and some of their associated treatments include those in Table 6, below.

Table 6: Treating the Disease State That Underlies Cirrhosis.



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Although this chapter addresses the management of liver disease, HCPs have an imperative to address the psychological and behavioral issues that may underlie their patients’ hepatologic problems.

Most patients with ALD have concurrent alcohol-use disorder (AUD). Clinicians should consider prescribing medications to reduce cravings and to reduce the risk of alcohol relapse. Some examples of pharmacotherapy for AUD include:

Specialized training is not necessary to prescribe these mediations.

HCPs should also encourage their patients with AUD to enter into treatment, whether that is attendance at a support group (eg, Alcoholics Anonymous) or participation in a formal counselling or rehabilitation program.

Elimination of precipitating factors

Acute bacterial and viral infections of any type put patients at risk for acute decompensation. HCPs should attempt to prevent such infections in their patients through vaccination, if possible.

The CDC recommends at least once-in-a-lifetime testing for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection for all US adults with:

Adults who are not immune to hepatitis B should be vaccinated as appropriate.

In this author’s practice, all chronic liver disease patients undergo testing for exposure to hepatitis A virus (HAV). Patients who test negative for anti-HAV Ab are strongly recommended to undergo immediate vaccination to help prevent HAV infection, a common and potentially deadly enteric pathogen.

As noted aearlier, both diabetes and obesity can accelerate a patient’s progression from chronic liver disease to compensated cirrhosis to decompensated cirrhosis.

Encouragement of positive lifestyle modifications

Changing one’s professional behavior as an HCP is challenging. Getting patients to change potentially injurious habits is even more difficult. As noted above, clinicians should make a concerted effort to help patients avoid alcohol use and cigarette smoking as well as aid them to maintain a healthy weight through good nutrition and exercise.

Avoiding alcohol use and cigarette smoking

Abstinence from alcohol has the potential to decrease the likelihood of decompensation in patients with established compensated cirrhosis.[45, 46]

Maintaining a healthy weight through good nutrition and exercise

Avoidance of potentially hepatotoxic medications and supplements

Patients with cirrhosis are commonly exposed to medications and over-the-counter products with hepatotoxic potential. Common causes of drug-induced liver (DILI) injury include:

Multiple herbal and dietary supplements (HDS) are potentially hepatoxic. Notable examples include:

Typically, hepatologists counsel patients with chronic liver disease to avoid using nonsteroidal anti-inflammatory drugs (NSAIDs) owing to the potential of these agents to inhibit platelet activity, induce GI ulceration, and cause kidney damage. Acetaminophen represents an alternative treatment for moderate pain.

Patients and clinicians frequently express confusion related to the potential hepatoxicity of acetaminophen. Each year, more than 60,000 people in the United States are hospitalized with acetaminophen-induced liver toxicity,[53] which is directly related to the drug dose. This drug is the leading cause of acute liver failure in the United States and the United Kingdom. Still, acetaminophen can provide safe and effective pain relief when it is used at appropriate doses in patients who are not drinking alcohol. The current recommended maximum dose of acetaminophen is 4000 mg per day.[54] In this author’s opinion, patients with cirrhosis can use acetaminophen at doses not exceeding 2000 mg per day for moderate pain.

Avoidance of physiologic stressful states

Patients with cirrhosis, like the general population, commonly expose themselves to unnecessary physiologic stress, including undergoing not-100%-necessary elective surgical procedures (eg, cosmetic surgery). Surgery and anesthesia have the potential to put patients at risk for hemodynamic instability as well as expose them to increased levels of circulating cytokines and infection. Unnecessary surgery should be discouraged. However, there are many elective surgical procedures (eg, umbilical hernia repair in a Child class A patient with a symptomatic umbilical hernia) in which the benefits of surgery vastly outweigh the risks.

Surveillance for HCC

HCC, also called liver cancer, is the sixth-most frequent new tumor worldwide, arising in about 3% of patients with cirrhosis per year. It is also curable, thereby justifying the performance of routine surveillance of all patients with cirrhosis, as well as patients with noncirrhotic hepatitis B-related liver disease. Surveillance programs are associated with early detection, implementation of curative strategies, and improved survival in cirrhotic patients.[55]

The AASLD recommends every-6-month performance of an abdominal ultrasound and an AFP blood test in patients with both compensated and decompensated cirrhosis. Contrast-enhanced CT scanning and MRI should be utilized in patients in which sonography-based surveillance is suboptimal (eg, in patients with obesity). CT scans and MRIs should be requested as 3-phase or 4-phase studies (ie, unenhanced, arterial, venous, and delayed phases) to maximize their effectiveness.

Other AASLD recommendations are shown in Table 7, below.[55]

Table 7. Recall Algorithm for Hepatcellular Carcinoma Surveillance.[55]



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Criteria set out by the Liver Reporting and Data System (LI-RADS) of the American College of Radiology (ACR) have revolutionized the approach to diagnosing and managing HCC.[56] The finding of a suspicious lesion (ie, LI-RADS score 3, 4, or 5) should prompt the referral of the patient to a liver specialist for ongoing diagnostic work-up and management.

Portal Hypertension

The pathophysiologic basis of portal hypertension

Portal hypertension is defined as elevated pressure within the portal venous system. From a physiologic perspective, portal hypertension and the hyperdynamic circulation of cirrhosis are the root causes of liver decompensation. This discussion will focus upon the portal hypertension seen in cirrhosis.

The healthy liver has the ability to accommodate large changes in portal blood flow without appreciable alterations in portal pressure. By Ohm’s law, the change in pressure along a vessel is proportional to the flow in the vessel and the resistance to flow. Portal hypertension results from a combination of increased portal venous inflow and increased resistance to portal blood flow.

Increased resistance across the sinusoidal vascular bed of the liver is caused by fixed factors and dynamic factors. Fixed factors include the production of collagen by activated stellate cells, the deposition of collagen within the space of Disse, the loss of sinusoidal fenestrae, and the formation of regenerating nodules. These all contribute to narrowing of the hepatic sinusoid and an increase in sinusoidal pressure.

Dynamic factors account for one third of intrahepatic vascular resistance. Stellate cells serve as contractile cells for adjacent hepatic endothelial cells. In turn, the nitric oxide produced by the endothelial cells controls the relative degree of vasodilation or vasoconstriction produced by the stellate cells. In cirrhosis, decreased local production of nitric oxide by endothelial cells permits stellate cell contraction, with resulting vasoconstriction of the hepatic sinusoid. (This contrasts with the peripheral circulation, wherein there are high circulating levels of nitric oxide in cirrhosis.) Increased local levels of vasoconstricting chemicals, such as endothelin, may also contribute to sinusoidal vasoconstriction.

In advancing cirrhosis, increased portal inflow appears to be driven by a nitric oxide-related hyperdynamic cardiac state. That is, an elevation in cardiac output leads to increased splanchnic arterial blood flow, which then leads to elevated splanchnic venous return. The resultant increase in portal flow subsequently contributes to portal hypertension.

At the root cause of these events appears to be a combination of increased levels of bacterial translocation into the bloodstream and gut dysbiosis.[57] Lipopolysaccharide (LPS, also known as endotoxin) is a component of the cell walls of gram-negative bacteria that is released from dying bacteria. The liver plays a key role in the clearance of LPS from the blood stream, a function that has the potential to be damaged in the setting of the altered sinusoidal architecture of cirrhosis.[58] Elevated levels of LPS and LPS-binding protein are seen in the bloodstream of cirrhotic patients.[59] LPS can stimulate the production of multiple proinflammatory cytokines, leading to the upregulation of inducible nitric oxide synthase (iNOS).[60] iNOS drives the production of increased circulating levels of nitric oxide in the splanchnic and peripheral arterial systems.

Peripheral arterial vasodilation and the resultant decrease in effective arterial blood volume have both cardiac and renal effects. Patients with decompensated cirrhosis typically experience an increase in cardiac output. Cardiac outputs of 8-10 L per minute are not uncommon.

Decreased effective arterial blood volume also leads to the activation of mechanisms to support sodium and water retention. These include activation of the renin-angiotensin system, activation of the sympathetic nervous system, and increased production of antidiuretic hormone. By promoting sodium and water retention, these processes help to increase circulating blood volume and are “compensatory” in the early phases of decompensated cirrhosis. Unchecked, these processes can eventually contribute to the development of ascites and HRS.

Assessment of portal hypertension in patients with compensated cirrhosis

The importance of portal hypertension in the patient with cirrhosis who transitions from a compensated state to a decompensated state is now known. Classically, portal hypertension is measured by hepatic venous pressure gradient (HVPG) testing. A balloon occlusion catheter is placed (typically via the transjugular route) into the right hepatic vein. In its deflated state, the catheter permits the operator to measure the free hepatic vein pressure (FHVP). The inflated balloon is used to measure the wedged hepatic vein pressure (WHVP). The WHVP minus the FHVP yields the hepatic venous pressure gradient (HVPG). The HVPG, in turn, correlates well with direct measurements of portal pressure.[61] Interpretations of the HVPG are as follows[62] :

CSPH is associated with an increased risk of liver decompensation and death.[63] CSPH is also associated with poor outcomes in other clinical settings. Increased rates of postoperative mortality are seen in[62] :

Clinicians may consider the performance of an HVPG measurement by interventional radiology as part of the preoperative evaluation of patients who preparing to undergo elective surgical procedures.

NILDAs like VCTE can be used to determine whether CSPH is present or not. Table 8, below, shows the 2023 AASLD practice guidance correlation of LSMs with the development of CPSH.[64]

Table 8. Vibration-Controlled Elastography (VCTE) Correlation With Clinically Significant Portal Hypertension (CSPH).



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Per the European Association for the Study of the Liver, an LSM of at least 20-25 kPA is sufficient to diagnose CSPH.[32]

As an alternative to VCTE testing, an MRE LSM result of at least 4.5 kPa also predicts the presence of CSPH.[64]

Recommendation to monitor LSM annually in patients with compensated cirrhosis

Clinicians should annually monitor serial LSM and platelet counts to rule out the progression to CSPH in adults with compensated cirrhosis.[64, 65] If high-quality VCTE and MRE are not available, clinicians can use surrogate markers to identify patients with CSPH who should undergo screening endoscopy or initiate beta blocker therapy. Examples include the findings of splenomegaly or portosystemic collaterals on imaging studies.[65]

By definition, patients with decompensated cirrhosis have CSPH.[65]

Use of beta blockers in patients with CSPH

Nonselective beta blockers (NSBBs) have been used since the early 1980s to help prevent bleeding from esophageal varices.[66] (See the sections below on the physiologic basis of esophageal varices and recommendations for variceal bleed prophylaxis.]

Almost 4 decades later, the PREDESCI trial assessed patients with compensated cirrhosis and CSPH.[67] Treatment with propranolol or carvedilol resulted in an average 10-12% decrease in HVPG, compared to no significant change in patients treated with placebo. At a median follow-up of 37 months, liver decompensation occurred in 16% of beta blocker-treated patients relative to 27% of placebo-treated patients (P = 0.041). This was primarily due to a decreased incidence of ascites in the beta blocker group. A reduction in the incidence of liver decompensation was particularly notable in patients who were able to achieve a decrease in the HVPG to below 10 mmHg.[67]

The AASLD has embraced the conclusions of the PREDESCI trial and supports the use of NSBBs in patients with suspected CSPH to prevent decompensation.[64]

Carvedilol 12.5 mg per day (typically dosed as 6.25 mg twice per day) is the beta blocker of choice. This agent produces a greater reduction in HVPG than propranolol or nadolol.[68] Still, propranolol (starting dose: 20-40 mg twice per day) and nadolol (starting dose: 20-40 mg once daily) remain as alternate drugs. With propranolol and nadolol, in contrast to carvedilol, clinicians should attempt to achieve true beta blockade in their patients to maximize the impact of the drugs on reducing HVPG.[65]

The AASLD provides a graphic that that can aid clinicians with their decision making regarding whether or not to initiate beta-blocker therapy.[65] The graphic depicts the progression from compensated advanced chronic liver disease (cACLD) (ie, compensated cirrhosis) to decompensated cirrhosis, as well as the associated changes in LSM, HVPG, and endoscopic findings. It can be found as figure 1 in Kaplan DE, Ripoll C, Thiele M, et al. AASLD Practice guidance on risk stratification and management of portal hypertension and varices in cirrhosis. Hepatology. 2024 May 1;79(5):1180-211. PMID: 37870298.[65]

Recommendation for screening endoscopy

Patients with CSPH (ie, an LSM ≥ 20) should undergo screening endoscopy to rule out esophageal varices that are risk for spontaneous bleeding.[36] Typically, endoscopy is performed every 2 years in patients with ongoing liver injury (eg, obesity or active alcohol use) or every 3 years in those with quiescent liver disease (eg, viral elimination or alcohol abstinence).[65]

In contrast, patients with an LSM below 20 kPa and a platelet count over 150,000/μL have a very low probability (< 5%) of high-risk varices, obviating the need for screening endoscopy.[36]

The 2023 AASLD practice guidelines state that patients with compensated cirrhosis who are already on NSBBs do not require endoscopy for variceal screening. If a patient with cirrhosis is taking a selective beta blocker for a different indication, the selective beta blocker should ideally be switched to treatment with an NSBB (carvedilol preferred).[65]

Screening endoscopy is important in a number of other circumstances:

Patients with decompensated cirrhosis who are not using NSBBs should undergo annual endoscopic screening. The discovery of varices should prompt the institution of NSBB treatment.

Esophageal varices: primary and secondary prophylaxis

Portosystemic shunts may arise as a consequence of portal hypertension. They may result from the opening of preexisting channels that connect the portal and systemic venous systems (eg, a recanalized periumbilical vein). They may also develop as a consequence of abnormal angiogenesis and the development of new portosystemic collaterals.[69] Esophageal and gastric varices are merely portosystemic collaterals in the submucosa of the esophagus or stomach. Varices are found in 42.7% of patients with Child class A cirrhosis as are 71.9% of patients with Child class B and C cirrhosis.[70]

A study that assessed patients with compensated cirrhosis and no varices reported the incidence of new esophageal varices in about 9% of patients per year.[71] The rate of progression to larger varices was 12% at 1 year, 25% at 2 years, and 21% at 3 years. Larger varices typically have increased wall tension compared to smaller varices and have a greater risk of spontaneous rupture. The risk is even higher in patients with so-called red color signs (eg, red wale signs), representative of superficial varices in the esophageal mucosa. The incidence of variceal bleeding is about 5% per year in patients with small varices and 15% per year in those with large varices.[72] Although survival after variceal bleeding has improved dramatically over the past few decades, variceal bleeding is still associated with a 10-15% mortality at 6 weeks.[65]

One of the goals of endoscopic screening is to determine whether a patient has varices that are at particularly high risk for spontaneous bleeding. So-called “high-risk” varices include:

The discovery of high-risk esophageal varices necessitates the institution of a primary prophylaxis strategy to prevent variceal bleeding. Beta blockers have been used as primary and secondary prophylaxis against variceal bleeding since the early 1980s.[74] NSBBs such as propranolol and nadolol reduce both cardiac output and splanchnic blood flow. These effects, as well as unopposed alpha-1 adrenergic effects on the splanchnic arterial system, work to decreases portal venous inflow and, as a consequence, portal pressures.

Carvedilol, which first received FDA approval in 1995, is both an NSBB and a mild antagonist of alpha-1 adrenergic receptors. Carvedilol is believed to induce vasodilation in the intrahepatic circulation. This agent achieves greater HVPG reductions than its older beta blocker counterparts.[75, 76]

Both the EASL and AASLD guidelines state that primary prophylaxis with NSBBs and EVL are equally effective. If the clinician opts for EVL prophylaxis, the procedure is typically performed every 4 weeks until varices are obliterated, and then it is repeated at 6 months followed by every 12 months to assess for the reappearance of varices. Recurrent varices necessitate additional EVL treatments.[65, 73] However, note that EVL carries an increased risk of serious adverse events.[77]

Regarding secondary variceal bleed prophylaxis, patients who do not undergo preemptive transjugular intrahepatic portosystemic shunt (TIPS) should be treated with a combination of beta blocker therapy and serial EVL procedures.[65, 73]

Beta blocker therapy is not without risk. This is particularly the case in patients with severely decompensated cirrhosis and depressed cardiac output, low blood pressure, ascites that is refractory to medical therapy, or renal insufficiency. EVL remains an alternate strategy in patients who have high-risk varices and are intolerant of beta blocker therapy.

Summary of primary prophylaxis recommendations

The following points summarize treatment recommendations to prevent an initial variceal bleed.

Summary of secondary prophylaxis recommendations

The following points summarize treatment recommendations to prevent variceal rebleeding.

Decompensated Cirrhosis

Liver decompensation is typically defined as the new onset of:

About 5-7% of patients with compensated cirrhosis experience the transition to decompensated cirrhosis each year. Ascites is typically the first complication to arise.[78] More recently, a distinction was drawn between patients with nonacute decompensation (NAD) and patients with acute decompensation (AD). As an example, a patient with NAD might experience the slow onset of ascites or hepatic encephalopathy and could be managed in an outpatient setting. Patients with AD might require hospitalization to address acute GI bleeding, the rapid recurrence of moderate or massive ascites, the acute onset of hepatic encephalopathy, or acute bacterial infection.[79] Not surprisingly, patients with AD experience a higher rate of early mortality than those with NAD.[80]

Esophageal Variceal Bleeding

Variceal bleeding remains one of the most dramatic events in clinical medicine. High intravariceal pressure and increased tension in the wall of these submucosal vessels puts patients at risk for spontaneous variceal rupture and, potentially, torrential GI bleeding. Short-term postbleeding mortality has improved from about 30% in the 1980s and 1990s to an estimated 10-15% in more recent years.[65] As with all acute medical events, clinicians should focus on maintaining patients’ airway, breathing, and circulation.

Key patient management steps include those outlined below.[65]

Support intravascular volume as needed with blood products.

Institute vasoactive drug treatment (to decrease portal pressures) as soon as possible in patients with suspected variceal bleeding. Treatment is usually continued for 2-5 days. Examples include:

Institute IV antibiotic treatment to reduce the risks of bacterial infection and endotoxemia (typically with ceftriaxone 1 gm IV once per day for up to 5 days).

Perform early esophagogastroduodenoscopy (EGD) to assess the source of bleeding, and perform emergent EVL as needed to control variceal bleeding.

In patients whose variceal bleeding is not controlled, proceed to a salvage TIPS to stop the bleed. These individuals are an extremely ill and unstable population. Although bleeding can be controlled in over 90% of patients, patient mortality may be as high as 27-55%, with death resulting from liver failure, renal failure, or infection.[82]

In patients with recurrence of early rebleeding (within 5 days), proceed to a rescue TIPS.

In patients with a Child-Turcotte-Pugh (CTP) score of 5-7 points (ie, Child class A and B+) in whom variceal bleeding is controlled endoscopically:

In patients with a CTP score of 8-9 points (ie, Child class B) and active bleeding at the time of initial endoscopy (despite vasoactive drug therapy), consider preemptive TIPS to prevent variceal rebleeding and improve survival. This is also called “early TIPS.”

In patients with a CTP score of 10-13 points (Child class C), consider preemptive TIPS to prevent variceal rebleeding and improve survival.[83]

In patients with a CTP score of 14-15 points (Child class “C), offer best supportive care and, if possible, liver transplant.[65] Performing TIPS may be too high risk in this population.

Glossary of TIPS definitions

TIPS can be classifed as follows[82] :

Gastric Variceal Bleeding

Nonbleeding gastric varices are identified in 17-25% of patient with cirrhosis and portal hypertension. Gastric varices arise as a consequence of high portal venous flow through large portosystemic shunts. They may also develop in the setting of relatively low portal pressures. Not surprisingly, gastric varices are more common in patients with concomitant portal vein or splenic vein thrombosis. They may also arise as a consequence of endoscopic obliteration of esophageal varices.[84]

As with esophageal varices, risk factors for gastric variceal bleeding include:

An estimated 16-45% of patients with gastric varices will experience bleeding within 3 years of follow-up.[65] If gastric varices are discovered, primary prophylaxis with an NSBB should be considered. However, there is little evidence-based medicine to demonstrate that NSBBs lower the incidence of spontaneous bleeding. Although prophylactic cyanoacrylate injections and transvenous obliteration procedures have been studied by various centers in India and Japan,[85, 86] they are relatively high-risk interventions and have not been adopted as routine care in the United States and Europe.

Acute bleeding tends to be more severe in cases of gastric variceal bleeding than in cases of esophageal variceal bleeding.[82] The initial supportive care of patients with acute gastric variceal bleeding parallels that of those with acute esophageal variceal bleeding. If the bleeding is massive and if definitive therapy is not readily available, patients can be stabilized by the placement of a balloon tamponade device (eg, Senstaken-Blakemore tube or Linton-Nachlas tube). The typically large size of gastric varices diminishes the efficacy of traditional endoscopic treatments such as EVL and endoscopic sclerotherapy.

TIPS, retrograde transvenous obliteration (RTO), and endoscopic cyanoacrylate injection are all considered first-line therapy. The choice of definitive therapy to control bleeding or prevent rebleeding, to a great extent, depends on patient stability, patient anatomy, and local expertise. It is essential that patients undergo cross-sectional imaging with attention to portal venous anatomy, either with CT or MRI, before finalizing a treatment plan. The performance of TIPS might not be feasible in the setting of complete portal vein thrombosis. RTO might not be feasible if a patent gastro-renal shunt cannot be identified on imaging studies.

Both TIPS and RTO are associated with lower rates of variceal bleed recurrence compared with endoscopic cyanoacrylate injection.[82] TIPS might help to improve ascites, but it could worsen liver function in Child class C patients or incite hepatic encephalopathy symptoms. RTO, by closing off a shunt, might improve encephalopathy symptoms but could worsen ascites. Cyanoacrylate injection offers the advantage of being able to be performed at the same time as the initial diagnostic endoscopy. However, this procedure can be complicated by embolization of the cyanoacrylate material to mesenteric vessels, the left renal vein, or the lungs.

Ascites

Overview

Ascites is an abnormal accumulation of fluid in the peritoneal cavity that can result from either nonperitoneal causes (eg, cirrhosis, congestive heart failure) or peritoneal causes (eg, malignant ascites, tuberculous peritonitis). In North America and Europe, cirrhosis and portal hypertension account for about 85% of cases of ascites, and malignant ascites accounts for about 10% of cases. Congestive heart failure and tuberculosis are the third and fourth most common causes of ascites, respectively.

The serum-ascites albumin gradient (SAAG) has come into common clinical use for differentiating these conditions.[87] Nonperitoneal diseases produce ascites with a SAAG of at least 1.1 g/dL. Peritoneal diseases produce ascites with a SAAG of less than 1.1 g/dL.

Nonperitoneal causes of ascites

Table 9. Nonperitoneal Causes of Ascites.[88]



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See Table

Chylous ascites, caused by obstruction of the thoracic duct or cisterna chyli, is most often due to malignancy (eg, lymphoma). It is occasionally observed postoperatively and following radiation injury. Chylous ascites also may be observed in the setting of cirrhosis and portal hypertension. The triglyceride concentration of chylous ascites is greater than 110 mg/dL and is more than that observed in plasma. Affected patients should be placed on a low-fat diet that is supplemented with medium-chain triglycerides. Treatment with diuretics and large-volume paracentesis may be required. Subcutaneous octreotide may be helpful.

Peritoneal causes of ascites

See Table 10, below.

Table 10. Peritoneal Causes of Ascites.[88]



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See Table

Diagnostic approach to the new onset of ascites

Measurent of the SAAG can be coupled with measurement of the ascites protein concentration to further differentiate the causes of ascites. (See Table 11, below.)

Table 11. Diagnostic Approach to the New Onset of Ascites.[89]



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See Table

This chapter will focus upon the intrahepatic sinusoidal portal hypertension that is seen in decompensated cirrhosis.

The role of portal hypertension in the pathogenesis of cirrhotic ascites

Patients with cirrhosis experience sodium retention, impaired free-water excretion, and intravascular volume overload. These abnormalities may occur even in the setting of a normal glomerular filtration rate. They are, to some extent, due to increased levels of renin and aldosterone.

The peripheral arterial vasodilation hypothesis states that peripheral splanchnic arterial vasodilation, driven by high nitric oxide levels, leads to decreased effective arterial blood flow.[90] This results in stimulation of the sympathetic nervous system and the renin-angiotensin system, as well as hypersecretion of antidiuretic hormone (ADH).

Activation of renin-angiotensin system contributes to sodium and water retention. ADH hypersecretion stimulates V1 receptors in the splanchnic circulations, leading to a reduction in splanchnic blood flow and portal pressure. ADH also stimulates V2 receptors in the kidney, increasing the water permeability of the collecting duct, resulting in solute-free water retention.

These events are followed by a rise in sodium and water retention and a subsequent increase in plasma volume. Initially, these developments are “compensatory” and temporarily reverse the state of decreased effective arterial blood volume. But they come at the expense of worsening the preexisting hyperdynamic state and worsening portal hypertension.

Furthermore, the upregulated sympathetic nervous system and renin-angiotensin system lead to renal vasoconstriction. If left unchecked, progressive renal vasoconstriction can result in HRS.

Clinical features of ascites and HRS

Uncomplicated ascites occurs in more than 50% of patients within 10 years of their diagnosis of cirrhosis. For many patients, symptoms can be controlled with attention to a low salt diet and the use of low-dose diuretics as needed. Unfortunately, the development of ascites that is sufficiently severe to lead to hospitalization is associated with a 40% chance of death within 2 years.[91, 92]

So-called refractory ascites—that is, ascites that cannot be controlled with medical therapy—can occur in up to 5-10% of cases of ascites. This is associated with an approximate 50% chance of death at 1 year.[93]

Once ascites develops, HRS may arise in up to 20% of patients by 1 year and 40% of patients by 5 years. HRS can be further characterized by its variants of chronic kidney disease (CKD) and acute kidney injury (AKI). Patients with HRS-CKD have a 30% mortality at 3 months, whereas those with HRS-AKI have a 90% mortality at 3 months.[91, 92]

Managing ascites

The 2021 AASLD practice guidance provides a straightforward road map to managing ascites.[89] Its recommendations for diagnosis and treatment are enumerated below, with commentary by this chapter’s author.

1. Obtain a diagnostic paracentesis.

In the author’s opinion, paracentesis should be performed in all patients with either the new onset of or worsening ascites. Paracentesis also should be performed when spontaneous bacterial peritonitis (SBP) is suggested by the presence of abdominal pain, fever, leukocytosis, or worsening hepatic encephalopathy. Some authors argue that paracentesis should be performed in all patients with cirrhosis who have ascites at the time of hospitalization, given the significant possibility of asymptomatic SBP.

Laboratory tests to be performed at initial paracentesis include:

Additional tests may include:

Ascitic fluid with more than 250 (polymorphonuclear leukocyte (PMNs) per mm3 defines neutrocytic ascites and SBP. Many cases of ascites fluid with more than 1000 PMNs/mm3 (and certainly > 5000 PMNs/mm3) are associated with appendicitis or a perforated viscus, with resulting bacterial peritonitis. Appropriate radiologic studies must be performed in such patients to rule out surgical causes of peritonitis.

Lymphocyte-predominant ascites raises concerns about the possibility of an underlying malignancy or tuberculosis. Although grossly bloody ascites may be seen in some patients with cirrhosis and portal hypertension, it may also be observed in cases of malignancy and tuberculosis. A common clinical dilemma is how to interpret the ascites PMN count in the setting of bloody ascites. This author recommends the subtraction of 1 PMN for every 250 red blood cells (RBCs) in ascites to ascertain a corrected PMN count.

The yield of ascites culture studies may be increased by directly inoculating 10 mL of ascitic fluid into aerobic and anaerobic culture bottles at the patient's bedside.[94]

2. Calculate the SAAG.

This will differentiate nonperitoneal from peritoneal etiologies.

3. Classify the ascites.

4. Restrict sodium.

Initial sodium restriction should be to less than 2 grams or 90 mmol per day.

5. Fluid restriction is not generally necessary.

An exception occurs in cases of concomitant hyponatremia (ie, serum sodium ≤ 125 mmol/L).

6. Initiate diuretic therapy.

The AASLD recommends that initial diuretic treatment may include spironolactone 100 mg daily and furosemide 40 mg daily.

In the author’s opinion, this therapy is more than what is needed by many patients. Ascites contol may be achieved with lower doses of diuretics or less frequent dosing (eg, once or twice per week).

Spironolactone (Aldactone) blocks the aldosterone receptor at the distal tubule. It is dosed at 50-300 mg once daily. Although the drug has a relatively short half-life, its blockade of the aldosterone receptor lasts for at least 24 hours. Adverse effects of spironolactone include hyperkalemia, gynecomastia, and lactation. Other potassium-sparing diuretics, including amiloride and eplerenone, may be used as alternative agents.

Furosemide (Lasix) may be used as a solo agent or in combination with spironolactone. This drug blocks sodium reuptake in the loop of Henle. It is dosed at 40-240 mg daily in 1-2 divided doses. Patients infrequently require potassium repletion when furosemide is dosed in combination with spironolactone. In one study, combination therapy with a potassium-sparing diuretic plus furosemide was superior for patients with moderate ascites without renal failure when compared with potassium-sparing diuretic monotherapy.[95]

Aggressive diuretic therapy in hospitalized patients with massive ascites can safely induce a weight loss of 0.5-1 kg daily, provided there is careful monitoring of renal function. Albumin-assisted diuresis may improve the efficacy and safety of such therapy. Diuretic therapy should be withheld in the event of electrolyte disturbances, azotemia, or induction of hepatic encephalopathy.

In this author’s opinion, one of the primary tasks of the clinician is to determine the patient’s intravascular volume status. Data from physical examination, chest X-ray, point-of-care ultrasonography, and echocardiography can aid in decision making. Indeed, not all patients with ascites have intravascular hypervolemia. Hypovolemic patients might actually be harmed by the use of diuretics. In such cases, ascites control might only be achieved through the careful use of large-volume paracentesis.

7. Avoid nephrotoxic drugs.

NSAIDs can induce renal vasoconstriction. Aminoglycoside antibiotics can damage the proximal convoluted tubules. Both classes of drugs should be avoided in patients with cirrhosis.

8. Large-volume paracentesis is the first-line treatment for refractory ascites.

Patients with massive ascites may experience abdominal discomfort, depressed appetite, and reduced oral intake. Diaphragmatic elevation may lead to symptoms of dyspnea. Pleural effusions (ie, hepatic hydrothorax) and dyspnea symptoms may also result from the passage of ascitic fluid across channels in the diaphragm. In the author’s opinion, large-volume paracentesis may help patients obtain relief from these symptoms. The procedure also may help to reduce the risk of umbilical hernia rupture.

Large-volume paracentesis was first used in ancient times. It fell out of favor from the 1950s through the 1980s with the advent of diuretic therapy and following a handful of case reports that described paracentesis-induced azotemia. In 1987, Gines and colleagues demonstrated that large-volume paracentesis combined with IValbumin could be performed with minimal or no impact on renal function.[96]

9. For large-volume paracentesis greater than 5 L, infuse albumin.

Typically, 6-8 grams of albumin are administered IV for every liter of ascites that is removed (eg, 12.5 g albumin for every 2 L removed).

10. Consider performing TIPS to address refractory ascites.

Typically, about half of appropriately selected patients undergoing TIPS achieve significant relief of ascites. Multiple studies have demonstrated that TIPS is superior to large-volume paracentesis when it comes to the control of ascites.[97] One meta-analysis of individual patient data demonstrated an improvement in transplant-free life expectancy in patients whose massive ascites was treated with a TIPS, as opposed to large-volume paracentesis.[98] However, the creation of a TIPS has the potential to worsen preexisting hepatic encephalopathy and liver function in patients with preexisiting severe liver dysfunction.[99]

Both a pre-TIPS bilirubin level of greater than 3 mg/dL and a pre-TIPS MELD score of greater than 18 are associated with an increased mortality when a TIPS is created for the management of ascites.[100, 101] In the author's opinion, TIPS use should be reserved for patients with Child Class B cirrhosis or individuals with Child class C cirrhosis without severe coagulopathy or encephalopathy.

Hernias

Umbilical and inguinal hernias are common in patients with moderate and massive ascites. The use of an elastic abdominal binder may protect the skin overlying a protruding umbilical hernia from maceration and may help to prevent rupture and subsequent infection. Timely, large-volume paracentesis may also help to prevent this disastrous complication.

Umbilical hernias should not undergo elective repair unless patients are significantly symptomatic or the hernias are irreducible. As with all other surgeries in patients with cirrhosis, herniorrhaphy carries multiple potential risks, such as intraoperative bleeding, postoperative infection, and liver dysfunction. However, these risks become acceptable in patients with severe symptoms from their hernia. Urgent hernia repair is necessary in those whose hernia has been complicated by bowel incarceration.

Spontaneous Bacterial Peritonitis

Spontaneous bacterial peritonitis (SBP)

SBP is observed in 15-26% of patients hospitalized with ascites. The syndrome arises most commonly in patients whose low-protein ascites (< 1 g/dL) contains low levels of complement, resulting in decreased opsonic activity. SBP appears to be caused by the translocation of GI tract bacteria across the gut wall and also by the hematogenous spread of bacteria. The most common causative organisms are Escherichia coli, Streptococcus pneumoniae, Klebsiella species, and other gram-negative enteric organisms.[102]

Classic SBP is diagnosed by the presence of neutrocytosis, which is defined as greater than 250 PMNs/mm3 of ascites, in the setting of a positive ascites culture. In fact, culture-negative neutrocytic ascites is observed more commonly than culture-positive ascites. Both conditions represent serious infections that carry a 20-30% mortality.

Managing SBP

The recommendations of the 2021 AASLD practice guideline are summarized below.[89]

1. When to start treatment

Initiate empiric IV antibiotics in all patient with an ascites or pleural (in the case of hepatic hydrothorax) PMN cell count over 250 per mm3.

2. Start a cephalosporin.

IV cephalosporins are first line.

3. Alternative antibiotics

Use broad-spectrum IV antibiotics in patients who have had either recent exposure to broad-spectrum antibiotics or sepsis.

4. Consider performing a repeat diagnostic paracentesis or thoracentesis.

Ideally, this should be performed 2 days after initiation of antibiotics to check therapeutic response.

5. Use albumin.

Patients with SBP should receive IV albumin in addition to antibiotics, which can provide a survival advanage. Typically, the dosing of albumin is 1.5 g/kg body weight per day on day 1 and day 2, and then albumin at 1 g/kg body weight beginning on day 3.[103]

6. Hold beta blockers.

NSBBs should be temporarily withheld in patients who develop either a mean arterial pressure below 65 mmHg or AKI.

7. Long-term prophylaxis

Patients who have recovered from an episode of SBP should receive long-term prophylaxis. Norfloxacin was previously favored, but it was withdrawn from the US market in 2014. This author notes that other articles have pointed to the utility of ciprofloxacin 250 mg once per day, ciprofloxacin 750 mg once per week, and trimethoprim-sulfamethoxazole (TMP-SMX) double-strength 5 days out of the week.[104]

8. Institute antibiotic prophylaxis for SBP in patients with cirrhosis and upper GI bleeding.

The classic antibiotic choice is ceftriaxone 1 g IV once per day, for a maximum of 7 days.

9. Consider primary SBP prophylaxis in patients with low protein ascites (< 1 g/dL).

This is particulary the case in patients with:

10. Based on currently available data, NSBBs are not necessarily contraindicated in patient with refractory ascites.

Hepatorenal Syndrome

Hyponatremia

Hyponatremia may arise on account of the ADH-driven stimulation of V2 receptors on the basolateral membrane of renal collecting duct cells. This leads to increased water permeability of the collecting duct and increased solute-free water retention. Hypervolemic hyponatremia, when defined as a serum sodium level below 130 mEq/L, is seen in more than 21% of patients with cirrhosis and ascites.[105] The presence of hyponatremia in the setting of ascites is a marker for patients’ increased risk for early mortality.[106]

In contrast to patients without liver disease, hyponatremia is typically asymptomatic in patients with cirrhosis. This may be on account of the chronicity of the condition and the adaptation of brain cells to the presence of hypo-osmolar extracellular fluid. However, patients with hyponatremia are at significant risk for developing symptoms of hepatic encephalopathy. This may be owing to their living in a state of low-grade cerebral edema.[90]

AASLD recommendations are outlined below.[89]

1. Mild hyponatremia (sodium 126-135 mEq/L)

In the setting of cirrhosis without symptoms, this can be treated with water restriction and monitoring.

2. Moderate hyponatremia (sodium 120-125 mEq/L)

Individuals with moderate hyponatremia equire water restriction to 1000 mL per day and the cessation of diuretics.

3. Severe hyponatremia (sodium < 120 mEq/L)

Treatment includes:

It is important to avoid overly rapid sodium correction. The goal should be an increase of the serum sodium level of 4-6 mEq/L (but not to exceed 8 mEq/L) over 24 hours. Overly rapid correction can put patients at risk for osmotic demyelination syndrome (ODS). Hyponatremia may be particularly problematic for patients who are about to undergo liver transplantation. Indeed, the aggressive fluid infusions that occur in the transplant operating room can lead to the occurrence of ODS in about 1% of liver transplant recipients.[107] Attempts should be made to carefully correct hyponatremia before, during, and after transplant surgery.

A treatment for hyponatremia that warrants additional investigation is the use of urea. Urea, with a starting dose of at least 30 grams per day, can produce osmotic diuresis. Its successful use in hypervolemic hyponatremia has been described in case reports.[108, 109] However, it is unclear whether or not urea can be used safely in patients with preexistent hyperammonemia.

Acute kidney injury

Considerable progress has been made in relatively recent years to simplifying our approach to managing AKI in patients with cirrhosis. The most common causes of AKI in these patients include hypovolemia, nephrotoxic agents, acute tubular necrosis (ATN), and HRS (also known as HRS-AKI).

AKI is diagnosed when the serum creatinine level acutely increases by at least 0.3 mg/dL within 48 hours. For cirrhotic patients in whom the serum creatinine increases to more than 1.5 mg/dL, the 2022 American Gastroenterological Association clinical practice update recommends initial plasma volume expansion with albumin 1 g/kg body weight per day for 2 days.[110] In addition, risk factor management is required, including[110] :

AKI is a very serious event when it arises in a patient with cirrhosis. In this author’s opinion, when AKI is identified, HCPs should consider early referral of their patient to a transplant center.

Hepatorenal syndrome

HRS represents an advanced stage of the continuum of renal dysfunction that is observed in cirrhotic patients with ascites. Both HRS-AKI and the more gradually occurring HRS-NAKI (ie, nonacute kidney injury) are caused by the vasoconstriction of large and small renal arteries.[111]

HRS results from an imbalance between renal vasoconstrictors and vasodilators. Plasma levels of a number of vasoconstricting substances—including angiotensin and epinephrine—are elevated in patients with cirrhosis. Renal perfusion appears to be protected by vasodilators, including prostaglandins E2 and I2 and atrial natriuretic factor.

HRS-AKI has a dismal prognosis, with 30-day mortality in the range of 29-44%.[89] A diagnosis of HRS-AKI is made when the following criteria are met[89] :

Clinicians need to exclude:

Almost all patients with HRS have preexisting ascites. HRS is particularly common in patients with preexisting hyponatremia and high plasma renin activity.[112] Less than 2% of patients experience HRS without a precipitant.[113] Common precipitants include large-volume paracentesis and infections, particularly SBP. In fact, one study described the occurrence of HRS-AKI in up to 1 in 3 patients with SBP.[114]

Most patients with HRS are noted to have minimal renal histologic changes. Kidney function usually recovers when patients with cirrhosis and HRS undergo liver transplanatation. However, with the persistence of HRS for weeks, histologic lesions of ATN can arise, particularly in the proximal tubules.[115] Cholemic nephropathy, also known as bile cast nephropathy, can cause kidney dysfunction; it is described in the kidneys of patients with HRS-AKI and a serum bilirubin more than 5 times the upper limit of normal.[116]

Treatment of HRS

In the 1980s and 1990s, drug treatment studies attempted to address the vasoconstriction of HRS by administering purported renal vasodilators. However, ACEIs, "renal dose" dopamine, and oral and IV prostaglandins were not effective.

In more recent years, attention has turned to the use systemic vasoconstrictors in an attempt to reverse the effects of nitric oxide on peripheral arterial vasodilation.

Terlipressin, a V1a-receptor agonist, was first synthesized in 1995 and received European approval for the treatment of HRS-AKI in the 2000s. US Food and Drug Administration approval for HRS-AKI was given in 2022. Treatment with terlipressin 0.85 mg IV every 6 hours (plus IV albumin) reversed HRS-AKI in 39% of treated patients, whereas albumin monotherapy achieved HRS reversal in only 18% of patients (P< 0.001).[117]

Alternatives to terlipressin include:

HRS-AKI reversal was seen in 43% of norepinephrine-treated patients in one trial.[118] The rate of HRS-AKI with midodrine/octreotide/albumin is typically reported to be about 30%.

In patients whose HRS-AKI continues to progress, appropriate institution of renal replacement therapy (RRT) may need to be considered in patients with electrolyte disturbances or volume overload. RRT is often used as a bridge to liver transplant.

The AASLD states that “all patients with cirrhosis and AKI should be considered for urgent liver transplant evaluation given the high short-term mortality, even in responders to vasoconstrictors”.[89] Indeed, liver transplantation remains the definitive therapy for HRS-AKI.

Hepatic Encephalopathy

Epidemiology

Hepatic encephalopathy is marked by personality changes, intellectual impairment, and a depressed level of consciousness. Guidelines classify this condition :

This section focuses upon Type C hepatic encephalopathy.

Hepatic encephalopathy is common. It is seen in 10-14% of patients at the time of their initial diagnosis of cirrhosis, and 16-21% of patients with decompensated cirrhosis have this condition. Overt hepatic encephalopathy develops in 30-50% of patients who undergo TIPS.[119]

Covert hepatic encephalopathy is described in upward of 40% of patients with cirrhosis worldwide.[120]

The presence of hepatic encephalopathy is associated with a markedly diminished quality of life.[121] It is a frequent reason for hospitalization and readmissions to the hospital.[122] Most importantly, the onset of the overt condition is linked with an increased risk of early mortality.[123] In a study that assessed patients presenting with their first episode of acute hepatic encephalopathy, Bustamante et al found only a 42% 1-year survival.[124] ;Thus, patients who present with overt hepatic encephalopathy should undergo an assessment of their candidacy for liver transplantation.

Pathogenesis

The diversion of portal blood into the systemic circulation appears to be a prerequisite for hepatic encephalopathy. This condition may develop in patients without cirrhosis who undergo portocaval shunt surgery. Other factors that contribute to its development in cirrhosis include:

Ammonia hypothesis

Ammonia is produced in the GI tract by bacterial degradation of amines, amino acids, purines, and urea. Ammonia is normally detoxified in the liver by conversion to urea and glutamine. In the setting of liver disease or portosystemic shunting, portal blood ammonia is not converted efficiently to urea. Increased levels of ammonia may enter the systemic circulation because of portosystemic shunting.

Ammonia has multiple neurotoxic effects, including alteration of the transit of amino acids, water, and electrolytes across the neuronal membrane. Ammonia can trigger the swelling of brain astrocytes as well as inhibit the generation of excitatory and inhibitory postsynaptic potentials. Therapeutic strategies to reduce serum ammonia levels tend to improve hepatic encephalopathy. However, approximately 10% of patients with significant encephalopathy have normal serum ammonia levels. Furthermore, many patients with cirrhosis have elevated ammonia levels without evidence of encephalopathy.

Gamma-aminobutyric acid (GABA)-related neurosteroids

GABA is an inhibitory neurotransmitter. Neurosteroids are synthesized in the brain and, by binding the GABA-A receptor, have neuroinhibitory properties. Brain levels of neurosteroids are increased in patients with cirrhosis.[125] Some investigators contend that neurosteroids may play a key role in hepatic encephalopathy.[126, 127]

Clinical features

The symptoms of hepatic encephalopathy may range in gravity from minimal to severe. The West Haven and ISHEN (International Society for Hepatic Encephalopathy and Nitrogen Metabolism) classification systems categorize patients as follows:

Symptoms are graded on the following scale[128] :

The presence of covert hepatic encephalopathy can impact quality of life. Patients with covert hepatic encephalopathy are at increased risk for developing the overt condition. Treatment can be offered on a case-by-case basis.[129]

The acute onset of overt hepatic encephalopathy typically necessitates in-hospital care. Once brought under control, patients should be treated with lactulose (with an option to add on rifaximin) to prevent recurrence.[129] Overt hepatic encephalopathy can be episodic, occurring less than once every 6 months. Other patients suffer from recurrent overt hepatic encephalopathy or from persistent encephalopathy, in which symptoms are unremitting.

The development of grade III or IV hepatic encephalopathy is a medical emergency. Such severe hepatic encephalopathy states are often associated with systemic inflammatory response syndrome (SIRS). Patients with grade III or IV hepatic encephalopathy should receive care in an intensive care unit setting.[130]

Laboratory abnormalities

An elevated arterial or free venous serum ammonia level is the classic laboratory abnormality reported in patients with hepatic encephalopathy. This finding may aid in the assignment of a correct diagnosis to a patient with cirrhosis who presents with altered mental status.

However, serial ammonia measurements are inferior to clinical assessment in gauging improvement or deterioration in patients under therapy for hepatic encephalopathy. No utility exists for checking the ammonia level in a patient with cirrhosis who does not have this condition.

Some patients with hepatic encephalopathy have the classic, but nonspecific, electroencephalogram (EEG) changes of high-amplitude, low-frequency waves and triphasic waves. EEG may be helpful in the initial workup of a patient with cirrhosis and altered mental status, when ruling out seizure activity may be necessary.

CT scan and MRI studies of the brain are important in ruling out intracranial lesions (eg, subdural hematoma) when the diagnosis of hepatic encephalopathy is in question.

Common precipitants

Some patients with a history of hepatic encephalopathy have normal mental status when under medical therapy. Others have chronic impairment of mental function in spite of medical management. Both groups of patients are subject to episodes of worsened encephalopathy. Common precipitants of hyperammonemia and worsening mental status include:

Medications—notably opiates, benzodiazepines, antidepressants, and antipsychotic agents—may also worsen encephalopathy symptoms. Dietary protein overload is rarely a cause of worsening encephalopathy.

Differential diagnosis

Conditions to consider in the differential diagnosis of encephalopathy include the following:

Management

In patients with severe overt hepatic encephalopathy (ie, grade III, grade IV), as with all critically ill patients, closely monitor their airway, breathing, and circulation. Nonhepatic causes of altered mental function—particularly intracranial bleeding and stroke—must be excluded. Severely abnormal mental function mandates the urgent or emergent performance of a head CT scan.

A check of the blood ammonia level may be helpful at time of presentation. A normal serum ammonia level has negative predictive value for hepatic encephalopathy.[130]

When patients with overt hepatic encephalopathy of any stage present to the emergency department, HCPs should rapidly identify and treat the precipitating factor.

ISHEN guidelines succinctly summarize acute care for patients with hepatic encephalopathy[129] :

Then, HCPs can concentrate on interventions to decrease ammonia levels:

Avoid medications that depress central nervous system (CNS) function, especially benzodiazepines.

Lactulose

Lactulose is efficacious in patients with the acute onset of severe encephalopathy symptoms and in patients with milder, chronic symptoms. This nonabsorbable disaccharide stimulates the passage of ammonia from tissues into the gut lumen and inhibits intestinal ammonia production.

In patients with mild hepatic encephalopathy, the initial lactulose dosing is 30 mL orally once or twice daily, and then it is increased until the patient has 2-4 loose stools per day. Dosing should be reduced if the patient complains of diarrhea, abdominal cramping, or bloating. Lactulose-induced hypovolemia can actually precipitate hepatic encephalopathy.

In hospitalized patients with severe hepatic encephalopathy, higher doses of lactulose are commonly administered up to every 4 hours via either a nasogastric or rectal tube. Other cathartics, including colonic lavage solutions that contain polyethylene glycol (PEG) (eg, Go-Lytely), may also be effective in patients with severe hepatic encephalopathy.

Lactulose should also be used as secondary prophylaxis to help prevent recurrent hepatic encephalopathy.[130]

Rifaximin

Rifaximin (Xifaxan) is a nonabsorbable antibiotic that has activity against both gram-positive and gram-negative enteric bacteria. In 2004, the FDA approved its use for the treatment of travelers diarrhea. In 2010, the FDA approved its use to reduce the risk of overt hepatic encephalopathy recurrence in adults. This approval was based on a phase III trial of 299 patients who were in remission from recurren thepatic encephalopathy. Patients received either rifaximin 550 mg or placebo twice daily. Each group also received lactulose. Breakthrough episodes of hepatic encephalopathy occurred in 22% of patients treated with rifaximin and in 46% of patients who were given placebo (P< 0.001), whereas hepatic encephalopathy–related hospitalization occurred in 14% of the rifaximin group and in 23% of placebo patients (P = 0.01).[131] A subsequent meta-analysis suggested that rifaximin-based treatment to prevent recurrent hepatic encephalopathy was associated with a lower risk for mortality.[132]

Other drugs

Other chemicals utilized in hepatic encephalopathy have included nitazoxanide, zinc, branched-chain amino acids, L-ornithine L-aspartate, glycerol phenylbutyrate, and sodium benzoate.[133]

Dietary management

Many patients with cirrhosis have protein-calorie malnutrition at baseline. In years past, low-protein diets were routinely recommended for these patients, because high levels of aromatic amino acids contained in animal proteins were believed to lead to increased blood levels of the false neurotransmitters tyramine and octopamine, and thereby with resultant worsening of hepatic encephalopathy symptoms. However, the practice of advising a low-protein diet must be avoided. In this author's experience, the vast majority of patients can tolerate a protein-rich diet (>1.3 g/kg daily), including well-cooked chicken, fish, vegetable proteins, and, if needed, protein supplements. A study that randomized hospitalized patients with hepatic encephalopathy to receive either a normal-protein diet or a low-protein diet (in addition to standard treatment measures) found no difference in hepatic encephalopathy outcomes between the two groups.[134] The low-protein diet, in fact, contributed to protein catabolism.

Fecal microbiota transplantation (FMT)

Preliminary work suggests that FMT is safe in outpatients with recurrent hepatic encephalopathy and may be able to improve mental function as assessed by psychometric testing.[135]

Portosystemic shunt embolization

Shunt embolization by interventional radiology can improve hepatic encephalopathy symptoms in some patients. However, its performance has the potential to both worsen ascites and increase the size of gastroesophageal varices.

Acute-on-Chronic Liver Failure

It is helpful to classify why a patient with chronic liver disease (CLD) requires hospitalization. Two of the major categories of liver decompensation leading to hospitalization are acute decompensation (AD) and acute-on-chronic liver failure (ACLF).

Acute decompensation

AD is defined as the development of one or more major complications of liver disease, including[79] :

In general, patients admitted for treatment of acutely decompensated cirrhosis have a 28-day mortality of 5% or less.[136]

Acute-on-chronic liver failure

ACLF is defined as[137] :

Typically, ACLF is marked by “excessive systemic inflammatory response” that may be triggered by bacterial infection (eg, SBP, pneumonia), severe alcohol-associated hepatitis, hemorrhagic shock, and a variety of other insults.[136] Cirrhotic patients hospitalized with ACLF have much higher circulating levels of proinflammatory cytokines (eg, TNF-α, IL-6, IL-8) than patients without ACLF.[138]

Making a distinction between AD and ACLF is clinically important. ACLF is not only more common in the present day than in prior years, being diagnosed in 35% of patients admitted for decompensated cirrhosis, it is also associated with a 28-day mortality of 45%.[139] Assignment of a diagnosis of ACLF should prompt early referral of the patient to a liver transplant center.

Pulmonary and Cardiac Complications of Cirrhosis

Patients with cirrhosis may have impaired pulmonary function. Pleural effusions and the diaphragmatic elevation caused by massive ascites may alter ventilation-perfusion relations. Interstitial edema or dilated precapillary pulmonary vessels may reduce pulmonary diffusing capacity.

Hepatopulmonary syndrome (HPS)

In HPS, pulmonary arteriovenous anastomoses result in arteriovenous shunting. This is a common phenomenon in patients with cirrhosis, occurring in 5-32% of patients.[140] Most of these patients have mild HPS and minimal symptoms. However, HPS can be progressive and potentially life-threatening. The diagnosis should be considered in any patient with cirrhosis and evidence of oxygen desaturation.

Classical HPS is marked by the symptom of platypnea (shortness of breath relieved when lying down and worsened when sitting or standing), and the finding of orthodeoxia (decrease in the arterial oxygen tension when the patient moves from a supine to an upright position).

HPS is detected most readily by echocardiographic visualization of late-appearing bubbles in the left atrium following the injection of agitated saline. Patients with an alveolar-arterial oxygen gradient ≥ 15 mm Hg, and a partial pressure of oxygen ≥ 60 to < 80 mm Hg are said to have moderate HPS. Patients with a partial pressure of oxygen < 60 mm Hg are said to have severe HPS.[141] Some cases of HPS may be corrected by liver transplantation. In fact, a patient's course to liver transplantation may be expedited when his or her PaO2 is less than 60 mm Hg on room air.

Portopulmonary hypertension (PPHTN)

PPHTN is observed in up to 2-16% of patients with cirrhosis. Its etiology is unknown. PPHTN is defined as:

The presence of a mean pulmonary pressure of greater than 35 mmHg significantly increases the risks of liver transplant surgery. Thus, routine Doppler echocardiography is performed as part of the regular workup in many liver transplant programs to rule out the interval development of PPHTN in patients on the transplant waiting list. Patients who develop severe PPHTN may require aggressive medical therapy to stabilize pulmonary artery pressures and reduce their risk of perioperative mortality.

Cirrhotic cardiomyopathy

Cirrhotic cardiomyopathy is increasingly appreciated as a cause of cardiac dysfunction in patients with decompensated cirrhosis. Patients may suffer from a prolonged QT interval and from either systolic dysfunction (with a decrease in the left ventricular ejection fraction to < 50%) or diastolic dysfunction.[141] Cirrhotic cardiomyopathy may result, at least in part, from the state of increased gut bacterial translocation and chronic inflammation that is seen in decompensated cirrhosis. Synthetic and metabolic defects involving cardiac proteins, lipids, and carbohydrates may also play a role.[141]

Hematologic Complications of Cirrhosis

Anemia and thrombocytopenia

Anemia may result from folate deficiency, hemolysis, or hypersplenism.[142] Thrombocytopenia is usually secondary to hypersplenism and decreased levels of thrombopoietin.

Coagulation disorders

Coagulopathy results from reduced hepatic production of coagulation factors. If cholestasis is present, decreased micelle entry into the small intestine leads to decreased vitamin K absorption, with resulting reduction in hepatic production of factors II, VII, IX, and X. Patients with cirrhosis also may experience fibrinolysis and disseminated intravascular coagulation.

Measurements of INR reflects the activity of the extrinsic and common coagulation pathways, notably factor II (prothrombin), factor V, factor VII, and factor X, as well as to a lesser extent, factor I (fibrinogen). In years past, it was a commonly held belief that the level of the INR could be used to assess the bleeding tendencies of patients with decompensated cirrhosis. However, the INR reflects the amount of thrombin generated as a function of procoagulant factors; it does not take into account the thrombin being inhibited by anticoagulant drivers.[143]

Patients with cirrhosis are impacted by a complex balance of anti-hemostatic and pro-hemostatic factors.

Anti-hemostatic factors include[143] :

Pro-hemostatic factors include[143] :

When these factors are in balance, patients with cirrhosis have normal hemostasis. An imbalance can either lead to bleeding or clotting events. Conditions that tip the balance in favor of bleeding include hemodynamic alterations due to portal hypertension, endothelial cell dysfunction, bacterial infection, and renal failure.[143]

Multiple international medical societies have attempted to address the issue of preprocedural transfusion support. Routine correction of an elevated INR with fresh frozen plasma is no longer recommended. Some societies recommend the transfusion of platelets to achieve a platelet count above 50 × 109/L; other societies do not. Some organizations advocate the correction of a low fibrinogen level with cryoprecipitate; most recommend against its routine correction.[144] Of course, patient care must be individualized, particularly in individuals with a known bleeding diathesis.

Portal vein thrombosis (PVT)

The potential for patients with cirrhosis to suffer from a hypercoagulable state is increasingly recognized. A notable complication of hypercoagulability is PVT, which is relatively common, occurring in 1.3-9.8% of patients with cirrhosis.[145]

A reduction of blood flow velocity in the portal vein is felt to be a risk factor for the development of PVT.[145] It remains to be determined whether PVT is the result of liver decompensation or whether, by PVT’s ability to decrease portal venous inflow, it is a factor that contributes to liver decompensation. A small nonblinded prospective trial randomized 70 Child class B and C patients without PVT to enoxaparin or no treatment, demonstrating that those in the enoxaparin-treated group experienced a lower rate of PVT development and a lower rate of liver decompensation.[146]

The discovery of PVT in a potential candidate for liver transplantation should prompt the performance of cross-sectional imaging (CT scan or MRI) to rule out HCC and the possibility of malignant portal vein invasion. Once malignant PVT is ruled out, imaging studies should be carefully reviewed to determine the location of the thrombus, whether the thrombus is recent (ie, present for < 6 months) or chronic, its length, and the percentage of portal vein lumen that is occluded. Then, clinicians need to consider treatment aims before embarking on therapy.

The goal of PVT treatment is to prevent the complete obstruction of the main portal vein or extension of thrombus into the superior mesenteric vein. Such events increase the challenge of performing liver transplant surgery and can even make liver transplantation technically impossible. Both the AASLD and EASL recommend that clinicians consider either initiating anticoagulation or creating a TIPS in patients with thrombosis of the main portal vein.[62, 145] Such treatments might not be appropriate for patients who have already developed cavernous transformation of the portal vein. In patients with cirrhosis who are not candidates for liver transplantation, it remains unclear whether the benefits of anticoagulation or TIPS exceed the risks.

Other Complications of Cirrhosis

Pruritus

Pruritus is a common complaint in both cholestatic liver diseases (eg, primary biliary cholangitis) and in noncholestatic chronic liver diseases (eg, hepatitis C). Although increased serum bile acid levels were once thought to be the cause of pruritus, endogenous opioids are more likely to be the culprit pruritogen.

Cholestyramine is the mainstay of therapy for the pruritus of liver disease. To avoid compromising GI absorption of medications, care should be taken to avoid coadministration of this organic anion binder with any other medication.

Other medications that may provide relief against pruritus include antihistamines (eg, diphenhydramine, hydroxyzine), ammonium lactate 12% skin cream (Lac-Hydrin), ursodeoxycholic acid, doxepin, and rifampin. Naltrexone may be effective but is often poorly tolerated. Gabapentin is an unreliable therapy. Patients with severe pruritus may require institution of ultraviolet light therapy or plasmapheresis.

Osteoporosis

Patients with cirrhosis may develop osteoporosis. Supplementation with calcium and vitamin D is important in patients at high risk for osteoporosis, especially individuals with chronic cholestasis or primary biliary cholangitis and patients receiving corticosteroids for autoimmune hepatitis. The finding of osteoporosis on bone densitometry studies may prompt the institution of therapy with an aminobisphosphonate (eg, alendronate sodium).

Malnutrition and frailty

Many patients complain of anorexia, which may be compounded by the direct compression of ascites on the GI tract. Care should be taken to ensure that patients receive adequate calories and protein in their diets. Patients frequently benefit from the addition of commonly available liquid and powdered nutritional supplements to the diet. Only rarely are patients not able to tolerate proteins in the form of chicken, fish, vegetables, and nutritional supplements.

At the author’s institution, dietary recommendations for patients hospitalized with cirrhosis include:

In addition, patients are assessed for micronutrient deficiencies, such as vitamin A, vitamin B1 (thiamine), vitamin B6 (pyridoxine), vitamin B12, methylmalonic acid (as a surrogate marker for vitamin B12 deficiency), vitamin D, vitamin E, folic acid, zinc, copper, and selenium. Liberal use is made of vitamin supplements, particularly water-miscible forms of fat-soluble vitamins A, D, E, and K.

Encourage regular exercise, including walking and even swimming, in patients with cirrhosis to prevent them from slipping into a vicious cycle of inactivity and muscle wasting. Debilitated patients frequently benefit from a formal exercise program supervised by a physical therapist.

Zinc deficiency

Zinc deficiency commonly is observed in patients with cirrhosis. Treatment with zinc sulfate 220 mg orally once or twice per day may improve dysgeusia and can stimulate appetite. Furthermore, zinc is effective in the treatment of muscle cramps and is adjunctive therapy for hepatic encephalopathy. Zinc should not be given as a “routine” in patients with cirrhosis; its administration needs to be guided by monitoring of serum zinc and copper levels.

Hypogonadism

Some male patients suffer from hypogonadism. Those with severe symptoms may undergo therapy with topical testosterone preparations.

Surgery in Patients With Cirrhosis

Surgery and general anesthesia carry increased risks in the patient with cirrhosis. Potential contributors to such risk include:

Surgery is typically safe in the setting of mild chronic hepatitis; its risk in patients with severe chronic hepatitis is unknown. Patients with compensated cirrhosis have increased, but acceptable, morbidity and mortality risks. As an example, in the modern era, laparoscopic cholecystectomy, when performed in patients with Child class A or B cirrhosis without portal hypertension, is associated with a 0-6% likelihood of postoperative mortality.[148]

Planning for surgery in a patient with cirrhosis can be a complex process. Physicians, surgeons, and anesthesiologists need to work in concert to address the following:

Care should be taken to avoid postoperative infection, fluid overload, unnecessary sedatives and analgesics, and potentially hepatotoxic and nephrotoxic drugs (eg, aminoglycoside antibiotics).

There are few, if any, contraindications to performing emergent surgery in patients with cirrhosis. In other clinical scenarios, clinicians might consider using the schema shown in Table 12, below.[148]

Table 12. How Liver Disease Severity Impacts Surgical Planning.



View Table

See Table

Liver Transplantation

Overview

Liver transplantation is an important strategy in the management of patients with decompensated cirrhosis, as well as for patients with ACLF, HCC, and acute liver failure. Cirrhotic patients should be referred for consideration of liver transplantation after the first signs of hepatic decompensation appear.

Advances in surgical technique, organ preservation, and immunosuppression have resulted in dramatic improvements in postoperative survival. In the early 1980s, the percentage of patients surviving 1 year and 5 years after liver transplant were only 70% and 15%, respectively. Currently, patients can anticipate a 1-year survival of 92% and a 5-year survival of more than 80%. More than 50% of patients who undergo liver transplantation are still alive 20 years later. Quality of life after liver transplantation is good or excellent in most cases.

Indications for liver transplantation

Liver transplant surgery is performed to save lives and improve the quality of life. Refer patients to a liver transplant center to consider their transplant candidacy once they have demonstrated signs of decompensation, especially:

There are many common clinical scenarios that are associated with poor 1-year survival, as shown in Table 13, below.[124, 139, 149] Such patients are also deserving of early referral.

Table 13. Specific Clinical Scenarios With Poor Short-Term Survival.



View Table

See Table

Liver transplant is the treatment of choice in many patients with:

Patients with these complications require careful assessment. They are only listed for liver transplant candidacy when it is clear that the benefits of transplantation exceed its potential risks.

In some cases, the estimation of a patient’s survival is relatively straightforward. In other cases, the estimation of the benefit:risk ratio of performing liver transplantation is not as clear cut.

Contraindications to liver transplant

Contraindications to listing a patient as a candidate for liver transplantation include:

Active alcohol abuse was previously considered be a contraindication to the performance of liver transplantation. In more recent years, particularly during and after the COVID-19 pandemic, about half of the US liver transplant programs contemplate the performance of liver transplant surgery in patients with a history of recent alcohol abuse and severe alcohol-associated hepatitis. At the author’s hospital, the transplant team focuses on the following factors as it assesses the patient's candidacy for liver transplantation:

Organ allocation

The need for a more efficient and equitable system of organ allocation resulted in dramatic changes in US organ allocation policy in 2002.[150] Previously, patients who were accepted as liver transplant candidates with 7-9 CTP points (Child class B) received low priority on the transplant waiting list maintained by the United Network for Organ Sharing (UNOS); those with 10 or more CTP points (Child class C) received a higher priority. Emergent liver transplantation with UNOS status 1 was reserved primarily for noncirrhotic patients suffering from acute liver failure.

Since 2002, livers from deceased donors (ie, cadaveric donors) have been allocated to cirrhotic patients using the MELD and PELD scoring systems. Over the years, the MELD and PELD calculators have been updated to achieve a more equitable distribution of organs.[151]

The current scoring system for indviduals over age 12 years, the so-called MELD 3.0 score, uses traditional variables including levels of bilirubin, INR, creatinine, and sodium as well as adds new variables, including albumin level and patient sex. The latter was added to account for the fact that women typically have a lower serum creatinine level than men with the same degree of renal dysfunction.[39]

The PELD system uses a formula that employs the candidate’s age; levels of albumin, total bilirubin, INR, creatinine; and the CDC's height or weight Z-score.[40]

Within any US region, a donor allograft in a particular ABO blood group is allocated to the patient within the same blood group who has the highest MELD or PELD score. As in the past, patients with UNOS status 1A (eg, patients with acute liver failure) and 1B (ie, chronically ill pediatric patients younger than 18 years) receive top priority for liver transplantation.

At this time, the US OPTN employs a so-called acuity circle policy in which concentric circles around the donor hospital are used. Per the OPTN: “Livers from all deceased donors will first be offered to the most urgent liver transplant candidates (Status 1A and 1B) listed at transplant hospitals within a radius of 500 nautical miles of the donor hospital. Following offers to the most urgent candidates, livers from adult donors will be offered to candidates at hospitals within distances of 150, 250 and 500 nautical miles of the donor hospital. These offers are grouped by medical urgency.”[152]

Special rules have been developed to address potentially life-threatening liver disease complications, such as HCC and HPS. Patients with these conditions, as well as other exceptional cases, can receive a higher MELD or PELD score than that calculated from the standard MELD and PELD variables.

Strategies to increase organ availability

Overview

Each year, the lives over 10,000 individuals in the United States are saved by liver transplantation. However, in the 2020s, as in previous decades, the demand for donor organs vastly outnumbers the supply. Approximately 12-13% of transplant candidates die while waiting for the procedure because of the scarcity of donor organs.[153] Strategies to improve the donor organ shortage include programs to increase public awareness of the importance of organ donation, increased use of living donor liver transplantation (LDLT) for pediatric and adult recipients, and the use of organs from non-heart beating donors (NHBDs). Effective antiviral therapy now also permits the use of liver allografts procured from donors infected with human immunodeficiency virus (HIV),[154] HBV,[155] and HCV.[153] Allografts from well-selected COVID-19–infected donors can also be utilized.[156]

Living donor liver transplantation

The advent of LDLT introduced a new variable into any discussion of the timing of transplantation. This procedure has the potential to make liver transplantation an elective procedure not only for the cirrhotic patient with significant complications but also for the cirrhotic patient with a poor quality of life.

LDLT became a reality for pediatric recipients in 1988 and for adult recipients a decade later. The procedure arose from advances in surgical technique and a worsening shortage of deceased donor organs. In LDLT, up to 60% of a healthy volunteer donor's liver is surgically resected and transplanted into the abdomen of a recipient. Graft survival in LDLT recipients is on par with that seen in the recipients of deceased donor organs. As of 2022, LDLT accounts for about 6% of US liver transplantations.[20]

However, LDLT has its limitations. The most obvious problem is the low but real risk of serious operative complications for the healthy volunteer liver donor. It is estimated that about 0.4% of healthy liver donors worldwide die as a consequence of their surgery. Transplant programs must not only maximize donor safety but also ensure that the benefits of LDLT to the potential recipient offset the risks to the donor.

Furthermore, not every potential recipient is sufficiently clinically stable to undergo safe and effective LDLT. The recipient's risk of posttransplant mortality increases when their MELD score is above 25. In this author's opinion, deceased donor transplantation–but not LDLT–should be performed in such recipients.

Liver donation after cardiac death

The shortage of donor organs has spurred interest in the use of liver allografts from NHBDs. Typically, an NHBD is an individual who has sustained irreversible neurologic damage but whose clinical condition does not meet formal brain death criteria. With this knowledge, a prospective donor's family will give consent for withdrawal of care and for organ donation. The donor is then brought to the operating room, with the anticipation that withdrawal of ventilator support will result in the cessation of the patient's cardiopulmonary function. Once death is declared, organ procurement surgery can proceed.

In contrast to the organ procured from a heart-beating donor (HBD), the allograft obtained from an NHBD may be subject to considerable warm ischemia time before it is perfused with cold preservative solution.

Unfortunately, the recipients from liver allografts from NHBDs are risk for higher rates of the following[157, 158] :

Transplant physicians and surgeons must carefully balance the need for urgent life-saving liver transplantation against the potential risks of utilizing an organ from an NHBD.

Normothermic machine perfusion

Traditionally, livers procured from an organ donor are transported to the recipient’s hospital with the use of ischemic cold storage. Ischemic damage to the liver during transit can increase the risk of posttransplant complications. The use of normothermic machine perfusion (NMP) has revolutionized liver transplant in the 2020s. Immediately after liver procurement surgery, canulae are placed into the hepatic vessels of the donor liver, and the liver is perfused with warm oxygenated blood supplied with nutrients. The use of NMP has the potential to decrease early allograft dysfunction, ischemia-reperfusion injury, early allograft dysfunction, and ischemic biliary injury. NMP can also increase the utilization of NHBD organs,[159] as well be utilized to reduce steatosis in donor organs.[160] Finally, plasma and bile levels of lactate, glucose, and pH can be sampled while the donor organ undergoes NMP. This data can aid clinicians in determining whether or not to proceed to organ implantation.[161]

The future of liver transplantation

Over the coming years, more routine use of liver transplantation is more likely in patients with cholangiocarcinoma, neuroendocrine tumors metastatic to the liver, and colon cancer metastatic to the liver.[162]

Exciting new technical advances may help to expand the donor pool and permit us to perform more life-saving transplants in needful recipients. As noted above, NMP has the potential to improve organ preservation, as well as our ability to select donor organs for implantation.

Xenotransplantation may become a reality over the next decade. Advances in genetic engineering may help us to overcome xenogeneic rejection and interspecies incompatibilities of coagulation-regulatory proteins.[163] Issues related to zoonosis will also need to be addressed.

It can also be anticipated that additional work that explores the feasibility of immunosuppression withdrawal in liver transplant recipients will take place.

What is the correlation between cirrhosis and chronic liver disease?How is cirrhosis defined histologically?What is the liver fibrosis?What are the complications of cirrhosis?How might the clinical presentation of cirrhosis vary among patients?What are the CDC risk-based testing guidelines for hepatitis C virus (HCV) infection?What are characteristics of Budd-Chiari syndrome in patients with cirrhosis?What is cirrhosis?What is the range of clinical presentations of cirrhosis?Which findings are suggest of ascites in cirrhosis?How are symptoms of hepatic encephalopathy graded in patients with cirrhosis?What are the physical findings of hepatic encephalopathy in cirrhosis?What are cutaneous signs and symptoms of cirrhosis?How is hepatorenal syndrome diagnosed in cirrhosis?How is portal hypertension diagnosed in cirrhosis?How is hepatic encephalopathy diagnosed in cases of cirrhosis?What is the role of electroencephalography in the evaluation of cirrhosis?What is the role of imaging in the 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hypothesis of encephalopathy pathogenesis in cirrhosis?What is the gamma-aminobutyric acid hypothesis of encephalopathy pathogenesis in cirrhosis?What is the grading system for encephalopathy in cirrhosis?What are the clinical findings suggestive of mild and moderate encephalopathy in cirrhosis?What are lab abnormalities characteristic of encephalopathy in cirrhosis?What are common precipitants of hyperammonemia and worsening mental status in hepatic encephalopathy?Which factors may worsen encephalopathy symptoms in cirrhosis?Which conditions should be included in the differential diagnoses of hepatic encephalopathy?What is the initial treatment of encephalopathy in patients with cirrhosis?What is the role of lactulose in the treatment of cirrhosis?What are the treatment options for severe encephalopathy in cirrhosis?What is the effectiveness of lactulose in the treatment of cirrhosis?What is the role of antibiotics in the treatment of encephalopathy in cirrhosis?Which drugs may be used to decrease blood ammonia in cirrhosis?What is the role of low-protein diets in the treatment of cirrhosis?When is protein restriction indicated in the treatment of cirrhosis?What is an extended criteria donor (ECD) for liver transplantation in cirrhosis?What is the role of liver transplantation in cirrhosis?Which factors have contributed to improved postoperative survival following liver transplantation for cirrhosis?What are the contraindications for liver transplantation in cirrhosis?When are patients with alcoholic cirrhosis considered for liver transplantation?When are patients with HIV infection and cirrhosis considered for liver transplantation?What is being done to decrease the donor shortage for liver transplantation in the treatment of cirrhosis?What criteria are used in the organ allocation system for liver transplantation in patients with cirrhosis?How is the Model for End-Stage Liver Disease (MELD) scoring system used to determine organ allocation in cirrhosis?What is the organ allocation formula used by Pediatric End-Stage Liver Disease (PELD)?How do hepatocellular carcinoma and hepatopulmonary syndrome affect organ allocation in patients with cirrhosis?How are the risks and benefits of liver transplantation weighed in cirrhosis?What is the role of living donor liver transplantation (LDLT) in the treatment of cirrhosis?What are the limitations to living donor liver transplantation (LDLT) in the treatment of cirrhosis?What are the risks of living donor liver transplantation (LDLT) for the treatment of cirrhosis?What are non–heart beating donors (NHBDs) and what are the risks in liver transplantation for cirrhosis?How do the outcomes of liver transplantation using allografts from non–heart beating donors (NBHDs) compare with those from heart-beating donors (HBDs) for patients with cirrhosis?What is the future of liver transplantation in the treatment of cirrhosis?What is the role of bioartificial livers in the treatment of cirrhosis?What is the role of xenotransplantation in the treatment of cirrhosis?What would be the ideal future treatment approach to cirrhosis?What is the leading cause of cirrhosis in the US?What are the causes of cryptogenic cirrhosis?What is the prevalence of cirrhosis in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)?What are the most common causes of cirrhosis in the US?What are the less common causes of chronic liver disease and cirrhosis?What is the pathogenesis of hepatic fibrosis?What is the role of stellate cells in the pathogenesis of cirrhosis?What is the role of serum cytokines in the pathogenesis of cirrhosis?What is the role of collagen in the pathogenesis of cirrhosis?What are future drug strategies to prevent hepatic fibrosis and cirrhosis?Which histologic features are characteristic of cirrhosis progression?What are the signs and symptoms of cirrhosis?How do reproductive hormones affect the clinical presentation of cirrhosis?What are the hematologic manifestations of cirrhosis?What is the role of oral thrombopoietin receptor agonists (TPO-RA) in the treatment of thrombocytopenia among patients with chronic liver disease?What are the pulmonary manifestations of cirrhosis?What is hepatopulmonary syndrome (HPS) in patients with cirrhosis?How is hepatopulmonary syndrome (HPS) diagnosed in cirrhosis?How is portopulmonary hypertension (PPHTN) diagnosed in cirrhosis?What are the increased risks of portopulmonary hypertension (PPHTN) in cirrhosis?What is the frequency of hepatocellular carcinoma (HCC) in cirrhosis?What is the frequency of cholangiocarcinoma in cirrhosis?Which conditions are common comorbidities of cirrhosis?What is Child-Turcotte-Pugh (CTP) system and how is it used to predict life expectancy in patients with cirrhosis?What is the Model for End-Stage Liver Disease (MELD) score and how is it used in patients with cirrhosis?What is the focus of medical treatment to prevent cirrhosis?What is the role of pharmacologic therapies in the treatment of cirrhosis?What is the role of combination therapy for the treatment of cirrhosis?What are the treatment options for zinc deficiency in cirrhosis?What are the treatment options for mild pruritus in cirrhosis?What is the role of cholestyramine in the treatment of cirrhosis?Which medications are used for the treatment of pruritus in cirrhosis?What are the treatment options for hypogonadism in cirrhosis?What are the treatment options for osteoporosis in cirrhosis?Which vaccinations should patients with cirrhosis receive?Which medications should be used with caution in patients with cirrhosis?What is the role of statins in the treatment of cirrhosis?What is the role of analgesics in the treatment of cirrhosis?What is the role of aminoglycoside antibiotics in the treatment of cirrhosis?What are the recommendations for safe use of medications in patients with cirrhosis?What dietary modifications are needed in the treatment of cirrhosis?What activity modifications are needed in the treatment of cirrhosis?What are the risks of surgery and general anesthesia in patients with cirrhosis?When is surgery considered safe in patients with cirrhosis?What are the mortality rates for abdominal surgeries in patients with cirrhosis?What is the efficacy of the Model for End-Stage Liver Disease (MELD) score for predicting postoperative outcomes in cirrhosis?What 30-day postoperative mortality rates are associated with Model for End-Stage Liver Disease (MELD) scores in patients with cirrhosis?What is included in routine follow-up monitoring for cirrhosis?How is surveillance of esophageal varices performed in patients with cirrhosis?What are the American Association for the Study of Liver Diseases guidelines for the monitoring of hepatocellular carcinoma (HCC) in patients with cirrhosis?How should hepatocellular carcinoma (HCC) be monitored in patients with cirrhosis?Which therapies are performed for patients with hepatocellular carcinoma (HCC) and cirrhosis awaiting liver transplantation?What are the AASLD treatment guidelines for cirrhosis?What are the AASLD treatment guidelines for variceal bleeding?What are the EASL treatment guidelines for cirrhosis?What are the EASL treatment guidelines for hepatocellular carcinoma?

Author

David C Wolf, MD, FACP, FACG, AGAF, FAASLD, Medical Director of Liver Transplantation, Westchester Medical Center; Professor of Clinical Medicine, Division of Gastroenterology and Hepatobiliary Diseases, Department of Medicine, New York Medical College

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Gilead; Intercept; Madrigal.

Chief Editor

BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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The stages of cirrhosis and advanced chronic liver disease. (A) Clinical features, histologic findings, hepatic venous pressure gradients (HVPG), and endoscopic features typical of compensated cirrhosis with and without clinically significant portal hypertension (CSPH), decompensated cirrhosis, and further decompensated cirrhosis. (B) Liver stiffness measurements and platelet counts used to characterize compensated advanced chronic liver disease (cACLD) and CSPH using noninvasive, nonhistological criteria. HE, hepatic encephalopathy; VH, variceal hemorrhage.{ref147}

Radiologic StudySensitivitySpecificity
Ultrasonography52-69%74-89%
CT scan77-84%53-88%
MRI87%54%
Fibrosure/FibroTestα2-macroglobulin, γ-glutamyltransferase (GGT), total bilirubin, haptoglobin, apolipoprotein A-1
FibroSpect IIα2-macroblobulin, hyaluronic acid, amino-terminal propeptide of type III procollagen (PIIINP)
HepaScoreTotal bilirubin, α2-macroglobulin, GGT, hyaluronic acid
Enhanced Liver Fibrosis TestHyaluronic acid, PIIINP, tissue inhibitor matrix metalloproteinase (TIMP-1)
AST to Platelet Ratio Index (APRI)[Divide the AST level (IU/L) by the AST upper limit of normal (ULN) (IU/L)]; then, divide the result by the platelet count (109/L); then, multiply that result by 100
Fibrosis-4 score (FIB-4)[Age (years) × AST (U/L)] divided by [platelet count (109/L) × √ALT (U/L)]
NAFLD Fibrosis Score (NFS)–1.675 + (0.037 × age in years) + (0.094 × body mass index [BMI] [kg/m2]) + 1.13 × (impaired fasting glucose or diabetes [yes = 1, no = 0]) + 0.99 × (AST/ALT ratio) – (0.013 × platelets [109/L] – (0.66 × albumin [g/dL])
Clinical Variable1 Point2 Points3 Points
EncephalopathyNoneGrade 1-2Grade 3-4
AscitesAbsentSlightModerate or large
Bilirubin (mg/dL)< 22-3> 3
Bilirubin in PBC or PSC (mg/dL)< 44-10> 10
Albumin (g/dL)> 3.52.8-3.5< 2.8
Prothrombin time (seconds prolonged) or INR< 4 s or INR < 1.74-6 s or INR 1.7-2.3> 6 s or INR > 2.3
INR = international normalized ratio; PBC = primary biliary cholangitis; PSC = primary sclerosing cholangitis.



Child class A = 5-6 points; Child class B = 7-9 points; Child class C = 10-15 points.



MELD ScoreMortality at 3 Months
≤ 91.9%
10-196.0%
20-2919.6%
30-3952.6%
≥ 4071.3%
Disease statePortential treatment
Metabolic dysfunction-associated steatohepatitis (MASH)Resmetirom and, potentially, glucagon-like peptide-1 receptor agonists (GLP-1RAs)
Hepatitis BEntecavir, tenofovir disiproxil fumarate, tenofovir alafenamide
Hepatitis CSofosbuvir/velpatasvir, glecaprevir/pibrentasvir
Autoimmune hepatitisPrednisone, azathioprine, mycophenolate
Hereditary hemochromatosisPhlebotomy
Primary biliary cholangitisUrsodeoxycholic acid, obeticholic acid (contraindicated in the setting of portal hypertension), elafibranor, seladelpar
Wilson diseasetrientine, zinc acetate, penicillamine
Alcohol-associated liver disease (ALD)Encourage alcohol abstinence
Diagnostic FindingAction
Lesion < 1 cm on ultrasoundRepeat US in 3-6 months. If lesion is stable in size, return to every-6-month surveillance
Lesion ≥ 1 cm on ultrasoundComputed tomography (CT) scanning or magnetic resonance imaging (MRI)
Alpha-fetoprotein (AFP) ≥ 20 ng/mL or a rising AFPCT or MRI
Liver Stiffness Measurement by (LSM) VCTEPresence of CSPH
< 15 kPaCSPH is not present.
15-20 kPa + Platelets < 110,000/mm3CSPH is probable.
20-25 kPa + Platelets < 150,000/mm3CSPH is highly probable.
> 25 kPACSPH is highly probable.
Type of Nonperitoneal AscitesExamples
Intrahepatic portal hypertension
  • Cirrhosis
  • Acute liver failure
  • Sinusoidal obstruction syndrome
Extrahepatic portal hypertension
  • Hepatic vein obstruction (ie, Budd-Chiari syndrome)
  • Congestive heart failure
  • Constrictive pericarditis
  • Inferior vena cava obstruction
Hypoalbuminemia
  • Nephrotic syndrome
  • Protein-losing enteropathy
  • Malnutrition
Miscellaneous disorders
  • Myxedema
  • Ovarian tumors
  • Pancreatic ascites
  • Biliary ascites
  • Chylous ascites: Secondary to malignancy, trauma, or portal hypertension
Type of Peritoneal AscitesExamples
Maliganant ascites
  • Primary peritoneal mesothelioma
  • Secondary peritoneal carcinomatosis
Granulomatous peritonitis
  • Tuberculous peritonitis
  • Fungal and parasitic infections (eg, Candida, Histoplasma, Cryptococcus, Schistosoma mansoni, Strongyloides, Entamoeba histolytica)
  • Sarcoidosis
  • Foreign bodies (eg, talc, cotton, wood fibers, starch, barium)
Vasculitis
  • Systemic lupus erythematosus
  • Henoch-Schönlein purpura
Miscellaneous disorders
  • Eosinophilic gastroenteritis
  • Whipple disease
  • Endometriosis
 SAAG ≥ 1.1 g/dLSAAG < 1.1 g/dL
Ascites protein < 2.5 g/dL
  • Cirrhosis
  • Portal vein thrombosis
  • Late Budd-Chiari syndrome
  • Nephrotic syndrome
Ascites protein ≥ 2.5 g/dLPostsinusoidal
  • Congestive heart failure
  • Constrictive pericarditis
  • Early Budd-Chiari syndrome
  • Inferior vena cava obstruction
  • Peritoneal carcinomatosis
  • Tuberculosis
  • Serositis
  • Pancreatic ascites
SAAG = serum-ascites albumin gradient.
Liver Disease SeverityAction
Child class A or MELD < 10Proceed to OR.
Child class B or MELD of 10-15 without portal hypertensionProceed to OR with careful postoperative monitoring.
Child class B or MELD of 10-15 with portal hypertensionPatient optimization before OR.



Consider preoperative TIPS.



Child class C or MELD ≥ 16Consider alternatives to surgery and work-up for liver transplantation.
MELD = Model for End-Stage Liver Disease; OR = operating room; TIPS = transjugular intrahepatic portosystemic shunt.
Clinical ConditionEstimated Survival
Child class C status50% at 1 year
Severe encephalopathy leading to hospitalization42% at 1 year
Ascites refractory to medical therapy50% at 1 year
HRS-CKD (type 2 HRS) with MELD score < 2050% at 11 months
HRS CKD (type 2 HRS) wtih MELD score > 2050% at 3 months
HRS-AKI (type 1 HRS)50% at 1 month
Acute-on-chronic liver failure65% at 1 month
AKI = acute kidney injury; CKD = chronic kidney disease; HRS = hepatorenal syndrome; MELD = Model for End-Stage Liver Disease.