Table of Contents
I. Cirrhosis and Acute-on-Chronic Liver Failure

Pathophysiology and Progression of Cirrhosis
ACLF: Definitions, Grades and Mortality
Precipitants in ACLF

II. Organ-Specific Complications in Cirrhosis/ACLF

Complications of Cirrhosis – Variceal Hemorrhage (VH)
Complications of Cirrhosis – Ascites
Complications of Cirrhosis – Hepatic Encephalopathy
Complications of Cirrhosis – Spontaneous Bacterial Peritonitis
Hepatorenal Syndrome/Acute Kidney Injury (HRS/AKI)

III. Summary

I. Cirrhosis and Acute-on-Chronic Liver Failure

Pathophysiology and Progression of Cirrhosis

Cirrhosis, the end stage of any chronic liver disease, is characterized by diffuse progressive fibrosis, severe disruption of the intrahepatic venous flow, portal hypertension (PH) and liver failure. [Arroyo 2016] According to current estimates, there are roughly 4.9 million people living with cirrhosis in the United States, and in 2019 was the eleventh most common cause of death. [US Dept of Veterans Affairs 2024; Heron 2019] With ongoing increases in both nonalcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease, combined with a continued high incidence of viral hepatitis, the impact of cirrhosis on the US health system is significant. [US Dept of Veterans Affairs 2024; Arroyo 2016]

The clinical prognosis and outcomes of cirrhosis are important to define. The course of cirrhosis can be divided into two stages: compensated and decompensated. In compensated cirrhosis, patients typically do not have symptoms related to their cirrhosis, but may have asymptomatic esophageal or gastric varices. Patients have a relatively long median survival time of more than 12 years. The presence of varices is the key prognostic factor for compensated patients and indicates a higher likelihood of decompensation. [US Dept of Veterans Affairs 2019] In decompensated cirrhosis, patients become symptomatic. The median survival time is approximately 2 years due to the presence of overt extrahepatic complications such as ascites, variceal hemorrhage (VH), hepatic encephalopathy (HE), or acute kidney injury (AKI). Patients with symptomless compensated cirrhosis experience a better quality of life compared to those patients with decompensated cirrhosis. [D’Amico 2017] There are no available direct treatments for cirrhosis other than surgical options; management is limited to addressing the etiology of liver disease, whereupon extrahepatic complications may improve. [US Dept of Veterans Affairs 2019]

[Arroyo 2016]

There are several pathophysiological changes that can occur in patients with progressive cirrhosis. Patients with cirrhosis initially have increased portal circulation, predominantly because of increased local nitric oxide production, which contributes to the development of ascites. [Nadim 2023] The cascade of changes that can occur includes PH that leads to splanchnic arterial vasodilation and a decrease in systemic vascular resistance (SVR). [Davenport 2012] With a decrease in total SVR, arterial underfilling occurs leading to a decrease in the effective arterial blood volume. [Davenport 2012] As cirrhosis proceeds, excessive nitric oxide spills over into the systemic circulation, leading to systemic vasodilation and activation of compensatory neurohumoral systems: renin-angiotensin-aldosterone system (RAAS), arginine vasopressin (AVP), and sympathetic nervous system (SNS). [Davenport 2012] It has become increasingly evident that patients rarely die because of an end-stage irreversible destruction of the liver, but rather, the cause of death is an acute deterioration in their clinical condition promoted by a precipitating event — a syndrome termed acute‑on‑chronic liver failure (ACLF). [Arroyo 2016] Extensive heterogeneity exists in the definition of ACLF globally, but typically speaking ACLF describes a patient with underlying chronic liver disease experiencing an acute insult such as infection in the context of intense systemic inflammation, accompanied by single- or multi-organ failure, that increases the risk of 28-day mortality. [Arroyo 2020]

ACLF: Definitions, Grades and Mortality

There are three major definitions for ACLF:

• The North American Consortium for the Study of End-Stage Liver Disease (NACSELD) defines ACLF by the presence of at least two severe extrahepatic organ failures including shock, grade III/IV HE, renal replacement therapy, or mechanical ventilation. [Bajaj 2014]
• The European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) consortium defines ACLF as a specific syndrome in patients with cirrhosis that is characterized by acute decompensation, organ failure, and high short-term mortality. The development of ascites, HE, gastrointestinal hemorrhage, and/or bacterial infections defines acute decompensation; however, patients may develop ACLF without a history of acute decompensation. Organ failures include liver, kidney, brain, respiratory system, circulation, and coagulation, and they are assessed by the CLIF-consortium organ failures score. [Jalan 2014]
• The Asian Pacific Association for the Study of the Liver (APASL) defines ACLF as “an acute hepatic insult manifesting as jaundice (serum bilirubin ≥5 mg/dL [85 µmol/L]) and coagulopathy (international normalized ratio [INR] ≥1.5 or prothrombin activity , <40%) complicated within 4 weeks by clinical ascites and/or hepatic encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease/cirrhosis and is associated with a high 28-day mortality.” Extrahepatic organ failure is not required to make the diagnosis. [Sarin 2019]

ACLF can be defined as a potentially reversible condition in patients with cirrhosis that is associated with the potential for multiple organ failure and mortality within 3 months in absence of treatment of the underlying liver disease, liver support, or liver transplantation. [Bajaj 2022] The severity of organ failure may be assessed by the EASL-CLIF sequential organ failure assessment score or the NACSELD organ failures score. [Jalan 2014] Patients with advanced stages of ACLF are best managed in the intensive care unit (ICU) and some may benefit from early liver transplantation. [Bajaj 2022]

[Hernaez 2017]

The mortality rate of patients with ACLF is related to the presence and number of organ failures. Renal dysfunction and/or cerebral dysfunction when associated with a single organ failure, were found to predict prognosis. [Perricone 2019] The following are ACLF grades based on the number of organ failures: [Perricone 2019]

• No ACLF: no organ failure or a single nonrenal organ failure without renal dysfunction and cerebral dysfunction
• ACLF grade 1 (ACLF‐1): single renal failure and single nonrenal organ failure that is associated with renal dysfunction and/or cerebral dysfunction
• ACLF grade 2 (ACLF‐2): two organ failures of any combination
• ACLF grade 3 (ACLF‐3): three or more organ failures of any combination

Among the different organ failures in ACLF, the most frequently affected organs are the kidneys. [Perricone 2019] Once patients start developing acute kidney injury and start showing symptoms of other organ failures, the prognosis and mortality increases. At three or more organ failures, then they have a substantial 28-day and 90-day mortality that can rise to well above 70%. [Moreau 2013]

Precipitants in ACLF

ACLF represents the summation of chronic liver disease and the associated extrahepatic organ failure that is understood to be initiated by precipitants such as systemic infection, viral hepatitis, alcohol use, or gastrointestinal (GI) hemorrhages. Infections are the most common precipitant of ACLF despite geographic variations in prevalence. Fungal infections represent only a small portion of the systemic infections that precipitate ACLF but are associated with worse prognostic outcomes. The most likely sources of infection include urinary tract infections, spontaneous bacterial peritonitis, pneumonia, secondary peritonitis, spontaneous bacteremia and skin and soft tissue infections. The preventative strategy of infection-precipitated ACLF is centered on prophylaxis and early rational antibiotic treatment, both of which have been associated with improved survival among patients with cirrhosis. [Cullaro 2020]

[Hernaez 2017]

Viral hepatitis is a common precipitant of ACLF. ACLF due to viral hepatitis is severe with high mortality rates, despite the availability of vaccines and curative treatments. [Cullaro 2020] Hepatitis B virus (HBV) is the most common viral infection to precipitate ACLF and can cause ACLF in acute infection or in the setting of HBV reactivation in the setting of treatment cessation, HBV resistance, chemotherapy, or immunosuppression. The presentation of ACLF due to HBV is typically acute and severe resulting in an up to 50% 28-day mortality rate. Prevention, close monitoring, and use of antiviral medications are recommended in patients with viral hepatitis and at risk for ACLF. [Cullaro 2020]

Alcohol use disorder as an etiology of cirrhosis results in some pathophysiologic differences as a precipitant of ACLF. One key difference seen in patients with alcohol-related ACLF is that there is an elevation in white blood cell count and C-reactive protein which causes systemic inflammation and immune dysfunction. [Moreau 2013, Cullaro 2020] This elevation in white blood cells and C-reactive protein suggests that alcohol-related liver injury may lead to more potent inflammatory reactions, as compared with other precipitants of ACLF. Another key difference is in the mechanism of cell death in alcohol-related ACLF. Cell death is a key driver of ACLF, irrespective of the etiology of liver disease, and it is now established that damage-associated molecular patterns (DAMPs) have immunologic properties that drive the inflammatory response. [Cullaro 2020] Alcohol-related cell death may be driven through mechanisms distinct from apoptosis, unlike nonalcohol-related cell death, which alter the immunologic response due to the different profile of DAMPs being released. [Macdonald 2018] Together, these findings suggest that alcohol-associated ACLF may cause a specific immunologic response that is distinct from other drivers of ACLF. [Cullaro 2020] Preventative strategies hinge on promoting abstinence from alcohol to mitigate ongoing liver damage, and include counselling to prevent recurrence, pharmacotherapy, and behavior change.

Gastrointestinal hemorrhage is another precipitant in ACLF although some complications in its consideration as a ACLF precipitant exist. APASL only considers variceal bleeding a precipitant if it results in liver failure, whereas EASL and AASLD consider it a precipitant in all cases. [Sarin 2019, Cullaro 2020] Presence of a GI hemorrhage may precipitate ACLF due to hepatic ischemia, increased bacterial translocation from the gut, and subsequent bacterial infections. [Sargenti 2015] Management of varices will be discussed later in this activity.

II. Organ-Specific Complications in Cirrhosis/ACLF

Principles of management of ACLF are typically directed toward the specific organ affected.

[Zaccherini 2020]

Most clinical studies to date have been conducted in critically ill patients with cirrhosis. Consequently, many guidelines and evidence-based recommendations are derived from studies on patients with organ-specific complications of cirrhosis.

[D’Amico 2018; Angeli 2018]

Complications of Cirrhosis – Variceal Hemorrhage (VH)

The hepatic venous pressure gradient (HVPG) is an indirect measure of portal pressure and predicts the development of both varices and decompensation. HVPG is the gold standard for determining PH, although non-invasive tests such as platelet count and spleen size can assist in identification.  Normal HVPG is 3–5 mmHg, whereas >5 mmHg indicates PH and >10 mmHg identifies clinically-significant portal hypertension (CSPH) and those patients at risk of developing varices and/or clinical decompensation. [de Franchis 2022] Varices develop in order to decompress the hypertensive portal vein, in order to return blood to the systemic circulation.

Esophageal varices and gastrointestinal hemorrhage are a frequent decompensating event in patients with cirrhosis, but its mortality differs whether it presents as an isolated complication of cirrhosis or whether it presents in association with other complications. [Garcia-Tsao 2017] VH occurs at a rate of around 10% to 15% per year and depends on the severity of liver disease, size of varices, and presence of red wale marks (areas of thinning of the variceal wall). [D’Amico 2014] Treatment for varices should be risk-stratified according to the different clinical stages of cirrhosis and portal hypertension. For example, patients with a liver stiffness score of <20kPa by elastography, and a platelet count of >150,000/mm³ are at generally very low risk of varices, and the objective of therapy for patients at this early stage is to prevent progression. [Garcia-Tsao 2017] There are three general types of therapy for prevention of VH; pre-primary prophylaxis (prevention of varices), primary prophylaxis (prevention of first bleeding events) and secondary prophylaxis.  Currently-available treatments are aimed at either reducing PH or treating the varices directly.

In patients who have yet to develop varices, treatment of the underlying liver disease will decrease the risk of varix formation, as will dietary and lifestyle changes aimed at reducing BMI and promoting abstinence from alcohol. These patients should be routinely screened by esophagogastroduodenoscopy (EGD) for varix formation. In these patients a series of trials with nonspecific beta-blockers (NSBBs) has failed to show any significant benefit, and their use is not recommended [de Franchis 2022, Garcia-Tsao 2017]

The treatment of patients with small varices depends on whether they are at an elevated risk of hemorrhage. [Garcia-Tsao 2017] Two approaches are recommended: pharmacologic prophylaxis using an NSBB such as propranolol or nadolol, carvedilol or endoscopic prophylaxis by endoscopic variceal ligation (EVL). NSBBs are the recommended therapy for patients with high-risk small esophageal varices. [Garcia-Tsao 2017] An older meta-analysis of eight randomized, controlled trials comparing NSBBs to no therapy vs placebo showed a benefit of NSBBs in preventing first VH. [D’Amico 1999] A subsequent study of 19 randomized, controlled trials comparing NSBBs to EVL showed that EVL was associated with lower rates of upper gastrointestinal bleeding and VH, without differences in mortality. [Gluud 2012] In cases in which NSBBs must be discontinued because of intolerance, the patient can be switched to carvedilol, which is becoming more widely used, being generally better tolerated than traditional NSBBs. [de Franchis 2022, Garcia-Tsao 2017] The use of EVL over NSBBs, particularly in the absence of VH, should be balanced with considerations over expense, potential risk, and inconvenience.  Combination therapy NSBB plus EVL is not recommended in this setting as well as TIPS placement in the prevention of first VH. [Garcia-Tsao 2017]

[Garcia-Tsao 2017]

Acute GI Bleeds

Extensive discussion of acute GI bleed management is beyond the scope of this activity. Learners wishing to review evidence-based algorithms for the management of acute VH should review [Zanetto 2019]. During an episode of acute GI bleeding, primary goals are to restore and maintain hemodynamic stability and adequate oxygenation, control bleeding and prevent complications. General resuscitative and supportive measures for patients with cirrhosis and GI bleeding, who have a history of or are at risk for varices include the following:

• Intravenous access and fluids
• Supplemental oxygen and airway protection: endotracheal intubation is preferred over nasal cannula to protect the patient’s airway in cases of hemodynamic instability.  This approach also facilitates endoscopic diagnosis and therapy [Rudolph 2003]
• Transfusion of red blood cells and platelets: goal is to maintain hemoglobin between 7-9 g/dL along with compensatory platelets to avoid volume dilution. Intravascular volume status must be monitored to prevent or to avoid volume overload due to the risk of rebound PH and induction of rebleeding [Villanueva 2013]
• Antibiotic prophylaxis: ceftriaxone is the initial antibiotic of choice, prior to endoscopy. The benefit of antibiotics has been demonstrated to lower risk of rebleeding, bacterial infections and overall mortality [Chavez-Tapia 2011]
• Other pharmacologic therapies: intravenous splanchnic vasoconstrictors for bleeding; select pre-existing outpatient medications when safe; electrolyte and vitamin repletion; NSBBs and other antihypertensives should be stopped during active bleeding; careful use of proton pump inhibitors if gastric ulcers are suspected to be a cause of bleeds
• Gastric lavage and endoscopy: should be performed within 12 hours of admission after fluid resuscitation.  When bleeding varices are confirmed or the only abnormality that would explain the bleed, all varices should be ligated.     

Complications of Cirrhosis – Ascites

Cirrhosis is the main cause of ascites, being responsible for about 80% of cases. [Angeli 2018] Ascites occurs at a rate of about 5% to 10% in compensated cirrhosis patients annually, and it is the most common cause of decompensation in cirrhosis. [Angeli 2018] Ascites development is due to renal sodium retention due to the activation of sodium retaining systems, such as the RAAS and SNS. [Angeli 2018, Biggins 2021] The resulting positive fluid balance leads to extracellular fluid volume expansion, with portal hypertension playing a role by acting as a compartmentalizing factor of the expanded extracellular fluid volume. The severity of ascites can be graded on a scale of 1 to 3 depending on the amount of fluid in the abdominal cavity: [Angeli 2018]

Grade 1. Mild ascites, only detectable by ultrasound examination

Grade 2. Moderate ascites, manifest by moderate symmetrical distension of abdomen

Grade 3. Large or gross (tense) ascites, provokes marked abdominal distension

The presence of ascites not only leads to further complications that may require hospitalization, but it is an indicator of poorer prognosis; the 5-year survival rate drops from about 80% in compensated patients to about 30% in decompensated cirrhosis patients with ascites. [D’Amico 2006]

Diagnosis and Management of Ascites

Diagnostic evaluation of a patient with ascites begins with the initial evaluation and should include history, physical examination, abdominal doppler ultrasound, laboratory assessment of liver and renal function, serum and urine electrolytes. A diagnostic paracentesis for analysis of the ascitic fluid is recommended for all patients with grade 2/3 ascites. [Biggins 2021] Upon examination of the etiology of ascites, the serum albumin ascites gradient (SAAG) is calculated. [Biggins 2021] A serum albumin ascites gradient of greater than or equal to 1.1 g/dL is highly suggestive of portal hypertension, and it is predictive with an accuracy of approximately 97%. [Biggins 2021] A serum albumin ascites gradient of less than 1.1 g/dL suggests other causes of ascites such as, peritoneal carcinomatosis, tuberculosis peritonitis, or other clinical conditions.

[Biggins 2021]

There is little evidence to suggest treatment of grade 1 improves patient outcomes, as such no treatment is recommended. [Biggins 2021] In patients with uncomplicated moderate grade ascites (no infection, normal renal function and treatment-responsive), treatments to reduce sodium retention are recommended, by diet and diuretics. [Angeli 2018, Biggins 2021] Moderate (but not extreme) sodium restriction of 2 g or 90 mmol/day ensures a negative sodium balance and a net fluid loss. [Biggins 2021] However, despite the dietary sodium restriction in patients with cirrhosis, this alone is insufficient to improve the clinical condition and diuretic therapy should be considered; spironolactone is generally the mainstay of uncomplicated ascites treatment, with amiloride or furosemide as reasonable options. [Biggins 2021] In addition to the management techniques, an assessment of 24-hour urinary sodium excretion may be useful to guide therapy. [Biggins 2021] For long-standing ascites, the best response to treatment was seen in a combined diuretic treatment. [Biggins 2021] Once ascites is mobilized, attempts should be made to taper the diuretics to the lowest dosages to maintain minimal or no ascites. [Biggins 2021]

For patients presenting with grade 3 ascites, large-volume paracentesis (LVP) is the safest and most effective approach. Studies suggest that overall TIPS has improved rates of survival than LVP in patients where transplant is not an option, and may be better at controlling ascites, but patients are at greater risk of hepatic encephalopathy and other complications after TIPS. [Bureau 2017, Angeli 2018, Biggins 2021] The complete volume should be removed in a single session, and must be followed by plasma volume expansion, usually by infusion with albumin (8 g per liter of ascites fluid removed). [Angeli 2018, Biggins 2021] Low-dose diuretics should be started to prevent fluid re-accumulation. [Biggins 2021]

Complications of Cirrhosis – Spontaneous Bacterial Peritonitis

There is a high prevalence of bacterial infections in patients with cirrhosis who are hospitalized. [Angeli 2018, Biggins 2021] These bacterial infections can be seen in up to one-third of patients, significantly higher rates than those patients without cirrhosis. [Tandon 2008] A common yet unique type of infection in this setting are “spontaneous” infections that occur in the absence of an obvious source of infection, such as spontaneous bacterial peritonitis (SBP), spontaneous bacteremia, and spontaneous bacterial empyema (SBE). Bacterial translocation, the passage of bacteria from the gut to the bloodstream and other extraintestinal sites, has been proposed in the pathogenesis of these spontaneous infections. Accordingly, the risk of SBP increases with the presence of VH, supporting this hypothesis [Biggins 2021]

Signs and symptoms specific to SBP include but are not limited to abdominal pain, tenderness on palpitation, and ileus. Recall that ACLF can be triggered by precipitants such as systemic infection, so it is important to treat SBP as soon as possible. [Cullaro 2020] The diagnosis of SBP and SBE is established using a diagnostic paracentesis or thoracentesis, and a fluid polymorphonuclear (PMN) leukocyte count greater than 250/mm³. [Biggins 2021] The paracentesis should be performed on all patients with cirrhosis at admission, and with any change in symptoms suggestive of an infection. IV antibiotics should be started empirically in all patients with an ascites PMN count greater than 250/mm³. [Biggins 2021] In principle, antibiotics should be used sparingly in patients without a prior history of SBP and reserved only for those at the highest risk of infection. [Biggins 2021] In patients without gastrointestinal hemorrhage and without a prior episode of SBP, antibiotic prophylaxis may be considered in selected patients at an elevated risk of SBP:

• Low protein (<1.5 g/L) ascites with
• Renal dysfunction (serum creatinine level >1.2 mg/dL, blood urea nitrogen level >25 mg/dL, or serum sodium level <130 mEq/L) or
• Liver failure (Child-Turcotte-Pugh score >9 and bilirubin >3 mg/dL)

Patients who have recovered from an episode of SBP should receive long-term prophylaxis with daily norfloxacin; if norfloxacin is unavailable, oral ciprofloxacin is a reasonable option. [Biggins 2021]

Complications of Cirrhosis – Hepatic Encephalopathy

HE is a brain dysfunction directly correlated to liver dysfunction or portosystemic shunting, most often recognized in advanced liver disease. [Vilstrup 2014, Reau 2016, Acharya 2018] HE is characterized by signs of altered consciousness, personality changes, impaired intellectual function, and neuromuscular dysfunction. Early recognition of HE is essential, as 3-year survival rates are less than 25%, and proactive identification can allow time to deploy preventative strategies and mitigate clinical consequences. [Fichet 2009, Reau 2016]

Diagnosis of HE

The diagnosis of HE is clinical. Since no test is completely able to confirm or exclude the diagnosis, a combination of high clinical suspicion, exclusion of alternative etiologies, and a favorable response to therapy is required for a diagnosis. Several conditions can mimic overt HE including delirium, cerebrovascular accident or hemorrhage, or uremia. There are a range of precipitating factors of overt HE including comorbid conditions such as gastrointestinal bleeding, infections, electrolyte abnormalities, renal failure, and medication noncompliance. [Reau 2016]

The West Haven Criteria is one of the most commonly used scales to grade HE. [Conn 1994] According to the West Haven Criteria for grading mental state in patients with cirrhosis, a grade of 0 to 1 indicates covert HE, while grades 2 to 4 indicate overt HE. [Conn 1994, Vilstrup 2014, Reau 2016]

• In covert HE, grade 0, there are no abnormalities detected.
• In covert HE grade 1, the patient starts presenting with a trivial lack of awareness, euphoria, or anxiety, shortened attention span, and/or impairment of addition or subtraction.
• Lethargy or apathy describe overt HE grade 2, in addition to disorientation concerning time, obvious personality changes and inappropriate behavior.
• In grade 3 overt HE, the patient portrays bizarre behavior, gross disorientation, somnolence to semi stupor, yet is still responsive to stimuli.
• In grade 4 overt HE, the patient is in a coma and is unable to be evaluated to determine mental state.

Nitrogen metabolism is altered in HE pathology, and a significant number of patients with overt HE have elevated blood-ammonia levels. [Reau 2016] However, many patients without clinical HE also have elevated ammonia levels. As such ammonia testing in HE is insufficient for diagnosis, and high blood-ammonia levels alone do not add any diagnostic, staging, or prognostic value in HE patients. [Lockwood 2004, Vilstrup 2014] However, in the event of ammonia testing, in which levels come back normal, the diagnosis of HE can be called into question. [Vilstrup 2014]

[Reau 2016]

Hepatorenal Syndrome/Acute Kidney Injury (HRS/AKI)

Definitions and Criteria

Renal dysfunction is a common, life-threatening complication occurring in patients with cirrhosis. [Angeli 2019] Portal hypertension results in initially splanchnic arterial vasodilation, but subsequently this effect becomes systemic. To prevent excessive tubular filtration, the renal vascular beds hyperconstrict; this is mediated by both the sympathetic nervous system as well as cytokine and vasodilatory hormones acting in concert. This results in acute kidney injury, classified as hepatorenal syndrome (HRS/AKI).  Traditionally, renal dysfunction in patients with liver disease has been defined by a serum creatinine (SCr) concentration of greater than or equal to 1.5 mg/dL. [Salerno 2007]

Originally called HRS type 1, HRS/AKI can be defined as a rapid reduction in renal function as seen by an absolute increase of SCr ≥0.3 mg/dL over baseline within a 48-hour time period, or ≥50% increase in SCr that is known or presumed to have occurred within the preceding 7 days. [Angeli 2019, Biggins 2021] A second type, HRS type 2 is characterized by renal dysfunction that does not progress rapidly and is associated with refractory ascites. [Angeli 2019] After the consensus definition of HRS/AKI in patients with cirrhosis by the International Club of Ascites (ICA) in 2015, professional society guidelines and publications have shown some diversity regarding the nomenclature, definitions, and criteria for HRS/AKI and HRS-2. [Angeli 2015, Angeli 2018, Angeli 2019, Biggins 2021, Flamm 2022, Bajaj 2022, Nadim 2024] It is clear that several etiologies of renal dysfunction can occur in patients with cirrhosis; they may be acute, sub-acute, or chronic, leading to the potential classifications of HRS/AKI, HRS-acute kidney disease (AKD), and HRS-chronic kidney disease (CKD), respectively.

[Angeli 2019]

Staging and Prognosis of HRS/AKI in Cirrhosis

AKI is defined as an abrupt (arbitrarily set at 48 hours) reduction in kidney function manifested by an absolute increase in SCr of 0.3 mg/dL or more, equivalent to a percentage increase in SCr 50% or more (1.5-fold from baseline) or a urine output of less than 0.5 mL/kg per hour for more than 6 hours. [KDIGO 2012] This AKI definition was used by the ICA to develop the framework for staging HRS/AKI; 3 stages indicate the severity of renal dysfunction and are based on SCr baseline levels and increases [Angeli 2015, Angeli 2018, Biggins 2021, Nadim 2024]

• Stage 1

Increase in SCr ≥0.3 mg/dL (≥26.4 µmol/L) or increase ≥1.5-fold to 2-fold from baseline

• Stage 2

Increase in SCr ≥2-fold to 3-fold from baseline

• Stage 3

Increase in SCr ≥3-fold to 4-fold from baseline with an acute increase ≥0.3 mg/dL (≥26.4 µmol/L), or initiation of renal replacement therapy

Clinicians should note that, unlike other etiologies of AKI, reduction in urine output has not traditionally been included in the criteria for HRS/AKI. [KDIGO 2012, Angeli 2015] However, patients with cirrhosis and ascites are often oliguric and sodium-avid, which negatively impacts their prognosis, and more recent guidelines including the Acute Disease Quality Initiative (ADQI) have incorporated urine output recommendations, because of its importance in assessing prognosis. [Amathieu 2017, Nadim 2024] It is also important to note that any patient requiring renal replacement therapy is automatically stage 3 HRS/AKI, and this aligns with ACLF Stage 3 (refer to Figure 2), putting patients at significant risk of multi-organ failure and low survival rates.

Serum creatinine, although limited as a biomarker, remains the most important predictor of mortality in HRS/AKI. A 2017 study assessed independent predictors of mortality in patients admitted for complications of cirrhosis. [Nuthalapati 2017] Incremental increases of SCr of ≥0.1-0.2 mg/dL had no impact on survival when SCr was within normal ranges (less than 1.2 mg/dL). However, any increase in SCr levels in patients where the peak levels were ≥1.5 mg/dL were associated with the worst outcomes. The worst survival outcomes were in the group with serum creatinine above 1.5 mg/dL (hazard ratio 2.27, 95% CI 1.58–3.25), compared to those with a maximum creatinine of 1.2 mg/dL or lower. [Nuthalapati 2017] Because of the prognostic importance of SCr levels above 1.5 mg/dL, some guidelines have recommended the use of Stage 1a (SCr<1.5 mg/dL) and Stage 1b (SCr≥1.5 mg/dL) as differentiating criteria; patients with Stage 1b could be treated in line with Stage 2 patients, even in the absence of an absolute 2-fold increase in SCr. [Angeli 2018, Flamm 2022]

Prevalence and Etiologies of AKI in Cirrhosis

Three general types of AKI are classified based on the location of pathology – either prerenal, intrarenal, or postrenal AKI. It is important to remember that many etiologies of AKI can occur in patients with cirrhosis: the most commonly identified are prerenal azotemia, HRS/AKI, acute tubular necrosis (ATN), glomerulonephritis, and postrenal AKI (typically obstructions); identifying many of these types exactly can often only be done based on how they respond to management. AKI occurs in approximately 19% of hospitalized patients with cirrhosis, and the most common cause is prerenal AKI, accounting for roughly two-thirds of the cases. [Garcia-Tsao 2008] Depending on the study, anywhere from 12%-20% of AKI etiologies are HRS/AKI. [Garcia-Tsao 2008, Patidar 2022, Nadim 2024]

[Compiled from multiple sources and expert opinion]

Diagnosis and Management of AKI in Cirrhosis

Differential diagnosis of HRS/AKI remains challenging and can still be considered a diagnosis of exclusion. Proposed algorithms for the diagnosis of HRS/AKI in cirrhosis use consensus criteria after excluding hypovolemia, shock, nephrotoxic agents, and structural kidney damage. [Angeli 2018, Biggins 2021, Flamm 2022, Nadim 2024] Post-renal AKI in patients with cirrhosis is rare, and HRS/AKI can be distinguished from pre-renal azotemia by volume expansion.  The major challenge is therefore establishing whether structural nephron damage has occurred (ATN), either alone or in combination with HRS/AKI pathophysiology, which can be difficult to establish in the absence of a biopsy. The structural biomarker NGAL has proven potentially useful in this regard, although it is not yet widely available. [Huelin 2019, Allegretti 2021, Nadim 2024]

[Biggins 2021]

If another specific diagnosis has not been made, and SCr elevations indicate an etiology of AKI, an investigation to uncover and treat precipitating factors must be conducted swiftly. Diagnosis of HRS/AKI typically relies on the following: [Angeli 2018, Biggins 2021, Flamm 2022, Nadim 2024]

• Cirrhosis with ascites
• Diagnosis of AKI according to ICA criteria
• No response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin infusion (1 g/kg body weight per day)
• Absence of shock
• No current or recent use of nephrotoxic drugs (NSAIDs, aminoglycosides, or iodinated contrast media)
• No signs of structural kidney injury, as indicated by proteinuria (>500 mg per day), microhematuria (>50 red blood cells per high-power field), and/or abnormal renal ultrasonography

The initial approach to managing HRS/AKI is the treatment or prevention of possible risk factors, particularly gastrointestinal bleeding, and bacterial infections, and avoiding large-volume paracentesis without albumin administration. [Nadim 2024] In addition, there are specific circumstances for which management recommendations may be helpful. Non-steroidal anti-inflammatories (NSAIDs) are in common use as analgesics among patients with cirrhosis, because they don’t require a prescription and there are concerns about acetaminophen and liver toxicity; clinicians must ask about them. Acetaminophen is the recommended pain medication in cirrhosis, as NSAIDs are nephrotoxic, and when used in accordance with guidelines there is no risk of liver toxicity with acetaminophen. In patients with vasoconstriction to the extent seen in the renal bed in HRS/AKI, ACE inhibitors and ARBs are deleterious and should be stopped. Lactulose should be dosed to achieve 2-3 bowel movements per day. It is also generally recommended that diuretics be stopped and any gastrointestinal varices be managed using EVL. Intravenous albumin, together with antibiotics improves survival in patients with SBP. [Angeli 2015, Biggins 2021, Nadim 2024] However, albumin alone in patients with decompensated cirrhosis neither prevents HRS/AKI nor improves survival and increasing levels of albumin significantly increases the risk of side effects related to fluid overload, such as pulmonary edema. [China 2021] Close daily monitoring of albumin is recommended to avoid fluid overload, and systematic administration is not recommended. [Nadim 2024]

Vasoconstrictors are the guideline-recommended mainstay of treatment for established HRS/AKI, most commonly either terlipressin or norepinephrine, in combination with albumin. [Angeli 2018, Biggins 2021, Flamm 2022, Bajaj 2022, Nadim 2024] In several randomized controlled trials and meta-analyses it has been shown that they are effective in improving kidney function in patients with HRS/AKI, although data for norepinephrine is much older and the evidence is of lower quality. [Facciorusso 2017] The orally active vasoconstrictor midodrine in combination with octreotide has also traditionally been used although it is of much lower efficacy than terlipressin. [Cavallin 2015] However, definitions of HRS/AKI have changed over the past twenty years, and as such clinical studies have often used different inclusion criteria, patient profiles, and endpoints; consistent outcomes have therefore been challenging to elucidate. [Biggins 2021]

Norepinephrine

Norepinephrine has been the vasoconstrictor of choice in the US until the recent FDA approval of terlipressin. Four clinical trials covering a total of around 150 patients have been included in meta-analyses to show that norepinephrine and terlipressin are roughly equivalent at reversing HRS/AKI; all studies were conducted prior to the ICA’s HRS/AKI criteria changes in 2015. [Facciorusso 2017] The requirement for a central line means that norepinephrine is ICU-restricted, and typically patients are transferred into the ICU when a less effective option such as midodrine-octreotide fails to restore renal function. With the approval of terlipressin, norepinephrine is recommended when terlipressin is not available or cannot be administered. Norepinephrine is administered by continuous i/v infusion starting at 0.5 mg/h to achieve an increase in mean arterial pressure of at least 10 mm Hg or an increase in urine output of >200 mL/4 h. If at least 1 of these goals is not achieved, increase every 4 h in increments of 0.5 mg/h up to a maximum of 3 mg/h.  [Biggins 2021, Bajaj 2022, Nadim 2024]

Terlipressin

Terlipressin is FDA-approved to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function. However, patients with serum creatinine of more than 5 mg/dL are unlikely to experience a benefit. Terlipressin also has warnings for serious or fatal respiratory failure, and patients with volume overload or with ACLF grade 3 are at increased risk. [TERLIVAZ PI]

[TERLIVAZ PI]

Three phase 3 studies have assessed terlipressin vs placebo in patients with HRS/AKI. [Sanyal 2008, Boyer 2016, Wong 2021] In all studies, terlipressin improved renal function significantly compared to placebo. Most recently in CONFIRM, verified reversal of HRS was reported in 32% of patients in the terlipressin group and 17% of patients in the placebo group (P=0.006). Verified HRS reversal is defined as 2 consecutive SCr values ≤1.5 mg/dL, at least 2 hours apart, with patient alive without RRT for ≥10 days after the second sCr ≤1.5 mg/dL. [Wong 2021] More adverse events, including abdominal pain, nausea, diarrhea, and respiratory failure, occurred with terlipressin than with placebo. Death within 90 days due to respiratory disorders occurred in 11% of patients in the terlipressin group and 2% of patients in the placebo group. In conclusion, terlipressin was more effective than placebo in improving renal function but was associated with serious adverse events, including respiratory failure. [Wong 2021]

In order to understand why some patients respond to treatment better than others, data from the three large-scale phase 3 clinical studies (OT-0401, REVERSE, and CONFIRM) were pooled together to perform a subgroup analysis. [Curry 2023] This pooled analysis revealed that baseline SCr levels were significantly associated with HRS reversal. Patients with HRS/AKI who were treated with terlipressin at a lower baseline SCr level experienced a higher rate of HRS reversal than those patients with a higher baseline serum creatinine. [Curry 2023] Moreover, survival outcomes for patients with HRS/AKI who were treated with terlipressin were inversely correlated with both baseline SCr levels and ACLF grade. [Curry 2023] These data underscore and support the boxed warning. [TERLIVAZ PI] Among terlipressin-treated patients, the incidence of serious adverse events increased as the baseline SCr subgroup level increased. This analysis supports the need to identify and treat patients with HRS earlier in the disease process, resulting in a greater probability of responding to an intervention. [Curry 2023]

[Curry 2023]

III. Summary

Cirrhosis is the end stage of any chronic liver disease, and the clinical impact of cirrhosis and end-stage liver disease are substantial. The course of cirrhosis can be divided into two stages: compensated and decompensated. The transition from compensated to decompensated cirrhosis occurs at a rate of about 5% to 7% per year and once progressed to decompensated cirrhosis, the median survival time drops from about 12 years to 2. [Angeli 2018] It has become increasingly evident that patients rarely die because of an end-stage irreversible destruction of the liver, but often, the cause of death is an acute deterioration in their clinical condition promoted by a precipitating event — a multi-organ syndrome termed ACLF. [Arroyo 2016] In patients with chronic liver disease and cirrhosis, ACLF is emerging as a major cause of mortality, and kidney failure is a significant driver of that. [Bajaj 2022] Significant extrahepatic complications of decompensated cirrhosis include variceal bleeding, ascites, encephalopathy, and HRS/AKI. [D’Amico 2017] Revised classifications of HRS type 1 align now with other existing definitions of AKI, and whether the kidney pathophysiology is acute, sub-acute, or chronic, leading to the subclassifications of HRS/AKI, HRS-AKD, and HRS-CKD, respectively. [Angeli 2019] Following albumin challenge to establish the diagnosis of HRS/AKI, vasoconstrictors are the mainstay of treatment to maintain kidney function, most commonly terlipressin or norepinephrine. [Nadim 2024]

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