Cirrhosis- Pathophysiology: Through various mechanisms—inflammatory, apoptotic, or necrotic injury to the liver—epithelial cells, endothelium, and hepatocytes converge to recruit and activate stellate cells. These activated stellate cells then become myofibroblasts that deposit collagen matrix and begin an unequal remodeling involving fibrogenesis and fibro-resorption among hepatic sinusoids. Understood as an end pathway, cirrhosis is characterized as a process that replaces healthy liver architecture with diffuse sinusoidal fibrosis and regenerative nodules predominantly within portal tracts. The liver receives two-thirds of its blood supply from the portal system and the derangement of its architecture directly impacts the venous portal pressures. Clinically significant portal hypertension is diagnosed when the hepatic venous gradient is greater than 10 mm Hg (normal <6 mm Hg). The complications of portal hypertension and synthetic dysfunction are intimately associated with critical illness in patients affected with cirrhosis.
- Epidemiology: Nearly 2% to 3% (~26 000 individuals) are admitted annually for cirrhosis-related complications, acute-on-chronic liver failure (ACLF), or acute liver failure (ALF). In cirrhosis, acute decompensations (ascites, variceal bleeding, spontaneous bacterial peritonitis [SBP], hepatic encephalopathy [HE], hepatorenal syndrome [HRS], hepatic hydrothorax) are common reasons for ICU admission. ACLF, which additionally manifests with extrahepatic organ failure, is a highly morbid pathway in the natural history of chronic liver disease with high short-term mortality approaching 60%. Studies suggest that 5% of intensive care unit (ICU) admissions belong to this subset of illness, and it may be the first acute decompensation in up to 20% of patients with cirrhosis. Globally, the triggering etiologies differ because alcohol-associated hepatitis (AH) and bacterial infection are more frequently recognized in the Western hemisphere, in contrast to the East, where reactivation of viral hepatitis from hepatitis B and superinfection with hepatitis E are more likely to be seen.
Acute AH is an important and rapidly increasing cause of liver-related hospitalizations in the United States. It is a clinical diagnosis, with diagnostic criteria including onset of jaundice and active alcohol use within 8 weeks, alcohol intake of greater than 40 g in women and greater than 60 g in men, aspartate aminotransferase (AST) greater than 50 and AST:ALT (alanine aminotransferase) ratio of greater than 1.5 (and both AST/ALT <400 IU/L), and T bilirubin greater than 3 mg/dL, with absence of other etiologies. Severe AH is generally defined when the Model for End-Stage Liver Disease (MELD) score is greater than 20. Approximately 70% of patients with severe AH have underlying cirrhosis, but even in the absence of cirrhosis there is a significant risk of mortality (30% at 90 days). Although therapeutic options are limited, early identification and management of this disease entity is imperative and more than 50% of transplant centers in the United States offer liver transplantation (LT) for carefully selected patients.
- Prognostication: The MELD score was created in 2001 to risk stratify patients before transjugular intrahepatic portosystemic shunt (TIPS) placement. It has replaced the Child-Pugh score as the preferred mechanism to stratify the risk of short-term (within 90 days) mortality in patients with cirrhosis. In 2008, sodium was added to the measure, improving its predictive accuracy of mortality. Patients who have an acute decompensating event may have a transiently increased MELD score; however, in a subset of patients, the MELD score remains persistently elevated. LT candidacy evaluation typically begins when a patient has a persistent MELD score of 15 or higher. Owing to the limited availability of organs and relatively poor uptake of liver donation, most patients with cirrhosis do not begin to receive offers until their MELD score is much higher, and often when it is greater than 30 (short-term mortality risk ~50%).
- Fundamentals: A few concepts are essential when caring for a patient with advanced liver disease complications.
- Infection: Patients with cirrhosis are at an exceptionally high risk for infection, which carries great morbidity and mortality (2-fold) compared to the general population. The incidence of infections in patients with decompensated cirrhosis ranges between 25% and 40%. Portal hypertension leads to enhanced intestinal permeability, enhanced activation of inflammatory cytokines, and compromised immune system function. Reduced bacterial clearance facilitates overgrowth and translocation via a more permeable intestinal tract. Activated proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 promote the development of sepsis. Infections are often the etiology of acute decompensations, especially spontaneous bacterial peritonitis (SBP) and variceal hemorrhages (VHs). The most common infections identified include SBP (25%-30%), bacteremia, urinary tract infections, community-acquired pneumonia, and soft tissue infections.
- Volume status: Decompensated cirrhosis is characterized by intravascular volume depletion, renal hypoperfusion, and extravascular volume overload. The extravascular volume overload is addressed with diuretics, and 20% to 40% of patients on diuretic therapy for ascites develop an adverse effect (typically, prerenal acute kidney injury [AKI], electrolyte abnormalities [hyponatremia, hypomagnesemia, hypo- or hyperkalemia], and, less commonly, HRS II). Best practices dictate the cessation of diuretic therapy in the presence of comorbid gastrointestinal (GI) bleeding, active uncontrolled infection, AKI, or severe hyponatremia (Na <125).
- Bleeding/coagulopathy: Among patients with cirrhosis, gastroesophageal varices (GEVs) are present in 30% to 40% of patients with compensated cirrhosis and greater than 60% of patients with decompensated cirrhosis, and VH occurs at a rate of 5% to 15% per year. There remains a 15% to 20% risk of mortality from VH but uncontrolled bleeding is not the most common cause: ACLF, HRS, and infection all are important contributors to mortality. The coagulopathy related to cirrhosis also represents a complex physiology and manifestations include both bleeding issues and abnormal clotting.
- Metabolic alterations: Another consideration is that medications may be metabolized differently in patients with cirrhosis. This can be secondary to multifactorial changes, including bowel edema and portal gastropathy, which can impair absorption, impaired renal excretion, the presence of portosystemic shunts that remove first-pass metabolism and subsequently increase bioavailability, and hypoalbuminemia that can reduce protein binding, potentially decreasing the therapeutic efficacy because the free drug is more rapidly cleared from sera. It is worth noting, however, that more than 90% of the liver’s metabolic capacity must be lost before dose adjustments for hepatic impairment are generally required.