What are the clinical features and pathophysiology of chronic liver disease (CLD) and decompensated CLD in patients?

Clinical Features and Pathophysiology of Chronic Liver Disease and Decompensated Chronic Liver Disease

Defining the Critical Transition

Chronic liver disease (CLD) encompasses the full spectrum of progressive liver damage from early fibrosis through advanced cirrhosis, while decompensated CLD represents the catastrophic transition marked by clinically evident complications—a watershed moment that reduces median survival from over 12 years to merely 1.8 years. 1, 2

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Pathophysiology: The Portal Hypertension Cascade

Primary Driver of Decompensation

• Portal hypertension serves as the fundamental pathophysiologic mechanism driving the transition from compensated to decompensated disease. 1, 3
• Clinically significant portal hypertension (CSPH) is defined as hepatic venous pressure gradient (HVPG) ≥10 mmHg, which represents the threshold above which decompensating events occur. 1, 3
• CSPH is present in approximately 50-60% of patients with compensated cirrhosis who have no varices. 1
• Portal pressure predicts the development of cirrhosis complications more accurately than liver biopsy. 1

Systemic Pathophysiologic Derangements

• Decompensated cirrhosis involves a complex interplay of systemic inflammation, circulatory dysfunction, metabolic derangements, mitochondrial dysfunction, and oxidative stress that perpetuate a vicious cycle of organ injury. 4
• Systemic inflammation drives progression to acute-on-chronic liver failure (ACLF), characterized by extrahepatic organ failures. 4
• Circulatory dysfunction and splanchnic vasodilation contribute to the development of ascites and hepatorenal syndrome. 4

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Clinical Features of Compensated CLD

General Characteristics

• Patients are largely asymptomatic with preserved hepatic function. 5
• Median survival exceeds 12 years in the compensated stage. 1
• Early cirrhosis is potentially reversible—treating the underlying etiology offers opportunity for fibrosis regression. 1, 5

Risk Stratification

• Child-Turcotte-Pugh (CTP) class A indicates compensated cirrhosis. 1
• Presence of CSPH (HVPG ≥10 mmHg) increases risk of developing varices, decompensation, and hepatocellular carcinoma. 1
• Risk factors for progression include minimal hepatic encephalopathy, infections, variceal bleeding, ascites, diabetes, and hepatitis C. 6

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Clinical Features of Decompensated CLD

Defining Decompensating Events

Decompensated CLD is definitively diagnosed by the presence of at least one clinically overt complication: ascites, variceal hemorrhage, hepatic encephalopathy, or jaundice. 2

Ascites

• The most frequent decompensating event. 3
• Develops as a consequence of portal hypertension, splanchnic vasodilation, and sodium retention. 4
• Grade 2 or 3 ascites requires diagnostic paracentesis in all patients. 2
• Refractory ascites carries particularly poor prognosis. 7

Variceal Hemorrhage

• Results from portal hypertension exceeding the CSPH threshold. 1
• Represents a life-threatening emergency requiring immediate vasoactive drug therapy even before endoscopic confirmation. 8
• Gastric varices may also develop and require specific management strategies. 7

Hepatic Encephalopathy (HE)

Hepatic encephalopathy is a brain dysfunction caused by liver insufficiency and/or portosystemic shunting, manifesting as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma. 6

Epidemiology of HE

• Prevalence of overt HE (OHE) at cirrhosis diagnosis is 10-14% overall, but 16-21% in those with decompensated cirrhosis. 6
• OHE will occur in 30-40% of cirrhosis patients at some point during their clinical course. 6
• Minimal or covert HE occurs in 20-80% of cirrhotic patients. 6
• Risk of first OHE bout is 5-25% within 5 years after cirrhosis diagnosis. 6
• After first OHE episode, 40% cumulative risk of recurrence at 1 year. 6
• After TIPS placement, 10-50% develop OHE within 1 year. 6

Clinical Presentation of HE

• The spectrum ranges from subtle psychometric test abnormalities affecting attention, working memory, psychomotor speed, and visuospatial ability to frank coma. 6
• Personality changes include apathy, irritability, and disinhibition reported by relatives. 6
• Sleep-wake cycle disturbances with excessive daytime sleepiness are frequent. 6
• Progressive disorientation to time and space, inappropriate behavior, acute confusional states with agitation or somnolence, stupor, and ultimately coma. 6
• The onset of disorientation or asterixis marks the beginning of overt HE. 6

Motor System Abnormalities in HE

• Hypertonia, hyperreflexia, and positive Babinski sign in noncomatose patients. 6
• Deep tendon reflexes may diminish or disappear in coma, though pyramidal signs persist. 6
• Extrapyramidal dysfunction: hypomimia, muscular rigidity, bradykinesia, hypokinesia, monotonous and slow speech, parkinsonian-like tremor. 6
• Asterixis ("flapping tremor") is present in early to middle stages preceding stupor or coma—it represents negative myoclonus (loss of postural tone) rather than true tremor. 6
• Asterixis is elicited by wrist hyperextension with separated fingers or rhythmic squeezing of examiner's fingers, but can occur in feet, legs, arms, tongue, and eyelids. 6
• Asterixis is not pathognomonic of HE as it occurs in other metabolic encephalopathies. 6

Jaundice

• Reflects severe hepatocellular dysfunction and impaired bilirubin metabolism. 2
• Presence indicates advanced decompensation with poor prognosis. 2

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Disease Progression and Substratification

Clinical Staging of Decompensated Disease

Decompensated cirrhosis can be further stratified into distinct prognostic categories based on disease stability and organ failure development. 2, 9

• Stable decompensated cirrhosis (SDC): Patients discharged without readmission during 3-month follow-up. 1, 9
• Unstable decompensated cirrhosis (UDC): Liver-related complications requiring readmission but without ACLF. 1, 9
• Pre-ACLF: Higher frequency of complications with increased risk of developing ACLF. 1, 9
• ACLF (grades 1-3): Most severe form with organ system failures and 28-day mortality ≥20%. 1, 9

Prognostic Implications

• The first decompensation event signals a drastic decline in survival, making early intervention in compensated CLD critical. 1, 5
• Median survival drops from 10-12 years in compensated disease to 1-2 years after first decompensation. 2, 5
• Generally requires non-elective hospital admission. 1
• Associated with 28-day mortality of approximately 5% or less without ACLF. 1
• CTP class B/C indicates mostly decompensated cirrhosis. 1
• CTP class C patients who stop drinking have approximately 75% 3-year survival versus 0% if drinking continues. 1

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Critical Management Pitfalls to Avoid

• Do not treat all CLD patients uniformly—risk stratification by presence of CSPH and varices is essential for appropriate management. 1
• Avoid nephrotoxic drugs in decompensated patients. 1
• Avoid large volume paracentesis without albumin replacement. 1
• Avoid beta-blockers during acute variceal bleeding. 1
• NSAIDs should be avoided as they can convert diuretic-sensitive ascites to refractory ascites. 1
• Propranolol in patients with refractory ascites is associated with poorer outcomes. 7
• Mean pulmonary arterial pressure ≥45 mmHg is an absolute contraindication to liver transplantation. 1
• Interferon-α is absolutely contraindicated in hepatitis B-related decompensation. 2