Liver Cirrhosis

Cirrhosis is a histologic diagnosis characterized by progressive hepatic fibrosis in response to chronic injury and resulting in formation of nodules, which in turn lead to altered hepatic function and blood flow. Clinically, cirrhosis begins as compensated disease, followed by decompensation characterized by the development of ascites, jaundice, variceal bleeding, and/or encephalopathy. The term compensated advanced chronic liver disease (cACLD) has been proposed to reflect the continuum of advanced chronic liver disease that is at risk of progressing to decompensated disease. cACLD can be diagnosed with noninvasive tests rather than liver biopsy. Progression of decompensated cirrhosis leads to liver transplantation or death.

In this section, we review the causes, diagnosis, classification, and treatment of liver cirrhosis and associated complications.

Causes

The most common causes of cirrhosis are metabolic dysfunction-associated steatotic liver disease (MASLD, previously known as nonalcoholic fatty liver disease [NAFLD]), alcohol-related liver disease, and viral hepatitis. However, cirrhosis can occur due to a range of liver diseases, as outlined in the following table:

Diagnosis

The gold standard for diagnosing cirrhosis is liver biopsy. However, noninvasive tests are routinely used for diagnosis and staging.

• Liver biopsy confirms the diagnosis of liver disease and provides information on fibrosis stage, etiology, type of inflammation, and degree of steatosis. Liver biopsy has the greatest value when the diagnosis of underlying liver disease and fibrosis is uncertain.

• Composite serologic tests, such as the fibrosis-4 (FIB-4) index, combine age, alanine aminotransferase, aspartate aminotransferase, and platelet count. FIB-4 is recommended for risk stratification of patients with MASLD or alcohol-related liver disease.

  • Scores can be classified as low (<1.3), intermediate (1.30-2.67), and high (>2.67) risk for advanced fibrosis.

• Vibration-controlled transient liver elastography (VCTE) is used increasingly as a noninvasive alternative to liver biopsy. VCTE provides liver stiffness measurements (LSM) in kilopascals (kPa) that correlate with the degree of fibrosis. Readings are unreliable in patients with obesity (BMI >30 kg/m²), ascites, congestive heart failure, or cholestatic liver disease.

  • Median LSM <8.0 kPa is considered low risk for advanced fibrosis. Median LSM >15.0 kPa suggests cACLD, and LSM >25.0 kPa suggests clinically significant portal hypertension.

• Tiered risk stratification using FIB-4 and VCTE is recommended for diagnosis of MASLD.

• Abdominal ultrasound is not sensitive for the diagnosis of cirrhosis but is useful for surveillance of hepatocellular carcinoma and diagnosis of portal vein thrombosis. Splenomegaly, collaterals, and reversal of blood flow on ultrasound are markers of clinically significant portal hypertension.

• Magnetic resonance (MR) elastography is associated with fewer technical limitations than VCTE but is expensive and not widely available. Other MR protocols can be used to quantify fat and iron content, evaluate tumors and space-occupying lesions, and assess the biliary and pancreatic ducts.

Classification

The Child-Turcotte-Pugh (CTP) classification is a scoring system used to stratify patients with cirrhosis and to assess disease prognosis based on the following clinical features of end-stage liver disease (e.g., ascites and hepatic synthetic function).

Treatment

Treatment of underlying disease: When possible, treat the underlying disease. Liver transplantation is the final potential treatment for all decompensated cirrhosis. The following table summarizes therapies used to treat common causes of cirrhosis:

Management of cirrhosis: Treatment of cirrhosis focuses on prevention of further disease progression and prevention of complications. A suggested clinical approach can be found here.

Complications of Cirrhosis

If the natural history of cirrhosis cannot be interrupted, severe and life-threatening complications can develop that require urgent hospital admission.

Portal Hypertension

Portal hypertension is the main pathophysiologic basis for the complications of cirrhosis. Portal hypertension results from resistance to hepatic blood flow caused by structural and dynamic changes in the cirrhotic liver.

• Hepatic venous pressure gradient (HVPG) is the surrogate measure and gold standard for portal pressure. However, HVPG measurement is nuanced and not always available. HVPG >5 mm Hg indicates sinusoidal portal hypertension.

• Portal hypertension leads to the formation of portosystemic venous collaterals in the splanchnic circulation, giving rise to esophageal, gastric, and rectal varices and caput medusae on the abdominal wall. Portal hypertension is also the main pathophysiologic basis of ascites and hepatic encephalopathy.

• Clinically significant portal hypertension (CSPH) is defined as HVPG ≥10 mm Hg. Patients with compensated cirrhosis and CSPH are at greater risk of decompensation and death than patients without CSPH. Patients with CSPH can benefit from beta-blockers to prevent decompensation.

  • Carvedilol is the beta-blocker of choice in patients with CSPH.

  • Beta-blockers should be decreased or held if patients develop low blood pressure (systolic BP <90 mm Hg), hepatorenal syndrome, or low serum sodium.

• Presence of varices and collaterals on imaging strongly suggest CSPH in patients with compensated cirrhosis.

  • LSM by VCTE ≤15 kPa plus platelet count ≥150x10⁹/liter rules out CSPH (sensitivity and negative predictive value >90%).

  • LSM ≥25 kPa is sufficient to rule in CSPH in patients with virus- and/or alcohol-related compensated cirrhosis and nonobese (BMI <30 kg/m²) MASLD-related compensated cirrhosis (specificity and positive predictive value >90%).

The morbidity and mortality associated with cirrhosis is primarily related to the following complications:

Variceal Bleeding

• Esophageal varices can be classified by diameter (generally, small varices are ≤5 mm and medium/large varices are >5 mm).

• Acute variceal bleeding is a medical emergency requiring urgent inpatient management including endoscopic control of bleeding, vasoconstrictors, antibiotics, and blood transfusion to control bleeding and prevent early rebleeding and death.

• Previously, endoscopic surveillance was recommended for all patients with cirrhosis with the primary goal of detecting large varices and preventing variceal hemorrhage with variceal banding or beta-blockers. Today, the main goal of treatment in patients with compensated cirrhosis is to detect CSPH (by VCTE as described above) and prevent decompensation.

  • Patients at low risk for CSPH or in whom beta-blockers are indicated do not require routine endoscopic surveillance.

  • Nonselective beta-blockers (e.g., propranolol, nadolol, and carvedilol) can be used to reduce portal pressure and risk of acute variceal bleeding and ascites.

  • Patients who are unable to tolerate beta-blockers should undergo endoscopic surveillance and banding for large varices.

• Preemptive transjugular intrahepatic portosystemic shunt (TIPS) with polytetrafluoroethylene (PTFE)-covered stents within 72 hours is indicated in patients with acute esophageal and gastric variceal bleeding who meet any of the following criteria: CTP class C <14 or class B >7 with active bleeding at initial endoscopy. Details on the use of TIPS, variceal embolization, and retrograde transvenous obliteration for the management of variceal hemorrhage can be found in the comprehensive American Association for the Study of Liver Diseases (AASLD) practice guideline.

Ascites

• Ascites is the pathologic accumulation of fluid in the peritoneal cavity as a result of portal hypertension.

• Complications of ascites are infection, refractory or recurrent ascites, and association with hepatorenal syndrome.

• The initial evaluation of ascites in patients with cirrhosis should include history, physical examination, abdominal Doppler ultrasound, assessment of renal and hepatic function, serum and urine electrolytes, and a diagnostic paracentesis for analysis of the ascitic fluid.

  • A serum albumin ascites gradient (SAAG) ≥1.1 g/dL is highly suggestive of portal hypertension.

  • A high ascitic fluid protein level (>2.5 g/dL) supports a cardiac source for ascites.

• Dietary sodium restriction and fluid restriction (if patient has hyponatremia) is advised for patients with ascites.

• Diuretic treatment with a combination of an aldosterone agonist (e.g., spironolactone) and a loop diuretic (e.g., furosemide) is the mainstay of treatment for uncomplicated ascites. Doses should be increased in a stepwise pattern, aiming for maximum weight loss of 0.5-1 kg/day.

  • A spot urine sodium-to-potassium (Na/K) ratio can be used to guide therapy. If the Na/K ratio is ≤1, diuretic increase should be considered. If the Na/K ratio is >1, the patient should be losing weight; if not, dietary noncompliance should be considered.

  • In patients receiving diuretics, serum electrolytes and creatinine should be periodically monitored for adverse effects (acute kidney injury, electrolyte imbalances).

• For tense ascites and refractory ascites, large-volume paracentesis (LVP) should be performed. Albumin infusion is indicated for patients with LVP >5 liters.

• Patients with ascites should be referred for liver transplantation.

• TIPS can be considered in patients with refractory ascites.

Spontaneous Bacterial Peritonitis

• All patients with ascites and cirrhosis who present emergently to the hospital for admission and hospitalized patients with ascites and cirrhosis who develop signs and symptoms of infection should undergo diagnostic paracentesis to evaluate for spontaneous bacterial peritonitis (SBP).

• Ascitic fluid polymorphonuclear (PMN) leukocyte counts >250 cells/μL is diagnostic of SBP.

• Treatment includes empiric broad-spectrum antibiotics (e.g., ceftriaxone or cefotaxime) until results of cultures and antibiotic sensitivities are available.

• Administration of albumin has been shown to reduce mortality in patients with SBP. Albumin should be administered in divided doses with careful monitoring of respiratory status. Patients with jaundice or acute kidney injury receive the maximum benefit from albumin infusion.

• Long-term SBP prophylaxis is indicated in patients with a previous episode of SBP, low ascitic protein, CPT score >9, bilirubin >3 g/dL, or renal dysfunction. Recommended agents include norfloxacin, trimethoprim-sulfamethoxazole, or ciprofloxacin.

Hepatopulmonary Syndrome

• Hepatopulmonary syndrome is defined as a triad of cirrhosis, pulmonary gas-exchange abnormalities, and evidence of intrapulmonary vascular dilatation.

• Clinical features include dyspnea, platypnea (dyspnea exacerbated by sitting up and improved with lying down), and orthodeoxia (arterial deoxygenation with partial pressure of oxygen [PaO₂] decrease ≥5% or 4 mm Hg from supine to upright position), resulting from preferential perfusion of the lung bases, and functional shunting when the patient is upright.

• Diagnostic criteria for hepatopulmonary syndrome are described in the following table:

  

  (Source: Hepatopulmonary Syndrome — A Liver-Induced Lung Vascular Disorder. N Engl J Med 2008.)

• Oxygen supplementation may be required in some patients.

• Definitive treatment is liver transplantation.

Hepatic Encephalopathy

• Hepatic encephalopathy is a brain dysfunction caused by liver insufficiency that manifests as a wide spectrum of neurologic and psychiatric abnormalities, ranging from subclinical alterations to coma.

• In patients with cirrhosis, the most common precipitating factors include infections, gastrointestinal bleeding, diuretic overdose, electrolyte disorders, and constipation.

• Ammonia is the main surrogate marker of hepatic encephalopathy, but blood ammonia concentration poorly correlates with the degree of psychomotor dysfunction.

• Treatment of hepatic encephalopathy involves:

  • elimination of precipitating factors (e.g., gastrointestinal bleeding, renal failure, and infection)

  • maintenance of a normal protein diet

  • reduction in colonic ammonia production with oral lactulose (20-30 mL daily) as needed with the aim of two to three soft stools per day

  • oral rifaximin when added to lactulose can reduce the frequency of hospitalization and time to recurrent encephalopathy

  • embolization of large portosystemic shunts in patients with cirrhosis and hepatic encephalopathy who do not respond to standard treatment

  • admission to the medical intensive care unit (ICU) and intensive measures for patients with acute or chronic liver failure and hepatic encephalopathy to reduce hyperammonemia and prevent and manage brain edema

Acute Kidney Injury

• Acute kidney injury (AKI) is a common condition in patients with cirrhosis, affecting up to 50% of hospitalized patients with cirrhosis and 58% of such patients in the ICU.

• Hypoperfusion from hypovolemia accounts for approximately half the cases of AKI in patients with cirrhosis, intrinsic causes (e.g., acute tubular necrosis) account for approximately 30% of cases, and hepatorenal syndrome accounts for 15% to 20%, with less than 1% of cases attributable to postrenal obstruction.

• Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a type of prerenal kidney injury specifically in patients with decompensated cirrhosis and AKI.

• HRS-AKI is characterized by rapid deterioration of renal function with reduced renal blood flow due to portal hypertensive splanchnic and systemic vasodilation. However, HRS-AKI is a potentially reversible condition with treatment with vasoconstrictors and albumin. It is a diagnosis of exclusion.

  • HRS-AKI (previously referred to as HRS type 1) definition has changed to require the following criteria:

    • increase in serum creatinine level >0.3 mg/dL within 48 hours, or increase in serum creatinine to >1.5 times baseline level, or urinary output <0.5 mL/kg/hour for 6 hours

    • cirrhosis with ascites

    • no response to diuretic withdrawal and volume expansion with albumin at 1 g/kg/day (maximum 100 g/day)

    • absence of shock

    • no recent treatment with nephrotoxic drugs (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], CT contrast)

    • absence of parenchymal liver injury (i.e., absence of proteinuria >500 g per 24 hours, hematuria >50 erythrocytes/high power field, or abnormal findings on ultrasonography)

    • fractional excretion of sodium (FENa) <0.2% is suggestive of HRS-AKI (FENa <0.1% is highly predictive)

  • HRS-NAKI (previously called HRS type 2) is a slowly progressive renal dysfunction in patients with decompensated cirrhosis and ascites.

    • HRS-NAKI in the context of chronic kidney disease (HRS-CKD) is defined as a patient with cirrhosis and a glomerular filtration rate (GFR) <60 mL/min/1.73 m² for more than three months in whom other causes have been excluded.

    • HRS-NAKI in the context of acute kidney disease (HRS-AKD) is defined as renal dysfunction that does not meet criteria for AKI and lasts for <90 days.

• The workup and management of AKI in patients with cirrhosis are described in the following algorithm:

(Source: Acute Kidney Injury in Patients with Cirrhosis. N Engl J Med 2023.)

Hepatocellular Carcinoma

• Liver cirrhosis is considered precancerous, although time of progression to hepatocellular carcinoma (HCC) varies depending on the underlying disease.

• In patients with cirrhosis secondary to chronic hepatitis C virus infection, the annual incidence of HCC is 1%-8%; in patients with cirrhosis secondary to chronic hepatitis B virus (HBV) infection, the annual incidence of HCC is 1%-15%.

• Worldwide, HBV infection is the main cause of HCC and can occur in the absence of cirrhosis.

• Hepatitis B vaccination of infants and children has resulted in a marked decrease in incidence.

• If a liver nodule is detected on screening ultrasonography, the following diagnostic algorithm can be used:

  

  (Source: Hepatocellular Carcinoma. N Engl J Med 2019.)

• A range of treatments are available for HCC depending on stage of disease, including tumor ablation, resection, transarterial therapies, and systemic therapies.

• Liver transplantation may be an option for patients with small or localized HCC.

Read this review article for a detailed overview of hepatocellular carcinoma diagnosis treatment.

Liver Transplantation

Patients with cirrhosis should be considered for liver transplantation if they have had an index complication such as ascites, hepatic encephalopathy or variceal hemorrhage, or hepatocellular dysfunction resulting in a Model for End-Stage Liver Disease (MELD) score ≥15. MELD is based on creatinine, bilirubin, international normalized ratio (INR), and sodium levels. Transplantation is considered the last option for management. As with all organ transplantation, detailed patient workup is required prior to consideration.