Complications of cirrhosis (Ascites, Spontaneous bacterial peritonitis, Esophageal varices, Hepatic encephalopathy, and Hepatorenal syndrome)

Summary

Cirrhosis represents the end-stage of chronic liver disease, characterized by extensive fibrosis and architectural distortion. The major complications - ascites, spontaneous bacterial peritonitis (SBP), esophageal varices, hepatic encephalopathy, and hepatorenal syndrome - arise from portal hypertension and hepatic insufficiency. These complications mark the transition from compensated to decompensated cirrhosis, dramatically reducing median survival from >12 years to approximately 2 years. Early recognition and management are crucial for improving outcomes.

The most common first decompensating event is ascites (50%), followed by variceal hemorrhage (25%) and hepatic encephalopathy (20%). Understanding the pathophysiology, clinical features, and management of each complication is essential for both clinical practice and examinations in Jordan.

Introduction

The major complications of cirrhosis discussed in this article are ascites, spontaneous bacterial peritonitis, esophageal varices, hepatic encephalopathy, and hepatorenal syndrome.  Causes of cirrhosis are discussed in separate articles.

Ascites

Ascites refers to the accumulation of fluid within the peritoneal cavity ( figure 1); it is often seen with cirrhosis (but can also develop due to other causes).  Fibrotic changes to the liver induce resistance to blood flow, leading to increased portal pressure (ie, portal hypertension).  Downstream hemodynamic effects on the splanchnic vasculature (eg, increased hydrostatic pressure, renin-angiotensin-aldosterone system [RAAS] activation) promote fluid and sodium retention, resulting in ascites.  In addition, reduced albumin synthesis by the cirrhotic liver reduces osmotic pressure, causing fluid transudation into the peritoneal cavity.

• Abdominal distension:  Patients often present with visible swelling of the abdomen and increased abdominal girth.  Examination findings can include a positive fluid wave, flank dullness, and shifting dullness.
• Weight gain, dyspnea, early satiety:  These manifestations can develop due to fluid accumulation, which results in increased intraabdominal pressure.

The work-up of ascites is directed at confirming the underlying etiology and ruling out infection.  In addition to imaging (eg, abdominal ultrasonography), a diagnostic paracentesis should be performed in all patients ( figure 2).  Ascites from cirrhosis is usually yellowish or straw-colored.  Analysis reveals high serum-ascites albumin gradient (SAAG) (≥1.1), which confirms elevated portal pressure (a low SAAG is not consistent with cirrhosis), and low total protein (<2.5 g/dL).  Cell count and differential should be obtained to rule out spontaneous bacterial peritonitis (ie, neutrophil count ≥250/mm³).

In addition to managing the underlying cause of cirrhosis (eg, alcohol avoidance), the following are used for management:

• Sodium restriction (<2 g/day):  Dietary modifications are aimed at reducing fluid retention.
• Diuretic therapy:  The combination of spironolactone and furosemide (at a ratio of 100 mg of spironolactone to 40 mg of furosemide) helps increase the efficacy of natriuresis and prevents electrolyte disturbances.
• Paracentesis:  In refractory cases, large-volume paracentesis (therapeutic removal of ascitic fluid) may be required.

Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis (SBP) refers to infection of ascitic fluid in patients with cirrhosis ( table 1).  The primary mechanism is believed to be translocation of enteric bacteria (eg, Escherichia coli).  Other than cirrhosis, risk factors for SBP include gastrointestinal bleeding and low ascitic protein.  SBP can be associated with complications such as renal failure (hepatorenal syndrome), worsening hepatic encephalopathy, and organ failure.

Classic manifestations are abdominal pain and tenderness (may be subtle or absent), fever, and altered mental status.  Some patients can be minimally symptomatic or asymptomatic, so a high index of suspicion is crucial.  Some guidelines recommend diagnostic paracentesis in all patients with ascites who are hospitalized for any cause.

Diagnostic paracentesis in SBP shows an elevated ascitic fluid neutrophil count (≥250/mm³).  Ascitic fluid culture may help identify the causative organism, although it is often negative.

• Empiric antibiotics:  Treatment should be initiated promptly, typically with broad-spectrum antibiotics such as a third-generation cephalosporin (eg, ceftriaxone) to cover the most common pathogens (gram-negative enteric bacteria).
• Albumin:  Administration of albumin with antibiotics can reduce mortality and improve kidney function.
• Prophylaxis:  In patients with prior episodes of SBP or in those at high risk (very low ascitic fluid protein), antibiotics may be used to prevent recurrence.

SBP in the setting of cirrhosis should be distinguished from secondary bacterial peritonitis (eg, from ulcer or intestinal perforation), mycobacterial/fungal ascites, and other causes of ascites (eg, malignancy).

Esophageal varices

Elevated portal pressure (portal hypertension) can cause dilation of small, preexisting vascular channels between the portal and systemic circulations, including in the inferior end of the esophagus.  This leads to esophageal varices ( figure 3), which become predisposed to rupture and can result in potentially life-threatening upper gastrointestinal bleeding.

Large-volume hematemesis may lead to hemodynamic instability and also increase the risk of hepatic encephalopathy (discussed below).

• For management of acute variceal bleed, a vasoactive agent (eg, octreotide) is administered and endoscopy therapy (eg, application of bands directly onto varices [ie, ligation]) can be used for thrombosis.
• In cases of refractory bleeding, transjugular intrahepatic portosystemic shunt (TIPS) can be considered ( figure 4).
• Nonselective beta blockers (eg, nadolol) are used for primary prophylaxis (patients with esophageal varices that have not yet bled) and secondary prophylaxis (patients with prior history of variceal bleeding) by lowering portal pressure.

Hepatic encephalopathy

The pathogenesis of hepatic encephalopathy (HE) is related to increased circulatory levels of ammonia and other neurotoxins due to failure of the liver to metabolize waste products.  Excess ammonia crosses the blood-brain barrier and disrupts neurotransmission, contributing to neurologic dysfunction.

HE is a spectrum of neurocognitive and motor abnormalities that range from mild cognitive deficits to profound coma.  Asterixis, a characteristic flapping tremor with outstretched hands, is indicative of advanced stages of hepatic encephalopathy.  The diagnosis is clinical and serum ammonia measurement is rarely necessary.

The underlying precipitants of HE usually involve disturbances in nitrogen metabolism ( table 2):

• Increased nitrogenous waste production:  infections such as SBP (increased bacterial catabolism of proteins), gastrointestinal bleeding (breakdown of blood products in gut lumen, associated hypovolemia), and metabolic triggers of glutaminolysis (hypokalemia, metabolic alkalosis)
• Decreased ammonia clearance:  worsening liver function (eg, ischemia, hepatocyte loss), decreased renal function (ie, impaired NH₄⁺ excretion), or constipation (eg, opioid-induced bowel slowing)
• New portosystemic shunting:  surgically placed portocaval shunts (eg, TIPS) that create a conduit for neurotoxins to bypass the liver and enter the CNS

• Addressing precipitating factors:  identification and treatment of triggers, such as gastrointestinal bleeding or infections.
• Lactulose ( figure 5):  Nonabsorbable disaccharides (eg, lactulose) are catabolized by intestinal bacterial flora to short chain fatty acids, lowering the colonic pH and increasing conversion of ammonia to ammonium.

• Rifaximin:  a nonabsorbable antibiotic that alters gastrointestinal flora to decrease intestinal production and absorption of ammonia.  In patients with hepatic encephalopathy, rifaximin is generally used in addition to lactulose.

Hepatorenal syndrome

Hepatorenal syndrome (HRS) is a life-threatening complication of advanced cirrhosis characterized by rapidly progressive kidney dysfunction.  HRS involves hormonally mediated renal vasoconstriction induced by portal hypertension and splanchnic arterial vasodilation.  The hormonal cascade contributes to chronically low blood pressure with activation of RAAS, leading to overwhelming renal vasoconstriction ( figure 6).  HRS can develop spontaneously or be triggered by a specific insult such as SBP, variceal bleeding, and excessive diuresis, all of which can compromise renal hemodynamics.

Diagnosing HRS is challenging and relies on the exclusion of other potential causes of acute kidney injury (AKI) ( figure 7).  Laboratory findings typically show an extreme prerenal pattern of AKI (urine sodium <10 mEq/L) and urinalysis is usually unremarkable.  Because prerenal AKI due to volume depletion presents similarly to HRS, a trial of intravascular volume expansion (eg, intravenous albumin) is needed to confirm the diagnosis.  A lack of improvement in renal function with volume expansion confirms HRS.  Depending on the severity of AKI, HRS is classified into:

• Type 1 HRS (HRS-AKI):  more severe type, characterized by a doubling of serum creatinine in <2 weeks.
• Type 2 HRS:  less severe type, typically associated with diuretic-resistant ascites.

Treatment for HRS prioritizes supportive care with a focus on optimizing circulatory volume.  In addition to intravenous albumin, vasoconstrictors (eg, terlipressin, norepinephrine) are given to counteract splanchnic vasodilation and help alleviate the hormonally induced renal vasoconstriction.  This is only a temporizing measure that can serve as a bridge to liver transplantation, which shuts off the overwhelming hormonal cascade and restores renal function.

Summary Table