What happens when the white blood cell (WBC) count is low in patients with liver failure?

White Blood Cell Count in Liver Failure

In liver failure, the white blood cell (WBC) count typically runs low due to cirrhosis-associated immune-deficiency syndrome, splenic sequestration from portal hypertension, and bone marrow suppression, but paradoxically, an elevated or rising WBC count often signals infection, systemic inflammation, or acute-on-chronic liver failure (ACLF) and is associated with worse outcomes.

Mechanisms of Low WBC Count in Liver Failure

• Portal hypertension leads to splenomegaly and splenic sequestration of white blood cells, similar to the mechanism causing thrombocytopenia in these patients 1
• Cirrhosis-associated immune-deficiency syndrome directly impairs immune cell production and function, predisposing patients to both low WBC counts and increased infection risk 1
• Bone marrow suppression can occur in advanced liver disease, particularly in alcohol-associated cirrhosis, contributing to pancytopenia 1

Clinical Significance of WBC Changes

When WBC Count is Low (Leukopenia)

• Baseline leukopenia reflects disease severity and the degree of portal hypertension, serving as a marker of advanced cirrhosis 1
• Low platelet-to-WBC ratio (PWR ≤ 12.1) predicts 28-day mortality in cirrhotic patients with acute decompensation, with a hazard ratio of 1.707 2
• Leukopenia increases vulnerability to infections, which are the most common precipitant of ACLF (48% of cases) 1

When WBC Count is Elevated or Rising

• A relative increase in WBC count signals infection or ACLF development, even if the absolute value remains within normal range 1
• Elevated WBC at baseline independently predicts 90-day mortality in infected ACLF patients 3
• High WBC count at admission predicts poor 30-day survival in hospitalized cirrhotic patients with infection 4
• The WBC count is incorporated into the CLIF-C Acute Decompensation score for prognostication: 10 × [0.03 × Age + 0.66 × Ln(Creatinine) + 1.71 × Ln(INR) + 0.88 × Ln(WBC) - 0.05 × Sodium + 8] 1

Critical Diagnostic Considerations

Infection Detection Challenges

• Fever is often absent in cirrhotic patients with sepsis, making WBC trends more important than absolute values 1
• Alcohol-associated hepatitis independently increases WBC count and other inflammatory markers, confounding infection diagnosis 1
• A 30% or higher drop in WBC count from baseline should prompt investigation for bone marrow suppression or overwhelming sepsis, similar to the principle used for platelet monitoring in DIC 5

When to Suspect Infection Despite Low WBC

Maintain high suspicion for sepsis when patients present with:

• New or worsening hepatic encephalopathy 1
• Acute kidney injury 1
• Hyponatremia 1
• Hemodynamic changes 1
• Higher ACLF grade 1

Even with leukopenia, these clinical signs mandate:

• Immediate diagnostic paracentesis for spontaneous bacterial peritonitis 1
• Urinalysis and urine culture 1
• Blood cultures (two sets) 1
• Chest imaging if respiratory symptoms present 1

Prognostic Implications

Short-term Mortality Predictors

Independent predictors of 30-day mortality in infected cirrhotic patients include:

• High WBC count at admission 4
• Development of ≥2 organ failures (infection-related ACLF) 4
• Second infection occurrence 3, 4
• High MELD score 3, 4
• Low mean arterial pressure 4

Special Populations

• Nosocomial infections with abnormal WBC counts carry particularly poor prognosis and increase risk of multi-drug resistant organisms 1
• Patients with low PWR (≤12.1) have higher adverse outcome rates regardless of ACLF presence, though the predictive value is lost in those with active bacterial infection 2

Common Pitfalls to Avoid

• Do not dismiss normal WBC counts as reassuring in cirrhotic patients with clinical deterioration; look for relative increases from baseline 1
• Do not attribute elevated WBC solely to alcohol-associated hepatitis without ruling out infection through appropriate cultures 1
• Do not wait for fever to develop before investigating infection in cirrhotic patients with rising WBC or clinical decompensation 1
• Do not overlook fungal infections in patients with persistent leukocytosis despite antibiotics, as fungi account for 15.9% of infections in ACLF with 30% mortality at 30 days 1, 3

Rare but Critical Consideration

Acute leukemia can present as acute liver failure with markedly elevated WBC count, lactate dehydrogenase, and uric acid, though this carries very poor prognosis 6