What are lymphoplasmacytic infiltration and hemophagocytic lymphohistiocytosis (HLH) of the liver, and what is their significance in a pregnant patient?

Lymphoplasmacytic Infiltration and Hemophagocytic Lymphohistiocytosis in Pregnancy

Hemophagocytic lymphohistiocytosis (HLH) presenting with hepatic involvement during pregnancy is a life-threatening emergency requiring immediate recognition and aggressive treatment, as maternal mortality can exceed 50% without prompt intervention, and expeditious delivery is often necessary for maternal survival.

Understanding the Pathology

Lymphoplasmacytic Infiltration

Lymphoplasmacytic infiltration of the liver refers to the accumulation of lymphocytes and plasma cells within hepatic tissue. In the context of pregnancy, this finding on liver biopsy can indicate:

• Autoimmune hepatitis: May present with severe hepatic necrosis accompanied by interface hepatitis, plasma cell infiltration, and hepatocyte rosettes 1
• HLH: Can manifest as acute hepatitis with lymphohistiocytic infiltration 2

Hemophagocytic Lymphohistiocytosis (HLH)

HLH is a severe hyperinflammatory syndrome characterized by uncontrolled activation of macrophages and cytotoxic T cells, resulting in widespread tissue damage 3, 4. The pathologic hallmark is hemophagocytosis—activated macrophages engulfing normal blood cells.

Critical Significance in Pregnancy

Maternal Mortality Risk

HLH during pregnancy carries exceptionally high maternal mortality rates, with death occurring in up to 50-75% of cases without appropriate treatment 5, 6. The condition can rapidly progress from initial symptoms to multiorgan failure within days.

Clinical Presentation

Pregnant patients with HLH typically present with:

• Fever (often persistent and unexplained)
• Hepatic dysfunction with marked transaminitis and hyperbilirubinemia 7, 2
• Cytopenias (particularly thrombocytopenia, leukopenia, neutropenia) 5, 6
• Markedly elevated ferritin (often >10,000 ng/mL)
• Coagulopathy
• Hepatosplenomegaly
• Neurological symptoms (headache, altered mental status) 6

Diagnostic Challenge

HLH in pregnancy is frequently misdiagnosed as pregnancy-specific liver diseases (HELLP syndrome, acute fatty liver of pregnancy) or sepsis, leading to delayed treatment and worse outcomes 7, 2, 8. The overlap in clinical features creates diagnostic confusion:

• Both HELLP and HLH present with thrombocytopenia, elevated liver enzymes, and coagulopathy
• HLH can occur concurrently with HELLP syndrome 8
• Ferritin levels are the key discriminator: ferritin >10,000 ng/mL strongly suggests HLH over HELLP

Diagnostic Approach

HLH-2004 Criteria

Diagnosis requires 5 of 8 criteria 3:

1. Fever ≥38.5°C
2. Splenomegaly
3. Cytopenias (affecting ≥2 cell lines)
4. Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL)
5. Hemophagocytosis in bone marrow, spleen, or lymph nodes
6. Low or absent NK cell activity
7. Ferritin ≥500 ng/mL (typically much higher in true HLH)
8. Elevated soluble CD25 (IL-2 receptor)

Tissue Diagnosis

Liver biopsy can establish the diagnosis when bone marrow biopsy is not feasible, showing hemophagocytosis and lymphohistiocytic infiltration 2. This is the first reported case where HLH was diagnosed on liver biopsy presenting as acute hepatitis 2.

Management Algorithm

Step 1: Immediate Recognition and Stabilization

• Suspect HLH in any pregnant patient with unexplained fever, hepatic dysfunction, cytopenias, and ferritin >10,000 ng/mL
• Obtain urgent hematology consultation
• Stabilize coagulopathy and metabolic derangements before delivery

Step 2: Confirm Diagnosis

• Bone marrow biopsy (preferred) or liver biopsy showing hemophagocytosis 7, 2
• Complete HLH-2004 criteria assessment
• Rule out infectious triggers (EBV, CMV, HHV6) and malignancy 2

Step 3: Treatment Initiation

For severe cases threatening maternal life:

• Etoposide-based therapy (HLH-2004 protocol) should be strongly considered despite pregnancy, as maternal survival takes precedence 5
• Etoposide 150 mg/m² IV twice weekly plus dexamethasone 10 mg/m² daily 3, 5
• This represents a departure from typical pregnancy management but is justified by the >50% maternal mortality without treatment

For less severe cases or when etoposide is declined:

• High-dose corticosteroids (prednisone 40-60 mg/day or equivalent dexamethasone) can be effective as monotherapy in select cases 6
• One case report demonstrated successful treatment with corticosteroids alone, resulting in healthy twin delivery at 30 weeks 6

Step 4: Obstetric Management

Expeditious delivery is recommended once maternal condition is stabilized, as pregnancy itself may be a trigger for HLH 2. However, timing must balance:

• Maternal stabilization (correct coagulopathy first)
• Fetal viability and maturity
• Severity of maternal disease

Delivery does not cure HLH but removes a potential trigger and simplifies treatment 2.

Step 5: Postpartum Care

• Continue HLH-directed therapy postpartum
• Monitor for relapse (occurs in some cases)
• Long-term follow-up for potential underlying autoimmune disease 6

Critical Pitfalls to Avoid

1. Attributing all findings to HELLP syndrome without checking ferritin: HELLP rarely causes ferritin >1,000 ng/mL; levels >10,000 ng/mL indicate HLH 8

2. Delaying etoposide in severe cases due to pregnancy concerns: Maternal mortality without etoposide exceeds fetal risks from exposure 5

3. Assuming delivery will resolve the condition: Unlike HELLP or acute fatty liver of pregnancy, HLH requires specific immunosuppressive therapy and may persist or worsen postpartum 7, 2

4. Missing the diagnosis on liver biopsy: Pathologists unfamiliar with HLH may misinterpret findings as acute hepatitis; hemophagocytosis must be specifically sought 2

5. Failing to recognize HLH as a contraindication to liver transplantation: If acute liver failure develops, liver transplantation is contraindicated as HLH will recur in the transplanted organ 9. Chemotherapy and bone marrow transplantation are the appropriate treatments 9.

Prognosis

With prompt recognition and aggressive treatment including etoposide-based therapy, maternal survival is possible, though fetal outcomes vary 5. Delayed diagnosis or treatment with corticosteroids alone in severe cases results in maternal mortality rates of 50-75% 5, 6. Fetal demise can occur even with maternal treatment 5.