Waldenstrom Macroglobulinemia Leading to Cholestatic Liver Injury and Rapid Progression to Liver Failure.

INTRODUCTION

Waldenstrom macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is an uncommon, indolent B-cell lymphoproliferative disorder characterized by small lymphocytes and immunoglobulin M (IgM) hypergammaglobulinemia, bone marrow infiltration, lymphadenopathy, bleeding, and hyperviscosity. 1 WM may also exhibit extramedullary hematopoietic tissue infiltration such as lymphadenopathy, hepatomegaly, and splenomegaly in about 25% of cases, but hepatic clinical manifestations and hepatic failure are unusual. 2 , 3

CASE REPORT

A 77-year-old man with no history of liver disease was admitted to the hospital for a myeloma workup due to several months of constitutional B symptoms, 30-lb weight loss, and elevated IgM 4,307 mg/dL. Additional laboratory findings included a hemoglobin 10 g/dL (baseline ∼12), mean cell volume 103 fL, aspartate aminotransferase (AST) 45 U/L, alanine aminotransferase (ALT) 30 U/L, platelet count 148 K/µL, international normalized ratio (INR) 1.0, lactate dehydrogenase 209 U/L, and albumin 3.2 g/dL. Bone marrow biopsy instead demonstrated a lambda-restricted B-cell lymphoproliferative disorder with plasmacytic differentiation (14% plasma cells). MYD88 mutation was also positive, supporting the diagnosis of WM. Positron emission tomography scan was negative for evidence of disease. Given his weight loss and new macrocytic anemia, his outpatient hematologist initiated Zanubrutinib, a Bruton tyrosine kinase inhibitor, though adherence was documented as intermittent (Table 1 ).

Three months after diagnosis, the patient developed jaundice with total bilirubin 8.8 mg/dL, direct bilirubin 3.8 mg/dL, alkaline phosphatase 154 U/L, AST 45 U/L, ALT 28 U/L, platelet count 118 K/µL, and INR 1.3. Zanubrutinib was stopped. Magnetic resonance cholangiopancreatography showed cholelithiasis with marked gallbladder thickening, normal liver morphology, and no biliary duct obstruction (Figure 1 ). He underwent an endoscopic ultrasound and endoscopic retrograde cholangiopancreatography with biliary sphincterotomy, which demonstrated biliary sludge and small nonobstructing gallstones, followed by a cholecystectomy a few days later. His cholestatic liver injury did not improve with these interventions. Liver biopsy was performed later in the admission, which showed marked cholestatic hepatitis, prominent sinusoidal fibrosis, and increased lambda plasma cells, compatible with patient's known WM (Figure 2 ). Congo Red stain was negative for amyloidosis. He was treated with a 5-day course of cyclophosphamide/dexamethasone to treat the underlying WM and was discharged. One week later, he was readmitted for worsening hyperbilirubinemia (total bilirubin 18.8 mg/dL, direct bilirubin 8.6 mg/dL, alkaline phosphatase 159 U/L, AST 165 U/L, ALT 111 U/L, platelet count 152 K/µL, INR 1.6), new hepatic encephalopathy, and acute kidney injury requiring dialysis. Abdominal computed tomography (CT) scan now showed a cirrhotic morphology of the liver with portal hypertension, ascites, anasarca, and pleural effusions (Figure 3 ). The hematology team considered a second cycle of cyclophosphamide, but the patient elected to discharge against medical advice. Five days after his against medical advice discharge, he was readmitted again for shock and worsening renal failure. CT scan showed a cirrhotic morphology once again (Figure 4 ). At this point, given his critical condition and poor prognosis, the decision was made to transition patient to comfort care. He was discharged to hospice the following day and died 4 days later (Figure 5 ).

DISCUSSION

We presented a rare instance of nonobstructive cholestatic liver injury and rapidly progressive liver failure secondary to WM. This presentation is striking because such fulminant hepatic deterioration — particularly one refractory to WM-directed therapy — is unexpected in a malignancy typically characterized by an indolent course. 4 Although hepatic involvement in WM is not uncommon and severe cholestasis has been described in cases of IgM-associated amyloid light-chain (AL) amyloidosis, our patient's liver biopsy demonstrated no amyloid deposition. 5 – 9 This is suggestive that the primary driver of hepatic failure was due to direct sinusoidal infiltration by lymphoplasmacytic cells rather than secondary amyloidosis. This distinction underscores a rare and aggressive manifestation of WM that expands the recognized spectrum of hepatic involvement.

Aside from AL amyloidosis, other possible mechanisms of liver injury were explored. One consideration is drug-induced liver injury (DILI) from either zanubrutinib or cyclophosphamide. Zanubrutinib has a LiverTox likelihood score of E*, indicative that it was a suspected but unproven cause of DILI. Zanubrutinib is more often associated with hepatocellular injury, with ALT elevations of 5 times above the upper limit of normal being infrequently observed, and even so, it rarely causes clinically apparent liver injury. 10 , 11 Thus, zanubrutinib is unlikely to fully explain the patient's clinical course, given that he had a cholestatic pattern of liver injury that progressed despite discontinuation.

Cyclophosphamide, a WM-directed cytotoxic therapy that the patient received in a later admission, has known hepatotoxicity with a LiverTox likelihood score of B, identifying it as a highly likely cause of DILI. It has been shown to cause cases of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) at myeloablative doses. 12 , 13 However, SOS/VOD in patients with cyclophosphamide use is typically seen at higher doses given intravenously, while our patient received oral cyclophosphamide at a lower dose than DILI would be expected to occur. 12

Systemic processes such as ischemic hepatitis from shock, sepsis-associated cholestasis, and acute bile acid nephropathy were considered for his rapid clinical deterioration. However, the patient did not have documented periods of shock, sustained hypotension, nor sepsis preceding the onset of his jaundice, and the pattern of liver enzyme elevation was also inconsistent with the marked aminotransferase elevations typically seen with ischemic hepatopathy. Acute bile acid nephropathy in the setting of worsened hyperbilirubinemia was likely contributive to his renal dysfunction later in his clinical course. Hemophagocytic lymphohistiocytosis was also considered, particularly given his cytopenias, possible organomegaly, and history of hematologic malignancy. However, this is also unlikely because he did not have fevers nor other laboratory test values consistent with the diagnostic criteria of hemophagocytic lymphohistiocytosis. 14

CT imaging demonstrated cirrhotic morphology, raising concern for rapid progression to cirrhosis. However, radiographic findings alone may be misleading, as acute hepatic congestion or pseudo-cirrhosis can produce similar appearances and may not reflect established fibrosis. Notably, the patient's magnetic resonance cholangiopancreatography performed just weeks earlier demonstrated normal liver morphology, making rapid progression to true cirrhosis unlikely. In this context, liver biopsy provided critical clarification, revealing prominent sinusoidal fibrosis with lymphoplasmacytic infiltration and supporting WM-related hepatic involvement as the primary driver of decompensation.

In conclusion, this case underscores the importance of recognizing potential aggressive hepatic involvement and sinusoidal infiltration by WM despite its typically indolent nature. Clinicians should suspect infiltrative malignancy when there is progressive worsening of liver function and cholestasis despite withdrawal of potential hepatotoxic medications and ruling out other common etiologies for cholestasis. An early liver biopsy can be useful in determining the etiology of unexplained cholestasis in the setting of hematologic malignancies. Differentiating between AL Amyloidosis, SOS/VOD secondary to medication hepatoxicity, and WM cell sinusoidal infiltration early may help in choosing specific therapies to slow or prevent further cholestatic liver damage and improve patient outcomes.

DISCLOSURES

Author contributions: H. Chi: Performed literature review, drafted initial draft and finalizations of case report. D. Kim: Performed literature review, drafted initial draft and finalizations of case report. G. Waidyaratne: Provided edits and finalization of case report. N. Hashi: Provided edits and finalization of case report. S. Sun: Provided the pathology images and interpretations. K. Maddocks: provided expert opinion on the hematologic aspects of the clinical case. S. Kelly: Provided expert opinion, edits, and finalization of case report and is the article guarantor.

Financial disclosure: None to report.

Previous presentation: American College of Physicians Internal Medicine Meeting 2025; April 3–5, 2025; New Orleans, LA.

All attempts have been exhausted in trying to contact the patient, next of kin, and/or parent/guardian for informed consent to publish their information, but consent could not be obtained.

ABBREVIATIONS:

acute kidney injury

amyloid light-chain

alanine aminotransferase

direct bilirubin

drug-induced Liver Injury

hemophagocytic lymphohistiocytosis

intensive care unit

immunoglobulin

International normalized ratio

aspartate aminotransferase

nothing by mouth

positron emission tomography

sinusoidal obstruction syndrome/veno-occlusive disease

total bilirubin

Waldenstrom Macroglobulinemia

Contributor Information

David Kim, Email: david.kim@osumc.edu.

Gavisha Waidyaratne, Email: gavisha.waidyaratne@osumc.edu.

Naima Hashi, Email: naima.hashi@osumc.edu.

Shaoli Sun, Email: shaoli.sun@osumc.edu.

Kami Maddocks, Email: kami.maddocks@osumc.edu.

Sean Kelly, Email: sean.kelly@osumc.edu.

REFERENCES

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