Nodular Regenerative Hyperplasia of the Liver Associated With Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor in a Patient With Metastatic Renal Cell Carcinoma

Background

Nodular regenerative hyperplasia (NRH) of the liver is rare, defined by an architecturally intact liver that contains nodules in the absence of fibrosis.¹ Patients with NRH are typically asymptomatic unless the disease leads to portal hypertension, which happens in half of the cases.² The typical presentation includes symptoms of portal hypertension with the absence of other signs of cirrhosis (eg, gynecomastia and spider nevi) and normal transaminase levels, although some patients may have mildly increased alkaline phosphatase. NRH diagnosis is made via biopsy showing regenerative nodules that are typically 1 to 3 mm in diameter; there must also be an absence of parietal thickening of portal venules as well as little to no fibrosis. Currently, the treatment for NRH is limited to treating portal hypertension via standard practices, such as spontaneous bacterial peritonitis antibiotic prophylaxis, usage of nonselective beta blockers, and if necessary transjugular intrahepatic portosystemic shunting.³

Although much is known about NRH, the pathophysiology of this disease remains unknown—some associations have been suggested, including rheumatoid arthritis and various myeloproliferative and lymphoproliferative disorders. Additionally, NRH has been associated with certain drugs, including glucocorticoids, oral contraceptives, antineoplastics, immunosuppressives, antiepileptics, and alcohol.⁴ It is thought that the association of NRH with immunosuppressants and chemotherapeutic drugs may stem from damage to endothelial cells of the small hepatic veins secondary to the accumulation of toxic metabolites.⁵ Specifically, oxaliplatin, methotrexate, vincristine, actinomycin D, and cyclophosphamide have been associated with NRH. There have been two cases of immune checkpoint inhibitor (ICI)–associated NRH.⁴ Although vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) have been associated with drug-induced liver toxicity, these cases were broadly identified as cases of hepatitis.⁶ No cases of VEGF TKI–associated NRH have been reported.

Case Presentation

This case involves a 45-year-old female patient with metastatic clear-cell renal cell carcinoma. Her medical history includes hypothyroidism, which was well controlled with levothyroxine, and early-stage cervical cancer cured by hysterectomy 17 years earlier (at age 28 years). She initially presented to an orthopedist for back pain and right leg weakness. A spinal magnetic resonance imaging at that time showed multiple osseous metastases throughout the cervical, thoracic, and lumbar spine as well as a 6.3-cm right renal mass. Further imaging revealed an enlarged right external iliac lymph node without any other evidence of visceral metastasis. An L3 bone lesion biopsy revealed metastatic clear-cell renal cell carcinoma. On the basis of the International Metastatic RCC Database Consortium model, she had intermediate-risk disease. She began first-line ipilimumab (1 mg/kg) plus nivolumab (3 mg/kg) intravenous injection (IV) once every 3 weeks 1 month after initial presentation. Three days after cycle 2 of ipilimumab/nivolumab, she required L3 tumor embolization, L3 left-sided partial-body resection, and T12-L5 fusion due to worsening bony metastases. She additionally began radiotherapy with 20 Gy in five fractions to T12-S3. Immunotherapy was continued despite disease progression, as it was thought to be a pseudoprogression.

After four cycles of ipilimumab/nivolumab, computed tomography (CT) scans showed disease progression of both the right renal mass and bony metastases as well as new splenomegaly (measuring up to 14.5 cm, previously 10.4 cm). Of note, at this time, there were no visible liver lesions, and the liver function tests (LFTs) were within normal limits. The patient thus started on a clinical trial of cabozantinib (40 mg once daily) plus radium-223 (1.49 microcurie/kg IV once every 28 days) as the next line of treatment 3 months after she began ipilimumab/nivolumab. Due to new spleen metastatic lesions and worsening bony metastasis found about two months later, she was removed from the clinical study. She received additional radiotherapy to T3-T11. Cabozantinib (60 mg once daily) was continued on the standard of care as the primary kidney tumor decreased in size. During the same visit, she was found to have grade 1 alanine transaminase (ALT) elevation, which was thought to be related to cabozantinib. Over the next three months, her G1 ALT elevation continued to rise, so her cabozantinib dose was decreased from 60 mg to 40 mg once daily, and nivolumab (480 mg IV once every 4 weeks) was added due to CT results showing an enlarged spleen, measuring up to 19.9 cm, with an increase in the size of numerous splenic lesions. The liver on this CT was normal in size and density with no focal lesions. When the cabozantinib dose was decreased, the LFTs remained mildly elevated but stable, with minimal improvement from the prior test.

CT scans at 11 months after diagnosis showed an enlarged spleen measuring up to 22.5 cm. There were multiple low-attenuation lesions in the spleen that were similar to the prior scan. The liver was diffusely decreased in attenuation, which was a new finding from the prior exam and thought to be compatible with hepatic steatosis (Fig 1). There were no focal liver lesions. Due to bony disease progression, lenvatinib 18 mg once daily and everolimus 5 mg once daily were started. The patient developed persistent G2 ALT and aspartate transaminase (AST) elevation despite the dose reduction of lenvatinib to 14 mg once daily 1 month later, so lenvatinib was held, and the patient was referred to hepatology. Hepatology diagnosed the patient with nonalcoholic fatty liver disease (NASH) and determined it could have been caused by an underlying metabolic disorder and that elevated LFTs were likely due to drug-induced liver injury. The chronic liver disease serologies were unremarkable (Table 1).

FIG 1.

Computed tomography imaging at (A) baseline and (B) 11 months after diagnosis. The image on (B) shows enlarged spleen measuring up to 22.5 cm (dashed arrow). There were multiple low-attenuation lesions in the spleen. The liver was diffusely decreased in attenuation, a new finding from the prior exam and thought to be compatible with hepatic steatosis (solid white arrow).

TABLE 1.

Chronic Liver Disease Panel

The liver fibroscan showed clinically significant hepatic fibrosis (F4) and steatosis (S > 3). After a 5-day treatment hold, LFTs improved to G1 and lenvatinib was restarted at 10 mg once daily with everolimus at 5 mg once daily. LFTs rose again 2 months later, leading us to hold chemotherapy. One week later, the patient was admitted for worsening ascites, despite improving AST and ALT. During this admission, paracentesis removed 3.1 L of ascites. The cytology was negative for malignancy. A transjugular liver biopsy showed no cirrhosis, a small focus of metastatic renal cell carcinoma, and a background liver parenchyma with features consistent with NRH (Fig 2). Figures 3 and 4 summarize the LFTs during treatment.

FIG 2.

Pathology image of liver biopsy with trichrome staining. Arrows point to the areas of nodular regenerative hyperplasia. There is a minimal amount of fibrosis in blue.

FIG 3.

ALT, AST, and ALP levels during the patient's cancer treatment. This graph demonstrates the changes in levels of ALT (shown in blue), AST (shown in orange), and ALP (shown in gray) throughout the patient's cancer treatment. The x-axis represents time measured in days. The y-axis represents liver function values in U/L. The green dashed lines represent the start and stop dates of chemotherapeutic agents. The red dashed lines represent when chemotherapy was held. ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase.

FIG 4.

Albumin, bilirubin, and INR levels during the patient's cancer treatment. This graph demonstrates the changes in albumin (shown in orange), bilirubin (shown in purple), and INR (shown in blue) throughout the patient's cancer treatment. The x-axis represents time measured in days. The y-axis represents liver function values in U/L. The green dashed lines represent the start and stop dates of chemotherapeutic agents. The red dashed lines represent when chemotherapy was held. INR, internationalized normalized ratio.

Discussion

The common chemotherapeutic agents associated with NRH are oxaliplatin, methotrexate, vincristine, actinomycin D, and cyclophosphamide. In this case, NRH was associated with the VEGF TKIs cabozantinib and lenvatinib as well as possibly ICI nivolumab. Another ICI, pembrolizumab, was previously associated with NRH in a case report.^7,8 Although VEGF TKIs are commonly associated with drug-induced liver toxicity, the mechanism is poorly understood.^1,2,8,9 It was often categorized broadly as hepatitis. In many cases, this hepatotoxicity can be very dangerous and unpredictable.¹⁰ VEGF TKIs induce vascular endothelial damage by blocking the VEGF signaling pathway. Normally, VEGF signaling is critical for angiogenesis and maintaining vascular health through promoting endothelial cell proliferation.¹¹ Theoretically, the small hepatic veins could be adversely affected by the use of VEGF TKIs, leading to the development of NRH.

When a patient being treated with TKI and/or ICI presents with hepatotoxicity, multiple methods can be used to identify potential causes. These include Roussel Uclaf Causality Assessment Method¹² and sometimes a trial of glucocorticoid steroid to exclude an immune-related adverse event. If it remains inconclusive, a liver biopsy may be necessary to establish a diagnosis. The most important treatment for NRH is the timely cessation of harmful agents. Therefore, in this patient, treatment with TKIs was stopped and systemic therapy was switched to a different class of drug, hypoxia-induced factor-2 alpha inhibitor. Other potential treatments include diuretics, spontaneous bacterial peritonitis antibiotic prophylaxis, and transjugular intrahepatic portosystemic shunting. These treatments are readily available but may not be used in the absence of a diagnosis through biopsy. Many drug-induced liver injuries resolve upon cessation of the drug; however, NRH can persist up to 9 months after chemotherapy cessation.¹³ Thus, NRH has a lasting impact on the patient, which can be timely detected and treated after a biopsy.

Before the liver biopsy, our working diagnosis for this patient's abnormal liver enzymes and imaging was cirrhosis due to NASH. Upon pathologic identification of NRH, cabozantinib was deemed the most likely cause, rather than a delayed immune-related adverse event or occult metastasis, due to the timing of transaminitis and improvement after holding VEGF TKIs. Therefore, this case highlights the importance of considering liver biopsy in cases of drug-induced liver injury, particularly related to VEGF TKI and/or ICI treatment.

AUTHOR CONTRIBUTIONS

Conception and design: Ming Yin, Yuanquan Yang

Administrative support: Steven K. Clinton

Collection and assembly of data: Shannon Rudolph, Mingjia Li, Jinesh Gheeya, Danielle Zimmerman, Anil V. Parwani

Data analysis and interpretation: Shannon Rudolph, Mingjia Li, Jinesh Gheeya, Steven K. Clinton

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

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