The Clinical Spectrum and Diagnosis of Oxaliplatin Liver Injury in the Era of Non-alcoholic Fatty Liver Disease

Introduction

Oxaliplatin is an alkylating agent given with fluorouracil and leucovorin (FOLFOX) as a mainstay adjuvant chemotherapy for stage III colorectal cancer (CRC). Liver injury from oxaliplatin ranges from mild liver enzyme elevations in 42-57% of patients in clinical trials¹ to rare severe injury leading to acute liver failure (ALF).² Chronic injury from endothelial cell damage and architectural distortion may manifest years later with nodular regenerative hyperplasia (NRH), portal sclerosis and non-cirrhotic portal hypertension (NCPH).^{2, 3} Chronic subclinical injury occurs in up to 78% of patients.³ Diagnosis may be confounded by non-alcoholic fatty liver disease (NAFLD), and long-term outcomes from chronic injury are unclear.

Methods

The Drug-Induced Liver Injury Network (DILIN) inclusion criteria are based on liver biochemistries.⁴ Patients not meeting criteria may enroll, if approved by the Exemptions Committee. Patients presenting years after drug exposure can enroll in DILIN’s retrospective arm. We identified 7 patients with oxaliplatin liver injury enrolled in the DILIN from 2014 to October 1, 2019. All 7 had biopsies with 5 retrieved for review by the DILIN hepatopathologist (DEK). Severity of SOS injury and immunostaining for vascular injury were assessed as described.^{5, 6}

Results

DILIN’s consensus expert opinion diagnosed 1 case as definite (> 95% likelihood), 4 as highly likely (75-95%) and 2 as probable (50-74%). All patients received FOLFOX after CRC surgery. Other drugs including fluorouracil and leucovorin were unlikely causal due to inconsistent histology and presentation. Three cases had acute cholestatic injury within 9 months of starting oxaliplatin. A 69-year-old woman presented with a bilirubin of 10.2 mg/dL. Liver biopsy showed SOS changes, NRH, and no cirrhosis. She recovered but died 151 days later from pneumonia and hepatic hydrothorax. Another woman, 70 years old, had a bilirubin of 3.6 mg/dL and recovered fully. Liver biopsy was read locally as possible venous outflow obstruction only. DILIN hepatopathologist identified NRH with sinusoidal injury and mild perisinusoidal fibrosis. New varices appeared on MRI 5 months later. A 46-year-old man died of ALF within 7 days after a cholestatic course. Autopsy showed severe acute injury with SOS related necrosis, sinusoidal dilation, bile stasis, and hepatic plate atrophy.

Four patients (53-64 years old) presented with portal hypertension 3.9 to 11.8 years after oxaliplatin. Three women had varices and 1 man had refractory ascites. None had chronic liver disease by blood test evaluation. Median follow-up after oxaliplatin was 13.8 years (range 7.9 - 15.3). Subspecialists (3 gastroenterologists, 1 oncologist) initially diagnosed cirrhosis in all 4 and likely NAFLD in 3 after local biopsy readings. DILIN hepatopathologist assessments suggested oxaliplatin liver injury. (Table) All 4 had HVPG measurement (range 7 to 20 mm Hg) and 2 had thrombocytopenia (<150,000/mL). All 4 had significant morbidity during follow-up.

Table 1:

Initial diagnoses, biopsy interpretations and follow-up in four cases with chronic oxaliplatin injury

Initial Diagnoses	Metabolic Syndrome Diagnoses	Local Biopsy Interpretation	DILIN Biopsy Interpretation*	Total Follow-up (yr)**	Presentation and Subsequent Course
NAFLD cirrhosis	Diabetes, Hypertension Dyslipidemia Obesity	Mild (10%) macrovesicular fat in the lobules No NASH No significant fibrosis	NRH CD34 NA SOS-I = 4	7.9	Variceal banding for prophylaxis PVT on anti-coagulation
NAFLD vs. cryptogenic cirrhosis	Obesity	Sinusoidal dilatation, patchy venous congestion No steatosis No significant fibrosis	NRH Hepatoportal sclerosis CD34 (+) SOS-I = 5	15.3	Variceal bleed Minnesota tube required Esophageal rupture, TIPS Prolonged recovery
NAFLD vs. cryptogenic cirrhosis	Diabetes	Normal No steatosis No significant fibrosis	Regenerative changes^ CD34 (+) SOS-I = 0	14.5	Refractory ascites TIPS Disabling HE after TIPS
NAFLD cirrhosis	Diabetes, Hypertension Dyslipidemia	Normal No steatosis No significant fibrosis	NRH Hepatoportal sclerosis CD34 (+) SOS-I = 4	13.0	Variceal bleed Endoscopic banding PVT on anti-coagulation New 1.2 cm LI-RADS-3 nodule

^*Interpretation by DILIN hepatopathologist (DEK) who was blinded to clinical information

^**Time in years from oxaliplatin exposure = latency from drug exposure to clinical presentation + years of follow-up after presentation.

^{^}Transjugular biopsy too fragmented to fully assess for NRH, but regenerative changes and (+) CD34 were seen. No significant fibrosis seen.

HE = Hepatic encephalopathy; LI-RADS 3 = intermediate probability of malignancy on Liver Reporting and Data System; NA = not available; NRH = Nodular regenerative hyperplasia; PVT = Portal vein thrombosis; SOS-I = Sinusoidal Obstructive Syndrome Injury Score (0 = no SOS injury; 8 = severe SOS injury)^{5, 6}; TIPS = Transvenous intra-hepatic portosystemic shunt.

Discussion:

Oxaliplatin liver injury has one of the broadest clinical spectrums in DILI ranging from cholestatic or hepatocellular acute liver failure to chronic NCPH presenting over 10 years later. Diagnosis can be challenging especially when presenting years later with NCPH. All 4 chronic cases were initially diagnosed with NAFLD or cryptogenic cirrhosis by gastroenterologists or oncologists. The inclination to diagnose cirrhosis and NAFLD is understandable. All 4 patients had at least one metabolic syndrome diagnosis (Table), and NRH livers can appear nodular on imaging. Getting another opinion from an experienced hepatopathologist can be crucial. On blinded review, the DILIN hepatopathologist found previously unappreciated NRH in one acute case and 3 of the chronic cases (Table). The 4^th chronic case had suggestive regenerative changes, positive CD34 staining and no significant fibrosis on a fragmented transjugular biopsy. On long-term follow-up, all 4 patients had significant morbidity including hepatic encephalopathy, portal vein thrombosis, Minnesota tube esophageal rupture and a regenerative nodule. Liver cancer in the setting of NRH has been reported.⁷

While we report just 7 patients, they cover the spectrum of clinical presentation and have the longest reported follow-up. They all had needle biopsies and were systematically diagnosed by consensus expert opinion. Clinically apparent portal hypertension from oxaliplatin is rare in the absence of hepatic resection or ablative therapy. However, it may be increasingly overlooked, as more colon cancer survivors develop the metabolic syndrome, and oxaliplatin use for CRC increases ⁸. Oxaliplatin is used for other cancers including lung, breast and prostate. Other chemotherapy agents also have been linked to NCPH. Therefore, a thorough chemotherapeutic history, no matter how remote, is imperative when assessing patients with portal hypertension. Liver biopsy assessment by an experienced hepatopathologist should be obtained when local interpretation is non-diagnostic. After making a diagnosis of oxaliplatin NCPH, long term monitoring may be warranted.

Abbreviations:

ALF

acute liver failure

Alk Phos

alkaline phosphatase

ALT

alanine aminotransferase

AST

aspartate aminotransferase

BMI

body mass index

DILI

drug-induced liver injury

DILIN

Drug-Induced Liver Injury Network

HVPG

hepatic venous pressure gradient

IRB

institutional review board

LI-RADS

liver reporting & data system

NAFLD

non-alcoholic fatty liver disease

NCPH

non-cirrhotic portal hypertension

NIDDK

National Institute of Diabetes and Digestive and Kidney Diseases

NRH

nodular regenerative hyperplasia

SOS

sinusoidal obstructive syndrome

TIPS

transjugular intrahepatic portosystemic shunt