Abstract
This cohort study examines the association of liver biopsy with management and outcomes of high-grade immune checkpoint inhibitor hepatitis.
The utility of liver biopsy in diagnosis and management of immune checkpoint inhibitor (ICI) hepatitis is uncertain.1,2,3 We examined the association of histology with management and outcomes of high-grade ICI hepatitis.
Methods
A total of 7046 patients with cancer (excluding hepatocellular carcinoma) received ICI treatment between January 2010 and June 2020. We performed a retrospective cohort study of the 213 patients who developed grade 3 or higher (alanine aminotransferase [ALT] level, >200 U/L [to convert to μkat/L, multiply by 0.0167]) liver injury that was associated with ICI treatment. Approval for the study was obtained from the Mass General Brigham institutional review board, and informed consent was waived due to the retrospective nature of the study.
The primary outcome was time to ALT normalization (≤40 U/L), and the secondary outcome was time to ALT improvement to ≤100 U/L (grade 1 injury). A Kaplan-Meier analysis was used for time-to-event data, and Cox regression was used for multivariable adjustment. Analyses were performed using SAS, version 9.4 (SAS Institute), and statistical significance was set at P < .05.
Results
Of 213 patients included in the study, a total of 107 patients (50.2%) underwent liver biopsy a median (interquartile range [IQR]) of 5 (1-14) days after first grade 3 to 4 ALT elevation, of whom 95 (88.8%) had histology results that were compatible with ICI hepatitis as documented by hepatopathologists. There were 2 major biopsy-related complications (splenic biopsy, hemothorax). The remaining 106 patients (49.8%) received a diagnosis of ICI hepatitis after exclusion of other causes of liver injury (eg, viral hepatitis, ischemia, other medications) and appropriate response to corticosteroids. Most patients had melanoma (115 [54%]). Patients who underwent biopsy (Table 1) had higher peak aminotransferase levels (ALT, 499 U/L vs 412 U/L; P = .04; aspartate aminotransferase levels, 329 U/L vs 262 U/L [to convert to μkat/L, multiply by 0.0167]; P = .06), were more likely to develop steroid-refractory hepatitis (39.3% vs 17.0%; risk ratio, 2.32; 95% CI, 1.41-3.79; P < .001), and were less likely to have a prior immune-related adverse event (38.3% vs 56.6%; risk ratio, 0.7; 95% CI, 0.5-0.9; P = .01).
Table 1. Clinical Characteristics and Laboratory Values.
| Characteristic | Biopsy, No. (%) | P value | |
|---|---|---|---|
| No | Yes | ||
| Patients, No. | 106 | 107 | NA |
| Mean (SD) age at time of grade 3-4 liver injury, y | 60.1 (16.3) | 58.9 (13.0) | .55 |
| Female | 56 (52.8) | 47 (43.9) | NA |
| Male | 50 (47.2) | 60 (56.1) | .19 |
| Race and ethnicity | |||
| Black | 0 | 3 (2.8) | NA |
| Hispanic | 4 (3.8) | 5 (4.7) | NA |
| White | 99 (93.4) | 94 (87.9) | .17 |
| Other/unknown | 3 (2.8) | 5 (4.7) | NA |
| Nonsmokera | 78 (73.6) | 73 (68.2) | .68 |
| Alcohol useb | 16 (15.1) | 18 (17.0) | .71 |
| Preexisting liver disease | 31 (29.3) | 32 (29.9) | |
| Nonalcoholic fatty liver disease | 23 (21.7) | 21 (19.6) | .92 |
| Alcoholic liver disease | 7 (6.6) | 4 (3.7) | |
| Other etiology | 1 (0.9) | 5 (4.7) | |
| Cancer type | |||
| Melanoma | 51 (48.1) | 64 (59.8) | NA |
| Non–small-cell lung cancer | 9 (8.5) | 11 (10.3) | |
| Kidney cell carcinoma | 12 (11.3) | 6 (5.6) | |
| Breast cancer | 6 (5.7) | 4 (3.7) | |
| Other | 26 (26.4) | 25 (26.2) | |
| Liver metastases | 26 (24.5) | 32 (29.9) | .38 |
| Prior immune-related adverse event | 60 (56.6) | 41 (38.3) | .01 |
| Monotherapy | |||
| Anti–PD-1 | 42 (39.6) | 34 (31.8) | .23 |
| Anti–PD-L1 | 5 (4.7) | 8 (7.5) | .40 |
| Ipilimumab | 12 (11.3) | 18 (18.4) | .25 |
| Combination ipilimumab + nivolumab | 47 (44.3) | 38 (35.5) | .19 |
| Maximum steroid dose, median (IQR), mg/kg/d | 1.5 (1.0-2.0) | 1.5 (1.0-2.0) | .89 |
| Developed steroid-refractory hepatitis | 18 (17.0) | 35 (39.3) | <.001 |
| Baseline laboratory values, median (IQR) | |||
| AST, U/L | 20 (16-27) | 21 (17-26) | >.99 |
| ALT, U/L | 18 (14-26) | 19 (15-27) | .63 |
| Alkaline phosphatase, U/L | 77 (32-96) | 77 (61-93) | .69 |
| Total bilirubin, mg/dL | 0.5 (0.3-0.6) | 0.4 (0.3-0.7) | .29 |
| Albumin, g/dL | 4.2 (3.9-4.5) | 4.2 (3.9-4.4) | .96 |
| Creatinine, mg/dL | 0.9 (0.7-1.0) | 0.9 (0.7-1.0) | .85 |
| Platelet count, ×103/μL | 221 (200-265) | 227 (195-267) | .83 |
| Laboratory values at time of peak ALT, median (IQR) | |||
| AST, U/L | 262 (181-426) | 329 (213-535) | .06 |
| ALT, U/L | 412 (289-613) | 499 (317-818) | .04 |
| Alkaline phosphatase, U/L | 216 (100-452) | 216 (116-375) | .94 |
| Total bilirubin, mg/dL | 0.7 (0.4-1.4) | 0.9 (0.5-1.6) | .25 |
| Albumin, g/dL | 3.8 (3.4-4.1) | 3.7 (3.4-4.0) | .85 |
| Creatinine, mg/dL | 0.8 (0.7-1.1) | 0.9 (0.7-1.0) | .71 |
| Platelet count, ×103/μL | 233 (174-272) | 207 (150-207) | .03 |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; IQR, interquartile range; NA, not applicable.
SI conversion factors: To convert albumin to g/L, multiply by 10; alkaline phosphatase, ALT, and AST to μkat/L, multiply by 0.0167; bilirubin to μmol/L, multiply by 17.104; creatinine to μmol/L, multiply by 88.49; platelet count to ×109/L, multiply by 1.
Smokers defined as having a 10 or greater pack-year history.
Alcohol use defined as 2 drinks or more per day for men and 1 or more drink per day for women.
Both groups received similar maximum corticosteroid doses (median [IQR], 1.5 vs 1.5 [1.0-2.0] mg/kg/d; P = .89). However, patients who underwent a biopsy were significantly less likely per day to begin taking steroids after the first grade 3 to 4 ALT elevation (hazard ratio [HR], 0.67; 95% CI, 0.50-0.90; P = .01) after adjusting for ALT, combination anti–cytotoxic T-lymphocyte−protein 4/programmed cell death 1 therapy, and melanoma (vs nonmelanoma cancers). Steroids were administered for 63 patients (58.9%) before biopsy. After biopsy, steroids were administered for 40 patients (37.4%) and discontinued for 8 patients (7.5%).
Patients who underwent a biopsy with ICI hepatitis had a significantly longer median (IQR) time to ALT normalization (42 [33-55] vs 33 [28-39] days; P = .01) and to ALT levels of 100 U/L or less (21 [17-26] vs 15 [14-17] days; P = .01). Liver biopsy was associated with trends toward a longer time to ALT normalization (HR, 0.76; 95% CI, 0.56-1.03; P = .07) and to ALT levels of 100 U/L or less (HR, 0.78; 95% CI, 0.58-1.05; P = .10) after adjusting for ALT level, combination anti–cytotoxic T-lymphocyte−protein 4/programmed cell death 1 therapy, liver metastases, steroid-refractory hepatitis, and prior immune-related adverse events using a Cox regression.
The most common pattern of liver injury in patients with ICI hepatitis was panlobular inflammation (61 [64.9%]) (Table 2). Of the 12 patients who underwent a biopsy who were determined not to have ICI hepatitis, 4 received a diagnosis of malignant biliary obstruction, 4 were judged to have liver injury from a contemporaneous drug, and 2 had diffuse malignant infiltration. The cause of injury remained unclear in the final 2 patients. Patients without ICI hepatitis were more likely to have portal-predominant inflammation (50.0% vs 8.5%; P = .001) and less likely to have panlobular hepatitis (8.3% vs 64.9%; P < .001) compared with patients with ICI hepatitis. Patients without ICI hepatitis also were more likely to manifest grade 3 bilirubin elevation (>3 mg/dL [to convert to μ mol/L, multiply by 17.104]) (50% vs 11.6%; P = .004) and higher peak total bilirubin levels before biopsy (median [IQR], 4.4 [1.2-6.9] vs 0.8 [0.5-1.6]; P = .002).
Table 2. Patients Who Received Liver Biopsy Stratified by Final Diagnosis.
| Characteristic | ICI hepatitis, No. (%) | P value | |
|---|---|---|---|
| No (n = 12) | Yes (n = 95) | ||
| Ultimate non-ICI hepatitis diagnosis | |||
| Malignant biliary obstruction | 4 (33.3) | NA | NA |
| Non-ICI drug-induced liver injury | 4 (33.3) | NA | |
| Tumor infiltration of liver | 2 (16.7) | NA | |
| Unknown | 2 (16.7) | NA | |
| Major patterns of inflammationa | |||
| Inflammation | |||
| Panlobular | 1 (8.3) | 61 (64.9) | <.001 |
| Lobular | 0 (0) | 18 (19.2) | .21 |
| Portal | 6 (50.0) | 8 (8.5) | .001 |
| Central vein endothelialitis (sparing rest of lobule) | 0 (0) | 2 (2.1) | >.99 |
| No inflammation | 5 (41.7) | 5 (5.3) | .001 |
| Specific histologic changesa | |||
| Inflammation | |||
| Lobular | 1 (8.3) | 79 (84.0) | <.001 |
| Portal | 7 (58.3) | 67 (71.3) | .51 |
| Histiocytic | |||
| Inflammatory infiltrate | 1 (8.3) | 53 (56.4) | .002 |
| Aggregates | 0 (0) | 25 (26.6) | .07 |
| Bile duct injury | 8 (66.7) | 26 (27.7) | .02 |
| Granulomas | 0 (0) | 16 (17.0) | .21 |
| Central vein endothelialitis | 0 (0) | 17 (18.1) | .21 |
| Laboratory values at time of peak ALT, median (IQR) | |||
| AST, U/L | 412 (279-589) | 322 (203-535) | .32 |
| ALT, U/L | 556 (385-912) | 488 (312-813) | .37 |
| Alkaline phosphatase, U/L | 299 (163-488) | 210 (111-374) | .25 |
| Total bilirubin, mg/dL | 2.3 (1.0-6.0) | 0.8 (0.5-1.4) | .01 |
| Albumin, g/dL | 3.5 (3.0-4.0) | 3.7 (3.4-4.0) | .12 |
| Creatinine, mg/dL | 0.9 (0.7-1.1) | 0.9 (0.7-1.0) | .58 |
| Platelet count, ×103/μL | 168 (135-280) | 208 (150-248) | .72 |
| Peak total bilirubin, median (IQR), mg/dL | |||
| Prebiopsy | 4.4 (1.2-6.9) | 0.8 (0.5-1.6) | .002 |
| Within first week of grade 3 injury | 5.7 (2.9-9.8) | 0.9 (0.5-1.7) | <.001 |
| Grade 3 total bilirubin elevation (>3 mg/dL) before biopsy | 6 (50) | 11 (11.6) | .004 |
| Time from ICI initiation to grade 3 hepatitis, d | 85 (34-233) | 77 (45-136) | .75 |
| Steroid treatment initiated before biopsy | 11 (91.7) | 55 (57.9) | .02 |
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ICI, immune checkpoint inhibitor; IQR, interquartile range; NA, not applicable.
SI conversion factors: To convert albumin to g/L, multiply by 10; alkaline phosphatase, ALT, and AST to μkat/L, multiply by 0.0167; bilirubin to μmol/L, multiply by 17.104; creatinine to μmol/L, multiply by 88.49; platelet count to ×109/L, multiply by 1.
Excludes 1 patient who underwent liver biopsy but had inadvertent splenic biopsy without obtaining liver tissue.
Discussion
The results of this cohort study suggest that liver biopsy in ICI-treated patients who develop grade 3 or higher liver injury delays the initiation of corticosteroids and is not associated with faster hepatitis resolution. A limitation of the study is its retrospective nature, which raises the possibility of unmeasured confounders. In patients with a hepatocellular pattern of liver injury and absence of other likely causes, empirical initiation of corticosteroids appears reasonable. Liver histology may be informative in patients who fail to improve with empirical corticosteroids before initiating additional immunosuppressive agents, or in those with elevated bilirubin levels without radiographic evidence of biliary obstruction.
References
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