Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy

Background and aims Immune checkpoint inhibitors (ICI) are increasingly used in cancer therapy. Elevated liver enzymes frequently occur in patients treated with ICI but evaluation is poorly described. We sought to better understand causes of liver enzyme elevation, investigation and management. Methods Patients treated with anti-PD-1, PDL-1 or CTLA-4 therapy in Phase I/II clinical trials between August 2012 and December 2018 were included. Clinical records of patients with significant liver enzyme elevations were retrospectively reviewed. Results Of 470 ICI-treated patients, liver enzyme elevation occurred in 102 (21.6%), attributed to disease progression (56; 54.9%), other drugs/toxins (7; 6.9%), other causes (22; 21.6%) and ICI immunotoxicity (17; 16.7%; 3.6% of total cohort). Immunotoxicity was associated with higher peak ALT than other causes of enzyme elevation (N = 17; M = 217, 95% CI 145–324 for immunotoxicity, N = 103; M = 74, 95% CI 59–92 for other causes; ratio of means 0.34, 95% CI 0.19–0.60, p = <0.001) and higher ALT:AST ratio (M = 1.27, 95% CI 0.78–2.06 for immunotoxicity, M = 0.69, 95% CI 0.59–0.80 for other causes, ratio of means 0.54, 95% CI 0.36–0.82, p = 0.004). Immunotoxicity was more often seen in patients with prior CPI exposure (41.2% of immunotoxicity vs 15.9% of patients without, p = 0.01), anti-CTLA-4 –containing ICI treatments (29.4% of immunotoxicity vs 6.8% of patients without, p = <0.001) and other organ immunotoxicity (76.5% of immunotoxicity vs 19.2% of patients without, p = <0.001). Cause for enzyme elevation was established in most patients after non-invasive investigation. Liver biopsy was reserved for four patients with atypical treatment response. Conclusions Liver enzyme elevation is common in patients receiving ICI, but often has a cause other than immunotoxicity. A biochemical signature with higher ALT and ALT/AST ratio, a history of prior ICI exposure and other organ immunotoxicities may help to identify patients at a higher likelihood of immunotoxicity. Liver biopsy can be safely deferred in most patients. We propose an approach to diagnostic evaluation in patients with liver enzyme elevations following ICI exposure.

A Case-Report of Drug-Induced Mixed Liver Injury Resulting From Cefepime Exposure

A 99-year-old African-American male presented to the hospital with severe sepsis secondary to a urinary tract infection. Upon initial presentation he was tachycardic, hypotensive and had leukocytosis. While he had signs of acute kidney injury, no signs of acute liver injury were present with his alanine transferase (ALT) and amino transferase (AST) levels measuring at 22 and 44 U/L, respectively. During the treatment course the patient began to show signs of clinical improvement. Despite this, his ALT and AST began to increase on day 2 of treatment and reached their peak of 210 and 239 U/L on day 4. Cefepime-induced liver injury was suspected and cefepime was discontinued. Upon cefepime discontinuation, liver enzymes downtrended and gradually returned to normal. No other likely medication causes of liver injury could be identified and alternative medical causes were ruled out. The lack of an alternative cause and the temporal relationship of cefepime use to hepatic dysfunction support the diagnosis of cefepime-induced liver injury. The patient’s Roussel Uclaf Causality Assessment Methods score was 7, indicating this was a possible case of cefepime-induced liver injury, and the Naranjo Nomogram score was 5 indicating this was a probable case of cefepime-induced liver injury. While cefepime-induced liver injury is rare, clinicians should be cognizant of the potential for this adverse effect if liver enzyme elevation is detected during cefepime therapy and other common causes have been ruled out.

Comparison of clinical features between immune-related sclerosing cholangitis and hepatitis

SummaryBackground Immune-related hepatotoxicity is often regarded as immune-related hepatitis (irHepatitis) despite including immune-related sclerosing cholangitis (irSC). This study examined the clinical differences between irSC and irHepatitis. Methods A single-center retrospective study of 530 consecutive patients who received immunotherapy between August 2014 and April 2020 was performed. IrSC and irHepatitis were respectively defined as the radiological presence and absence of bile duct dilation and wall thickness. Results Forty-one patients (7.7%) developed immune-related hepatotoxicity. A CT scan was performed on 12 patients, including 11 of 12 with ≥ grade 3 aminotransferase elevations. IrSC and irHepatitis were diagnosed in 4 (0.8%) and 8 (1.5%) patients, respectively. All the irSC patients had been treated with anti-PD-1. IrHepatitis was more common among patients receiving anti-CTLA-4 than among those receiving anti-PD-1/PD-L1 inhibitors (14%, 7/50 vs. 0.2%, 1/480, P < 0.001). A ≥ grade 2 alkaline phosphatase (ALP) elevation resulting in a cholestatic pattern was seen in all 4 irSC patients. Among the irSC patients, 3 (3/4, 75%) developed ≥ grade 3 aminotransferases elevation. The median duration from the start of immunotherapy until ≥ grade 2 liver enzymes elevation was 257 and 55.5 days in irSC and irHepatitis patients. The median times for progression from grade 2 to 3 liver enzyme elevation were 17.5 and 0 days, respectively. Conclusions IrSC and irHepatitis have different characteristics in the class of immune checkpoint inhibitor and onset pattern. Radiological examination for the diagnosis of irSC should be considered for patients with ≥ grade 2 ALP elevation resulting in a cholestatic pattern. (Registration number J2020-36, Date of registration June 3, 2020)

Comparison of Clinical Features between Immune-Related Sclerosing Cholangitis and Hepatitis

Background Immune-related hepatotoxicity is often regarded as immune-related hepatitis (irHepatitis) despite including immune-related sclerosing cholangitis (irSC). This study examined the clinical differences between irSC and irHepatitis.Methods A single-center retrospective study of 530 consecutive patients who received immunotherapy between August 2014 and April 2020 was performed. IrSC and irHepatitis were respectively defined as the radiological presence and absence of bile duct dilation and wall thickness.Results Forty-one patients (7.7%) developed immune-related hepatotoxicity. A CT scan was performed on 12 patients, including 11 of 12 with ≥grade 3 aminotransferase elevations. IrSC and irHepatitis were diagnosed in 4 (0.8%) and 8 (1.5%) patients, respectively. All the irSC patients had been treated with anti-PD-1. IrHepatitis was more common among patients receiving anti-CTLA-4 than among those receiving anti-PD-1/PD-L1 inhibitors (14%, 7/50 vs. 0.2%, 1/480, P <0.001). A ≥grade 2 alkaline phosphatase (ALP) elevation resulting in a cholestatic pattern was seen in all 4 irSC patients. Among the irSC patients, 3 (3/4, 75%) developed ≥grade 3 aminotransferases elevation. The median duration from the start of immunotherapy until ≥grade 2 liver enzymes elevation was 257 and 55.5 days in irSC and irHepatitis patients. The median times for progression from grade 2 to 3 liver enzyme elevation were 17.5 and 0 days, respectively.Conclusions IrSC and irHepatitis have different characteristics in the class of immune checkpoint inhibitor and onset pattern. Radiological examination for the diagnosis of irSC should be considered for patients with ≥grade 2 ALP elevation resulting in a cholestatic pattern. (Registration number J2020-36, Date of registration June 3, 2020)

Risk Factors Associated with Chronic Liver Enzyme Elevation (cLEE) in Persons Living with HIV without Hepatitis B or C co-infection in the Combination Antiretroviral Therapy Era

Background As morbidity due to viral co-infections declines among HIV-infected persons, changes in liver related morbidity are anticipated. We examined data from the US Military HIV Natural History Study (NHS), a cohort of military beneficiaries, to evaluate incidence and risk factors associated with chronic liver enzyme elevation (cLEE) in HIV mono-infected patients in the combination antiretroviral therapy (cART) era. Methods Participants who were HBV and HCV seronegative with follow-up after 1996 were included. We defined chronic liver enzyme elevation (cLEE) as alanine aminotransferase (ALT) elevations ≥ 1.25 times the upper limit of normal on at least two visits, for a duration of six months or more within 2 years. We used multivariate Cox proportional hazards models to examine risk factors for cLEE. Results Of 2,779 participants, 309 (11%) met criteria for cLEE for an incidence of 1.28/100 PYFU (1.28 – 1.29). In an adjusted model, cLEE was associated with Hispanic/other ethnicity [Reference Caucasian: HR 1.744 (1.270 – 2.395)], non–nucleoside reverse transcriptase (NNRTI) based cART [Reference boosted protease inhibitors: HR 2.232 (1.378 – 3.616)], being cART naïve [HR 6.046 (3.686 – 9.915)] or having cART interruptions [HR 8.671 (4.651 – 16.164)]. African American race [HR 0.669 (0.510 – 0.877)] and integrase strand transfer inhibitor (INSTI) based cART [HR 0.222 (0.104 – 0.474)] were protective. Conclusions Our findings demonstrate initiation and continued use of cART is protective against cLEE and supports the hypothesis HIV infection directly impacts the liver. INSTI based regimens were protective and could be considered in persons with cLEE.

Sonographic findings in coronavirus disease-19 associated liver damage

Purpose This study was conducted to evaluate the role of liver sonography in patients with coronavirus disease 2019 (COVID-19) and elevated liver enzymes. Materials and methods In this retrospective study, patients tested positive for SARS-CoV-2 in our emergency ward between January 01 and April 24, 2020 and elevated liver enzymes were included (Cohort 1). Additionally, the local radiology information system was screened for sonographies in COVID-19 patients at the intensive care unit in the same period (Cohort 2). Liver sonographies and histologic specimen were reviewed and suspicious findings recorded. Medical records were reviewed for clinical data. Ultrasound findings and clinical data were correlated with severity of liver enzyme elevation. Results Cohort 1: 126 patients were evaluated, of which 47 (37.3%) had elevated liver enzymes. Severity of liver enzyme elevation was associated with death (p<0.001). 8 patients (6.3%) had suspicious ultrasound findings, including signs of acute hepatitis (n = 5, e.g. thickening of gall bladder wall, hepatomegaly, decreased echogenicity of liver parenchyma) and vascular complications (n = 4). Cohort 2: 39 patients were evaluated, of which 14 are also included in Cohort 1. 19 patients (48.7%) had suspicious ultrasound findings, of which 13 patients had signs of acute hepatitis and 6 had vascular complications. Pathology was performed in 6 patients. Predominant findings were severe cholestasis and macrophage activation. Conclusion For most hospitalized COVID-19 patients, elevated liver enzymes cause little concern as they are only mild to moderate. However, in severely ill patients bedside sonography is a powerful tool to reveal different patterns of vascular, cholestatic or inflammatory complications in the liver, which are associated with high mortality. In addition, macrophage activation as histopathologic correlate for a hyperinflammatory syndrome seems to be a frequent complication in COVID-19.