Bilirubin has strong antioxidant properties that have been hypothesized to be preventive against the development of cancer. Thus, we aimed to investigate the association between serum total bilirubin (STB) and risk of overall and site-specific cancers in the large Swedish Apolipoprotein Mortality Risk (AMORIS) cohort. We also performed a systematic review and meta-analysis for specific cancer types (colorectal, breast and lung). We found no association between high levels of STB and risk of overall cancer. Regarding site-specific cancer, there was an inverse association between increased STB and lung cancer (Hazard Ratio (HR) for the 4th quartile (Q4) vs. Q1: 0.50; 95%CI: 0.44–0.59) and gynecological cancer (HR for Q4 vs. Q1: 0.86; 95%CI: 0.76–0.99). A positive association was found with melanoma (HR for Q4 vs. Q1: 1.25; 95%CI: 1.06–1.47) and breast cancer (HR for Q4 vs. Q1: 1.13; 95%CI: 1.01–1.25) risk. The meta-analysis showed an inverse association between high levels of STB and risk of lung cancer (Relative risk (RR): 0.69; 95%CI: 0.55–0.86). No associations were seen for colorectal and breast cancer risk. Further studies are required to establish if bilirubin can be used as a biomarker for risk assessment and/or as a novel therapeutic target.

Serum Total Bilirubin and Risk of Cancer: A Swedish Cohort Study and Meta-Analysis.

What is known and objective Mebendazole (MBZ) is a broad-spectrum antihelminthic agent of the benzimidazole type. Although MBZ has been reported to cause hepatic injury, case reports of severe hepatic injury are very rare. We report a case of severe hepatitis after administration of MBZ in a patient with Gilbert's syndrome affected by pinworms infestation. Case summary Differently from other cases of hepatitis due to MBZ reported in the scientific literature, our patient received standard doses of MBZ for a short period of time. After 18 days from the start of therapy, he developed hepatomegaly, and increases in hepatic enzymes and bilirubin. Hepatic enzymes returned to normal over the following 5 weeks. What is new and conclusion This is the first case report of important liver injury after administration of MBZ in a patient with Gilbert's syndrome. We suspected that a diminished hepatic glucuronidation of MBZ due to the reduced activity of the glucuronosyltransferase enzyme in our patient could have caused an increase in unconjugated toxic metabolites of MBZ and the consequent liver damage.

Hepatotoxicity caused by mebendazole in a patient with Gilbert's syndrome

Biochemical liver function tests

BACKGROUND AND AIMS This study aimed to evaluate whether serum bilirubin levels were associated with cancer development in a population without liver disease. METHODS A retrospective longitudinal study was performed by including participants who underwent a health checkup at St. Luke's International Hospital in Tokyo from 2005 to 2019. We excluded those with liver diseases or prior history of cancer at baseline. All participants were classified into four groups according to their total bilirubin (T-Bil) level: very low (<0.5 mg/dl), low (≥0.5 mg/dl, <1.0 mg/dl), intermediate (≥1.0 mg/dl, <1.5 mg/dl), and high (≥1.5 mg/dl). Our primary outcome was to observe cancer development. This study received IRB approval (19-R041). RESULTS A total of 77 855 patients were included. During a median follow-up of 1751 days, 5110 participants developed some type of cancer during the study period. Compared to the very-low group, odds ratio (OR) for developing any type of cancer in a concentration-dependent manner decreased as the T-Bil category shifted to higher groups: OR 0.89, 95% confidence interval (CI) 0.79-1.01 for low group; OR 0.81, 95% CI 0.71-0.94 for intermediate group, and OR 0.80, 95% CI 0.65-0.99 for high group. In terms of secondary outcome, neoplasms of the female genital organs showed the same trend; OR 0.69, 95% CI 0.51-0.93 for low group; OR 0.63, 95% CI 0.44-0.92 for intermediate group, and OR 0.52, 95% CI 0.24-1.09 for high group. CONCLUSION Increased serum bilirubin negatively correlated with cancer development in a concentration-dependent manner, especially for neoplasms of the female genital organs.

Negative correlation of high serum bilirubin with cancer development in adults without hepatobiliary disease.

This study evaluated the inhibitory effects of bilirubin on colony formation and cell migration of melanoma and non-melanoma skin cancer cell lines SK-MEL-3 and A431, compared with normal human dermal fibroblasts (HDF). The IC50 obtained from the MTT assay was 125, 100, and 75 μM bilirubin for HDF, A431, and SK-MEL-3 cells, respectively. The colony formation and cell migration of cancer cells, treated with 100 μM bilirubin, were reduced significantly (p < 0.05). Bilirubin decreased cell adhesion and inhibited cell colonization via inducing apoptosis and cell death. Also by interaction with migration main factors, bilirubin caused inhibition the cell migration.

Inhibitory Effects of Bilirubin on Colonization and Migration of A431 and SK-MEL-3 Skin Cancer Cells Compared with Human Dermal Fibroblasts (HDF).

### Key learning points

Gilbert’s syndrome (GS) is a benign hereditary disorder of bilirubin conjugation resulting in an isolated, elevated blood level of unconjugated bilirubin.1 GS affects 2%–10% of the Caucasian population in the Western world.2,3 The inheritance pattern for GS is commonly autosomal recessive, but can be dominant as well; however, genetic counselling is not necessary as there is no impact on life expectancy. For the patient, however, the condition may be an initial cause for concern as they commonly present with painless, non-pruritic jaundice or an incidental finding of hyperbilirubinaemia on routine blood testing. Episodes of jaundice may be exacerbated by heavy physical exertion, fasting, sleep deprivation, alcohol, dehydration, surgery and concurrent illness. Patients will have normal liver enzymes, normal liver synthetic function (clotting, albumin) and a negative haemolysis screen. GS is a diagnosis of exclusion. The primary care practitioners’ main aim is to confirm the diagnosis, reassure the patient and clarify any concerns related to the condition. GS does not require secondary care referral and is largely asymptomatic. Observational studies highlight that the antioxidant effect of unconjugated bilirubin may confer a survival benefit to patients,4,5 and indeed, the greatest risk to those with the condition is in pursuit of an alternative diagnosis. Patients should …

D King

Papers

Overview of Gilbert's syndrome.