Jaundice During Antitubercular Treatment: Not Only Drug-induced Liver Injury

To the Editors: Tuberculosis (TB) is highly endemic in Southwestern China. Drug-induced liver injury (DILI) due to first-line antitubercular drugs in children is an important situation that often leads to treatment interruption and consequent loss of therapeutic efficacy.1 The etiology of DILI should be thoroughly investigated to ensure effective antitubercular therapy.2 A 13-year-old boy who presented with cough, fever and night sweats for 2 months was admitted to our department on November 12, 2021. He had close contact with TB patients 6 months prior. No jaundice was noticed at the onset. Computed tomography revealed multiple lesions in the right lung and left upper lung combined with pleural effusion and mediastinal lymphadenopathy. GeneXpert mycobacterium tuberculosis/rifampin of sputum was positive for TB nucleic acid and negative for the rifampin resistance gene. Pulmonary TB was certified. He was treated with isoniazid, rifampin, pyrazinamide, and ethambutol. Ten days later, he experienced jaundice, and his liver function tests revealed cholestasis (total bilirubin 88.9 µmol/L and direct bilirubin 71.8 µmol/L). The DILI was indicated. The antitubercular treatment was discontinued, and adenosylmethionine succinate was added. The patient’s jaundice persisted with conjugated hyperbilirubinemia (direct bilirubin from 71.8 to 50.6 µmol/L). Testing for hepatitis viruses, Epstein-Barr virus and cytomegalovirus was negative. The autoantibodies, blood lipids and ceruloplasmin were normal. Then a modified antitubercular treatment of ethambutol, levofloxacin and amikacin was reinitiated after 1 month of discontinuation with antitubercular treatment. The whole exome sequencing was performed to further seek the cause of persistent jaundice. The results finally revealed compound heterozygous mutations of multidrug-resistance protein 2/ABCC2 (c.3928C>T and c.3655-3658delGTCT) which indicated Dubin–Johnson syndrome (DJS). Isoniazid, rifampin, and pyrazinamide were reintroduced one after another each week. The levofloxacin and amikacin were discontinued. The conjugated bilirubin elevated after rifampin was reintroduced (from 50.6 to 104.8 µmol/L). The transaminase was continuously normal, and no gastrointestinal symptoms occurred. Tuberculosis and DJS were diagnosed in this patient. The antitubercular treatment with isoniazid, rifampin, pyrazinamide, and ethambutol lasted for 2 months and isoniazid and rifampin lasted for 7 months. The boy resolved completely. Diseases underlying DILI should be searched intensively to ensure proper antitubercular treatment. Genetic or metabolic liver diseases account for approximately one-third of liver dysfunction in children. The underlying inherited metabolic liver disease in tuberculosis patients may have been underestimated before. With the genetic sequencing method, an increasing number of underlying inherited metabolic liver disease will be identified. DJS is a rare autosomal recessive disorder characterized by intermittent jaundice of conjugated hyperbilirubinemia resulting from mutations of the multidrug-resistance protein 2/ABCC2 gene.3 It is a benign disorder and does not require specific therapy. To date, 2 patients4,5 with combined TB and DJS have been reported, and conjugated bilirubin elevated after rifampin introduction was observed. It may result from the increased expression of MRP3. We add another case of TB-combined DJS with the same phenomenon. However, the conjugated bilirubin did not return to baseline during one month with temporary discontinuation of antitubercular drugs. We consider that the bilirubin change of DJS with tuberculosis needs further explanation as the infective state may be involved in it.