Seventeen-year-old girl, Guinea native, living in Portugal, was screened for tuberculosis after pulmonary tuberculosis was diagnosed in a girl living in the same school residence. She had a positive tuberculin skin-test and interferon-gamma release assay, and a nodular image on the chest X-ray. Mycobacterium tuberculosis was isolated on the sputum, susceptible to all first-line antituberculosis drugs. Treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was started, with daily-observed administration, achieving negative sputum cultures in the first month of treatment.
Three weeks after starting treatment, elevation of Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST), 136 and 89 UI/L, respectively, and palmoplantar desquamation was first detected, with further increase (ALT 281 IU/L and AST 186 IU/L) by the 5th week of treatment, leading to the interruption of the classic scheme and initiation of a second-line one with amikacin, levofloxacin, and ethambutol.
By the third month of treatment, maintaining changes on serum transaminases, despite the changes on treatment, without jaundice, cholestasis, or liver dysfunction, she was referred and admitted by the first time to our hospital. At this point, she had 31 doses of HRZE, 9 days without treatment followed by 34 doses of amikacin, levofloxacin, and ethambutol.
With a suspected DILI, withdraw of the antituberculosis drugs was determined and other causes of liver injury were excluded, such as viral hepatitis, concomitant HIV infection, alcohol consumption, and the use of other hepatotoxic offenders. During investigation, an alpha-thalassemia trait (-alpha/-alpha homozygotic), Hope Hemoglobin in beta chains, and hepatitis B immunity due to past infection (HBs and HBe antigen negative; anti-HBs and anti-HBe antibody positive) were diagnosed. Without treatment, liver enzymes rapidly normalized. Progressive introduction of antituberculosis HRZE was then made: gradual increase in the dose each day until therapeutic dose was reached; at the third day of each drug, serum ALT and AST were measured and then another drug was added. By 12th day of treatment, because of nausea complaints, worsening of the palmoplantar desquamation, and a sevenfold increase of ALT (283 IU/L), pyrazinamide was stopped. However, there was still clinical and analytical deterioration, with a peak serum ALT of 600 IU/L and AST of 300 IU/L, and all antituberculosis drugs were suspended five days later.
Further investigation to rule out autoimmune and metabolic causes was completed, all negative with exception of a positive anti-smooth-muscle antibody (ASMA 1/80). Intradermal skin tests with HRZE tested positive for rifampicin, raising the possibility of DILI by mechanisms of hypersensitivity.
Considering the patient previous treatment schemes, and based on expert's opinion, after normalization of liver enzymes, a slower reintroduction of second-line drugs was made: starting with levofloxacin 750 mg/day and amikacin 750 mg/day, twenty days later adding ethionamide 500 mg/day and 27 days later adding cycloserine 500 mg/day. There was no elevation on serum transaminases, the palmoplantar desquamation got progressively better, and she remained asymptomatic. She was discharged having 37 doses of levofloxacin plus amikacin, 17 doses of ethionamide, and 9 doses of cycloserine.
Two months later, during follow-up visits, she complained again of nausea, anorexia, weight lost, pruritus, and palmoplantar desquamation. Serum transaminases increased again (ALT 466 IU/L and AST 656 IU/L; normal alkaline phosphatase) and a mild hypergammaglobulinaemia (1580 mg/dL) with normal IgA levels (135 mg/dL), positive anti-nuclear (ANA 1/80), anti-neutrophil cytoplasmic (ANCA 1/80), smooth-muscle (ASMA 1/40), and F-actin (23.3 U) antibody were detected, raising the suspicion of drug-induced autoimmune hepatitis. Other organ autoimmune injuries (namely, thyroiditis and celiac disease) were negative. Liver biopsy showed mild lymphocytic infiltrate on histology, with no signs of interface hepatitis or portal plasma cell infiltration. Focal lymphocytic infiltrate and reticular collapse, reflecting focal hepatocytic necrosis, was evident at a lobular level.
Facing a possible immune-mediated DILI, treatment with the same antituberculosis drugs was reestablished simultaneously with prednisolone 1 mg/kg/day (40 mg/day) and maintained for a month, followed by a gradual decrease until a dose of 5 mg/day of prednisolone was reached, showing clinical improvement, no signs of liver cytolysis, normalization of hypergammaglobulinaemia, and negative autoantibodies. While still under treatment, 5 mg in alternate days was tried but liver enzymes slightly increased (ALT 42 U/L and AST 52 U/L), so she maintained 5 mg/day until 18th months of TB treatment was completed, with no side effects of steroids. After that gradually reduction of prednisolone dose to complete suspension was accomplished, maintaining normal liver enzymes and with no relapses.