Cirrhosis

Autoimmune hepatitis (AIH) is a chronic self-perpetuating inflammatory liver disease by increased serum aminotransferase levels and autoantibodies; elevated serum immunoglobulin G (IgG) concentration, lymphoplasmacytic infiltration of the portal tract; interface hepatitis. Misdiagnosis or treatment failure can lead to liver cirrhosis, liver cancer, liver transplantation, and rapid death.
The first-line treatment for AIH involves predniso(lo)ne as initial therapy; followed by the addition of azathioprine (AZA) after 2 weeks. The initial dosage of AZA should be 50 mg ⋅ d−1, which can increase based on the toxicity and response up to the maintenance dose of 1–2 mg ⋅ kg−1. However, most recent studies implied that neither Thiopurine S-methyltransferase (TPMT) heterozygosity nor 6-mercaptopurine (6-MP); metabolite levels reliable predictors of AZA efficacy or toxicity in patients with AIH and related cirrhosis; cytopenia is frequently encountered due to advanced fibrosis.
Therefore the progressive cytopenia, white blood cell (WBC) counts below 3 × 109/L, or platelet counts below 50 × 109/L are severe hematological side effects that justify the discontinuation of the AZA treatment. Leukopenia, which is one of the most common and life-threatening adverse effects of AZA treatment; poses a substantial challenge to clinical practice and treatment outcomes.

Active metabolite 6-thioguanine nucleotide

TPMT is a key enzyme involving in AZA metabolism. Deficiency or low activity of TPMT may generate high concentrations of the active metabolite 6-thioguanine nucleotide (6-TGN), which accounts for the therapeutic effects of AZA but is also with bone marrow toxicity. The gene encoding the TPMT enzyme is by germline polymorphisms that lead to varying levels of enzyme activity among individuals.

The risk allele frequency of rs1142345 is high in Caucasians (4%), Latino (4.8%); African (5.4%) populations but low in East Asian (1.3%) populations. The results found that the rs116855232 but not the rs1142345 genotype was significantly associated with AZA-induced leukopenia and the maintenance dose in Chinese patients with AIH and related cirrhosis. Safety and efficacy can be maintained in most heterozygous genotype patients on AZA at lower doses of approximately 1 mg ⋅ kg−1 ⋅ d−1.

The TPMT genetic deficiencies

The gene encoding the TPMT enzyme is highly polymorphic; thus leading to varying levels of enzyme activity in different individuals. However, only approximately 20% of leukopenia cases can by TPMT genetic deficiencies. A large subset of patients with the wild-type genotype develops leukopenia, so implying that the utility of routine TPMT testing is and that other factors are responsible for the inter-individual variation in thiopurine sensitivity.

We found that a NUDT15 polymorphism; but it was significant with AZA-induced leukopenia in Chinese patients with AIH and related cirrhosis. For patients with the heterozygous variants; low-dose AZA (0.96 mg ⋅ kg−1 ⋅ d−1) is safe for maintaining remission and achieving efficacy comparable to that observed in wild-type patients. Even for patients with previous leukopenia or cirrhosis; AZA treatment may not contraindicated if NUDT15 genotypes permitted.