The Management of Autoimmune Hepatitis
The Management of Autoimmune Hepatitis
The guidelines of the AASLD and BSG affirm the importance of treatment with prednisone (or prednisolone) alone or in combination with azathioprine in autoimmune hepatitis. The combination regimen is preferred by both the AASLD and BSG, except in patients who are cytopenic (white blood cell counts below 2.5 × 10/L or platelet counts below 50 × 10/L), pregnant or completely deficient of thiopurine methyltransferase (TPMT) activity. Restrictions on the use of combination therapy reflect concerns about azathioprine toxicity, but they are not supported by strong clinical evidence. Furthermore, the guidelines provide weak recommendations regarding pre-treatment testing for TPMT activity, the continuation of azathioprine during pregnancy and the treatment of asymptomatic mild disease ( Table 2 ).
Thiopurine methyltransferase is an enzyme involved in one of three competing enzymatic pathways that convert azathioprine to its active and inactive metabolites ( Table 5 ). Azathioprine is converted in blood to 6-mercaptopurine (6-MP) by a non-enzymatic, glutathione-based pathway, and this intermediate metabolite (6-MP) is then converted in the liver to either 6-tioguanine (thioguanine) nucleotides by a pathway mediated by hypoxanthine guanine phosphoribosyl transferase, 6-thiouric acid by a pathway mediated by xanthine oxidase or 6-methyl mercaptopurine by a pathway mediated by TPMT. The 6-tioguanine nucleotides are the active metabolites of 6-MP, and 6-thiouric acid and 6-methyl mercaptopurine are the inactive metabolites.
The 6-tioguanine nucleotides are responsible for the immunosuppressive and anti-inflammatory actions of azathioprine by inhibiting the synthesis of purine-based nucleotides, reducing the expression of pro-inflammatory genes, promoting apoptosis of activated T and B lymphocytes and reducing the number of natural killer cells in blood and tissue. The 6-tioguanines can also cause myelosuppression, which is the principal toxic effect of azathioprine. Impaired conversion of 6-MP to 6-thiouric acid or 6-methyl mercaptopurine can increase the delivery of 6-MP to the pathway favouring its conversion to the 6-tioguanine nucleotides. An increase in the amount of substrate delivered to this pathway can enhance the therapeutic and toxic actions of a fixed dose of azathioprine.
The activity of TPMT can be measured in blood (phenotyping), and the alleles associated with deficient TPMT activity can also be assessed (genotyping). Low TPMT activity has been associated with at least 10 variant alleles, and the *3A allele is the most common deficiency allele. Heterozygosity for the deficiency alleles is associated with intermediate TPMT activity in 6–16% of the normal population, and homozygosity is associated with low or absent TPMT activity in 0.3%. Importantly, phenotyping and genotyping for TPMT activity have been variably successful in predicting azathioprine-related complications in autoimmune hepatitis.
Patients with azathioprine intolerance have significantly lower TPMT activity than patients with azathioprine tolerance, but individuals who develop azathioprine-related side effects cannot be reliably identified by measuring TPMT activity. Indeed, most patients with azathioprine intolerance have normal or near-normal TPMT activity. Cytopenia compels discontinuation of azathioprine therapy in 6% of patients with autoimmune hepatitis, but cirrhosis is associated with cytopenia more commonly than azathioprine toxicity or TPMT deficiency.
Similarly, alleles associated with low TPMT activity are present in only 50% of patients with azathioprine intolerance, and the presence of deficiency alleles does not preclude tolerance of the drug. Difficulties in identifying patients at risk for azathioprine toxicity by phenotyping or genotyping for TPMT activity probably relate to the integrity of the alternative xanthine oxidase pathway of drug metabolism, the degree of penetrance of the deficiency alleles and the possibility that azathioprine increases TPMT activity by substrate induction. Furthermore, there are other factors that influence the relative dominance of the enzymatic pathways involved in azathioprine metabolism, including the race and age of the patient and the nature of other medications used concurrently with azathioprine.
Bone marrow failure has been associated with absent or nearly absent levels of TPMT activity, and concern about this complication has been the principal reason for favouring routine assessments of TPMT activity prior to instituting azathioprine treatment ( Table 5 ). The frequency of little or no TPMT activity in the normal population is 0.3%, and the occurrence of bone marrow failure in patients with little or no TPMT activity is unknown. Indeed, it may not be absolute depending on the integrity of the alternative xanthine oxidase pathway and the dose and method by which azathioprine is administered. Furthermore, the dose threshold for severe myelosuppression is unknown, and the low doses of azathioprine used in the treatment of autoimmune hepatitis (typically, 50 mg daily) may be insufficient to overload the alternative metabolic pathways.
Clinical judgment regarding pre-treatment TPMT testing must be based on the perceived risk of low-dose azathioprine therapy to the individual patient and the availability of TPMT testing ( Table 5 ). Pre-treatment TPMT testing in patients with pre-existent cytopenia, those who develop cytopenia during therapy and patients receiving high-dose azathioprine therapy (≥150 mg daily) is a strategy that restricts testing to the most vulnerable populations, but it is not all-encompassing. This highly selective approach has been endorsed by the AASLD guidelines, and it is acknowledged by the BSG guidelines.
Routine pre-treatment TPMT testing is the strategy that provides the broadest level of assurance about the absence of a pre-existent risk for serious azathioprine toxicity, and it can be an important and necessary consideration in strengthening patient and physician confidence in the treatment regimen. This reassurance may outweigh the evidence-based arguments against universal pre-treatment TPMT testing, and it is a strong justification for assessing TPMT activity in all patients before azathioprine therapy, especially in centres in which TPMT testing is readily available ( Table 5 ).
Direct measurement of the 6-tioguanine nucleotide concentrations in erythrocytes has the theoretical advantage of bypassing the uncertainties associated with the TPMT correlations. These determinations, however, have correlated inconsistently with the clinical findings in autoimmune hepatitis, and they have been most useful in documenting patient compliance with the treatment regimen. The major difficulty may relate to the uncertain lag time between detecting the 6-tioguanine nucleotides in erythrocytes and their action on the lymphocytes and bone marrow.
The guidelines of the AASLD and BSG for treating asymptomatic mild autoimmune hepatitis are based on divergent opinions and low-quality clinical evidence ( Table 2 ). These individuals constitute 25–34% of all patients with autoimmune hepatitis, but their management remains controversial. Some individuals may have inactive disease and protracted survival without therapy, whereas others may have mild disease that is unassociated with symptoms, but still progressive. Autoimmune hepatitis is a disease characterised by fluctuating disease severity, and its behaviour without treatment is unpredictable.
Asymptomatic patients have moderate–severe lobular hepatitis (91% vs. 95%), periportal fibrosis (41% vs. 39%) and bridging fibrosis (41% vs. 48%) on histological examination as frequently as symptomatic patients,94 and 26–70% of asymptomatic patients become symptomatic. Furthermore, untreated asymptomatic patients can have progressive liver failure with the development of ascites, hepatic encephalopathy or hepatocellular carcinoma during a mean observation interval of 10.4 years (range, 2.7–19.9 years). These untreated asymptomatic patients with mild disease also improve less commonly (12% vs. 63%) and more slowly than treated symptomatic patients with severe disease, and they have a lower 10-year survival (67% vs. 98%).
The uncertainty that mild disease remains mild compels a conservative management strategy that is based not on the urgency of treatment, but its likelihood. The clinical judgment must counterbalance the frequency of treatment-related side effects (12%) against the frequency of eventual symptomatic disease (34–70%), rarity of spontaneous complete resolution (0–10%), possibility of subclinical disease progression and prospect that mild disease will respond completely and quickly to treatment ( Table 5 ).
Uncertainties in Implementing Treatment
The guidelines of the AASLD and BSG affirm the importance of treatment with prednisone (or prednisolone) alone or in combination with azathioprine in autoimmune hepatitis. The combination regimen is preferred by both the AASLD and BSG, except in patients who are cytopenic (white blood cell counts below 2.5 × 10/L or platelet counts below 50 × 10/L), pregnant or completely deficient of thiopurine methyltransferase (TPMT) activity. Restrictions on the use of combination therapy reflect concerns about azathioprine toxicity, but they are not supported by strong clinical evidence. Furthermore, the guidelines provide weak recommendations regarding pre-treatment testing for TPMT activity, the continuation of azathioprine during pregnancy and the treatment of asymptomatic mild disease ( Table 2 ).
Pre-treatment Thiopurine Methyltransferase Activity
Thiopurine methyltransferase is an enzyme involved in one of three competing enzymatic pathways that convert azathioprine to its active and inactive metabolites ( Table 5 ). Azathioprine is converted in blood to 6-mercaptopurine (6-MP) by a non-enzymatic, glutathione-based pathway, and this intermediate metabolite (6-MP) is then converted in the liver to either 6-tioguanine (thioguanine) nucleotides by a pathway mediated by hypoxanthine guanine phosphoribosyl transferase, 6-thiouric acid by a pathway mediated by xanthine oxidase or 6-methyl mercaptopurine by a pathway mediated by TPMT. The 6-tioguanine nucleotides are the active metabolites of 6-MP, and 6-thiouric acid and 6-methyl mercaptopurine are the inactive metabolites.
The 6-tioguanine nucleotides are responsible for the immunosuppressive and anti-inflammatory actions of azathioprine by inhibiting the synthesis of purine-based nucleotides, reducing the expression of pro-inflammatory genes, promoting apoptosis of activated T and B lymphocytes and reducing the number of natural killer cells in blood and tissue. The 6-tioguanines can also cause myelosuppression, which is the principal toxic effect of azathioprine. Impaired conversion of 6-MP to 6-thiouric acid or 6-methyl mercaptopurine can increase the delivery of 6-MP to the pathway favouring its conversion to the 6-tioguanine nucleotides. An increase in the amount of substrate delivered to this pathway can enhance the therapeutic and toxic actions of a fixed dose of azathioprine.
The activity of TPMT can be measured in blood (phenotyping), and the alleles associated with deficient TPMT activity can also be assessed (genotyping). Low TPMT activity has been associated with at least 10 variant alleles, and the *3A allele is the most common deficiency allele. Heterozygosity for the deficiency alleles is associated with intermediate TPMT activity in 6–16% of the normal population, and homozygosity is associated with low or absent TPMT activity in 0.3%. Importantly, phenotyping and genotyping for TPMT activity have been variably successful in predicting azathioprine-related complications in autoimmune hepatitis.
Patients with azathioprine intolerance have significantly lower TPMT activity than patients with azathioprine tolerance, but individuals who develop azathioprine-related side effects cannot be reliably identified by measuring TPMT activity. Indeed, most patients with azathioprine intolerance have normal or near-normal TPMT activity. Cytopenia compels discontinuation of azathioprine therapy in 6% of patients with autoimmune hepatitis, but cirrhosis is associated with cytopenia more commonly than azathioprine toxicity or TPMT deficiency.
Similarly, alleles associated with low TPMT activity are present in only 50% of patients with azathioprine intolerance, and the presence of deficiency alleles does not preclude tolerance of the drug. Difficulties in identifying patients at risk for azathioprine toxicity by phenotyping or genotyping for TPMT activity probably relate to the integrity of the alternative xanthine oxidase pathway of drug metabolism, the degree of penetrance of the deficiency alleles and the possibility that azathioprine increases TPMT activity by substrate induction. Furthermore, there are other factors that influence the relative dominance of the enzymatic pathways involved in azathioprine metabolism, including the race and age of the patient and the nature of other medications used concurrently with azathioprine.
Bone marrow failure has been associated with absent or nearly absent levels of TPMT activity, and concern about this complication has been the principal reason for favouring routine assessments of TPMT activity prior to instituting azathioprine treatment ( Table 5 ). The frequency of little or no TPMT activity in the normal population is 0.3%, and the occurrence of bone marrow failure in patients with little or no TPMT activity is unknown. Indeed, it may not be absolute depending on the integrity of the alternative xanthine oxidase pathway and the dose and method by which azathioprine is administered. Furthermore, the dose threshold for severe myelosuppression is unknown, and the low doses of azathioprine used in the treatment of autoimmune hepatitis (typically, 50 mg daily) may be insufficient to overload the alternative metabolic pathways.
Clinical judgment regarding pre-treatment TPMT testing must be based on the perceived risk of low-dose azathioprine therapy to the individual patient and the availability of TPMT testing ( Table 5 ). Pre-treatment TPMT testing in patients with pre-existent cytopenia, those who develop cytopenia during therapy and patients receiving high-dose azathioprine therapy (≥150 mg daily) is a strategy that restricts testing to the most vulnerable populations, but it is not all-encompassing. This highly selective approach has been endorsed by the AASLD guidelines, and it is acknowledged by the BSG guidelines.
Routine pre-treatment TPMT testing is the strategy that provides the broadest level of assurance about the absence of a pre-existent risk for serious azathioprine toxicity, and it can be an important and necessary consideration in strengthening patient and physician confidence in the treatment regimen. This reassurance may outweigh the evidence-based arguments against universal pre-treatment TPMT testing, and it is a strong justification for assessing TPMT activity in all patients before azathioprine therapy, especially in centres in which TPMT testing is readily available ( Table 5 ).
Direct measurement of the 6-tioguanine nucleotide concentrations in erythrocytes has the theoretical advantage of bypassing the uncertainties associated with the TPMT correlations. These determinations, however, have correlated inconsistently with the clinical findings in autoimmune hepatitis, and they have been most useful in documenting patient compliance with the treatment regimen. The major difficulty may relate to the uncertain lag time between detecting the 6-tioguanine nucleotides in erythrocytes and their action on the lymphocytes and bone marrow.
Treatment of Mild Asymptomatic Autoimmune Hepatitis
The guidelines of the AASLD and BSG for treating asymptomatic mild autoimmune hepatitis are based on divergent opinions and low-quality clinical evidence ( Table 2 ). These individuals constitute 25–34% of all patients with autoimmune hepatitis, but their management remains controversial. Some individuals may have inactive disease and protracted survival without therapy, whereas others may have mild disease that is unassociated with symptoms, but still progressive. Autoimmune hepatitis is a disease characterised by fluctuating disease severity, and its behaviour without treatment is unpredictable.
Asymptomatic patients have moderate–severe lobular hepatitis (91% vs. 95%), periportal fibrosis (41% vs. 39%) and bridging fibrosis (41% vs. 48%) on histological examination as frequently as symptomatic patients,94 and 26–70% of asymptomatic patients become symptomatic. Furthermore, untreated asymptomatic patients can have progressive liver failure with the development of ascites, hepatic encephalopathy or hepatocellular carcinoma during a mean observation interval of 10.4 years (range, 2.7–19.9 years). These untreated asymptomatic patients with mild disease also improve less commonly (12% vs. 63%) and more slowly than treated symptomatic patients with severe disease, and they have a lower 10-year survival (67% vs. 98%).
The uncertainty that mild disease remains mild compels a conservative management strategy that is based not on the urgency of treatment, but its likelihood. The clinical judgment must counterbalance the frequency of treatment-related side effects (12%) against the frequency of eventual symptomatic disease (34–70%), rarity of spontaneous complete resolution (0–10%), possibility of subclinical disease progression and prospect that mild disease will respond completely and quickly to treatment ( Table 5 ).
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