With regard to asymptomatic patients, some studies suggest that untreated patients have a lower survival rate than treated patients, whereas others suggest that survival is similar
Referral to a hepatologist should be considered for patients who fail to go into remission with glucocorticoid therapy, who worsen despite therapy, or who have cirrhosis at the time of diagnosis. Patients presenting with fulminant hepatic failure should immediately be admitted to a hospital with liver transplantation capabilities whenever possible
AASLD 2010 guidelines. criteria:
- ALT or AST level greater than 10-fold the ULN
- Serum ALT, AST, or gamma globulin level greater than twice ULN if any of the following are present:
- Symptoms
- An elevated conjugated bilirubin or, even if less than twice the ULN
- Interface hepatitis on biopsy
- Histologic features of bridging necrosis or multiacinar necrosis
- Cirrhosis with any degree of inflammation on biopsy
- Children with autoimmune hepatitis
However, it is reasonable to offer treatment to a patient with histologic evidence of interface hepatitis particularly if the patient is younger (age less than 50 years) and is unlikely to have severe side effects related to therapy.
We generally rebiopsy patients who are not receiving treatment to look for histologic evidence of disease progression after two years.
No indication for treatment — absence of inflammatory cells on liver biopsy and normal or near-normal serum aminotransferases. The diagnosis of autoimmune hepatitis may be presumed in such patients based upon the clinical setting, the presence of serologic markers of autoimmune hepatitis, and the absence of other causes of liver disease. Such patients may be at increased risk for the development of glucocorticoid-related side effects, and the benefit of treatment is uncertain. However, patients with cirrhosis and active inflammation may be candidates for treatment.
Special circumstances —
High risk of drug side effects — The
risk of glucocorticoid-related side effects is increased in patients
with brittle diabetes, osteoporosis, emotional lability or a history of
psychosis, or poorly controlled hypertension.
not necessarily contraindications but may influence the decision to
use azathioprine or 6-mercatopurine or use a lower dose of prednisone. Budesonide may also be in option.Cirrhosis — treatment is generally not recommended for patients with cirrhosis and inactive disease. treatment should not be withheld for compensated or decompensated cirrhosis who have active disease. The response to treatment may be excellent, even those with bleeding varices or ascites. Many patients respond when treatment is initiated, and the 10-year survival for treated patients, including those with cirrhosis, exceeds 90 percent
Pregnancy — Women appropriately treated for autoimmune hepatitis can have successful pregnancies. Usual therapy consists of glucocorticoids and/or azathioprine, both of which appear to be safe during pregnancy, though azathioprine is listed as pregnancy class D. Cessation of therapy during pregnancy in such patients has been associated with relapse of the disease
-an increased risk of prematurity, low birth weight, and fetal loss
-monitor during pregnancy and several months post-partum because of the risk of flares in disease activity
Children — Autoimmune hepatitis tends to be more severe in children compared with adults,
Coexisting HCV — treatment should first be directed toward autoimmune hepatitis because of the danger of exacerbating autoimmune hepatitis with interferon-based therapy. Although this approach may result in increased viral levels of HCV, it is the safer initial strategy.
EXPECTED RESPONSES TO TREATMENT AND PROGNOSIS — The goal of therapy is to achieve a sustained remission without the need for medications- 10 to 40 % of patients. Up to 90% of patients with moderate to severe autoimmune hepatitis will respond to treatment, with a decrease in serum transaminases along with symptom improvement within two weeks. Serum transaminases will fall into the normal range, after 12 or more months of treatment.
incomplete response in 13 %of patients, and they worsen in 10 %(treatment failure)
Risk of treatment failure — :
- Those with established cirrhosis
- Those who develop disease at a younger age or have had a longer duration of disease before therapy
- Those who possess the HLA-B8 and/or HLA-DR3 phenotypes
Risk of relapse — 50 to 90 % of patients will relapse within 12 months of drug withdrawal. With retreatment, over 80 % of patients will again achieve remission. 13% of patients will achieve a sustained remission when drug withdrawal is again attempted, but the majority will require maintenance therapy.
Patients who achieve histologic remission have a 20 to 30 percent chance of relapse once treatment is withdrawn, whereas those who have evidence of interface hepatitis have a 75 to 90 percent chance of relapse.
Risk of cirrhosis — Patients who suffer from multiple relapses are at increased risk for cirrhosis compared with patients with a sustained remission after initial treatment (38 versus 4 percent). They are also at increased risk for death from liver failure or the need for liver transplantation (20 versus 0 percent).
30 percent of adult patients and almost half of pediatric patients will have cirrhosis at the time of diagnosis and cirrhosis develops in another 30 to 50 percent of patients during follow-up. While 10-year survival is similar to that in patients with autoimmune hepatitis without cirrhosis, survival is lower after 10 to 20 years. Ultimately, 10 to 20 percent of patients will require liver transplantation. 5 percent of patients will develop hepatocellular carcinoma. patients who undergo transplantation, 20 to 30 percent will have a recurrence of autoimmune hepatitis.
INITIAL THERAPY — glucocorticoid with or without azathioprine. Patients with fulminant hepatitis and liver failure, will require liver transplantation.
Fulminant hepatitis and acute liver failure — Patients with fulminant hepatitis and acute liver failure often require liver transplantation. trial of glucocorticoids (for two weeks or less) can then be given while performing the transplant evaluation and closely monitoring the patient's clinical status and Model for End-stage Liver Disease (MELD) score, reserving liver transplantation for patients who do not improve. Steroid in fulminant hepatitis-variable result.
limited data and clinical experience suggest that the two approaches have similar efficacy as initial therapy
Azathioprine monotherapy is used for maintenance therapy but is not effective for induction therapy. For patients who cannot tolerate prednisone, combination therapy with azathioprine and budesonide may be an alternative
The AASLD recommends glucocorticoid monotherapy or combination of a glucocorticoid and azathioprine. The BSG guidelines recommend glucocorticoid and azathioprine and do not recommend initial treatment with glucocorticoid monotherapy.
Because azathioprine is a prodrug of 6-mercaptopurine and, on occasion, toxicity to azathioprine occurs to the prodrug only, we may substitute 6-mercaptopurine at one-half of the azathioprine dosage.
azathioprine at a dose of 1 to 2 mg/kg daily is often used. Since azathioprine and 6-mercaptopurine have been associated with aplastic anemia in patients lacking TPMT enzyme activity, we obtain TPMT phenotyping prior to initiating therapy
Serum transaminase, bilirubin, or gamma globulin levels are checked weekly during the taper. If the patient develops recurrent symptoms or worsening laboratory values during the taper, we maintain the patient at the lowest dose that controls symptoms
When TPMT activity is low, there is an increase in 6-TG, which likely accounts for much of the drugs' toxicity. Measurement of metabolites can also be useful, particularly in patients who have not responded to treatment
However, toxicity to azathioprine can occur independent of TPMT activity, and some patients intolerant of azathioprine can take 6-mercaptopurine without side effects. In addition, allopurinol, a xanthine oxidase inhibitor, can lead to the increased production of active metabolites and should generally be avoided
For patients on combination therapy, monitoring includes [11]:
- Weekly liver tests, blood sugar, and blood cell count for four weeks and then every one to three months also including an IgG.
- Bone density testing at the beginning of glucocorticoid therapy and then every one to two years.
- Screening for glaucoma and cataracts after one year on glucocorticoids.
Remission — defined by :
- Resolution of symptoms
- Normalization of serum aminotransferase levels
- Normalization of serum bilirubin and gamma globulin levels
- Improvement in liver histology to normal or only mild portal hepatitis (or minimal to no activity in patients with cirrhosis)
-aminotransferase remain elevated in presence of coexisting non-alcoholic fatty liver disease. -gamma globulin levels remain elevated, may be secondary to other chronic inflammatory and/or autoimmune diseases.
In patients receiving azathioprine for maintenance therapy, 6-thioquanine (6-TG) metabolite levels may predict the ability to maintain remission. 6-TG levels of >220 pmol/[8 x 108 red blood cells] were more likely than those with lower average levels to have normal alanine aminotransferase levels (odds ratio 7.7)
the presence of normal or near-normal serum aminotransferases does not necessarily indicate histologic normalization
Withdrawing therapy — Once remission has been established, drug withdrawal can be attempted. The decision to use maintenance azathioprine or to wait for and treat the first relapse depends upon the estimated likelihood of relapse, severity of liver disease, and anticipated side effects. The British Society of Gastroenterology guidelines recommend routine maintenance therapy in younger patients and in patients who are LKM antibody or soluble liver antigen-positive.
Treatment is generally continued long enough to permit histologic resolution. - at least two years, with normal aminotransferase levels for 18 months. While a liver biopsy may help predict successful drug withdrawal, it has not shown to affect long-term outcomes and not required prior withdraw therapy. However, our preference is to obtain a biopsy prior to withdrawing therapy and to continue treatment if there is significant interface hepatitis or other histologic evidence of active disease.
We gradually taper the glucocorticoid over a six-week period in patients who achieve clinical remission. We monitor the serum transaminases, total bilirubin, and gamma globulin levels every three weeks during withdrawal and for three months after withdrawal. We then monitor the levels every six months for one year, and yearly thereafter.
For azathioprine, we generally withdraw it after glucocorticoids have been discontinued. For patients taking 50 mg daily, we simply stop the azathioprine. For patients taking higher doses, we reduce the dose by 50 mg every three months with careful monitoring every three months. In some cases, azathioprine cannot be successfully withdrawn, and patients may need maintenance therapy.
Incomplete response to initial therapy — 13 percent of patients after 36 months
- Some or no improvement in clinical, laboratory, and histologic features despite compliance with therapy for two to three years
- No worsening of the condition
Treatment failure — 10 percent
- Sustained biochemical and histologic activity, leading to the development or worsening of cirrhosis with eventual complications and death.
- The need for orthotopic liver transplantation.
The optimal therapy of resistant disease is not well established. We generally administer azathioprine (2 mg/kg/day up to a maximum dose of 200 mg daily) or 6-mercaptopurine (1 mg/kg/day up to 100 mg daily), while increasing prednisone to 40 to 60 mg/day. In responding patients, we taper the dose of prednisone by 10 mg per month until conventional maintenance doses are reached (10 mg/day) or to the lowest dose associated with clinical improvement (minimum of 10 mg/day). We continue the azathioprine or 6-mercaptopurine for up to one year before considering a dose reduction. After one year of clinical improvement, we taper the dose of azathioprine by 50 mg each month until a dose of 50 mg/day is reached. For patients who enter remission with this regimen, we will consider withdrawing therapy. However, other patients may require long-term maintenance therapy.
AASLD includes either monotherapy with prednisone (60 mg daily) or combination therapy with prednisone (30 mg daily) and azathioprine (150 mg daily). The regimen is continued for at least one month, after which the dose of prednisone is reduced by 10 mg and the dose of azathioprine reduced by 50 mg after each month of clinical improvement. Dose reduction is continued until conventional maintenance doses are reached.
Cyclosporine, tacrolimus, budesonide, methotrexate, infliximab, and mycophenolate mofetil have also been used in small numbers of patients who fail or cannot tolerate conventional therapy. AASLD, has been to try mycophenolate mofetil (a total of 2 g daily orally)
Finally, allopurinol has been tested in patients who are nonresponsive or intolerant to azathioprine or 6-mercaptopurine. When allopurinol is given in conjunction with a thiopurine, the metabolism of the thiopurine is shunted toward increased production of the metabolically active 6-thioguanine and decreased production of the toxic thiopurine metabolites. In a study of eight patients who received allopurinol in conjunction with a thiopurine, biochemical improvements were seen in all eight, with a sustained response in seven. However, if allopurinol (or other xanthine oxidase inhibitors) is used in conjunction with a thiopurine, it is important to monitor thiopurine metabolite levels
Medication intolerance — 10 percent.
- treat with either glucocorticoids or azathioprine alone (whichever was tolerated) at a dose that controls disease activity.
If there is disease progression on the single agent, alternative therapies, such as mycophenolate mofetil can be considered.
RELAPSE FOLLOWING SUCCESSFUL DRUG WITHDRAWAL — Relapse may be heralded by the development of fatigue, arthralgias, and anorexia accompanied by a rise in serum aminotransferase levels and/or an increase in serum gamma globulin levels. A rise in serum aminotransferases to more than three times normal or a rise in serum gamma globulins to more than 2 g/dL correlates strongly with the presence of histologic deterioration
Treatment of relapses — to resume the drug therapy that initially leads to remission at induction doses. Once clinical remission, to withdraw the drug(s), since some patients will achieve a sustained remission despite multiple relapses
Patients who continue to relapse can be treated with the lowest dose of either azathioprine or prednisone. Both strategies are effective in controlling the disease in the majority of patients. The decision to use azathioprine either as a steroid-sparing agent or as monotherapy involves weighing long-term steroid-induced side effects against those of azathioprine.
The following are reasonable approaches to making drug changes in patients taking azathioprine or prednisone for maintenance therapy:
In patients taking combination therapy in whom a prednisone alone strategy is desired, the prednisone dose is typically reduced first to the lowest level that maintains stability of the serum aminotransferases. The dose of prednisone can be decreased by 10 mg per week until a dose of 20 mg/day is reached. Tapering should then be by 5 mg increments per week until a dose of 10 mg/day is reached. At that point, tapering should be done in increments of 2.5 mg per week down to a dose of 5 mg daily. If laboratory tests worsen or symptoms return, the taper should stop and the previous dose resumed.
Azathioprine can then be discontinued by reducing the dose by 50 mg every three months with an increase in the dose of prednisone if needed. A typical maintenance dose of prednisone is less than 10 mg daily. Budesonide may have a role in this setting.
In patients taking combination therapy in whom maintenance therapy with azathioprine alone is desired, the azathioprine dose can be increased to 2 mg/kg/day, and then the dose of prednisone can be decreased by 2.5 mg each month until complete withdrawal. If 6-mercaptopurine is chosen, the corresponding dose of 1 mg/kg/day is used.
In patients taking prednisone alone in whom prednisone-free maintenance therapy with azathioprine alone is desired, azathioprine (2 mg/kg/day) or 6-mercaptopurine (1 mg/kg/day) can be added, after which the dose of prednisone can be reduced by 2.5 mg each month.
Once on a stable dose of medication, we monitor the patient's serum aminotransferases, bilirubin, and gamma globulin levels every six months. In addition, we obtain repeat liver biopsies to assess for disease progression every two years or prior to withdrawing therapy
Partial suppression in frequent relapsers — refers to treating patients to alleviate symptoms and to maintain serum aminotransferase levels that are mildly to moderately elevated. Partial suppression can be achieved with low doses of prednisone, with or without azathioprine
Their long-term outcomes (mean follow-up four years) were similar to those seen in 31 patients receiving conventional treatment. Only 1 of the 22 patients entered sustained remission, while 16 continued therapy. Morbidity was less than in conventionally treated patients since steroid-induced side effects usually resolved with low-dose prednisone.
LIVER TRANSPLANTATION —
We refer patients for a transplantation evaluation if they have:- Fulminant hepatitis and acute liver failure
- Decompensated cirrhosis with a MELD score ≥15
- Hepatocellular carcinoma meeting criteria for transplantation
AASLD indications for treatment —
- Immunosuppressive treatment can be considered in adults without symptoms and with mild laboratory and histological changes. The decision should be individualized and balanced against the risks of therapy. Referral of such patients to a hepatologist should be considered.
- Immunosuppressive treatment should not be instituted in patients with minimal or no disease activity or inactive cirrhosis, but such patients should be followed every three to six months.
- Immunosuppressive treatment should not be instituted in patients with serious preexisting comorbid conditions (vertebral compression, psychosis, brittle diabetes, uncontrolled hypertension) or previous known intolerances to prednisone unless the disease is severe and progressive and adequate control measures for the comorbid conditions can be instituted.
- Azathioprine should not be started in patients with severe pretreatment cytopenia (white blood cell counts below 2.5 X 109/L or platelet counts below 50 X 109/L) or known complete deficiency of thiopurine methyltransferase (TPMT) activity. TPMT activity should be assessed prior to starting azathioprine in a patient with cytopenia.
- Immunosuppressive treatment should be instituted in children at diagnosis regardless of symptoms.
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