A recent retrospective study (MA Sheiko et al JPGN 2017; 65: 80-5) examines the issue of azathioprine (AZA) metabolites and outcomes in pediatric autoimmune hepatitis (AIH).
- 66 children
- Mean age of diagnosis 9.6 years
- Mean follow-up 2.9 years
- Study period 2002-2013
- 79% achieved biochemical remission (defined as ALT ≤50 U/L); mean time was 6.2 months
- 6% required liver transplantation
- 18% were weaned off immunosuppression and remained in remission
- 6-thioguanine (6-TGN) levels ranging from 50 to 250 (pmol/8 x 10 to 8th red blood cell count) were associated with biochemical remission
“Our study suggests that AZA dosing of approximately 1.2 to 1.6 mg/kg/day will achieve 6-TGN levels of 50 to 250 pmol, which is sufficient to maintain biochemical remission in the majority of patients.“
This is significantly lower than dosing recommended for inflammatory bowel disease (recommended levels 250-450). The associated editorial (pg 2-3, N Kerkar) cautions that while “lower levels are sufficient for maintaining biochemical remission…higher levels, similar to that used in IBD, are required for inducing remission.”
My take: Lower doses of azathioprine are likely to maintain biochemical remission and cause fewer side effects. Metabolite levels can be helpful to assure reasonable levels of 6-TGN and to assure medication adherence.
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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
Shem Creek, SC
A recent study (AN Zizzo et al. JPGN 2017; 65: 6-15) performed a systematic review and meta-analysis of pediatric autoimmune hepatitis (AIH) studies.
The most remarkable finding was that there were only 76 patients from 15 qualifying studies.
- Response to mycophenolate mofetil (MMF) with 34 patients was 36% (according to abstract) at 6 months (discrepancy in article –results state 38% response)
- Response to cyclosporine with 15 patients was 83% (discrepancy in article –results state 86% response)
- Response to tacrolimus with 4 patients was 50%
- Adverse effects were very common, particularly with cyclosporine (64% noted at least 1 adverse effect)
The article has an associated editorial (N Kerkar, pg 2-3). “The adverse event profile of cyclosporine with gingival hyperplasia, hypertrichosis, nephrotoxicity, and neurotoxicity made it challenging for long-term use in children.” Besides the small number of patients, “the studies that were included were largely “observational”‘ which limits their findings as well. The study authors recommend MMF as the preferred option for 2nd-line therapy.
My take: Fortunately, most patients with autoimmune hepatitis respond to first line therapy with azathioprine/steroids. It is unclear what is the optimal 2nd-line treatment for refractory patients.
Related blog entries:
Egret, Shem Creek
A recent review (Full text: LJ Saubermann et al. JPGN 2017; 64: 639-52) discusses the hepatic issues and complications associated with inflammatory bowel disease.
- Primary Sclerosing Cholangitis (PSC)
- Autoimmune Hepatitis (AIH)
- Autoimmune Sclerosing Cholangitis (ASC)
- Portal Venous Thrombosis/hypercoagulability
- Cholelithiasis (more common in Crohn’s disease if diseased terminal ileum)
- Viral hepatitis
- Drug-Induced Liver Disease
- Fatty Liver disease
Many of these topics have been discussed previously on this blog. A couple of pointers in this review:
- Greater risk of colorectal carcinoma
- IBD-PSC patients are at higher risk for pouchitis
- GGT of >252 U/L “was highly sensitive (99%) and had good specificity (71%) for PSC” [or ASC]
- The authors recommend “screening all newly diagnosed patients with IBD with ALT and GGT
- Immunosuppressive therapy is NOT effective
- Vancomycin therapy is currently being tested (clinical trials: NCT02137668 & NCT01802073)
- Less frequent in IBD patients than PSC
- Most common treatment is prednisone/azathioprine
- 40-80% of children have cirrhosis at AIH diagnosis, but “progression to end-stage liver disease is rare and …with appropriate treatment, 80% of patients achieve remission.”
- ASC is an overlap syndrome between AIH and PSC
- “It is important that children with IBD and apparent AIH are routinely investigated for evidence of biliary disease with MRCP”
- “ASC responds to the same immunosuppressive combination therapy used for AIH”
- HAV vaccination is effective in patients with IBD…although the rate [seroconversion] was significantly lower” in patients receiving anti-TNF therapy (92.4% vs 99.1% in one study).
- In those needing HBV immunization: “One strategy evaluated to improve HBV immunity in adults with IBD is an accelerated course with double vaccine doses at 0, 1, and 2 months.”
- “The extent of histological features of hepatotoxicity secondary to long-term MTX use in IBD has been infrequently described; however, the inicdence of significant abnormal histological findings appears to be rather low.”
My take: This article is a good starting point for liver-related issues in IBD. For concerns regarding medications, the NIH livertox website is more useful and much more comprehensive.
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I’ve attached (with permission) the syllabus from the World Congress 2016 Postgraduate Course: 2016-world-congress-postgraduate-course-syllabus
One lecture that I will highlight with a few slides is from Dr. Martin Martin (pg 53-62) which emphasizes a new model for evaluating neonatal intestinal failure/congenital diarrhea by using whole exome sequencing –see slides below.
- Pg 82. Breastmilk associated with shorter duration of TPN dependence in short bowel syndrome
- Pg 137. Look for vasculopathy (MRI/MRA) and renal disease in Alagille syndrome
- Pg 152. Lactated ringer’s likely better in acute pancreatitis than normal saline.
- Pg 171. If constipation at less than 1 year is untreated, >60% have issues with constipation at age 3.
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
Between Journals and online resources, textbooks are increasingly less useful. Case in point -this past month, Clinical Gastroenterology and Hepatology published a special issue: The Art and Science of Managing Liver Disease. Some of the articles are excellent reviews.
With autoimmune hepatitis (AIH), the authors make a number of useful points and concisely summarized diagnosis and management. A few points:
- Anti-soluble liver antigen/liver-pancreas (SLA/LP) and Asialoglycoprotein receptor (ASGPR) useful in diagnosis of AIH type 1 or 2 and is prognostic for severe disease.
- In U.S. current guidelines suggest an azathioprine dose of 50 mg (for adults) whereas in Europe the dose is typically 1-2 mg/kg/day. The authors suggest that the U.S. guidelines could lead to undertreatment, particularly with increasing rates of obesity.
- The authors state that routine “testing for TPMT deficiency before AZA treatment of AIH is unnecessary, because severe TPMT deficiency occurs in 0.3%-0.5% of the general population and does not invariably cause AZA-induced bone marrow toxicity.” [I will probably continue to check TPMT activity.] They do recommend TPMT testing in cirrhotic patients and those with cytopenias.
- The authors note that successful long-term withdrawal can occur in 19-40% but recommend biochemical remission (>12-24 months) and histologic remission. They caution against withdrawal in patients after a relapse due to increased risks of progression to cirrhosis and/or death.
- When discussing alternative therapies, the authors note that mycophenolate mofetil (MMF) is typically effective for patients intolerant to AZA but not likely to work in AZA nonresponders.
- Alternative agents reviewed included tacrolimus, cyclosporine, sirolimus/everolimus, rituximab, and infliximab.
Other topics in this issue included NAFLD, HCC, Varices, Hepatic encephalpathy, HBV, HCV, Acute-on-Chronic Liver Failure, PSC and Malignancy, DILI, and noninvasive imaging for liver fibrosis.
A recent large single center study (Pusateri AJ et al. JPGN 2015; 60: 592-97) provides some very practical information regarding elevated liver enzymes in the setting of inflammatory bowel disease (IBD). Because there are some serious liver diseases associated with IBD and due to the potential for liver toxicity from many of the medications, bumps in liver enzymes need to be carefully considered.
This retrospective study with 514 patients indicates that 77% of these elevations are transient. Table 1 lists the definitions (chronicity, severity) and patterns that were analyzed. Transient elevations were broken down into brief (<30 days), prolonged <180 days, chronic >180 days and either intermittent or continuously abnormal. The three types were the following:
- Hepatic: elevated ALT and/or AST; normal alkaline phosphatase (AP), GGT, and direct bilirubin (DB)
- Cholestatic: elevated AP, GGT, and/or DB; normal ALT and AST
Severity or degree was classified as follows:
- 1 –peak liver enzyme 0-1 x ULN
- 2 –peak liver enzyme >1-2 x ULN
- 3 –peak liver enzyme >2-4 x ULN
- 4 –peak liver enzyme >4 x ULN
- 219 of 514 patients had 1 or more episode of abnormal liver enzymes; five patients with preexisting liver disease were excluded from the analysis.
- Of 214 patients (152 with Crohn’s disease [CD], 62 with Ulcerative colitis [UC]) with abnormalities, 69% had a hepatitic pattern, 8% had a cholestatic pattern, and 23% had a mixed pattern. There was no association between the pattern and the final diagnosis (eg. idiopathic vs defined etiology)
- Only 128 had adequate data to assess chronicity. In this group, 77% had transient elevations (CD 75%, UC 80%)
- 87% of elevations were considered idiopathic. 65% of patients with idiopathic elevation had levels < 2 times ULN.
- Among patients with levels <2 times ULN, 95.3% had an idiopathic etiology.
- Among patients with levels >4 times ULN, 63% had a benign idiopathic etiology
- Figure 1 provides a pie chart of diagnoses. Among the 12.6% with a specific etiology for elevated liver tests, drug toxicity was the most common reason: 51.9% were considered due to 6-MP therapy, 3.7% due to methotrexate, 3.7% due to acetaminophen.
- Other identified causes among the 12.6% with a defined etiology included NAFLD in 11.1%, infections (CMV,EBV, Histoplasmosis) in 14.8%, cholelithiasis in 3.7%, autoimmune hepatitis in 3.7%, primary sclerosing cholangitis/overlap in 3.7%, and vascular malformation in 3.7%.
As with any retrospective study, there are a number of limitations, especially underdiagnosis given a lack of uniform approach to evaluation. That being said, all patients had a minimum follow-up of at least nine months and most patients with prolonged liver enzyme elevation would have been examined closely.
Bottomline: This study provides reassurance that liver enzyme elevations are common in children with IBD, occurring in >40% of patients over 3 years at this center; most often these elevations are benign and transient.
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Recently, the first genome-wide association identified mutations associated with type 1 autoimmune hepatitis (AIH1) (Gastroenterol 2014; 147: 443-52).
Cohort: 649 Dutch adults with AIH1 and 13,436 controls
Findings: prominent association with rs2187668 (associated with variants in the major histocompatibility complex region) and with variants of SH2B3 (rs3184504) and CARD10 (rs6000782)
Interpretation (from authors): “These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.”
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