Tag Archives: autoimmune hepatitis

PSC 2013 Review

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A recent review of PSC was published (Gastroenterology 2013; 145: 521-36).  This review is a little more detailed than a previous review noted in this blog less than 6 months ago (Staying current with PSC | gutsandgrowth).

A couple of useful comments from the review:

  • “An increased serum level of alkaline phosphatase is the most common biochemical abnormality detected in patients with PSC.  In some cases, it is the only biochemical alteration observed, such as in patients with intrahepatic involvement.”
  • “Typically, a liver biopsy is not required to diagnose PSC unless small duct PSC is suspected or if there are concerns that a patient also has AIH.”  Cholangiography is the best way to identify PSC.
  • “Patients diagnosed with PSC should undergo colonoscopy… to determine if they have IBD, even when there are no symptoms.”
  • Autoimmune hepatitis-PSC overlap is thought to occur in ≤6% of cases.  AIH-PSC should be suspected if there are biochemical features of AIH (positive serology, increased transaminases), histology suggestive of AIH, or in AIH patients that become refractory to treatment.
  • No controlled trials have identified effective medical treatments.  Studied medications have included corticosteroids, etanercept, tacrolimus, cyclosporine, azathioprine, methotrexate, infliximab, and ursodeoxycholic acid.  The latter may increase disease progression, particularly at higher doses.

Also noted:

Hepatology 2013; 58: 1392-1400. “Primary Sclerosing Cholangitis, Autoimmune Hepatitis, and Overlap in Utah Children: Epidemiology and Natural History”

In this study the authors identified 607 cases of IBD, 29 cases of PSC, 12 cases of ASC (overlap), and 44 cases of AIH.  “Cholangiocarcinoma developed in 2 of the 29 PSC patients (6.9%).  PSC occurred in 9.9% of patients with ulcerative colitis (UC) and 0.6% of patients with Crohn’s disease.”

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Postgraduate Course Notes – Hepatitis Module

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Notes from NASPGHAN’s postgraduate course:

Refractory Autoimmune Hepatitis (AIH):  — Vicky Ng

Dr. Ng’s talk started with an overview of AIH and referred to AASLD guidelines: Diagnosis and Management of Autoimmune Hepatitis – AASLD

Recommendations included the following:

  • Cholangiography for all new cases of AIH
  • Starting azathioprine after seeing some improvement in transaminases with steroids
  • Monitoring for HCC
  • Monitor bone density/bone protection strategies discussed
  • Long term Rx needed in majority, though small number may be able to come off therapy if doing well for 2 years and normal liver biopsy

Refractory mgt:

  • This is applicable in 15-20% of patients
  • Reasons for refractory disease: non response, drug intolerance, non-compliance, overlap syndrome, comorbidities
  • If treatment failure, options could include increasing steroids and azathioprine.  If concerns for decompensation, refer for liver transplant evaluation.
  • NO standard Rx for refractory, but consider MMF (mycophenolate mofetil), cyclosporin (CYA), or tacrolimus (FK)
  • MMF most promising agent for refractory disease.  Small studies of MMF in adults/pediatrics indicates response in about 2/3rds of patients; best for those intolerant to azathioprine & helpful in dropping steroid dosing.  In pediatrics, a starting dose of 20 mg/kg/day is typical and increasing up to 40 mg/kg/day.  Pediatric study: 18/26 (69%) with response and 14/18 with normal AST w/in 2 months.
  • Tacrolimus –small study showed about ~90% response.  Dose was 0.1 mg/kg/day & target trough was 3 ng/mL
  • Briefly discussed budesonide.  More data in pediatrics needed.

Postgraduate Course Syllabus (posted with permission): PG Syllabus

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Staying current with PSC

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A recent article provides a useful review for primary sclerosing cholangitis (PSC) (Clin Gastroenterol Hepatol 2013; 11: 898-907).

This blog has previously discussed PSC (links below); however, the above reference is succinct and covers the key issues.  A couple of points that I found particularly helpful:

Cancer surveillance:

  • Cholangiocarcinoma (CCA): recommends “consider annual imaging (MRCP or Ultrasound) along with serum CA19-9 levels” to monitor for cholangiocarcinoma.  If there is a dominant stricture, proceed with ERCP with brushings. In pediatrics, the age to start screening is less clear, usually not presenting until beyond the late teen years, though CCA has been diagnosed in one case report at 14 years of age (NEJM 2003; 348: 1464).
  • Gallbladder cancer (30-40-fold higher risk than general population): If gallbladder polyp identified that is ≥0.8 cm, recommends cholecystectomy.  If smaller, may also want to remove if normal synthetic function; otherwise repeat imaging in 3-6 months.
  • Colon cancer: colonoscopy every 1-2 years in those with coexistent IBD (70% of patients with PSC have IBD).

Diagnosis: 44-56% of patients are asymptomatic at time of diagnosis, picked up due to abnormal serum liver tests or on cross-sectional imaging.

Small-duct PSC: occurs in the setting of features of PSC (histology, biochemistry) without abnormal cholangiogram.  This represents 11-17% of PSC patients and is difficult to identify in patients without IBD. Over time, 25% will develop large-duct PSC. Small-duct PSC does not appear to result in increased risk of CCA.

Overlap syndrome with autoimmune hepatitis: patients with typical PSC but with 5- to 10-fold aminotransferase elevations should be suspected of having an overlap syndrome and may benefit from treatments directed at autoimmune hepatitis.  Other features often include histology with an interface hepatitis and the presence of auto-antibodies. This situation is more common in children and young adults.

Immunoglobulin G4-Related sclerosing cholangitis: this occurs most commonly in conjunction with autoimmune pancreatitis.  Since steroids can be effective, IgG4 levels should “be tested in all patients with suspected PSC, and, if elevated to consider an evaluation for IgG4-related disease.”

Medical management: “to date, there are no medical therapies that have been proven to alter the natural course of PSC.”  The discussion notes that standard doses of ursodeoxycholic acid (UDCA) may have protective effects against colorectal cancer in patients with coexisting IBD.  Higher doses of UDCA have been associated with a 2-fold risk of increased disease progression. Specific treatments for dominant strictures, pruritus, metabolic bone disease, and malabsorption are discussed.  In patients with cholestasis, monitoring fat-soluble vitamins is important.

Related blog posts:

Celiac hepatopathies

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There has been a longstanding recognition that celiac disease can be associated with elevated liver enzymes.  Two articles provide further information about celiac hepatopathies.

  • JPGN 2013; 56: 663-70
  • JPGN 2013; 56: 671-74

The first study describes a review of nine studies identified in a MEDLINE search for celiac disease and hypertransamminasemia (HTS) or autoimmune hepatitis (AIH). In total 2046 patients were identified.

Key findings:

  • 12% of patients with mild persistent HTS had celiac disease.  Among individuals with HTS, the relative risk for celiac disease was 11.59 compared to general population.
  • 36% of newly diagnosed children with celiac disease, has elevated aminotransferases.  A gluten-free diet normalized transaminases in 77% within 4 to 8 months.
  • Among children with celiac disease, 1.4% had AIH.  Among children with AIH, 6.3% had celiac disease.

While this meta-analysis had many limitations, it is clear that celiac disease needs to be considered in patients presenting with elevated aminotransferases and in patients with AIH.  In addition, other liver conditions like primary biliary cirrhosis and sclerosing cholangitis, which are infrequent in the pediatric population, are more common in patients with celiac disease.

The second study involved both retrospective (1995-2000) and prospective evaluation (2000-2012) of patients followed at a single center.  The authors sought to determine the long-term response to immunosuppressive treatment in children with autoimmune hepatitis (AIH) and celiac disease.

In their cohort of 79 AIH patients, 15 (9%) had celiac disease.  There was a similar frequency of type 1, type 2 and seronegative AIH among the celiac patients (47%, 20%, and 33%) compared with the entire cohort (55%, 34%, and 11%).  All 15 patients responded to treatment with prednisone and azathioprine or cyclosporine, along with a gluten-free diet.  When immunosuppressive treatment was withdrawn in 9 patients, 4 relapsed and 5 were maintained off immunosuppression for a mean period of 89 months. A much lower rate of immunosuppression withdrawal was achieved in those AIH patients without celiac disease.  24 of 64 attempted to stop immunosuppression; 5 (8%) were successful.

Take-home point of second study: All AIH patients should be screened for celiac disease as a gluten-free diet may increase the likelihood of withdrawal of immunosuppression.

Azathioprine metabolite measurement for Autoimmune Hepatitis

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While obtaining azathioprine (AZA) metabolite levels in inflammatory bowel disease has proven clinical utility, there is less data with regard to autoimmune hepatitis (AIH).  Now a study of 70 adults with AIH reports that therapeutic levels of 6-thioguanine (TGN) (>220 pmol/8 x 10 to the 8th) are associated with remission (Hepatology 2012; 56: 1401-8).

Patients in this study had an average age of 61 years; the average participant had a diagnosis of AIH for 8 years at the start of the study. For induction of remission, patients had received a combination of prednisolone along with AZA.  AZA was started at 1 mg/kg/day and gradually increased to 2 mg/kg/day.  All patients had a complete response to steroids prior to AZA dose escalation.

Outcome from this study was characterized by ability to maintain remission with ALT <33 IU/L and/or relapse which was indicated by ALT >2 x ULN (upper limit of normal) or liver histology showing active disease.

Serial measurements of red blood cell TGN and methylmercaptopurine nucleotides (MeMPNs) were obtained over two years.

Results:

  • 53 patients maintained remission and 17 did not.
  • Those in remission tended to be receiving lower doses of AZA (1.7 vs 2 mg/kg/day) but had higher average TGN levels (237 vs 177 pmol/8 x 10 to the 8th)
  • TGN levels >220 pmol/8 x 10 to the 8th best predicted remission
  • There was no measurable difference in thiopurine methyltransferase (TPMT) activity between the two groups (remission vs relapse).
  • Two patients developed cholestasis and this was associated with high MeMPN levels.

The authors note that several previous studies did not demonstrate a relationship between TGN levels and efficacy.  This is likely related to patient selection (all in remission at start in current study), repeated TGN levels, and the definition of remission.

Conclusion: Obtaining metabolites in adherent patients may be beneficial in patients with active disease to assist with dose modification and in individuals with potential AZA toxicity.

Related blog entries:

Diagnosing autoimmune hepatitis

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Criteria for autoimmune hepatitis (AIH) have been simplified over the last decade.  The 2008 AIH criteria have a high sensitivity and specificity in children (Clin Gastroenterol Hepatol 2012; 10: 417-21).

This study examined 238 patients: 41 AIH patients and 197 non-AIH patients.  Among these patients, 37 of the 41 AIH had sufficient data to calculate 2008 score using IgG or globulin & 40 of the 197 of the non-AIH had sufficient data.  Within the 37 AIH patients, 31 had IgG levels; all 37 had either IgG or globulin.  Similarly, among the 40 non-AIH patients, 26 had IgG levels available.

Among AIH patients:  the 1999 criteria categorized 29 of 31 (94%) as definite AIH and 2 of 31 (6%) as probable AIH.  The 2008 criteria: 25  definite AIH, 2 as probable AIH, and 4 were not identified as AIH; all four had fulminant hepatic failure (FHF).

The authors conclude that the simplified 2008 guidelines have high sensitivity/specificity and are easier to use.  Patients with FHF require the 1999 criteria.

  • -Hepatology 2008; 48: 10, 169. Simplified diagnostic criteria: points for autoabs, IgG, histology, & absence of viral hepatitis.

Autoantibodies:

ANA or SMA 1:40                  1
ANA or SMA 1:80
or LKM
or SLA 1:40                           2*

IgG:
IgG >Upper normal limit        1
>1.10 times ULN                   2

Liver histology (evidence of hepatitis is a necessary condition)
Compatible with AIH             1
Typical AIH                            2
Absence of viral hepatitis      2

Scoring Total:

>/=6: probable AIH
>/=7: definite AIH
*Addition of points achieved for all autoantibodies (maximum, 2 points).

Additional references on AIH criteria:

  • -Clinical Gastro & Hep 2011; 9: 57, 3 (editorial). Many AIH meet criteria w/o liver biopsy.
  • AIH 1999 criteria:  Hepatology 2009; 50: 538. diagnosis with scoring system vs. simplified. 1999 criteria more precise. See page 539 for details:

Scoring (points in bold):
if female gender,  +2
if ALP: AST (or ALT) less than 1.5, then +2
if globulin >2 (+3), +2 if >15, +1 if >1
if ANA, >1:80 +3, 1:80 =2, 1:40 +1
if neg viral markers, +3
drug hx neg, +1
if alcohol <25g/d, +2
liver histology: if interface hepatitis +3, lymphoplasmacytic infiltrate +2
if autoimmunity in pt or 1st degree relative, then +2
if response to Rx, +2
Interpretation: if pretreatment >15 definite AIH, 10-15 probable
if posttreatment: >17 definite, 12-17 probable

Additional AIH references:

  • -Gastroenterology 2011; 140: 1980. n=229. in single center, 93% achieved NL ALT w/in 12 months –though still with increased mortality compared to general population.
  • -Liver Tx 2011; 17: 393. 86% 5yr pediatric (n=113) OLTx survival (same as entire cohort)
  • -Hepatology 2010; 53: 926. AIH steroid failures (~20%) more likely to have worse disease at presentation. n=72
  • NAPGHAN 2010 Pointers:  Rx: Typical prednisone dose is 2 mg/kg/day, max 60 mg/day (“Mieli-Vergani regimen”). 90% of patients have dramatic improvement in LFTs within 2 weeks of starting corticosteroids, 80% achieve in remission in ≤18 mos. For the 10-20% failure rate, consider non-adherence to medications or make sure that you have the right diagnosis. Most children with AIH require prolonged or indefinite treatment with steroids, albeit at low dose
  • -Hepatology 2008; 48: 863. n=243. Risk factors for HCC in AIH. Main risk is cirrhosis with HCC occuring ~102 months after cirrhosis develops
  • -Hepatology 2010; 52: 2247. Suggested protocol to minimize steroids: Combined Azathioprine (~1.5/kg in adults) with steroids. Use steroids for 3 months then taper to 5-10mg/day. If doing well, try to d/c steroids at 1 yr of Rx.
  • -JPGN 2010; 51: 524. Use of allopurinol when Azathioprine toxicity (3 cases). Allopurinol dosed between 25mg-50mg and Azathioprine reduced to 0.5-1mg/kg/day.
  • -Hepatology 2008; 48: 10, 169. Simplified dx criteria: points for autoabs, IgG, histology, & absence of viral hepatitis.
  • -Hepatology 2008; 47: 9494-57. Asymptomatic PSC common in AIH –might be higher than 10%.-Clinical Gastro & Hep 2008; 6: 379. genetic factors affecting phenotype of AIH.
  • -Clin Gastro & Hep 2008; 6: 1036. Use of cellcept/mycophenolate for AIH.
  • -JPGN 2006; 43: 635. Use of cyclosporine initially for 6 months, then changing to AZA/steroids, n=84. Goal of CYA trough 250 +/- 50 for 1st 3 months.
  • -Hepatology 2006; 43: (Suppl 1): S132. Nice review.
  • -NEJM 2006; 354: 54. AIH Review.
  • -Clin Gastro & Hepatology 2004; 2: 935. Reviews AIH/PSC criteria in children; use of GGT recommended.

Challenges with primary sclerosing cholangitis

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Although primary sclerosing cholangitis (PSC) is an infrequent liver problem in pediatrics, it remains important.  PSC accounts for 2-3% of pediatric liver transplant cases.  A recent report updates some of the challenges for pediatric hepatologists (Shneider BL. Liver Transplantation 2012: 18: 277-81).

First the article examines some of the salient differences between children and adults.  The approach in adults may not apply well to children.  Some inherited diseases and immunologic defects may produce a similar clinical picture.   Specific differences include the following:

  • Defects in the adenosine triphosphate-binding cassette B4 (ABCB4 gene) (multidrug resistance protein 3) may cause a number of small-duct PSC in children
  • Cystic fibrosis can have a similar appearance
  • Overlap syndrome with autoimmune hepatitis is more common in children
  • Children with PSC often have higher alanine aminotransferase enzyme values than adults
  • Cholangiocarcinoma is rare in childhood, with 17 being the youngest reported case

Diagnosis usually requires, in addition to blood tests, cholangiography (eg MRCP), liver biopsy or both.  ERCP may not be needed depending on MRCP results.

Management: Pruritus may be managed with ursodeoxycholic acid (UDCA), bile acid binding resins, and rifampin.  Bone disease needs to be monitored along with fat soluble vitamin status.

  • While pruritus may improve with UDCA, high-dose UDCA (28-30mg/kg/day) has been associated with increased likelihood of negative endpoints.  It is not clear whether there may be detrimental effects at lower doses.
  • What about immunosuppression?  This (corticosteroids/thiopurines) is accepted in cases with AIH overlap.  Of course, what constitutes overlap is not certain.  So, in many cases, a trial of corticosteroids is considered.
  • Antibiotics?  Oral vancomycin has been tried in a small number with preliminary success.

As noted above, liver transplantation is a needed treatment in some cases. One concern with this approach has been recurrent PSC in about 10% at an average of 18 months after liver transplantation.

Additional references:

  • -Am J Gastro 2011; 106: 1638.  Use of high dose Urso increases risk of colonic neoplasia. n=150.
  • -Hepatology 2011; 54: 1842.  Guidelines on surveillance for PSC.  IF IBD yearly scope.  **Yearly U/S + CA 19-9 or yearly MRI.
  • -Liver Transplantation 201; 17: 925-933.  n=79 pediatric pts.  49% w IBD prior to OLT (46% w UC, 3%) & 9.8% developed IBD p OLT.  1 & 5yr survival for OLT 99% & 87%.  Recurrence in 9.8%.
  • -Clin Gastro & Hepatology 2011; 9: 434.  37% of PSC pts with CA 19-9 >129U/mL do NOT have cholangiocarcinoma.  n=7.
  • -Hepatology 2010; 51: 660-678.  update on dx/mgt.
  • -Gastroenterology 2010; 138: 1102.  genome associations with PSC.
  • -Hepatology 2009; 50: 808, 671 (ed).  Use of urso ~30/kg associated w WORSE outcome @5yrs. n=76 (& 74 controls)
  • -Clin Gastro & Hep 2009; 7:239. n=47 children w PSC.  59% w IBD, 25% w overlap syndrome
  • -JPGN 2008; 47: 61.  Use of oral vancomycin, 50mg/kg/day in patients with PSC/IBD was effective. n=14.
  • -Liver Tx 2008; 14: 735.  Review.  5 yr OLT survival 85%  ReTx rate higher (9.6% vs 4.9%).
  • -Hepatology 2008; 47: 9494-57.  Asymptomatic PSC common in AIH –might be higher than 10%.
  • -Gastroenterology 2008; 134: 975.  Natural hx/o small duct PSC in 83 pts (compared to controls).  Not likely increase in cholangiocarcinoma unless also large duct involvement.
  • -Gastroenterology 2008; 134: 706.  IAC is similar; IAC=IGG4 Associated Cholangitis
  • -Hepatology 2008; 47: 949.  8/79 w AIH also had PSC.
  • -J Pediatr 2007; 151: 255, 230.  association of CFTR mutations in PSC (26%); also present in disease control group with IBD (43%).
  • -Clin Gastro & Hep 2007; 5: 32.  Review vis-a-vis possible cholangiocarcinoma.
  • -Hepatology 2006; 44: 1063.  Review along w secondary causes.
  • -Liver Transplantation 2006; 12: 1813.  Recurrence post Tx 22% AIH, 18% PBC, 11% PSC.  (Review of 43 studies).
  • -Gastroenterology 2005; 129:1464.  High-dose actigall ineffective in 5 yr randomized controlled study.
  • -Gastroenterology 2003; 125: 1364.  Incidence of PSC.
  • -JPGN 2003; 37: 345 (57A). Use of vanco 50/kg/day x 4-6weeks in PSC, n=10, (56A) some pts c normal cholangiograms.
  • -Gastroenterology 2003; 124: 889. Urso prevents colon ca.
  • -Am J Gastro 2001; 96: 1558-62.  High dose UDCA, 25-30/kg/day may help long-term outlook
  • -JPGN 2001; 33:296. PSC-IBD.
  • -NEJM 2002; 346: 271-277.  case c Crohn’s.  PSC assoc c UC, celiac dz, pancreatic insufficiency.
  • -Ann Intern Med 2001; 134: 89-95.  Urso decreases colonic neoplasia in pts c UC & PSC.
    -NEJM 1997; 336: 691. Ursodeoxycolic acid & PSC.
  • -Gregorio et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology 2001;33:544-553

NASPGHAN 2010 Pointers:
I. -“STOPSC criteria”: 2 of 3 diagnostic criteria needed:
1) elev GGT or alk phos
2) intra and/or extrahepatic bile duct irregularities on cholangiography (i.e. PTC, MRCP, ERCP) c/w PSC
3) liver biopsy abnormalities c/w chronic biliary injury

AND no evidence of a secondary cause of sclerosing cholangitis

 

II. SUMMARY OF KEY CLINICAL FEATURES:

 

  • -Sclerosing cholangitis  is associated with IBD, autoimmune and connective tissue disorders, abnormalities of immune function (i.e. immunodeficiencies, GvHD), infiltrative disorders (i.e. Langerhans cell histiocytosis, lymphoma).
  • -PSC may sometimes affect only small intrahepatic bile duct (“small duct PSC”), which may have a better outcome based on adult studies
  • -PSC may have overlapping features of AIH  (“autoimmune sclerosing cholangitis”)
  • -IgG4 –associated cholangitis: patients appear to have PSC with elev IgG4.  They seem to respond very well to steroid therapy in adult studies
  • -No therapy of proven benefit for PSC (ursodiol, antibiotics), some case series have suggested antibiotics may help PSC
  • -5 times higher rate of Colorectal Ca when UC pt has PSC.  Consider yearly endoscopy