Autoimmune Hepatitis -Early Response Associated with Remission

Briefly noted: S Pape et al .Clin Gastroenterol Hepatol 2020; 18: 1609-1617. Full Text: Rapid Response to Treatment of Autoimmune Hepatitis Associated With Remission at 6 and 12 Months

Methods: This was a retrospective cohort study, collecting data from 2 independent cohorts of adults (each with n=370) with AIH from 12 centers in 7 countries in Europe.

Key findings:

  • The authors found that a significant decrease in level of AST after 8 weeks of treatment was significantly associated with normalization of transaminase levels at 26 and 52 weeks (P < .001)
  • In both cohorts, rapid responders (≥80% decrease in level of AST after 8 weeks) were more likely to achieve normalization of transaminases at 26 and 52 weeks when compared to non-rapid responders
  • Rapid responders in the discovery cohort had lower risk of liver-related death or transplantation (adjusted hazard ratio 0.18)
  • Slow responders (without normalization of transaminases after 1 year) had the highest risk of liver transplantation or liver-related death.

My take: It is no surprise that patients who respond rapidly to treatment would fare better.  This study establishes a target of >80% improvement in AST at 8 weeks.

Related blog posts:

Online Aspen Webinar -COVID-19, Autoimmune Hepatitis (Part 8)

For those who want to view the actual lectures, you can sign up and view the recordings:  Aspen Webinar Lecture Series


Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.

COVID-19 and the Liver — Fred Suchy

Key Points:

  • The extent and severity of liver disease related to COVID-19  is still being determined.  Many individuals have mild liver test abnormalities (5-60%)
  • Avoid imaging unless it will change your management (eg. thrombus)
  • In those with worsening/significant liver abnormalities, look for other etiologies of elevated liver tests (eg. other viral hepatitis, drugs, myositis, coinfection, clots, multi-system inflammatory disorder)
  • Currently, no change in immunosuppression is recommended in the post-transplant population WITHOUT COVID-19. In those with severe COVID-19 infection, reduction in immunosuppression is recommended

 

How I Manage Patients with Autoimmune Hepatitis -Diagnosis and Treatment   Amy Taylor.

Key points:

 

 

 

 

Online Aspen Webinar (Part 3) -Primary Sclerosing Cholangitis

Below I’ve included a few slides and some notes; my notes may have errors of omission or transcription.

Primary Sclerosing Cholangitis: Beyond Anecdotal Medicine  Jim Squires

Key points:

  • MMP-7 is emerging as better biomarker than alk phos or GGT
  • Patients with PSC-IBD often have PUCAI scores which underestimates severity of IBD activity. Even PSC-IBD patients in “clinical remission” often have disease activity.
  • PSC-IBD phenotype includes pancolitis (often with rectal sparing and backwash ileitis
  • Long-term prognosis is associated with level of GGT values
  • Prognosis: ~70% have event-free survival at 5 years
  • Adult prognosis models are inadequate due to frequent differences between disease in children and disease in adults.  Adults also have more comorbidities: obestiy, smoking, alcohol and medications
  • SCOPE index is a useful prognostic model for children (scores of 3 or less indicate very low risk of disease progression over next 5 years)
  • Actigall is current first line treatment in children based on biochemical improvement (no long term proof of efficacy); vancomycin has only anecdotal evidence of effectiveness

Related blog posts:

Autoimmune Hepatitis Outcomes, Grand Rounds on Splenomegaly, Hydroxychloroquine for SARS-CoV-2 & Zantac Warning

Here’s a commentary explaining why hydroxychloroquine is NOT proven effective:

Annals of Internal Medicine -Link: A Rush to Judgment? Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine for COVID-19

Some of the key points:

  • While the study suggested more rapid clearance of SARS-CoV-2 virus at day 6 in those treated with hydroxychloroquine/azathioprine (n=20), the authors excluded 6 from the treatment group including one patient who died and three who were transferrred to the ICU.  In addition, the treatment group had a lower viral load at the start of treatment.
  • Other viral infections, including influenza, have also had in vitro data suggesting efficacy with hydroxychloroquine but this did not translate into clinical efficacy in clinical trials.
  • “The hydroxychloroquine shortage not only will limit availability to patients with COVID-19 if efficacy is truly established but also represents a real risk to patients with rheumatic diseases who depend on HCQ for their survival.”

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A Di Giorgio et al (J Pediatr 2020; 218: 121-9) provide long-term data (median f/u of 14.5 years) from a retrospective review on 83 children with autoimmune hepatitis (AIH, n=54)/autoimmune sclerosing cholangitis (ASC, n=29). Median age at presentation, between 2000-2004 was 12.1 years

Key findings:

  • 29% had histologic evidence of cirrhosis at diagnosis
  • At a median followup of 14.5 years, 99% were alive, 11 underwent transplantation.  In those who underwent transplantation, 5-year and 10-year survival was 95% and 88% respectively.
  • ASC was associated with IBD in 73% of cases, compared to 33% of AIH patients.
  • Treatment: 95% of all patients had normalization with transaminases with immunosuppressive treatment (most commonly azathioprine with prednisone 2.5-5 mg/day). ASC patients also received ursodeoxycholic acid 15-20 mg/kg/day.
  • Immunologic remission: 47% achieved immunologic remission which required normal IgG levels and negative/low ANA/SMA <1:20 in addition to normal transaminases.
  • Liver transplantation was needed in 28% of ASC compared to 9% of AIH patients; overall, 83% experienced 15-year transplant-free survival. Median age of those needing a liver transplant was 19.3 years.
  • Immunosuppression withdrawal was attempted in 12 patients after a median of 4.5 years of treatment.  9 were able to stay off immunosuppression.
  • An increase in case frequency was noted during the last 4 decades at this center, from 3.6 cases/year to 5.4 case/year.
  • Four patients had isolated infrequent autoantibodies of anti-SLA (n=3) nad antiLC-1 (n=1). SLA =liver soluble antigen, LC-1 =liver cytosol antibody type 1.  Thus, in those with suspected AIH/ASC, testing for these autoantibodies is important in ~5%.
  • Pathology: 18% did not have classical features of interface hepatitis.  Instead, some had lymphocytic/lymphoplasmocytic infiltrate without spillover into the parenchyma.
  • Progression from AIH to ASC occurred in 3 patients on followup cholangiography.
  • ASC would have been overlooked in 41% if one relied on pathology alone -reaffirming need for biliary imaging.

My take: This article has a number of useful points and with an overarching message that long-term outcomes are good for children with AIH/ASC.

Related blog posts:

B Freiberg et al. 2020; 218: 221-31. This grand rounds describes the extensive workup of a 12 year old with splenomegaly ultimately due to splenic vein stenosis.  The report provides a nice review of hepatologic, hematologic, infectious, and other causes of splenomegaly as well as a work-up algorithm. (look for everything).

Initial evaluation per algorithm should start with CBC/d, retic, blood smear, liver biochemistries, GGT, coags, EBV VCA IgM, CMV IgM, Parvovirus IgM, and complete abdominal ultrasound with doppler.

Hepatologic causes of splenomegaly include the following:

  • cirrhosis with portal hypertension
  • autoimmune hepatitis/autoimmune sclerosing cholangitis
  • congenital hepatic fibrosis
  • hepatoportal sclerosis
  • nodular regenerative hyperplasia
  • storage disease and inborn errors of metabolism which includes lipidosis (Gaucher, Niemann-Pick), mucopolysaccharidoses, defects in carbohydrate metabolism (galactosemis, hereditary fructose intolerance), sea-blue histiocyte syndrome
  • anatomic disorders: portal/splenic thrombosis, Budd-Chiari, cysts, hamartomas, hemangiomas, hematoma, peliosis

Other causes of splenomegaly: infecions, hematologic-oncologic, and rheumatic disorders

Related blog posts:

The U.S. Food and Drug Administration today announced it is requesting manufacturers withdraw all prescription and over-the-counter (OTC) ranitidine drugs from the market immediately. This is the latest step in an ongoing investigation of a contaminant known as N-Nitrosodimethylamine (NDMA) in ranitidine medications (commonly known by the brand name Zantac). The agency has determined that the impurity in some ranitidine products increases over time and when stored at higher than room temperatures and may result in consumer exposure to unacceptable levels of this impurity. As a result of this immediate market withdrawal request, ranitidine products will not be available for new or existing prescriptions or OTC use in the U.S.

New FDA testing and evaluation prompted by information from third-party laboratories confirmed that NDMA levels increase in ranitidine even under normal storage conditions, and NDMA has been found to increase significantly in samples stored at higher temperatures, including temperatures the product may be exposed to during distribution and handling by consumers. The testing also showed that the older a ranitidine product is, or the longer the length of time since it was manufactured, the greater the level of NDMA. These conditions may raise the level of NDMA in the ranitidine product above the acceptable daily intake limit.

Using Less Steroids for Autoimmune Hepatitis

A recent retrospective study (S Pape et al. Clin Gastroenterol Hepatol 2019; 17: 2068-75) with 451 adults (1978-2017) examined outcomes among patients based on steroid dosing.

A high-dose group (n=281) with initial prednisone/prednisolone dose of ≥0.5 mg/kg/day was compared with a low dose group (n=170) <0.5 mg/kg/day.  The low dose group had higher rates of cirrhosis (25.9% vs. 15.3%) but lower median ALT values (7.1 ULN vs. 13.4 ULN) and lower median bilirubin values (48 vs 29 micromol/L).

Key findings:

  • There was no difference in rates of transaminase normalization at 1 year: 76.2% vs 77.6%
  • Transaminase normalization was lower in patients with cirrhosis 58.1% compared to 70.7% with cirrhosis
  • Most patients were receiving low-dose steroids at 6 months, 87.4% in high-dose group compared to 83.5% in low-dose group
  • Cumulative steroid dose was lower in low-dose group, with median of 2573 mg over 6 months compared to 3780 mg

Though, not studied in this report, AASLD has recommended use of immunoglobulin levels may help with immunosuppression titration. The editorial (pg 1948-49) notes that budesonide is another alternative for AIH without cirrhosis, though “long-term outcomes including histologic remission and appropriate tapering strategy for budesonide are currently lacking.”

My take: Particularly in patients without severe inflammation, lower steroid doses can be considered for autoimmune hepatitis.

Related blog posts:

Atlanta Botanical Garden

Steroid-Free Approach in Autoimmune Hepatitis

A recent case report (A Wehrman et al. J Pediatr 2019; 207: 244-7) described steroid free treatment of autoimmune hepatitis (AIH) in 8 patients.

This retrospective review of all patients with AIH at CHOP between 2009-2014 compared patients who had AIH treated with (n=12) and without steroids (aka azathioprine monotherapy). Near normalization of ALT was defined as less than 2 x ULN.

Key findings:

  • All children in the steroid group had normalization of liver enzymes by 12 months of therapy compared with only 2 of 8 in the steroid-free group. Though, near normalization of ALT occurred at a median of 5.5 months in the steroid free group (compared with 1.8 months in the steroid group).
  • Adverse effects were evident in 75% of the steroid group compared with 11% of the steroid-free group

The authors conclude that “liver enzymes may take longer to normalize without steroids, but this difference was not statistically significant in our small cohort, nor did it lead to any adverse outcomes.”

My take: Standard therapy for AIH is prednisone for induction with subsequent azathioprine.  This study shows that in patients unwilling to take steroids or with intolerance that azathioprine monotherapy may be an effective alternative though liver enzymes are likely to take much longer to improve.

Related blog posts:

Barcelona/Mediterranean Sea

Mortality Rate with Autoimmune Hepatitis –Increased if Cirrhosis

Briefly noted: Using a Dutch database to identify 449 patients with autoimmune hepatitis, a recent study (FF van den Brand et al. Clin Gastroenterol Hepatol 2019; 17: 940-7) found that having associated cirrhosis increased the mortality rate over a 10-year followup.  In this circumstance, the standardized mortality ratio (SMR) was 1.9.  In contrast, if cirrhosis was not present, there was no significant increase in SMR (1.2).  Patients with overlapping PSC had the greatest increase in mortality with an SMR of 4.7.

View from Sofia Reina museum. Madrid

Liver Articles -Spring 2018

C Sikavi et al. Hepatology 2018; 67: 847-57.  This systematic review highlights that the combination of hepatitis C virus (HCV) infection and HIV infection is no longer a difficult-to-treat population with the implementation of direct-acting antivirals (DAAs). There are similar sustained virologic responses (SVRs) among those with and those without HIV.  In clinical trials, patients with combined HCV-HIV had SVRs of 93.5-98% with DAA treatment; “real-world cohorts” had SVRs of 90.9%-98%.

MS Middleton et al. Hepatology 2018; 67: 858-72.  Using data from the prospective CyNCh trial (cysteamine for NAFLD), the authors examined MRIs for diagnostic accuracy among 169 enrolled children.  In this group, 110 (65%) and 83 (49%) had MRI and liver biopsy at baseline. MRI-PDFF (proton density fat fraction) was able to classify grade 1 steatosis from grade 2-3 steatosis with area under receiving operator characteristic curve of 0.87.  Thus, this study shows MRI-estimated PDFF has high diagnostic accuracy.

G Mieli-Vergani et al. JPGN 2018; 66: 345-60.  Position paper for Pediatric Autoimmune Liver Disease (AIH, ASC, de novo AIH after liver transplantation). This is a very useful review.  A couple of pointers from the authors:

  • “Present experience with budesonide as the first-line treatment is limited and does not appear to offer clear clinical advantage over the standard treatment”[prednisone]
  • Fecal calprotectin should be obtained to evaluate for IBD in patients with autoimmune liver disease, “even in asymptomatic children.”

JM Cotter et al. JPGN 2018; 66: 227-33. This retrospective study with 39 patients with primary sclerosing cholangitis (PSC) showed a lack of correlation between liver tests and fibrosis at presentation.  Average age of PSC diagnosis was 11.2 years, 74% had inflammatory bowel disease and 51% had autoimmune hepatitis. Related blog post: Big Pediatric PSC Study (with 781 children)

Autoimmune Hepatitis Associated with Anti-TNF Therapy

A recent study (A Ricciuto et al. J Pediatr 2018; 194: 128-35) identified an index case of autoimmune hepatitis (AIH) associated with anti-tumor necrosis factor (TNF) therapy and reviewed liver biochemistries in a cohort of 659 children.

Key findings:

  • In the index case, features of autoimmune hepatitis (AIH) on liver biopsy were noted 23 weeks after starting infliximab.   These findings resolved entirely within 4 months after withdrawal of infliximab
  • Overall, 7.7% of cohort had elevations of ALT while receiving anti-TNF therapy.  Most were mild and attributable to other causes than drug toxicity. No other cases of AIH were identified.

The authors recommend a careful investigation in those with elevations >2-3 times ULN which persists >3 months. Livertox (NIH) website notes the following for infliximab:

“The liver injury caused by infliximab is usually mild and rapidly reversed once therapy is stopped.  However, fatal instances of HBV reactivation and induction of autoimmune hepatitis due to infliximab have been reported, and regular monitoring of patients early during the course of infliximab is recommended.”

My take: Serious liver injury related to anti-TNF therapy is rare. A great place to understand the spectrum of liver problems potentially related to infliximab is the livertox website:

Related blog entries:

AIH:

Views from inside Hoover Dam, including Mike O’Callaghan–Pat Tillman Memorial Bridge

Autoimmune Liver Disease in Children with Sickle Cell Disease

A recent retrospective study (S Jitaruch et al. J Pediatr 2017; 189: 79-85) documents the important association of autoimmune liver disease in children with sickle cell disease (SCD).  I have seen  children with hemoglobinopathy and autoimmune hepatitis.

Key findings:

  • 13 of 77 patients with SCD were diagnosed with autoimmune liver disease
  • 2 patients presented with acute liver failure
  • 6 patients had cholangiopathy on cholangiogram “suggesting autoimmune sclerosing cholangitis”
  • At median follow-up of 3.8 years, 5 achieved full remission, 4 partial remission, 1 had liver transplant, 1 died of subdural hemorrhage (prior to liver disease treatment), and 2 were lost to followup

My take: this report is a good reminder that though there are a good number of reasons for abnormal liver blood tests in children with SCD, it is important to follow these children closely and to obtain serology (including ANCA) in those with persistent elevations.

Related blog post: Blood is not enough

South Kaibab Trail at the basin of the Grand Canyon (Colorado River)