This is highly technical study of 60 patients with AIH. “Our key finding was a clearly biased signature of TRBV-J gene usage in peripheral and liver-infiltrating T-cells of patients with AIH, independent of AIH predisposing HLA-DRB1 alleles. This signature was unaffected by immunosuppressive treatment and not related to complete biochemical disease remission. This suggests that treatment acted on T-cell functionality rather than on the underlying pathological T-cell architecture in this disease that has a high relapse rate.”
My take (borrowed from authors): “Patients with AIH show profound and persisting T-cell architectural changes that may explain high relapse rates after tapering immunosuppression.”
Using a community-based sample of 235 children, the authors found that there was a significant negative relationship between liver MRI-PDFF and BMD z score R = −0.421, P < .001).
There was no significant association between vitamin D status and BMD z score (P = .94).
Children with clinically low BMD z scores were found to have higher alanine aminotransferase (P < .05) and gamma-glutamyl transferase (P < .05) levels compared with children with normal BMD z scores.
My take: This study shows another organ that is affected in children with fatty liver disease; other associated problems include increased risk for cardiovascular disorders, pancreatic dysfunction/diabetes, cancer, polycystic ovary syndrome, and neurologic disorders
This was a population-based prospective study from Canterbury, New Zealand
Overall incidence rates were 1.93 per 100,000 for AIH (95% CI, 1.58–2.34), 0.51 per 100,000 for PBC (95% CI, 0.33–0.73), and 0.92 per 100,000 for PSC (95% CI, 0.68–1.21).
The incidence rateof AIH was significantly higher during the period of 2014–2016 (2.39 per 100,000; 95% CI, 1.76–3.23) than during the period of 2008–2010 (1.37 per 100,000; 95% CI, 0.91– 2.06) (P < .05). Incidences of PBC and PSC did not change significantly.
In 2016, prevalence values were 27.4 per 100,000 for AIH (95% CI, 23.58–32.0), 9.33 per 100,000 for PBC (95% CI, 7.13–12.05), and 13.17 per 100,000 for PSC (95% CI, 10.56–16.42).
My take: This study indicates that autoimmune hepatitis has been increasing in incidence.
This study was an analysis of data from the Scientific Registry of Transplant Recipients (2002 through 2019).
In 2002, the most common etiologies of non-acute liver failure on the liver transplant waitlist (in patients without HCC)
In 2019, among patients without HCC, NASH was the second leading indication for liver transplantation (28% of patients), after ALD (38% of patients). were chronic HCV infection (37%) and ALD (16%), whereas only 5% had NASH
HCC accounted for 27,799 patients (16.5%) and was commonly due to chronic HCV throughout study period
My take: Demand for liver transplantation has NOT improved despite curative therapy for chronic hepatitis C. This is due to increased liver failure related to fatty liver disease and alcoholic liver disease.
After the start of immunosuppressive therapy, bilirubin, albumin, and INR normalized in 70%, 77%, and 69%, respectively, in a median of 2.6 months, 3 months, and 4 weeks, respectively, in patients with A-AIH and AS-AIH
Deterioration of liver function (bilirubin, INR) after 2 weeks of treatment should lead to rapid evaluation for LT and consideration of second-line medication.
The cumulative incidence of waitlist mortality was 5.2%. Median waitlist time was 83 days.
In multivariable analysis (n = 2253), increasing bilirubin level ( P < .001), portal vein thrombosis ( P = .03), and ventilator dependence ( P < .001) at listing were associated with a higher risk, whereas weight ≥10 kg at listing ( P = .009) was associated with a lower risk of waitlist mortality.
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
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.
At presentation, check TPMT activity and look for other autoimmune diseases (especially thyroid, autoimmune hemolytic anemia, and celiac disease)
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.”
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
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.
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:
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
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.
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).
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.
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.
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.