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.

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 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)

 

Liver Problems with Inflammatory Bowel Disease

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.

Key topics:

  • 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:

PSC:

  • 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)

AIH:

  • 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:

  • 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/HBV Immunization:

  • 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.”

Methotrexate (MTX):

  • “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.

Related blog entries:

DILI:

PSC:

AIH:

 

 

Liver Briefs 2017

Briefly noted:

RJ Fontana et al. Hepatology 2016; 64: 1870-80.  In this study of 681 adults with acute liver failure in U.S., only 3 had detectable anti-HEV IgM and all three were negative for HEV-RNA.  In addition, other putative causes of acute liver failure were present in all three.  My take: Hepatitis E is very rare explanation for acute liver failure in the U.S.

RA Rosencrantz et al. Hepatology 2016; 64: 2253-6. Case report of 2.5 yr old with autoimmune sclerosing cholangitis with Kawasaki disease. This was a well-described case with MRCP and liver histology. My take: In patients with Kawasaki with protracted liver disease, another etiology to consider.

Related blog posts:

St Maarten

St Maarten