AASLD 2023 Practice Guidance for Primary Sclerosing Cholangitis and Cholangiocarcinoma

CL Bowlus et al. Hepatology 2023; 77: 659-702. Open Access! AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma

This is a lengthy article with a great deal of useful information. Here are some of the important recommendations most relevant for pediatric gastroenterologists/hepatologists:

  • In patients with PSC without known inflammatory bowel disease (IBD), diagnostic colonoscopy with histological sampling should be performed and may be repeated every 5 years if IBD is not initially detected
  • In patients with PSC in whom IBD is diagnosed, high‐definition surveillance colonoscopy with biopsies should start at age 15 years and be repeated at 1‐year to 2‐year intervals to evaluate for colonic dysplasia
  • New clinical risk tools for PSC are available for risk stratification, but probabilities of events in individual patients should be interpreted with caution
  • All patients with PSC should be considered for participation in clinical trials; however, ursodeoxycholic acid (13–23 mg/kg/day) can be considered and continued if well tolerated with a meaningful improvement in alkaline phosphatase (γ‐glutamyl transferase in children) and/or symptoms with 12 months of treatment
  • Upper endoscopy to screen for varices should be performed if the LS is >20 kPa by TE or the platelet count is ≤150,000/mm3
  • Bone density examinations should be performed to exclude osteopenia or osteoporosis at diagnosis and at 2‐year to 3‐year intervals thereafter based on risk factors

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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.

Long-Term Outcomes of Pediatric Patients with Sclerosing Cholangitis in the Setting of Inflammatory Bowel Disease

KO Hensel et al. J Pediatr 2021; 238: 50-56. Sclerosing Cholangitis in Pediatric Inflammatory Bowel Disease: Early Diagnosis and Management Affect Clinical Outcome

This was a retrospective study of 82 pediatric patients (31% female) with IBD-SC and a mean age at diagnosis of 11.9 ± 2.8 years who were followed up for a mean of 6.8 ± 3.3 years. Tests for SC included immunoglobulins and serology (ANA, ASMA, LKM-1, and SLA). Patients with ASC were maintained on low dose prednisolone (5 mg/day) and azathioprine (up to 2 mg/kg/day).

Key findings:

  • Autoimmune SC (ASC) was diagnosed in 72%, and small duct SC was diagnosed in 28%
  • Complication-free and native liver survival were 96% and 100%, respectively, at 5 years after diagnosis and 75% and 88%, respectively, at 10 years after diagnosis

The discussion notes generally better outcomes in this cohort than in previous studies. The authors note that this may be due to earlier diagnosis (though lead-time bias could be a factor as well). To increase earlier diagnosis, the gastroenterology diagnostic pathway at one institution (CUH) includes mandatory assessment of liver function and a low threshold for performing a liver biopsy (with initial panendoscopy). Diagnosis of ASC was based on the ESPGHAN diagnostic score for AILD (JPGN 2018; 66: 345-360, related post has image with scoring: Aspen Webinar 2021 Part 5 -Autoimmune Liver Disease & PSC). Also, they note that SCOPE score “seemed to overestimate the risk for developing complications.”

My take: In those with IBD and abnormal liver enzymes/GGT, looking for SC/ASC may improve outcomes.

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Chattahoochee River, Atlanta

Recurrent PSC in Children After Liver Transplantation

M Martinez et al. Hepatology 2021; 74: 2047-2057. Recurrence of Primary Sclerosing Cholangitis After Liver Transplant in Children: An International Observational Study

In this retrospective study, the authors examined recurrent PSC (rPSC) in children who had undergone liver transplantation (LT) with 3 yrs of median followup. Key findings:

  • rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively
  • Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01)
  • After LT, rPSC subjects had more episodes of biopsy-proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid-refractory rejection (41% vs. 20%; P = 0.04)

My take: rPSC, not surprisingly, was associated with a more agressive, immunoreactive phenotype prior to LT characterized by younger age, faster progression to end-stage liver disease, higher prevalence of IBD and more frequent/difficult allograft rejection

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Bahamas (courtesy of Mark Martin)

Aspen Webinar 2021 Part 5 -Autoimmune Liver Disease & PSC

More from Aspen Webinars. This blog entry has abbreviated/summarized several presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Dr. Mieli-Vergani presented case report of a boy with autoimmune sclerosing cholangitis and associated colitis who presented with minimal symptoms. 

This case report highlights the evaluation and management of autoimmune liver disease hepatitis. Workup included autoimmune serology, GGT, celiac serology, calprotectin, and ultrasonography.   EGD-Colonoscopy was prompted by elevated calprotectin.  MRCP was prompted by elevated GGT (GGT were normal at the time of biopsy and MRCP) and liver biopsy findings.  

“My message is that MRCP and colonoscopy should be done in all cases of autoimmune liver disease in children and adolescents, irrespective of calprotectin levels or elevated GGT and biliary changes on histology, as both IBD and sclerosing cholangitis can be present without any of the classical symptoms and signs. Only by doing this it is possible to reach an early diagnosis which is essential for early treatment and for a good outcome.” 

Outcome data indicate that 11 of 83 (13%, 5 AIH, 6 ASC)) required transplantation. “I have shown our long-term outcome data not to stress the number of patients who have required transplantation, but the number of patients who are well and have a normal life after over 14 years of follow-up. This can be only achieved if one thinks of autoimmune liver disease even if the child appears to have something non-specific, initiating correct treatment for the liver, and the gut if there is bowel disease, as soon as possible. At the beginning, treatment should be monitored very closely (at least weekly), to be able to decrease the dose of steroids swiftly, introduce azathioprine if needed, and avoid side affects.”

Key points:

  • Budesonide is not a good substitute for prednisone in autoimmune hepatitis
  • Mycophenolate is frequently used as a 2nd line agent
  • Consider calprotectin in patients with autoimmune liver disease to screen for IBD  (though calprotectin can be falsely-negative)
  • Consider followup liver biopsy after normalization of liver enzymes for ~3 yrs (when consideration of stopping medications)
  • Recommends MRCP for all patients with AIH

Some slides:

Key points:

  • Better understanding of immune basis of PSC is developing
  • MMP-7 appears to help differentiate PSC/ASC from AIH
  • Small duct PSC is more common in children
  • SCOPE index can help predict outcomes
  • Treatment: no clear benefit of vancomycin, ursodeoxycholic acid compared to placebo but need for randomized controlled study
  • Several studies of new agents for PSC in adults are ongoing, including nor-UDCA, cilofexor, bezafibrate
  • Vedolizumab does not appear to be effective for PSC
  • Related blog post: Online Aspen Webinar (Part 3) -2020 lots of links to other related blog posts

Some of the slides:

Milo Rezvani -case report

Child with FTT, elevated LFTs, sporadic mild hypoglycemia, and neurologic symptoms. DDx: congenital disorders of glycosylation (CDG), mitochondrial d/o, peroxisomal d/o, urea cycle d/o and lysosomal d/o.  Diagnosis was made after liver biopsy and whole exome sequencing (which showed PMM2 mutations).  Diagnosis of most CDG can be made by serum transferrin isoforms. Discussion among many participants noted that liver biopsy often not needed in age of genetic testing.

Liver Shorts: Stopping immunosuppression after transplant, toxicity of acetaminophen at therapeutic dosing, best imaging of PSC

S Feng et al. Hepatology 2021; 73: 1985-2004. Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Toward Personalized Management. iWITH study found that in highly-selected patients (n=88), immunosuppression could be withdrawn in 38%. Criteria included consistently normal liver biochemistries, >4 years after transplantation, and transplants unrelated to autoimmune etiologies or HBV/HCV.

A Louvet et al. Hepatology 2021; 73: 1945-1955. Acute Liver Injury With Therapeutic Doses of Acetaminophen: A Prospective Study This prospective study (2002-2019) showed that 89 of 400 adult patients with acetaminophen-induced acute liver injury (ALI) had received therapeutic doses of acetaminophen (<6 g). Especially in individuals with underlying alcoholic liver disease or fasting, acetaminophen (more than 2 gm/day) can trigger liver injury.

JE Eaton et al. Hepatology 2021; 73: 1868-1881. Early Cholangiocarcinoma Detection With Magnetic Resonance Imaging Versus Ultrasound in Primary Sclerosing Cholangitis This multicenter retrospective study showed that MRI is superior to ultrasound for the detection of early-stage CCA in patients with PSC. Identification of CCA before the onset of symptoms with MRI is associated with improved outcomes. The authors note that individuals diagnosed with CCA while asymptomatic had a 36% reduction in 5-year mortality and that MRI allowed for a 77% reduction in 5-year mortality among asymptomatic persons. One important limitation of this study would be lead-time bias; that is, those with disease detected at an earlier stage will live longer than those detected at a later stage and thus earlier diagnosis may be ascribed as conferring a greater longevity even with no intervention.

Trends in Liver Diseases: Autoimmune Liver Diseases and Fatty Liver

1st Study: M Lamba et al. Clin Gastroenterol Hepatol 2021; 19: 573-579. Full text: Trends in Incidence of Autoimmune Liver Diseases and Increasing Incidence of Autoimmune Hepatitis

This was a population-based prospective study from Canterbury, New Zealand

Key findings:

  • 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 rate of 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.

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2ndStudy: ZM Younossi et al. Clin Gastroenterol Hepatol 2021; 19: 580-589. Full text: Nonalcoholic Steatohepatitis Is the Most Rapidly Increasing Indication for Liver Transplantation in the United States

This study was an analysis of data from the Scientific Registry of Transplant Recipients (2002 through 2019).

Key findings:

  • 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.

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Figure 1 Prevalence of the most common CLD etiologies in waitlisted liver transplant candidates without HCC. (A) Proportion of all non-HCC listings with known etiology; (B) the proportion relative to that seen in 2002.

FITCH Study of Bezafibrate for Pruritus Due to Cholestatic Liver Disease

In the Fibrates for Itch (FITCH) study, (E de Vries, R Bolier e al. Gastroenterol 2021; 160: 734-743. Full text pdf: Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies:A Double-Blind, Randomized, Placebo-Controlled Trial), the authors study bezafibrate, a broad peroxisome proliferator-activated receptor (PPAR) agonist.

Key findings:

  • 70 patients completed the trial (44 PSC, 24 PBC, 2 SSC) (SSC =secondary sclerosing cholangitis). Treated patients received bezafibrate 400 mg once a day for 21 days.
  • For the primary end point, bezafibrate led in 45% (41% PSC, 55% PBC) and placebo in 11% to >/=50% reduction of severe or moderate pruritus (P ¼ .003).
  • Bezafibrate also reduced serum alkaline phosphatase (35%, P ¼ .03 vs placebo) correlating with improved pruritus (VAS, P ¼ .01) suggesting reduced biliary damage.
  • Serum bile acids and autotaxin activity remained unchanged.

My take: While the majority of patients did not reach the primary end point, bezafibrate merits further investigation and may be a useful agent for pruritus in the setting of cholestatic liver disease. From the associated editorial (pg 649, JK Dyson et al. Bezafibrate for the Treatment of Cholestatic Pruritus: Time for a Change in Management?): “FITCH is an important study and provides novel and important data. It suggests that bezafibrate can be part of the answer to cholestatic pruritus.”

From Editorial:

Current treatment ladder for pruritus and the potential positioning of bezafibrate in the future.

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Yesterday’s post alluded to alcoholic liver disease. More on that topic from NPR:

Link: Sharp, ‘Off The Charts’ Rise In Alcoholic Liver Disease Among Young Women

Cases of alcoholic liver disease — which includes milder fatty liver and the permanent scarring of cirrhosis, as well as alcoholic hepatitis — are up 30% over the last year at the University of Michigan’s health system, says Dr. Jessica Mellinger, a liver specialist there….

In the U.S., more than 44,000 people died of alcoholic liver disease in 2019. And although liver diseases still affect more men, younger women are driving the increase in deaths, a trend that began several years ago and is now supercharged by the pandemic

Surprise, Surprise: Inadequate Physical Activity is a Predictor of Fatty Liver Disease (Plus 2)

Briefly noted:

Hepatology 2020; 72: 1556-1568. Inadequate Physical Activity and Sedentary Behavior Are Independent Predictors of Nonalcoholic Fatty Liver Disease. D Kim et al found that leisure‐time physical activity (≥150 minutes per week) demonstrated 40% lower odds of NAFLD. This study used the 2007‐2016 US National Health and Nutrition Examination Survey with 24,588 participants; the authors defined NAFLD based on three noninvasive panels.

Liver Transplantation 2020; 26: 1409-1421. Low Health Literacy Is Associated With Frailty and Reduced Likelihood of Liver Transplant Listing: A Prospective Cohort Study. T Bittermann et al showed that low health literacy was independently associated with physical frailty (adjusted odds ratio [aOR], 3.59; 95% confidence interval [CI], 1.50‐8.59; P = 0.004) and not being wait‐listed (aOR 1.96; 95% CI, 1.03‐3.75; P = 0.04).

Liver Transplantation 2020; 26: 1477-1491. Impact of Preexisting Inflammatory Bowel Disease on the Outcome of Liver Transplantation for Primary Sclerosing Cholangitis. In this retrospective study with 87 patients who underwent liver transplantation for PSC, 52 (60%) had pre-existing IBD. Key findings:

  • Excluding those who died within the first 3 months, the 10‐year patient survival and graft survival rates were 92.6% and 77.1%, respectively, in the PSC with IBD (PSC‐IBD) group and 97.1% and 83.2% in the isolated PSC group, respectively.
  • The rate of recurrent PSC was 21% in the PSC‐IBD group and 11% in the isolated PSC group

Thus, it appears that having pre-existing IBD did not significantly influence survival after transplantation.

How Primary Sclerosing Cholangitis Alters Outcomes in Inflammatory Bowel Disease

PJ Trivedi et al. Gastroenterol 2020; 159: 915-928. Effects of Primary Sclerosing Cholangitis on Risks of Cancer and Death in People With Inflammatory Bowel Disease, Based on Sex, Race, and Age

Methods: The authors linked prospectively collected data from national health care registries maintained for all adults in England on hospital attendances, imaging and endoscopic evaluations, surgical procedures, cancer, and deaths.

Key findings:

  • Over 10 years, we identified 284,560 incident cases of IBD nationwide; of these, 2588 patients developed PSC. This study excluded patients <18 years of age.
  • Development of PSC was associated with increased risk of death and CRC (hazard ratios [HRs], 3.20 and 2.43, respectively; P < .001) and a lower median age at CRC diagnosis (59 y vs 69 y without PSC; P < .001)
  • Compared to patients with IBD alone, patients with PSC-IBD had a 4-fold higher risk of CRC if they received a diagnosis of IBD at an age younger than 40 years
  • Development of PSC also increased risks of cholangiocarcinoma (HR, 28.46), hepatocellular carcinoma (HR, 21.00), pancreatic cancer (HR, 5.26), and gallbladder cancer (HR, 9.19) ( P < .001 for all)
  • The greatest difference in mortality between the PSC-IBD alone group vs the IBD alone group was for patients younger than 40 years
  • Patients with PSC-UC had >40% risk of colonic resection compared to patients with IBD alone (aHR 1.65)

My take: This study shows the impact the added diagnosis of PSC has for patients with IBD. One of the limitations in assessing outcomes is determining whether someone with IBD has PSC as there are a lot of patients with IBD who have asymptomatic changes in their biliary tree.

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Vedolizumab -Not Likely to Help Primary Sclerosing Cholangitis

A recent retrospective study (TJ Laborda et al. JPGN 2020; 71: 459-464 Vedolizumab Therapy in Children With Primary Sclerosing Cholangitis: Data From the Pediatric Primary Sclerosing Cholangitis Consortium) indicates that vedolizumab (VDZ) is unlikely to be helpful for primary sclerosing cholangits (PSC).

VDZ was initiated at median age of 16 years [IQR 15–18], 69% were male, 65% had large duct involvement, 19% had (Metavir F3/F4) fibrosis and 59% had ulcerative colitis.

Key findings:

  • Overall, there was a mild increase in median GGT after initiation of VDZ. Of 32 patients with abnormal GGT at baseline, 22% had a liver biochemical response (defined as GGT <50 or at least a 75% decline) after 9 to 12 months
  • For IBD, 32% achieved remission, 30% had a clinical response, and 38% had no response

In the discussion, the authors note that their findings are in agreement with three retrospective studies in adults which have shown that VDZ is not effective for PSC in patients with IBD.

My take: This study indicates that VDZ is not likely to help with PSC, though 62% of IBD patients had improvement in their GI disease.

From The Onion