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).
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.
Methods: A retrospective cohort study using anonymized UK primary care records (2002-2016). All adults without a baseline diagnosis of AILD (autoimmune liver disease) were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database.
1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34–2.60); PSC, 0.74 (95% CI, 0.67–0.82); and AIH, 1.94 (95% CI, 1.83–2.06) per 100,000 per year.
A more northerly latitude was associated strongly with incidence of PBC: 2.16 to 4.86 from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 to 3.28 (P = .003), but not incidence of PSC: 0.82 to 1.02 (P = .473)
After adjustments, PBC was more frequent in smokers than those who had never smoked at 3.40 (3.03–3.77) per 100,000/y and 1.96 (1.80–2.12) cases per 100,000/y; there was a lower incidence of PSC in smokers 0.47 (0.33–0.61) per 100,000/y compared with those who had never smoked 0.95 (0.83–1.07) per 100,000/y. For AIH, there was no difference between current smokers and those who had never smoked
The authors speculate in the discussion about potential reasons why latitude could correlate with disease incidence. Some potential explanations include sunlight/vitamin D metabolism (though this is at odds with the fact that those with increased skin pigmentation are NOT at increased risk), environmental exposures (related to geology, diet, air quality) or unrecognized genetic tendency based on geography.
My take: In the UK, there is an association between a more northernly latitude and both PBC and AIH.
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
Related blog posts:
PSC -Aspen 2021 Webinar This lecture highlights studies show lack of efficacy with vancomycin, ursodeoxycholic acid and vedolizumab. Also, there is potential utility of MMP-7 for distinguishing between PSC and AIH
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.”
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….
A recent study (O Olen et al. Gastroenterol 2019; 156: 614-22) was summarized quite succinctly by NEJM journal watch:
Using the Swedish National Patient Registry data, investigators identified 9442 incident cases of IBD diagnosed in patients under age 18 years from 1964 through 2014. Based on 139,000 person-years of follow-up, results were as follows:
There were 259 deaths among people with IBD (133 were from cancer and 54 from digestive disease).
The all-cause mortality rate in these patients was 2.1/1000 person-years, compared with 0.7 in matched reference individuals from the general population.
The average age at death was 61.7 compared with 63.9 years in the reference group.
The hazard ratio for death was 3.2 and was higher in those with ulcerative colitis (HR, 4.0), especially if they had concomitant primary sclerosing cholangitis (HR, 12.2), a first-degree relative with ulcerative colitis (HR, 8.3), or a history of surgery (HR, 4.6).
Mortality risks were similar when limited to the period after the introduction of biologics (2002–2014).
My take: This study found that having IBD diagnosed in childhood increased the risk of mortality (~1 extra death for every 700 patients followed for 1 year) especially in patients with concomitant PSC and in patients with severe ulcerative colitis. The study did not see an effect of the newest therapies but was underpowered to directly assess this effect.
In children with IBD, elevated liver enzymes raise the concern for primary sclerosing cholangitis (PSC). PSC is thought to develop in up to 5% of patients with IBD. To look more closely at this issue, a group of investigators examined 73 children (median age 12 years) with IBD with MRCP to look for evidence of PSC (JPGN 2012; 55: 308-13).
The majority of these patients had an MRCP at the time of an MRE; this was ordered independently from specific laboratory or clinical factors. On average, the date for MRCP was about one year after the date of diagnosis. In this group, 49 (67%) had Crohn’s disease (CD), 19 (26%) had indeterminate colitis (IC), and 5 (6.8%) had ulcerative colitis (UC) [In the results section, the authors state a discrepancy from previous: 47 with CD, 18 with IC, and 8 with UC.]
11 (15%) children had PSC-type lesions identified by MRCP. 6 of these patients had CD, 3 had IC, and 2 had UC. Among the PSC group, 5 had abnormal AST & ALT, 4 had abnormal GGT, and 1 had abnormal bilirubin at time of diagnosis & similar numbers were present at the time of MRCP. A much lower percentage of the non-PSC group (n=62), had abnormal LFTs. Though, at time of MRCP, 9 (14.5%) had abnormal ALT.
An editorial in the same issue (page 238), concludes that “screening for PSC by MRCP in all of the newly diagnosed patients with IBD seems promising.” Really? Given a lack of therapeutic options, I don’t think identifying preclinical PSC makes any sense. An exception would be in patients with persistent liver test abnormalities to avoid attributing this to medication toxicity.
While primary sclerosing cholangitis (PSC) has been associated with inflammatory bowel disease, and ulcerative colitis (UC) in particular, the pathogenesis of this relationship has not been established. A fascinating observation on this relationship is that an inflamed colon is important in PSC development (Clin Gastroenterol Hepatol 2012; 10: 439-41).
In this study which reviewed 2754 Irish patients with IBD, 59 (2.2%) had PSC. PSC incidence correlated with increasing colonic involvement. Among the 13 patients with Crohn’s disease, none had isolated small bowel disease. The second part of the study involved a review of 82 separate PSC patients attending the Irish National liver transplant unit. The majority of ulcerative colitis patients had a pancolitis; all 10 PSC patients with Crohn’s disease had colonic involvement.
Since PSC occurs without IBD, colonic inflammation is not necessary for PSC development. However, in patients with IBD, colonic inflammation is very important. In fact, in a previous study of 53 PSC-IBD patients, no UC patient status post a colectomy had recurrent liver disease following liver transplantation whereas seven patients with intact colons had recurrent disease following liver transplantation.
The authors speculate that bacterial translocation along with subsequent portal bacteremia may be an important step in pathogenesis among these patients.
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.
-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