A recent clinical practice update (CL Bowlus et al. Clin Gastroenterol Hepatol 2019; 17: 2416-22) makes several recommendations on surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis (PSC).
Full Text Link: AGA Clinical Practice Update on Surveillance for Hepatobiliary Cancers in Patients With Primary Sclerosing Cholangitis: Expert Review
I will highlight the most important recommendation for pediatric hepatologists:
- Best practice advice 6: Surveillance for cholangiocarcinoma should not be performed in PSC patients with small-duct PSCs or those younger than age 20.
In the text, the authors note that “in pediatric PSC patients, cholangiocarcinoma is very rare, with only 8 of 781 (1%) …developing cholangiocarcinoma” (MR Deneau et al. Hepatology 2017; 66: 518-27)
Here are the other recommendations:
- Best practice advice 1 Surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with PSC regardless of disease stage, especially in the first year after diagnosis and in patients with ulcerative colitis and those diagnosed at an older age.
- Best practice advice 2 Surveillance for cholangiocarcinoma and gallbladder cancer should include imaging by ultrasound, computed tomography, or magnetic resonance imaging, with or without serum carbohydrate antigen 19-9, every 6 to 12 months
- Best practice advice 3 Endoscopic retrograde cholangiopancreatography with brush cytology should not be used routinely for surveillance of cholangiocarcinomas in PSC.
- Best practice advice 4 Cholangiocarcinomas should be investigated by endoscopic retrograde cholangiopancreatography with brush cytology with or without fluorescence in situ hybridization analysis and/or cholangioscopy in PSC patients with worsening clinical symptoms, worsening cholestasis, or a dominant stricture.
- Best practice advice 5 Fine-needle aspiration of perihilar biliary strictures should be used with caution in PSC patients considered to be liver transplant candidates because of concerns for tumor seeding if the lesion is a cholangiocarcinoma.
- Best practice advice 7 The decision to perform a cholecystectomy in PSC patients with a gallbladder polyp should be based on the size and growth of the polyp, as well as the clinical status of the patient, with the knowledge of the increased risk of gallbladder cancer in polyps greater than 8 mm.
- Best practice advice 8 Surveillance for hepatocellular carcinoma in PSC patients with cirrhosis should include ultrasound, computed tomography, or magnetic resonance imaging, with or without α-fetoprotein every 6 months.
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From The Onion
In several prior posts, the issue of cancer and inflammatory bowel disease (IBD) has been discussed. In my view, even the word “cancer” is so scary that it can make people make bad choices (related: Facts, “Misfearing” and Women’s Health | gutsandgrowth). An up-to-date succinct summary (Laurent Beaugerie, M.D., Ph.D., and Steven H. Itzkowitz, M.D. N Engl J Med 2015; 372:1441-1452) provides a fairly good overview of “Cancers Complicating Inflammatory Bowel Disease.”
- “Smokers are overrepresented among the patients with Crohn’s disease…results in an excess rate of smoking related cancers.” (Smoking also is associated with more aggressive Crohn’s)
- Colorectal cancers risk factors (Table 1), specific to IBD, include coexisting primary sclerosing cholangitis (PSC), and increasing duration & extent of colonic IBD.
- A “progressive decrease in the excess risk of colorectal cancer in patients with IBD has been noted over time.” This may be due to better control of inflammation, surveillance, and colectomy. Still, the risk of colorectal cancer in patients with IBD is 1.5 to 2 times greater than the general population risk.
- Small-bowel adenocarcinoma –risk is 20-30 times that of the general population, typically arises more than 8 years after diagnosis. Absolute risk in those with disease more than 8 years is estimated at “0.5 per 1000 patient-years.”
- Intestinal lymphomas –absolute risk is about 0.1 per 1000 patient-years.
- Cholangiocarcinoma (CCA)–absolute risk is approximately “0.08 per 1000 patient-years.” CCA is mainly evident in patients with PSC who have a risk ~160 times the general population and lifelong risk of 5-10%.
- Non-Hodgkin’s lymphoma –“whether TNF-alpha antagonists promote lymphomas by themselves in patients with IBD is difficult to assess…” A recent study found no excess risk in patients receiving TNF-alpha antagonists after adjustments for cotreatments.
- Skin Cancers –nonmelanoma skin cancer, though not life-threatening, occur more often in those with current thiopurine usage.
- HPV-Related Cervical Cancer –“it is still unclear whether the risk of HPV-related cervical cancer is intrinsically increased in woman with IBD or independently worsened by exposure to an immunosuppressant.”
- Thiopurines: “after adjustment for confounders, current use of thiopurines for IBD has been shown to be associated with an overall relative risk of cancer of 1.3 to 1.7.”
- TNF-alpha antagonists: “There is no overall excess risk of cancer in patients treated with TNF-alpha antagonists for IBD.” However, more long-term data are needed.
- Figure 2 provides recommendations for colorectal cancer surveillance based on the American Gastroenterological Association (AGA), British Society of Gastroenterology (BSG) and European Crohn’s and Colitis Organisation (ECCO) recommendations. Typically, 8-10 years after diagnosis of colitis, starting surveillance (with chromoendoscopy if available) is recommended. In patients with Crohn’s disease, “the excess risk appears when more than 30 to 50% of the colonic surface is ever involved.” However, with PSC, the excess risk of colorectal cancer is significant at the time of diagnosis.
- For cholangiocarcinoma screening in those with PSC, “most experts recommend noninvasive annual imaging of the biliary tract (MRCP or ultrasound) and serum CA 19-9.”
- For HPV, vaccination is recommended and regular Papanicolaou tests
Take-home message: Some cancers are increased in association with IBD. However, the medications, particularly immunosuppressants, may reduce the incidence of inflammation-related cancers…or promote immunosuppression-related cancers.
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A study from the Netherlands examined the outcomes for Primary Sclerosing Cholangitis (PSC) (Hepatology 2013; 2045-55). Using four independent hospital databases with 44 hospitals, allowed the investigators to identify 590 PSC patients from a population of almost 8 million. Median followup was 92 months. Mean age at diagnosis was 38.9 years. A second comparison cohort of 450 patients was identified from three Dutch transplantation centers outside the study area. 134 (30%) of this cohort were present in the population-based cohort. An IBD comparison group of 722 cases was identified as well from a population of 271,000 patients.
- Prevalence: 6 per 100,000. This is significantly lower than previous estimates. The authors emphasize the problem with previous epidemiology studies and the need for population-based studies with rigorous case-finding.
- Survival, estimated at 21.3 years for the entire cohort following diagnosis, was better than previous studies and this may indicate less selection bias than tertiary referral center studies. It could also reflect diagnosis of milder cases with newer imaging techniques.
- 402 (68%) of PSC patients were diagnosed with inflammatory bowel disease.
- 23 (4%) had autoimmune hepatitis overlap.
- Colorectal cancer was 10-fold increased compared to ulcerative colitis controls and developed at a younger age (39 years compared with 59 years).
- Cholangiocarcinoma (CCA) was nearly 400-fold increased risk. The cumulative risk of CCA was estimated at 20% after 30 years following PSC diagnosis.
- During followup, there were 97 deaths; 73 (75%) were PSC-related.
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A recent article provides a useful review for primary sclerosing cholangitis (PSC) (Clin Gastroenterol Hepatol 2013; 11: 898-907).
This blog has previously discussed PSC (links below); however, the above reference is succinct and covers the key issues. A couple of points that I found particularly helpful:
- Cholangiocarcinoma (CCA): recommends “consider annual imaging (MRCP or Ultrasound) along with serum CA19-9 levels” to monitor for cholangiocarcinoma. If there is a dominant stricture, proceed with ERCP with brushings. In pediatrics, the age to start screening is less clear, usually not presenting until beyond the late teen years, though CCA has been diagnosed in one case report at 14 years of age (NEJM 2003; 348: 1464).
- Gallbladder cancer (30-40-fold higher risk than general population): If gallbladder polyp identified that is ≥0.8 cm, recommends cholecystectomy. If smaller, may also want to remove if normal synthetic function; otherwise repeat imaging in 3-6 months.
- Colon cancer: colonoscopy every 1-2 years in those with coexistent IBD (70% of patients with PSC have IBD).
Diagnosis: 44-56% of patients are asymptomatic at time of diagnosis, picked up due to abnormal serum liver tests or on cross-sectional imaging.
Small-duct PSC: occurs in the setting of features of PSC (histology, biochemistry) without abnormal cholangiogram. This represents 11-17% of PSC patients and is difficult to identify in patients without IBD. Over time, 25% will develop large-duct PSC. Small-duct PSC does not appear to result in increased risk of CCA.
Overlap syndrome with autoimmune hepatitis: patients with typical PSC but with 5- to 10-fold aminotransferase elevations should be suspected of having an overlap syndrome and may benefit from treatments directed at autoimmune hepatitis. Other features often include histology with an interface hepatitis and the presence of auto-antibodies. This situation is more common in children and young adults.
Immunoglobulin G4-Related sclerosing cholangitis: this occurs most commonly in conjunction with autoimmune pancreatitis. Since steroids can be effective, IgG4 levels should “be tested in all patients with suspected PSC, and, if elevated to consider an evaluation for IgG4-related disease.”
Medical management: “to date, there are no medical therapies that have been proven to alter the natural course of PSC.” The discussion notes that standard doses of ursodeoxycholic acid (UDCA) may have protective effects against colorectal cancer in patients with coexisting IBD. Higher doses of UDCA have been associated with a 2-fold risk of increased disease progression. Specific treatments for dominant strictures, pruritus, metabolic bone disease, and malabsorption are discussed. In patients with cholestasis, monitoring fat-soluble vitamins is important.
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In a previous blog entry (Hepatic ciliopathies), I briefly discussed congenital hepatic fibrosis (CHF). A more detailed review and handy reference: Srinath A, Shneider BL. JPGN 2012; 54: 580-87.
This invited review details information related to 1230 CHF patients from 155 articles (available at http://links.lww.com/MPG/A88). Median and mean age of diagnosis were 2 and 11.2 years respectively.
Distribution of CHF cases/associated conditions: 118 isolated CHF, 788 autosomal recessive polycystic kidney disease, 315 with Caroli disease/syndrome, 9 with type V choledochal cyst
- Sequelae of portal hypertension in 409 patients: 164 with varices, 74 with bleeding varicose, 81 underwent portosystemic shunting. Portal hypertension itself was identified in 71-97% depending on the patient subset examined.
- Cholangitis in 152 patients –often recurrent. This was fatal in 3 of 23 children after renal transplantation.
- Malignancy in 21 patients (2%). 19 were cholangiocarcinoma. Of these cases, 10/19 had Caroli disease/syndrome, 7 had isolated CHF, 1 had ARPKD, and 1 had Type V choledochal cysts. Youngest patient with cholangiocarcinoma was 33 years, all other cases involved patients >40 years.
Transplantation: Isolated kidney 91 (95% in ARPKD), Isolated liver 173 (87% had Caroli), Combined 23. Three renal patients subsequently had combined transplantation.
Other important points:
- CHF is not ‘typically associated with progressive hepatic insufficiency.’ Only rarely is hepatic synthetic function compromised
- Predisposition to cholangitis may affect transplantation decisions and timing
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