Primary Sclerosing Colangitis (PSC)

Autoimmune hepatitis/cholangitis in patient with Crohn’s disease.
Short Summary

18 years old male. 4 months ago the patient was hospitalized due to epigastric abdominal pain, lack of appetite and weight loss. He was diagnosed with Crohn’s disease.
Hepatic biopsy, that was performed during this hospitslization, showed evidence of an overlap syndrome picture (cholangitis/hepatitis). He was initially treated with Cortisone and Azathioprine.

During the last 4 months, the patient was hospitalized 7 times. He had recurrent attacks of infective cholangitis.
He was treated with antiobiotics and papillotomy through ERCP.
Later on, laparoscopic cholecystectomy was carried out. During postsurgery, after a short period of wellness, the patient suffered from an abdominal pain. Reappearance interpreted, at the beginning, as a light pancreatitis (treated with antibiotic therapy). Subsequently, persisting painful crises were observed despite blood tests substantial stability.
Therefore, a MR cholangiography was carried out and revealed an appearance of intra- and extrahepatic bile duct dilatation, evident also at common bile duct level where the picture seems revealing a relevant stenosis. a biliary stent was placed during ERCP in order to guarantee bile ducts patency.

After the procedure, the patient was hospitalized twice due to ascending cholngitis . US showed an occlusion of the biliary stent with overlapped cholangitis. Following the US, an antibiotic therapy has been started with Meropenem, and an ERCP was carried out. ERCP didn’t show any materials obstructing the stent. Biliary washing was within normal limits.

Last hospitalization was due to reappearance of epigastric pain in the attempt to interrupt the antibiotic therapy. During hospitalization, bringing back the antibiotic therapy, the situation progressively improved and allowed patient discharge.

Patient's Questions

1) Do you confirm the therapy?

2) Any alternative and/or experimental treatment for a complete recovery?

3) What is your opinion on the possible use of stem cells in this case?

4) Can you advise Italian and international centers of excellence and their relevant reference specialists?

5) In this case, can you express your opinion on the Imperial College of London in which some doctors (Prof. Nagy Habib, Prof. F. Dazzi) use a stem cells therapy?

6) Prognosis?
 

Medical Background

18 years old male.

Previous illness:

1 year old: Roseola.
4 years old: Salmonellosis.
6 years old: Varicella.
18 years old: Surgery in endoscopy due to left varicocele.

Clinical History:
4 months ago hospitalization following epigastric abdominal pain, at times postprandial, from 2 weeks linked to ingravescent lack of appetite and weight loss (3 kgs in a month). During hospitalization the most significant medical tests carried out were:
- Ultrasound scan and MR cholangiography with evidence of bile ducts dilatation.
- Endoscopy of the bowel with evidence of terminal ileitis and colitis with histological diagnosis of Crohn’s disease.
- Hepatic biopsy with evidence of an overlap syndrome picture (cholangitis/hepatitis).
- Lab examinations with finding of elevate levels of IgG (2937) and positive results of C-ANCA antibodies.
Therapy started with Cortisone 50 mg and Azathioprine 100 mg.

Second hospitalization, 1 month later, following appearance of arising colics, difficult to treat with pain medications, high body temperature and increase in inflammation ratings, symptoms consistent with picture of infective cholangitis. Therefore, the picture was resolved with antibiotic therapy and with carrying out a papillotomy by means of ERCP. Discharged under antibiotic therapy with Ciprofloxacin, Cortisone and Azathioprine.

Third hospitalization, 3 days after discharge from previous hospitalization, following arising colics with progressive ultrasound scan dilatation of bile ducts and evidence of dropsy of the gallbladder. Moreover, 48 hours following hospitalization, amylase increase (600 UI/l) was detected. The IgG4 dosage (18 mg/dl) was within normal limits, excluding a possible autoimmune hepatitis/pancreatitis syndrome.
ERCP performed with dilatation and cleaning of the common bile duct that involved the spillage of corpuscular material and bile with purulent appearance bringing about a fast improvement of symptomatology and a rapid reduction in the amylase values.
Later on, laparoscopic cholecystectomy was carried out. During postsurgery, after a short period of wellness, the patient suffered from an abdominal pain. Reappearance interpreted, at the beginning, as a light pancreatitis (treated with antibiotic therapy). Subsequently, persisting painful crises were observed despite blood tests substantial stability.
Therefore, a MR cholangiography was carried out (images enclosed on CD) that has revealed an appearance of intra- and extrahepatic bile duct dilatation, evident also at common bile duct level where the picture seems revealing a relevant stenosis: “Intrahepatic bile ducts with clear wall irregularity and with minimal stenosis followed by dilatations in a picture to be related to the base pathology. Irregularity at the extrahepatic bile ducts and at the common bile duct level too…, the common bile duct distal region appears moderately reduced in diameter, also in papillary region, also as a result of papillotomy.”
In the light of the aforesaid, a biliary stent was placed during ERCP in order to guarantee bile ducts patency. The clinical picture, after surgery, was stable with occasional presence of pains involving mainly the right hypochondrium without any characteristics of biliary colics. At discharge, blood tests with evidence of improvement of the hepatic cytolisys index (AST 28, ALT 38) with still elevated values of gammaGt (197) and APC 2.02 mg/dl probably linked to the inflammatory pathology rather than to an infective event. Discharge with indication to follow a therapy with Deltacortene to scale down the Azathioprine and antibiotic therapy with Augmentin.

Fourth hospitalization, 1 month later, in gastroenterology department for clinical test: The patient reported slight painful crisis in epigastric region; at examinations APC negativization (0.59) and a further reduction in GGTs with transaminase substantially stable. Therefore, the therapy with Amoxicillin + Clavulanic Acid was suspended and Metronidazole 250 mg was prescribed 3 times a day every other week.

Fifth hospitalization during the same month, following an episode of infective cholangitis with blood tests that showed transaminase on the increase (ALT 248, AST 114, GGT 281) with leukocytosis (WBCs 13,000, Nuetrophyls 88%, Lymphocytes 7.9%) and elevated APC (4.48). Therapy started with Augmentin (1 g x 3 times a day) for 7 days and then end. At the end of the 7 days, preventive treatment prescribed with Cotrimoxazole (tablet 160+800) 1 tablet twice a day.

Sixth hospitalization, 2 weeks after the privious one, following epigastric pain and nausea occurred after 1 day from Augmentin interruption and 1 day after the beginning of therapy with Cotrimoxazole.
The most significant lab examinations at admission: CRP=1.92 mg/dl; GGT 129 U/L; AST= 29 u/l, ALT=97 U/L.
Abdomen ultrasound scan with evidence of common bile duct dilatation. “Dilatation of the proximal and medial segment of the common bile duct, with diameter up to 10 mm, in whose context binary images are appreciated referable to the well-known stent. A moderate ectasia of intrahepatic bile ducts is connected, in particular in the left parts.”
To treat the severe painful symptomatology, a therapy with Keterolac 90 mg in 250 cc in continuous infusion was started
Because of the increase in the inflammation ratings and in the dilatation of the common bile duct at the abdominal ultrasound scan, supposing an occlusion of the biliary stent with overlapped cholangitis, an antibiotic therapy has been started with Meropenem 1 g x 3 and an ERCP was carried out.
ERCP didn’t show any materials obstructing the stent. Biliary washing was within normal limits.
Therapy prescribed at home:
Augmentin (1 g x 3); Ciproxin (500 mg x 2); Folina 5 mg (1 tablet every other day); Deltacortene (25 mg daily); Azathioprine (100 mg daily); Lansoprazole (30 mg daily); Ursodesossicolic Acid (300 mg 3 times a day).

During this latest hospitalization the young patient is sent for second opinion to hospitalization in different hepatology and gastroenterology unit. Medical tests carried out confirmed what already known from the first hospitalization and the current therapy is confirmed.

Last hospitalization was due to reappeared epigastric pain in the attempt to interrupt the antibiotic therapy. During hospitalization, bringing back the antibiotic therapy, the situation progressively improved and allowed his discharge with the following therapy:
Augmentin (1 g x 3); Ciproxin (500 mg x 2); Folina 5 mg (1 tablet every other day); Deltacortene (15 mg daily); Azathioprine (100 mg daily); Lansoprazole (30 mg daily); Ursodesossicolic Acid (300 mg 4 times a day).
 

Expert's Opinion

1) Do you confirm the therapy?
I have reviewed the case in detail but unfortunately I have not been able to see the report of the CT scan or colonoscopy. But, based on my experience we are dealing with Primary Sclerosing Colangitis (PSC) with either Crohn’s disease (CD) or more likely Ulcerative colitis (UC). MRCP based bile duct dilation along with picture of inflammatory bowel disease confirms the diagnosis. I would like to review the histology, but in any case both CD and UC can be associated with PSC. Autoimmune hepatitis can also be seen in this condition particularly in patients that are young. We see an association of pANCA with UC or a CD variant called pANCA positive Crohn’s disease which primarily affects the colon. ASCA IgA and ASCA IgG may help us distinguish CD from UC.
I do have some concerns about the therapy. We try our very best not to insert biliary stents in PSC patients. We conservatively manage patients (IV antibiotics, IV fluids and steroids). Stents can lead to recurrent infections in immune suppressed patient. Recurrent attacks of colangitis will lead to stricture formation. Currently, I suggest the following:
a) Antibiotic Rx (long term, on rotation basis), start with ½ dose Augmentin (875 md a day), next month take ½ dose Bactrim (1 DS a day) and third month take Ciprofloxin 500 mg a day. After the end of 3 months, please restart the cycle of antibiotics. This approach will prevent acute colangitis flares and while we dial up the immune suppression.
b) Switch Deltacortene with Entocort (Budesonide) 9 mg a day for 3 months. This drug is effective in autoimmune hepatitis but does not cause systemic steroid side effects
c) Azathioprine (AZA) is a good choice and the patient seems to be tolerating it well. But 100 mg dose may not be correct. Please check therapeutic metabolite of AZA, 6TGN and hepatotoxic agent 6MMPN. Based on these results, adjust dose of AZA. Majority of patients require 2.5 mg per Kg body weight. So if the patient is 50 kg, his dose will be 125 mg AZA, daily. Once 6TGN is in therapeutic range I wait 6 weeks or so to assess response. Remember, AZA is at best 40% efficacious, which means it will be ineffective in more than half of the patients treated.
d) If AZA is infective, or if the patient continues to progress we would consider remicade 5mg a kg at weeks 0, 2 and 6. Since he is only 18 years old, I would suggest remicade monotherapy as AZA plus Remicade increases the risk of hepato-splenic T cell lymphoma in the young. However, Remicade should be given in conjunction with Entocort and antibiotics. Suggest using a clinical score to assess his disease score before and after remicade induction. If results are favorable, he can be put in a Remicade maintenance program, where the patient receives remicade 1 dose every 6-8 weeks. Results with Remicade are significantly better than AZA both with simple efficacy score but also in terms of lifestyle. It is important that he completes school and is able to achieve his career goals.

2) Any alternative and/or experimental treatment for a complete recovery?

In immune disorders, there is no concept of complete recovery. There is a good chance of bringing him in sustained disease remission by treating him with lifelong immune therapy. Risks a lifelong immune therapy is low compared to the benefits. As long as he has good medical support he should be able to handle immune suppression and continue with his life, career, marriage and even having children.
After anti TNF treatment with remicade, the patient has 2 other alternatives within this class of drug. These include humira and cimzia. Both these drugs are self injectable and less imuunogenic than remicade. Anti integrin approach with natalizumab (Tysabri) is also approve for anti TNF failures. Anti IL12/23 antibody or ustekinumab is currently under clinical trials.

3) What is your opinion on the possible use of steam cells in this case?

Stem cell therapy can be very effective as stem cells isolated from patient’s blood or bone marrow can be re-injected. After re-injection, these cells home to sites of inflammation and can cause healing. Unfortunately, we have no data on these studies. Major clinical trials in the USA had to be stopped because of high placebo effect. We were participating in these trials but had to stop. My opinion is that the patient needs to be treated by anti-TNF approach first before pursuing experimental therapy.

4) Can you advise Italian and international centers of excellence and their relevant reference specialists?

I know Dr Silvio Danese who was in Rome and maybe now in Milan, if you give me permission, I can email him and find you a doctor who is close to your home and is familiar with PSC in CD.

5)In this case, can you express your opinion on the Imperial College of London in which some doctors (Prof. Nagy Habib, Prof. F. Dazzi) use a stem cells therapy?
I am not familiar with UK scene, but at this stage, any doctor who has training in IBD should be able to help the patient.

6) Prognosis?
The patient is at risk for liver transplant. Young patients that have recurrent PSC with minimal bowel symptoms are usually not effectively immune suppressed and end up developing strictures, cirrhosis and bile duct cancer. After transplant, the immune suppression is mandatory and usually help luminal CD (both large and small intestine). If rotating antibiotics plus immune suppression is effective, he will do very well. He will need to be followed at a center that has experience in such diseases. With the advances in genetics, immune and stem cell therapy we are anticipating even bigger breakthroughs in medical treatment. Therefore, if can help him pull through this recurrent colangitis phase, we can be optimistic about his case.
 

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