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Immune Mediated Liver Diseases

A Randomized Study of Intraductal Mitomycin C Therapy for Primary Sclerosing Cholangitis

Principal Investigator

Zhiping Li, M.D.

Research Team

Marcia Canto, M.D., M.P.H.
Po-hung Chen, M.D.
Anthony Kalloo, M.D.
Mouen Khashab, M.D.
Anne Marie Lennon, M.D.
Patrick Okolo, M.D.
Eun Ji Shin, M.D.
Vikesh Singh, M.D., M.Sc.

Contact Information 

410-614-3530

Study Focus 

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation, fibrosis and multifocal biliary strictures. Currently, there is no proven therapy to alter PSC progression except liver transplant. 

Endoscopic retrograde cholangiography (ERC) is the standard of reference for diagnosis of PSC.  Advantages of ERC include increased visual sensitivity to evaluate peripheral intrahepatic duct abnormalities and interventional capabilities such as mechanical dilation of obstructing strictures with or without stent placement.

While ERC acutely manages symptoms, the technique has a limited role, if any, in slowing the progression toward cholestatic liver failure. Dominant extrahepatic strictures, managed mechanically by balloon dilation and stent deployment, frequently recur, necessitating repeat ERC. Moreover, the small caliber of intrahepatic ducts is not amenable to mechanical manipulation by our current technologies.

Adjuvant mitomycin C (MMC) has been used to prevent scar formation following varied surgical interventions. MMC’s mechanism of action is to slow fibroblast cell division and proliferation. The fibroblast cells are the main source of the synthesis and deposition of scar tissue. Interruption of this process with MMC would therefore delay and perhaps prevent recurrent scar tissue formation in the bile ducts that lead to obstruction. The biliary strictures found in PSC present similar pathophysiology to that successfully treated with adjuvant mitomycin elsewhere.

The primary aim of the study is to determine the efficacy of mitomycin C intrabiliary bolus on survival and the progression of PSC. Other aims of the study are to determine the durable effect of mitomycin on interval duration between procedures, the total number of procedures needed over a two-year period for the routine management of PSC and the change of serum biochemical markers.

Publications

  1. Li Z, Lin HZ, Yang SQ and Diehl AM. Murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system. Gastroenterology. 2002; 123:1304-1310
  2. Li Z, Clark J and Diehl, AM. The liver in obesity and type 2 diabetes mellitus. Clin Liver Dis. 2002; 6:867-877
  3. Li Z, Yang SQ, Lin HZ, Huang JW, Watkins PA, Moser AB, DeSimone C, Song XY, Diehl AM. Probiotics and antibodies to TNF inhibit inflammatory activity and improve non-alcoholic fatty liver disease. Hepatology. 2003; 37:343-350
  4. Li Z, Oben JA, Yang S, Lin H, Stafford EA, Soloski MJ, Thomas S and Diehl AM. Norepinephrine regulates hepatic innate immune system in leptin deficient mice with nonalcoholic steatohepatitis. Hepatology. 2004; 40:434-441
  5. Li Z, Soloski MJ and Diehl AM. Dietary factors alter hepatic innate immune system in mice with non-alcoholic fatty liver disease.  Hepatology. 2005; 42:880-885
  6. Ma X, Hua J, Mohamood AR, Hamad AR, Ravi R and Li Z. A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury. Hepatology. 2007; 46:1519-1529
  7. Price J and Li Z. Hepatitis B – recent developments in therapy. European Gastroeneterology & Hepatology Review. 2009; 5:38-42
  8. Ma X, Hua J and Li Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol. 2008; 49:821-830
  9. Hua J, Liang S, Ma X, Webb TJ, Potter JP and Li Z. The interaction between regulatory T cells and NKT cells in the liver: A CD1d bridge links innate and adaptive immunity. PLoS One. 2011; 6(11):e27038
  10. Xia L, Hua J, Drey X, Khashab M, Kim YS, Jimeno-Ayllon C, Kalloo AN and Li Z. Endoscopic visceral fat removal as therapy for obesity and metabolic syndrome: a sham-controlled pilot study (with video). Gastrointest Endosc. 2011; 74:637-44

 

 

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