QOTW – “Since C1inh is produced in the liver would a liver transplant be a cure for an HAE patient?”
Jul 6, 2016
Dr. C: I would like to wish everyone a Happy Fourth of July–we have much to celebrate. Our reader raises the tantalizing question of a way to “cure” HAE. This will give us the opportunity to indulge in one of our favorite activities during these discussions—speculation. As best I am aware there has not been a liver transplant conducted with the intent to treat HAE.
To begin, the risk benefit ratio of liver transplant is critical to consider with the safe and effective treatment options that we have today. An example of the “dark side” occurred in 2010 with the publication of a case report of a liver transplant inducing angioedema. The swelling appeared to be kinin mediated as the patient responded to the kallikrein inhibitor, kalbitor. Serial C1 esterase inhibitor levels were suppressed during severe attacks of angioedema with elevated C1q—thus consistent with acquired C1 inhibitor deficiency. In this circumstance the liver transplant actually caused recurrent angioedema with the same clinical profile as HAE—this would certainly give one to pause before proposing this as a therapy for the disease.
I’m also not aware of any reports that liver transplantation has been performed or shown curative in individuals with C1INH deficiency. In theory, replacing the liver would result in improved C1INH protein production. Research over the years, including some by Dr. Zuraw’s lab, has shown that C1INH is produced by a number of different cell lines in the body, but that liver cells (hepatocytes) are particularly capable of making C1INH. This is true for a number of important plasma proteins, which is part of the reason that liver failure is a devastating and fatal medical problem. Of course in HAE, the liver generally works normally except for the very specific C1INH gene mutation that prevents normal C1INH production by the cells. While not used to date for HAE, liver transplantation has been used to treat other specific protein-deficiency conditions such as alpha-1 antitrypsin (AAT) deficiency. The difference between AAT deficiency and C1INH deficiency is that AAT deficiency often leads to progressive and fatal lung and/or liver damage over time whereas C1INH deficiency doesn’t appear to cause any chronic or long-term organ damage. That doesn’t make HAE any less dangerous or disabling, but it’s a clear difference in the natural course and complications of the conditions. So for other protein-deficiency conditions, liver transplantation has typically been used as an option when the progressive organ damage has reached the point of generalized and ultimately fatal liver failure. Liver transplants still have substantial short and long-term risks including death during the surgical period. Lifelong immunosuppressive medications are required in most cases so medication side-effects and infection are major issues. I think it’s unlikely we’ll ever see liver transplantation as an important treatment option in HAE due to these risks. More likely, targeted repair of the specific gene mutation with gene therapy or gene editing will be the major curative strategy. These gene-specific treatments may allow us to increase the C1INH protein production of cells without the risks of replacing an entire organ that is otherwise working just fine.
Thank you Marc. Bruce, could you share some of your research on the liver and production of C1 inhibitor? I know that we have also brought it up in prior QOTWs but could you also touch again on the case of Evan’s syndrome with HAE where bone marrow transplantation did result in a cure?
My guess is that a liver transplant could indeed cure HAE-C1INH. As we all recognize, however, the risks and complications of a liver transplant far outweigh the potential benefits, and therefore I would speculate that nobody will ever perform a liver transplant for the purpose of treating HAE. It would be far more feasible to consider gene therapy to supplement C1INH production by liver cells, and there are several groups looking into this approach. We began studying C1INH synthesis in the mid-1980s. We showed that human liver cells were able to make C1INH, and that the production of C1INH could be increased by stimulating the cells with a number of cytokines including interferon gamma and interleukin-6. At the time, we hoped to show how androgens regulated C1INH synthesis, but we could never find any direct effect of androgens on C1INH synthesis. We also studied whether other cells could make C1INH. Among those that do, are mononuclear phagocytes (monocytes and macrophages) as well as fibroblasts, each of which come from bone marrow stem cells. This is very interesting with respect to the patient with Evans syndrome that you bring up. Evans syndrome is an autoimmune disorder in which blood cells are destroyed. This patient had a severe case that required a bone marrow transplantation. He also suffered from HAE-C1INH. The remarkable finding was that his HAE-C1INH was cured by the bone marrow transplantation. While we don’t fully understand the basis of this response, it is tempting to speculate that the bone marrow transplant provided normal stem cells that were able to produce sufficient C1INH to result in a clinical cure. Bone marrow transplantation can be far safer than liver transplantation. Furthermore, the mutation causing HAE-C1INH could potentially be corrected in a patient’s own bone marrow cells and then given back to the patient. This is a process called gene editing, which is advancing at a rapid pace. It’s also important to know that non-curative therapies for HAE are also likely to get much more effective. Ultimately, it may be a tough choice whether to control HAE with medicines are go for a cure.
Thank you Bruce and Marc. I hope that this information and “speculation” was of interest to our reader and followers with HAE. We look forward to hearing from you and our next QOTW.