First published online May 31, 2007
Stem Cells
Vol. 25 No.
9
September 2007, pp.
2383
-2384
doi:10.1634/stemcells.2007-0056; www.StemCells.com
© 2007 AlphaMed Press
Stem Cell Therapy for Human Liver Cirrhosis: A Cautious Analysis of the Results
Stefania Lorenzini,
Pietro Andreone
Department of Internal Medicine, Cardioangiology and Hepatology, University of Bologna, Bologna, Italy
Key Words. Bone marrow • Stem cells • Liver cirrhosis • Cell therapy
Correspondence: Stefania Lorenzini, M.D., Ph.D., Department of Internal Medicine, Cardioangiology and Hepatology, via Massarenti 9, 40138 Bologna, Italy. Telephone: 00390516363618; Fax: 0339051345806; e-mail: lorenzini{at}med.unibo.it
Received on March 7, 2007;
accepted for publication on May 21, 2007.
First published online in STEM CELLS EXPRESS May 31, 2007.
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ABSTRACT
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End-stage liver disease, and in particular human liver cirrhosis, represents a worldwide health problem. Currently, liver transplant is the only effective treatment, but it is affected by many problems, including relative lack of donors, operative damage, risk of rejection, and high costs. Stem cell therapy is very attractive in this setting because it has the potential to help tissue regeneration while providing minimally invasive procedures and few complications. Only a few clinical studies on the administration of bone marrow-derived stem cells to cirrhotic patients have been published up to now. Although preliminary results seem to be encouraging, the number of treated patients is too small and the study design not completely appropriate to demonstrate safety and efficacy of stem cell therapy in liver cirrhosis. Well designed, randomized, controlled studies are needed to confirm preliminary results and eventually clear doubts.
Disclosure of potential conflicts of interest is found at the end of this article.
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INTRODUCTION
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Since the late 1990s, because of the increasing shortage of livers for transplantation, several experiments have been carried out to demonstrate and optimize the supposed ability of adult bone marrow stem cells to generate mature and functioning hepatocytes. Most of those studies have been carried out in rodent models of liver injury using either whole/fractionated bone marrow transplantation/injection or peripheral blood stem cells obtained through the administration of growth factors [1–13]. The basis of those experiments was the discovery of the ability of bone marrow stem cells to differentiate into mature cells other than blood cells in different adult tissues [4, 14], a concept known as "plasticity." Nevertheless, even if numerous studies have been published, the mechanisms (mainly transdifferentiation vs. cell fusion) and the bone marrow subpopulation involved in stem cell plasticity are still poorly understood and controversial. It is possible that the basic mechanism of the bone marrow stem cell plasticity in liver damage varies depending on the type of injury involved, or different subpopulations of bone marrow stem cells could be able to engender hepatocytes via transdifferentiation or cell fusion, or even both. In particular, transdifferentiation into hepatocytes, even if at a low level, has been demonstrated to occur after CD34+ hematopoietic stem cells are administered to rodents treated with liver toxins [1, 15]. On the other hand, cell fusion between hepatocytes and cells from the myelomonocytic lineage of the bone marrow has been shown to work well in metabolic/genetic liver diseases, as in the fumarylacetoacetate hydrolase deficiency model in mice [8, 16].
Chronic viral hepatitis and alcohol abuse are the main causes of liver cirrhosis among humans worldwide. These conditions are not present in rodents and are not completely reproducible experimentally. Thus, using the data obtained from experiments carried out in rodent models of liver injury to design human studies can be complex.
Liver cirrhosis in humans represents the end stage of chronic liver injury (that could have lasted more than 20 years, as is the case of chronic viral hepatitis) and it is characterized by the disorganized proliferation of hepatocytes and biliary cells, excessive scarring, and loss of the three-dimensional architecture of the hepatic lobule, which leads to chronic liver failure eventually requiring transplantation. Therefore, from a pathophysiological point of view, supplying the cirrhotic liver with "brand new" stem cells would not be sufficient to restore the lost of function, even if some studies have shown that bone marrow infusion can be of some benefit in terms of tissue remodelling as well as having a paracrine effect on endogenous hepatocytes [9].
In two recently published studies, Gordon et al. [17] and Terai et al. [18] evaluated the effects of CD34+ hematopoietic stem cell intrahepatic injection and whole bone marrow peripheral infusion in five and nine patients with liver cirrhosis, respectively. After examining the results, the authors concluded that bone marrow stem cells are able to improve the residual liver function in cirrhotic patients. In the study by Gordon et al. [17], a decrease in serum bilirubin and an improvement in serum albumin were observed in three and four of the five patients, respectively, with the disappearance of ascites observed in one patient. In the study by Terai et al. [18], significant increases in albumin and total protein level and an improvement of the Child-Pugh score were observed in all of the nine patients, and a reduction in ascites was observed in six patients.
These results, which originated from ongoing research on bone marrow stem cells and liver, may be considered both controversial and remarkable, demonstrating that clinical results may sometimes precede scientific evidence. However, a more cautious analysis of the results is necessary, considering the clinical course and potential new therapies for complex disorders such as human liver cirrhosis.
The first concerns about the studies by Gordon et al. [17] and by Terai et al. [18] is that both studies are conducted on small groups, are not randomized, and also lack a control group of stem cell untreated patients. Clinical studies to investigate the efficacy of potential new therapies should be designed carefully. Using a control group (that should be homogeneous to the experimental group for both epidemiological and clinical characteristics) reduces the likelihood that modifications observed during treatment are accidental and not directly dependent on the therapy administered, and randomization increases the probability that other variables, not considered in the study design, are distributed evenly in both the experimental and control groups. We would suggest that a study designed to understand the effect of stem cell therapy on human liver cirrhosis must have a control group where the control and the experimental groups are comparable for baseline characteristics: age and sex, etiology of liver disease, liver function (albumin, international normalized ratio [INR], bilirubin levels), and renal function (blood urea nitrogen and creatinine levels). The liver and renal functions are strictly related to each other in end stage cirrhosis; thus, the blood tests mentioned above should be examined concurrently throughout the course of the study.
Secondly, Terai et al. [18] employed the Child-Pugh score to evaluate the effect of bone marrow stem cell therapy on the residual liver function. The Child-Pugh and the Mayo Model for End Stage Liver Disease (MELD) are the scoring systems used by clinicians to define the severity of liver failure, and therefore prognosis, and to list patients for transplantation. The Child-Pugh scoring system assigns different scores to albumin, bilirubin, and prothrombin levels and to the severity of the ascites and encephalopathy. The MELD score is the result of a standardized equation in which the clinician adds the values of bilirubin, creatinine, and the INR [19]. Considering that a standardized method to evaluate ascites and encephalopathy severity does not exist, the Child-Pugh score may be biased because the severity evaluation of these clinical complications of cirrhosis depends on the opinion of the examining clinician. This is one reason why most of the liver transplant centers worldwide have recently begun to use MELD instead of the Child-Pugh score to list patients for liver transplantation. It is generally accepted that all scoring systems, MELD included, are not 100% accurate and objective. In fact, laboratory tests may also be biased, as they can be modified by drug administration, as in the case of albumin and plasma infusions that can modify albumin and INR values, as well as diuretics that can increase creatinine levels.
Finally, both papers [17, 18] stress the observation that, after the administration of stem cells, some patients had a significant reduction of ascites. It must be pointed out that those same patients were also given diuretics and, therefore, it is not possible to discern if the ascites improvement was because of the drug or the stem cell administration. Although the dosage of the diuretics was not modified during the treatment period, what is questionable is that both studies do not specify the renal function of the patients. Hepatologists know that renal function is one of the most important determinants of a patient's response to diuretics and subsequently of ascites control.
In conclusion, although both studies cited above [17, 18] provide new interesting data about the effects of stem cells in human liver cirrhosis and show that bone marrow stem cells can be used in this setting apparently without significant comorbidity, well designed randomized controlled studies are still needed to prove the effectiveness of bone marrow stem cell administration on the clinical course of human liver cirrhosis.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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The authors indicate no potential conflicts of interest.
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ACKNOWLEDGMENTS
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We thank Rebecca Aucott from the Queen's Medical Research Institute in Edinburgh for her kind help with revisions. S.L. is supported by the "Ordini dei Medici Chirurghi ed Odontoiatri di Bologna" Grant and by the European Association for the Study of the Liver Disease (EASL) Sheila Sherlock Fellowship Post-Doc.
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Abstract
Introduction
