REVIEW ARTICLE Artificial Liver Support Potential to Retard Regeneration? Emma J. Mullin, MBChB; Matthew S. Metcalfe, FRCS; Guy J. Maddern, MD Hypothesis: The concept of an “artificial liver” has been growth-promoting factors from these cultured hepato- in development for over 40 years. Such devices aim to cytes? temporarily assume metabolic and excretory functions of the liver, with removal of potentially hepatotoxic sub- Data Sources, Extraction, and Study Selection: stances, thereby clinically stabilizing patients and pre- Data were obtained using PubMed search for reports in- venting deterioration while awaiting transplantation. If volving liver support, extracorporeal circuits, dialysis, sufficient numbers of viable hepatocytes remain, regen- growth factors, and cytokines. Those reports specifi- eration and subsequent recovery of innate liver func- cally looking at the effect of artificial liver support on cy- tion may occur. However, these devices have not yet be- tokines and growth factors are discussed. come part of routine clinical use. Much less is known regarding the effect such devices have, if any, on circu- Conclusions: There is a paucity of information on the lating cytokines and growth factors and the subsequent key events and substances involved in hepatic regenera- effects on the regenerating liver. If these devices remove tion. In addition, there is a potential impact of liver sup- or reduce factors known to promote regeneration, is the port devices on the regeneration of substances associ- rate of regeneration retarded? Conversely, does the in- ated with hepatic regeneration. Further study is needed. corporation of hepatocytes into bioartificial support sys- tems confer an advantage through the production of Arch Surg. 2004;139:670-677 HE LIVER HAS A REMARK- of the liver, with removal of potentially able capacity for regene- hepatotoxic substances, thereby clini- ration, a role it is able to cally stabilizing patients and preventing de- fulfill while performing terioration while they await transplanta- complex metabolic and ex- tion. If sufficient numbers of viable Tcretory functions. hepatocytes remain, regeneration and sub- Fulminant hepatic failure remains a sequent recovery of innate liver function significant cause of morbidity and mor- may occur. Patients who may benefit from tality. With best medical management such devices are those with fulminant he- alone, mortality approaches 80%, which patic failure, acute-on-chronic (ie, an acute can be improved to 55% to 75% if liver condition verging on being chronic) liver transplantation is a therapeutic option.1 failure, primary liver allograft nonfunc- However, 33% to 50% of patients with ful- tion, and posthepatectomy liver failure. minant hepatic failure will die awaiting a However, the task is complex, as the liver liver transplant.1 affects almost every body system through After resection or injury, the liver will metabolic, endocrine, immune, and physi- regenerate as long as there is enough func- ological processes. tional parenchyma remaining. Up to 75% Although biochemical, hormonal, and of a noncirrhotic liver can be resected safely hematologic changes accompanying liver in humans2; beyond that, increasing prob- failure are well known, development of a lems with hepatic dysfunction and post- support device is complicated by the fact operative morbidity and mortality oc- that many of the pathophysiological re- 3 From the University of Adelaide cur. sponses involved in hepatic failure are in- Department of Surgery, The concept of an “artificial liver” has completely understood. For example, a The Queen Elizabeth Hospital, been in development for more than 40 leading cause of death in fulminant he- Woodville, South Australia, years. Such devices aim to temporarily as- patic failure is brainstem herniation sec- Australia. sume metabolic and excretory functions ondary to glial swelling and cerebral (REPRINTED) ARCH SURG/ VOL 139, JUNE 2004 WWW.ARCHSURG.COM 670 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 edema, but the exact processes leading to this are not yet 10% of hepatocytes; however, this figure increased sub- clear. stantially when these substances were infused into rats Much less is known regarding the effect, if any, that undergoing 30% hepatectomy, which suggests that a prim- such devices have on circulating cytokines and growth ing stimulation occurred at hepatectomy.9 Substances that factors and the subsequent effects on the regenerating initiate priming include TNF-␣ and interleukin 6 (IL-6), liver. If these devices remove or reduce factors known and it is during this stage that early genes are induced.10 to promote regeneration, does this retard the rate of re- These genes cover many different classes, including tran- generation? Conversely, does the incorporation of hepa- scription factors, metabolic enzymes, inflammatory re- tocytes into bioartificial support systems confer an ad- sponses, and responses involved in cytoskeletal and ex- vantage through the production of growth-promoting tracellular matrix modification.11 factors from these cultured hepatocytes? The molecular mechanisms of regeneration have per- This review summarizes what is known of the key haps been most extensively investigated in the two- events and substances involved in hepatic regeneration thirds hepatectomy of the rat model, which was de- and examines the potential impact of liver support de- scribed in 1931.12 In this model, DNA synthesis begins vices on regeneration and substances associated with it. 12 to 16 hours after hepatectomy, peaking at 24 to 48 hours. Hepatocyte mitosis follows 6 to 8 hours later, with MECHANISMS OF LIVER REGENERATION near restoration of volume at 3 days.13 Proliferation of bile duct epithelium peaks at 48 hours, Kupffer and stel- Cells late cells at 72 hours, and sinusoidal endothelial cells at 96 hours.14 Once the liver has reached optimal size, hepa- Under physiologic conditions, hepatocytes are in the rest- tocytes return to a quiescent G0 phase. ing (G0) phase with low proliferative activity. However, The rate of mitotic activity after liver resection, based after resection, most hepatocytes will undergo at least 1 on indirect measurements, is greatest 4 to 5 days post- round of replication before returning to a resting state. operatively.15 In humans, two thirds of liver regenera- This process is stimulated by a highly controlled, com- tion occurs within 2 weeks after major hepatectomy.16 plex, and incompletely understood sequence of events. Final regenerative volume ranges from 74%16 to 100% The liver is a unique organ, as regeneration does not re- at 1 year after resection.17 Normal livers regenerate twice quire the presence of progenitor stem cells, although they as fast as cirrhotic livers with comparable resection vol- play an as-yet ill-understood role. Instead, proliferation umes.18,19 of all mature hepatic cell types occurs, including hepa- After resection, regenerating hepatocytes are ini- tocytes, biliary epithelial cells, endothelial cells, Kupffer tially arranged in nonvascularized clusters. Once hepa- cells, and stellate cells.4 tocyte proliferation has ceased, stellate cells move into Hepatic oval cells are pleuripotential progenitor cells the clusters and neovascularization occurs. Normal his- capable of differentiation into hepatocytes, bile duct epi- tological structure is seen 8 to 10 days after surgery.20 thelia, intestinal epithelia, and possibly exocrine pan- The modulation of extracellular matrix, collagen, ma- creas. The theory that these cells originate from within trix metalloproteinases, and tissue inhibitors of metal- the biliary system is supported by their phenotypic simi- loproteinases during liver regeneration may help ini- larity to bile duct epithelia, their expansion from the peri- tiate and terminate the progression of quiescent portal area into the mesenchyme, and the reduction in hepatocytes into the cell cycle.21 numbers seen with selective damage to the periportal zones.5 However, some evidence suggests a bone mar- Regulatory Substance row origin for some oval cells.6 Although their exact role is incompletely understood, the liver may regenerate by The process of liver regeneration requires a combina- using oval cells in circumstances where large numbers tion of cytokines and growth factors. Evidence of the role of hepatocytes are damaged or hepatocyte replication is of circulating growth hormones arises from studies show- suppressed by hepatotoxins.7 Oval cells have receptors ing that after partial hepatectomy of the host animal, he- for hepatocyte growth factor (HGF), epidermal growth patic tissue transplanted into extrahepatic sites also un- factor (EGF), and transforming growth factor ␣ (TGF- dergoes DNA synthesis and replication.22 We characterize ␣),8 and it has been shown that HGF promotes hepato- EGF, TGF-␣, and HGF as complete mitogens, ie, each is cyte differentiation in bone marrow stem cells and oval capable of stimulating hepatocyte DNA synthesis in cul- cells.4 However, the mechanism of oval-cell activation, ture independently. Comitogens such as insulin, gluca- recruitment, and differentiation has not been fully elu- gon, epinephrine, and norepinephrine potentiate the ac- cidated, and further work is needed to clarify their role.7 tion of mitogens, but are unable to stimulate DNA synthesis alone23,24 (Figure 1). Proliferation Epidermal growth factor is a complete mitogen. In rats, sialoadenectomy (and