How does the liver regenerate after resection or injury?
The liver is a remarkable organ and a bit of an unsung hero in medicine. It’s a tremendously resilient organ that just trucks along and does its many, many jobs to keep us alive. One of the reasons it can maintain function is its ability to heal from injury. And this ability to regenerate is truly remarkable. A biological superpower. Even more, the liver can withstand and bounce back from not one but two distinct types of injuries.
Regeneration is the ability to regrow tissue after a portion of it has been damaged or removed. Many animals can regenerate parts of their bodies. Salamanders regrowing limbs is a well-known example. Lizards can regrow severed tails. Deer regenerate their antlers each year. Even sharks regenerate the thousands of tiny teeth they have in their mouths. Regeneration seems to be a normal part of complex animal life.
For humans, certain parts of the body regenerate all of the time, like the skin or the mucosa of the intestines. But in terms of internal organs that regenerate in any significant way, it’s really just the liver. Maybe the lungs a little bit, which we’ll probably cover in another episode, and peripheral nerve axons can too. But the liver is in a class of its own. This ability evolved approximately 500 million years ago in the Cambrian period when livers as a distinct organ first emerged.
The ancient Greeks may have had some working knowledge of the liver’s regenerative ability, as evidenced by the myth of Prometheus. That myth has come back into the popular imagination recently because of the movie Oppenheimer, which was based on the book American Prometheus, because of Robert Oppenheimer’s role in developing the first atomic bomb. Prometheus as a mythological character was portrayed by the Greek poet Hesiod as having given humanity the ability to use fire, after stealing it from Zeus. Zeus then punished him by binding him to a mountaintop and having an eagle eat his liver. Prometheus’ liver would grow back or regenerate each night, and the next day the eagle would return and eat his liver again. It’s been questioned by some scholars whether this implies an actual knowledge of liver regeneration on the part of the ancient Greeks, since this knowledge does not appear in any writing outside of Greek mythology. It’s worth mentioning that there’s another ancient Greek myth, that of a giant named Tityus, that also mentions liver regeneration, but again these references are limited to mythology. So it may be that this reference to regeneration in Prometheus is really more symbolic since the ancient Greeks believed that the liver housed a person’s soul.
In 1879, a German surgeon named H. Tillmans published a report of his research on rabbits, where he would surgically remove pieces of their kidneys and livers to see what happened and how those organs healed. The kidneys would scar over but, to his immense surprise, the livers would regenerate, growing back tissue in the area that had been removed. He looked at the tissue under the microscope and there was new, functioning liver tissue there. This was the first time liver regeneration had been observed scientifically.
Subsequent research confirmed these findings. Regeneration is established in the surgical literature, especially after living donor liver transplantation, where someone donates a portion of their liver to someone with hepatic failure. Regeneration happens in both the transplanted organ and the remnant that remains in the donor. Both regrow to normal size within a few weeks. And there’s evidence that you can resect up to 80% of a healthy liver and it will grow back, although in living donor transplants they remove a smaller portion than that.
The liver actually can undergo two distinct types of regeneration: (1) regeneration after resection; and (2) cellular regeneration. Regeneration after resection or partial hepatectomy occurs when part of the liver is physically removed. Cellular regeneration occurs after cellular injury from ischemia, viral hepatitis, alcohol-induced damage, or other toxic injuries.
The liver is divided into functional units called hepatic lobules. Each lobule has 3 zones, containing hepatocytes, bile ducts, and capillaries. Blood flows from zone 1, through zone 2, and into a central vein in zone 3. Studies from mice suggest that zone 2 hepatocytes mediate cellular regeneration, migrating into zones 1 and 3 to replace lost or damaged cells.
Although speculative, from a functional perspective it makes sense to have zone 2 be the regenerative zone. It lies in the middle of the hepatic lobule and is the transition between zones 1 and 3, which have more defined functions. The hepatocytes in zone 1 engage in oxidative metabolism for things like gluconeogenesis, and hepatocytes in zone 3 perform detoxification. Zone 2 acts as a regenerative reservoir for the other zones, helping sustain their essential functions. It is an elegant arrangement.
Regeneration after resection (i.e., partial hepatectomy) is more global with en masse hepatocyte proliferation. There also is hypertrophy of existing cells. Each major liver cell type, including sinusoidal endothelial and bile duct cells in addition to hepatocytes, undergoes regeneration. Within several days to a few weeks the liver is back to full size and functioning normally.
Incredibly, regeneration happens within minutes of resection. Based on animal studies, almost immediately there is an alteration in cytokine and paracrine signaling in the liver, as well as changes to growth factor activity and hepatocyte gene expression. All of this switches to a pro-growth milieu immediately, and then within an hour regeneration has begun. Macrophages, sinusoidal endothelial cells, stellate cells, biliary ductal cells, and hepatocytes communicate through a complex network, sending signals including TGF, TNF, hepatocyte growth factor and IL-6, turning on genes mediating cell growth and division.
There appears to be more than one trigger for regeneration after partial hepatectomy with 3 main proposed mechanisms: (1) hemodynamic changes, (2) the innate immune response, and (3) platelets.
After a part of the liver is resected, there is a proportional increase in blood flow to the remaining liver segments. This results from the same amount of portal blood flow going to a smaller organ. In animal models, that hemodynamic shift seems to be a crucial trigger for regeneration. A 2004 rat study found that if blood flow to the remnant liver is kept constant after resection then regeneration does not occur. The researchers accomplished this by creating a porto-systemic shunt. When the shunt was present, regeneration did not happen. One potential mechanism they identified was that increased blood flow to the remnant segments was required for plasmin to activate hepatocyte growth factor, which is a key component of stimulating and sustaining regeneration.
Platelets help initiate regeneration by migrating into the liver and making direct contact with hepatocytes. This activates growth factors and stimulates hepatocyte proliferation. This has been shown experimentally. A 2008 study in mice found that when platelets made contact with hepatocytes it induced them to proliferate and divide. There is also clinical data from the transplant surgical literature, where living donor liver transplant recipients who received perioperative platelet transfusion had enhanced graft regeneration at 2 weeks post-op. This suggested that platelets play an important role.
Regarding inflammation, it makes sense that this response to liver injury would play a role in regeneration. The hypothesis is that the innate immune response to liver injury involves macrophage activation which leads to increased NF-kB and IL-6 signaling, which then stimulates increased hepatocyte survival and proliferation.
Turning off regeneration is as important as initiating it. Otherwise, one would be dealing with a situation where hepatocytes and other liver cells proliferate and grow out of control, akin to cancer. Although the exact mechanism remains elusive, it likely involves the combination of growth factors like TGF-beta and hepatocyte growth factor binding to new extracellular matrix that gets laid down as the liver regeneration process progresses. This appears to be the signal that turns regeneration off. Because extracellular matrix and growth factors are produced from the very beginning of regeneration, the off-signal is being applied from the start.
Take Home Points
- The liver has a biological superpower called regeneration. Other than possibly the lung, no other internal solid organ is able to regenerate.
- Regeneration after toxic or cellular injury involves zone 2 hepatocyte proliferation.
- Regeneration after partial hepatectomy or resection is triggered by increased portal vein blood flow, platelet contact with hepatocytes, and growth factors and inflammatory cytokines.
CME/MOC
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Credits & Citation
◾️Episode written by Avi Cooper
◾️Show notes written by Tony Breu and Avi Cooper
◾️Audio edited by Clair Morgan of nodderly.com
This episode was sponsored by Brooklinen! Use promo code “CURIOUS” for $20 off your first order + free shipping.
Cooper AZ, Abrams HR, Breu AC. Radical Regeneration. The Curious Clinicians Podcast. September 6, 2023.
Image credit: https://www.science.org/doi/10.1126/science.abc4346
The Curious Clinicians 
Part of the kidneys can also regenerate. After low bloodpressure and low oxygen state the tubular cells die and kidneys stop functioning. A condition known as acute tubular necrosis. However over days to weeks they regenerate from dormant stamcells inside the tubuli with often full recovery of kidney function.
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