ALPPS Procedure: How Rapid Liver Regeneration Works

ALPPS is a two-stage liver surgery designed to make otherwise unresectable liver tumors removable by forcing the remaining portion of the liver to grow rapidly between operations. The name stands for Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy, and the procedure’s defining feature is speed: the future liver remnant can grow in days to weeks what older techniques need months to achieve. That speed, though, comes with tradeoffs that have kept ALPPS controversial since it was first performed in 2007, and patient selection remains the central challenge in deciding when the procedure is worth its risks.

How the Procedure Works

ALPPS was discovered accidentally by German surgeon Hans Schlitt while performing a complex right-sided liver resection that involved splitting the liver tissue along with tying off the right portal vein.¹ When imaging afterward showed unexpectedly dramatic growth of the remaining liver, the principle was formalized into a deliberate two-stage strategy.

In the first stage, the surgeon divides (or partially divides) the liver along the planned resection line and ligates the portal vein branch feeding the side that contains the tumor. This combination of cutting and redirecting blood flow sends a powerful regenerative signal to the future liver remnant. The patient then recovers for a period, typically one to four weeks, while the remnant grows. In the second stage, the surgeon removes the tumor-bearing portion of the liver, which by now has been largely deprived of portal blood flow and has often shrunk, while the remnant has expanded enough to sustain the patient’s liver function after surgery.

The reason ALPPS exists at all is that many patients with liver tumors, especially those with multiple metastases spread across the liver, cannot safely undergo resection because the liver remnant left behind would be too small to keep them alive. Before ALPPS, the main option for inducing remnant growth was portal vein embolization, or PVE, in which a radiologist blocks the portal vein branch on the tumor side without any surgical cutting. PVE works, but it is slower and sometimes fails to produce adequate growth.

Why the Liver Grows So Fast

The growth rate after ALPPS is not just modestly faster than PVE. A multi-center analysis found the kinetic growth rate after ALPPS averaged roughly 33 cubic centimeters per day, compared with about 4 cubic centimeters per day after PVE.² A systematic review and meta-analysis confirmed that ALPPS induces a significantly higher kinetic growth rate than both PVE and liver venous deprivation, another newer technique, and that the hierarchy held across studies.³

Comparisons at matched time points make the difference vivid. One week after the first-stage operation, the liver remnant after ALPPS had grown by a factor comparable to what conventional two-stage hepatectomy achieved at three weeks.⁴ That compressed timeline is what allows surgeons to move to the second stage quickly, before the tumor has time to progress or the patient loses ground to chemotherapy side effects.

The biological mechanisms driving this accelerated growth are still being mapped. Research using a pig model identified specific circular RNAs that are upregulated in liver cells after ALPPS, and experiments showed that knocking out two of these molecules suppressed liver cell proliferation, suggesting they play a direct role in the regenerative cascade.⁵ Understanding these pathways could eventually lead to drugs that enhance liver regeneration without surgery, but for now the findings mainly help explain why ALPPS triggers such a potent growth response.

The Gap Between Volume and Function

One of the most important lessons surgeons have learned about ALPPS is that a bigger remnant on a CT scan does not necessarily mean a remnant that works well enough to keep the patient alive. Hepatobiliary scintigraphy, a nuclear medicine scan that measures how well the liver actually processes and excretes bile, has revealed that function increases by only about half as much as volume after ALPPS.⁶ In practical terms, a remnant that has doubled in size may have gained only about half that improvement in its ability to do the liver’s metabolic work.

Animal studies have confirmed this mismatch, showing that the rapidly proliferating liver cells in the early days after ALPPS are immature and not yet fully functional.⁷ The implication is clinically important: if a patient’s remnant is only marginally large enough by volume, its actual working capacity could still be dangerously low. This is one reason many centers now use functional imaging, not just volumetric CT, to decide when the remnant is ready for the second stage. A case report demonstrated this approach in action, where scintigraphy on the third day after the first stage showed the remnant’s function had not yet crossed the safety threshold, but by the eighth day it had, and the second stage proceeded safely.⁸

The volume-function gap has practical consequences for timing. Rushing to the second stage based on volume alone, which some early adopters did within a week, likely contributed to the high mortality seen in the procedure’s first years. Allowing more time between stages lets the new liver tissue mature. One series that used a median interval of 28 days between stages reported zero mortality and a median remnant volume increase of 38%.⁹

Oncological Results for Colorectal Liver Metastases

Colorectal liver metastases are the most studied and most favorable indication for ALPPS. The LIGRO trial, the first randomized controlled trial comparing ALPPS with conventional two-stage hepatectomy for advanced colorectal liver metastases, found that ALPPS dramatically improved the chance of actually completing the resection. About 92% of patients randomized to ALPPS completed both stages compared with 57% in the conventional two-stage group, with no difference in serious complication rates or 90-day mortality between the two arms.¹⁰ The reason so many patients in the conventional arm failed to reach the second operation was inadequate liver growth or tumor progression during the longer waiting period.

Long-term follow-up from the same trial showed estimated median overall survival of 45 months in the ALPPS group versus 27 months in the conventional group, with five-year survival rates of 31% and 20%, although the difference did not quite reach conventional statistical significance.¹¹ Given that these patients were considered unresectable by standard means, even partial survival gains are meaningful. A large international cohort study further supported these findings, concluding that patients with favorable tumor biology and good chemotherapy response achieved particularly appealing long-term outcomes after ALPPS.¹²

The emphasis on tumor biology matters. ALPPS does not change the underlying cancer’s aggressiveness. Patients whose tumors respond well to preoperative chemotherapy tend to do the best, while those with chemotherapy-resistant disease may achieve a technically successful resection but still face early recurrence.

The Risk Profile

ALPPS carries higher perioperative risk than standard liver surgery, and the early experience was sobering. An analysis of 320 patients from the international ALPPS registry found an overall 90-day mortality of about 9%, with liver failure accounting for three-quarters of those deaths.¹³ More recent series, benefiting from better patient selection and technical refinements, have pushed mortality lower, but liver failure remains the primary threat.

Liver fibrosis appears to amplify the danger. In one study of ALPPS for primary liver cancer, all four patients who developed liver failure had severe fibrosis, suggesting that a stiff, scarred liver simply cannot regenerate fast enough to keep up with the demands placed on it by the procedure.¹⁴ This finding has practical implications for screening: patients with significant background liver disease, whether from hepatitis, alcohol, or chemotherapy-associated injury, need especially careful evaluation before being offered ALPPS.

Biliary leakage after the first stage is another common complication, particularly when the liver is split completely and especially in procedures that involve removing a larger portion of the liver. The leak typically occurs at the raw transection surface of the deportalized liver, where tissue ischemia makes healing unreliable.¹⁵ While many bile leaks can be managed with drainage, they can delay the second stage and increase the overall burden of the two-operation sequence.

The Cholangiocarcinoma Warning

Not all liver cancers respond equally to ALPPS, and perihilar cholangiocarcinoma stands out as a dangerous indication. Data from the international ALPPS registry showed a 48% 90-day mortality when ALPPS was used for this bile duct cancer, compared with 13% mortality in a broader series of patients who underwent major liver resection for the same tumor without ALPPS. Matched comparison yielded median survival of just 6 months after ALPPS versus 27 months without it.¹⁶ These results led many centers to abandon ALPPS for this particular diagnosis, or at minimum to restrict it to highly selected cases. The likely explanation is that the bile duct reconstruction required for cholangiocarcinoma surgery adds surgical complexity and septic risk to an already demanding procedure.

Technical Modifications That Reduce Morbidity

The original ALPPS technique involved completely dividing the liver along the resection plane during the first stage. Surgeons quickly realized that a full split was not always necessary to trigger robust hypertrophy and that partial transection could reduce complications. In the partial ALPPS approach, only 50% to 80% of the parenchyma is divided, preserving collateral blood supply. An initial series reported zero mortality and equivalent hypertrophy to the full split, with a median remnant volume increase of 60% in seven days.¹⁷ Protecting the middle hepatic vein during the first stage also helps maintain venous drainage and reduce congestion-related complications.

Minimally invasive approaches, using laparoscopy or robotic assistance for one or both stages, represent another evolution. A review of the available evidence found that minimally invasive ALPPS appears feasible and safe, with potentially better short-term outcomes in terms of blood loss, complications, and mortality compared with open surgery.¹⁸ A systematic review and meta-analysis reinforced that conclusion, finding reduced mortality and shorter hospital stays with the minimally invasive approach while hypertrophy and R0 resection rates remained comparable.¹⁹ The smaller first-stage incision likely makes the second stage easier by reducing adhesions in the abdomen.

The trend overall has been toward gentler first stages: less splitting, less open surgery, more time between stages, and more functional assessment before proceeding. Each of these refinements chips away at the procedure’s historically high complication rate while preserving the core advantage of rapid liver growth.

Rescue ALPPS After Failed Portal Vein Embolization

Some patients undergo PVE as the first-line attempt at growing their liver remnant, only to find that the growth stalls short of what is needed for safe resection. For these patients, ALPPS can serve as a rescue strategy. In one series of seven patients who had insufficient hypertrophy after PVE, rescue ALPPS successfully induced further remnant growth and allowed all seven to proceed to surgery, with six achieving complete tumor removal. Without the rescue procedure, these patients would have been left with only palliative options.²⁰

A separate study of rescue ALPPS specifically in colorectal liver metastasis patients found that the powerful hypertrophy stimulus of ALPPS was maintained even after a prior failed portal vein occlusion.²¹ This is reassuring because one concern was that a liver that had already failed to respond to PVE might also fail to respond to the additional stimulus of parenchymal transection. In practice, the physical splitting of the liver appears to trigger regenerative pathways that portal vein blockage alone cannot fully activate, making rescue ALPPS a legitimate salvage option rather than a last-ditch gamble.

Patient Selection and Risk Scoring

The single biggest improvement in ALPPS outcomes over the past decade has come not from surgical technique but from better patient selection. Several validated scoring systems now exist to help surgeons identify patients who are likely to benefit versus those at high risk of a futile outcome.

The ALPPS Risk Score was developed from the international registry specifically to predict futile outcomes, defined as death or failure to complete both stages, and its developers concluded it has excellent predictive ability for identifying patients who should not be offered the procedure.²² A separate risk score was developed specifically for colorectal liver metastasis patients, identifying older age, a very small remnant liver, treatment at an inexperienced center, and complications after the first stage as the key predictors of mortality.²³ The CAPRA score takes a broader approach, assessing the patient’s overall preoperative condition, including comorbidities, and has shown strong ability to predict postoperative mortality.²⁴

The common thread in all these scores is that ALPPS outcomes depend heavily on factors that exist before the surgeon picks up a scalpel. A younger patient with colorectal metastases, no significant liver fibrosis, a reasonable remnant volume, and treatment at a high-volume center faces substantially different odds than an older patient with cholangiocarcinoma and a background of chemotherapy-damaged liver. The procedure itself is the same; the context around it determines whether the rapid growth is a bridge to cure or a path to liver failure.

What ALPPS Costs

Because ALPPS involves two major operations within weeks, it is inherently more resource-intensive than a single hepatectomy, and the question of whether the additional cost is justified matters for healthcare systems considering whether to offer it. A health economic analysis from the LIGRO randomized trial found that ALPPS cost on average about €12,700 more than conventional two-stage hepatectomy, but the difference was not statistically significant. The gain in quality-adjusted life years was also modest and not statistically significant, yielding an incremental cost-effectiveness ratio above €90,000 per quality-adjusted life year.²⁵

Those numbers land in uncertain territory for most healthcare systems. The cost difference is not enormous in the context of complex cancer surgery, but the quality-of-life gains are also not clearly demonstrated in a statistical sense. What the economic analysis cannot fully capture is the value to the individual patient who would have had no surgical option at all without ALPPS. For someone facing palliative chemotherapy as the alternative, even a modest probability of long-term survival may be worth the additional institutional expense and personal surgical burden. That calculus is deeply individual, and it is one reason ALPPS continues to be offered selectively rather than broadly.