Liver Transplantation Treatment & Management

Medical management before liver transplantation is aimed at preventing and treating the complications associated with end-stage liver disease (ESLD). Thus, many patients take various medications to control the consequences of liver failure and portal hypertension. These complications include (but are not limited to) the following:

• Ascites
• Spontaneous bacterial peritonitis (SBP)
• Hepatorenal syndrome (HRS)
• Encephalopathy
• Esophageal varices
• Intense pruritus

Ascites

Ascites presents a difficult treatment problem. As a first step, paracentesis should be performed to confirm portal hypertension as the etiology. Initially, salt restriction may be tried, although this is effective in less than 20% of patients. Fluid restriction should be avoided unless patients have gross anasarca, a serum sodium level less than 120 mEq/L, or both.

Diuretics remain the mainstay of medical management. The most commonly used are spironolactone, furosemide, and hydrochlorothiazide. Diuretic therapy should be adjusted or discontinued if serum sodium levels fall below 120 mEq/L or if the creatinine level rises to more than 2 mg/dL. Other diuretics that may be used include amiloride, triamterene, or ethacrynic acid.

If the ascites become refractory because of an inability to diurese patients and/or the development of electrolyte abnormalities and renal failure, repeat paracentesis may be performed every 2-3 weeks. A TIPS may result in a significant decrease in ascites; however, the risks of ischemic hepatic failure and intractable encephalopathy are higher, which limits its use in patients with cirrhosis classified as Child class C because the morbidity and mortality rates are increased. Other options include using peritoneovenous (LeVeen and Denver) shunts, although these are prone to occlusion, disseminated intravascular coagulation, and increased perioperative mortality.

Spontaneous bacterial peritonitis

SBP manifests in patients with cirrhosis who have ascites as an unexplained clinical deterioration, with or without the classic signs of peritonitis, and is associated with a high mortality rate. Paracentesis findings that are diagnostic include an absolute neutrophil count in the ascitic fluid of greater than 250/µL and positive results from peritoneal fluid cultures.

Antibiotic therapy, directed mostly toward gram-negative enteric organisms, should be started early. Secondary peritonitis, such as that due to a perforated viscus, should always be excluded prior to instituting therapy. Prophylactic antibiotics are frequently used in patients with cirrhosis who have severe ascites, previous SBP episodes, or recent variceal bleeding. In this context, rifaximin (Xifaxan) is commonly used, with or without a concomitant quinolone.

Hepatorenal syndrome

HRS is present in approximately 10% of hospitalized patients with cirrhosis and is common in patients with ascites. HRS is defined as a deterioration of renal function in a patient with advanced cirrhosis, with a creatinine level of more than 1.5 mg/dL, a urine volume of less than 500 mL/d, and a lowproducing  urinary sodium level (< 10 mEq/L).  There are two types of HRS: type 1 is rapidly progressive, necessitating dialysis and producing rapid deterioration that is responsive only to emergency transplantation, while type 2 is more indolent, with the above-mentioned minor elevation of creatinine.

Before a diagnosis of HRS can be established, other specific causes of renal dysfunction must be excluded. The diagnostic workup frequently includes insertion of a Foley catheter, renal ultrasound, and fluid challenge. Frequently unsuccessful, the medical treatment of HRS has been disappointing. Preliminary data suggest that a TIPS may be useful, but its precise role remains to be defined for this indication.

Encephalopathy

As many as 70% of decompensated patients with cirrhosis have some degree of encephalopathy, ranging from subtle neurological dysfunction to frank coma. Seek and correct potential precipitating causes such as GI bleeding, constipation, infection, medications with CNS effects, or electrolyte abnormalities. If ascites is present, exclude SBP via paracentesis. A search for other reasons, such as portal vein thrombosis or occult hepatocellular carcinoma (HCC), should be made. Transjugular intrahepatic portosystemic shunting (TIPS) can also lead to severe encephalopathy.

In addition to correction of precipitating causes, treatment is with lactulose, administered orally, via nasogastric tube, or through enemas, with doses titrated to achieve both 2-4 soft bowel movements daily and improvement in mental status. Neomycin may be added, although its potential for nephrotoxicity and ototoxicity can limit its usefulness. The usefulness of flumazenil, a benzodiazepine antagonist, remains to be defined.

Esophageal varices

Esophageal variceal bleeding (EVB) is a major cause of morbidity and mortality in patients with ESLD. The mortality rate during the initial EVB incident is as high as 50%, with an additional risk of recurrent bleeding of 70% within the first year.

EVB may manifest overtly, with hematemesis and hemodynamic instability, or more insidiously, with melena, hematochezia, or encephalopathy.

Initial treatment includes aggressive fluid resuscitation, administration of blood products to replace blood loss and/or to correct coagulopathy, and emergent endoscopic evaluation with both diagnostic and therapeutic aims. Intubation may become necessary because of encephalopathy and for airway protection. Patients are usually placed on intravenous octreotide to reduce the portal hypertension, H2 blockers to prevent stress ulceration, and antibiotics for SBP prophylaxis.

After achieving hemodynamic stability, perform an endoscopic evaluation of the upper GI tract with the goals of diagnosis and endoscopic control via rubber band ligation, sclerotherapy, or both. In approximately 5-10% of patients, these maneuvers fail to control bleeding; therefore, consider a TIPS, balloon tamponade, or surgical shunts. Reserve the placement of emergency surgical shunts for patients in Child class A to minimize morbidity and mortality.

Pruritus

Pruritus is also common in persons with liver disease, mostly in cholestatic liver diseases such as primary biliary cirrhosis and sclerosing cholangitis, although it is also common in persons with hepatitis C virus (HCV)–related cirrhosis. In approximately 90% of patients, the condition responds to sequential therapy with use of antihistamines, ursodeoxycholic acid, and cholestyramine. The remaining 10% can be treated with rifampicin, with a significant reduction of pruritus. Because of the potential for bone marrow and hepatic toxicity, regular complete blood cell counts and liver tests are necessary. Opiate antagonists (eg, naloxone, nalmefene, naltrexone) have increasingly been used in the treatment of refractory pruritus.

The elements involved in a successful LT are donor procurement, recipient implantation, and surgical coordination of these two procedures.

Cadaveric donor availability is made known to the transplant center with a suitable recipient, usually with a certain margin of time. The allocation follows the rules of the United Network for Organ Sharing (UNOS), and those are in a constant state of change.  The reader is referred to the UNOS website for current allocation policies.

Surgical coordination of both the donor and the recipient operations is made when declaration of death is made, proper consent is obtained, and adequacy of the donor liver for the prospective recipient is confirmed. The donor team is then transported to the donor's hospital, where the procedure takes place on the cadaver. Donors so procured can either be brain dead or thay may donate after cadiac death (DCD), a more risky procedure for the viability of the allograft.

LT can also use living donors. Because living-donor LT subjects a healthy individual to major surgery, donor safety is essential and informed consent is crucial. The risks and benefits of the living-donor operation must be explained to the donor, the recipient, and their immediate families. In addition, donors should be thoroughly evaluated by an unbiased physician. The workup should include a full medical, psychosocial, and anatomical evaluation of prospective donors. Finally, although the donor operation has been associated with low morbidity and mortality rates, long-term follow-up is necessary to confirm the safety of this procedure for donors, especially for donors of right lobe grafts. ^[26]

During multiorgan procurements, the goal of management is to maintain physiologic stability (ie, oxygenation, perfusion) so that the organs are in the best possible condition at harvest. Donors are brain dead and, thus, do not require an anesthetic, although they may still exhibit visceral, somatic, and autonomic reflexes. Additionally, the anesthesiologist may be asked to administer certain medications (eg, mannitol, furosemide, heparin) as part of the organ procurement protocol. In general, the goal is to provide supportive care during the procurement to avoid any insult to the organ(s) being harvested.

Anesthetic management during the organ implantation procedure follows the same general provisions as for other procedures: hypnosis, amnesia, analgesia, neuromuscular blockade, and hemodynamic stability. A rapid-sequence induction is used. Nasal intubation is avoided because of the potential for severe epistaxis. Isoflurane in air plus a narcotic is the usual anesthetic regimen, and long-acting drugs, such as pancuronium, lorazepam, and methadone, may be used. Nitrous oxide is avoided because of its effect on enteric distension. Regional anesthesia for postoperative analgesia is contraindicated because of actual or potential coagulopathies.

Besides the standard intraoperative monitors, arterial and pulmonary artery catheters are placed. In some centers, transesophageal echocardiography is added if questions arise concerning cardiac function or to help detect significant pulmonary emboli after reperfusion. An oral gastric tube is inserted, which later may be changed to a nasogastric tube.

Intraoperatively, the Rapid Infusor System (RIS; Haemonetics Corporation, Braintree, Mass) is routinely used. This device can warm and pump the contents of a reservoir at rates up to 1.5 L/min through large-bore venous access. Blood products and crystalloid solution are administered via the RIS.

Venovenous bypass (VVB) is used to divert blood flow from the inferior vena cava and portal vein around the retrohepatic portion of the inferior vena cava when it is clamped. The use of VVB is dictated by the operating surgeon, patient anatomy, and the circumstances of the procedure. Cannulas are usually placed in the femoral vein and the right internal jugular or axillary vein. A third cannula is inserted intraoperatively into the recipient's native portal vein. Blood from the femoral and portal cannulas is then pumped via a centrifugal bypass pump toward the internal jugular or axillary vein cannula. Placement of these cannulas can be accomplished percutaneously or via direct cutdown. The right internal jugular cannula also serves as the infusion site for the RIS. These cannulae are not needed if bypass is not a requirement of the surgical procedure.

After reperfusion, inotropics, vasoconstrictors, calcium chloride, and nitroglycerin should be immediately available. Epinephrine, norepinephrine, and phenylephrine are the agents most commonly used at the author's institution. Nitroglycerin is occasionally needed after reperfusion if pulmonary artery pressures are elevated.

Transfusion of blood products is often required in LT. Packed red blood cells and fresh frozen plasma (FFP) are administered via the RIS. Platelets and cryoprecipitate are generally administered via a peripheral or central vein after proper filtration. For full discussion, see Transfusion Requirements in Liver Transplantation.

Other important intraoperative considerations include the use of antibiotics, immunosuppression, cytoprotection, and adequate temperature homeostasis. Prophylactic antibiotics are used frequently and dosed around the operative procedure, which can be quite lengthy. After complete revascularization of the allograft, methylprednisolone (1 g) is administered as immunoinduction.

In addition, prostaglandin E₁ may be administered at a rate of 0.3-0.6 mg/kg/h in the postanhepatic portion of the surgery as a renal cytoprotective agent, adjusted to blood pressure levels. Finally, maintenance of temperature is important because it plays a vital role in optimizing the function of the coagulation system. Methods to achieve this include maintenance of room temperature, warm air blankets, fluid warming via the RIS, low fresh gas flow rates, and heat-moisture exchangers. If the venovenous bypass circuit is used, a heating element may be placed in-line.

The donor operation proceeds in cooperation with any other procurement teams present. A long midline incision from the suprasternal notch to the pubis is performed to gain full exposure to the abdomen. The chest is opened via a median sternotomy. This maneuver properly exposes the intrathoracic structures, allowing both cardiac and pulmonary organ harvest; it also allows easier hepatic dissection and extraction for the abdominal surgeon.

The dissection starts with the mobilization of the liver by dividing its ligamentous attachments. Sequentially, the left triangular and falciform ligaments are divided with the aid of electrocautery and are joined in the midline. Next, the gallbladder is emptied of its bile content by incising it at the fundus and irrigating it with warm saline until the returns are clear.

Attention is then directed toward the hepatic hilum, which is carefully examined and palpated by placing a finger in the Winslow foramen to assess for the presence or absence of anatomic variations. The following are the most frequently encountered variations:

• Accessory left hepatic artery from the left gastric artery (12%)
• Accessory left gastric artery from the left hepatic artery (7%)
• Replaced left hepatic artery from the left gastric artery (3%)
• Replaced right hepatic artery from the superior mesenteric artery (SMA) (10%)
• Accessory right hepatic artery from the SMA (5%)
• Hepatomesenteric trunk (3%)
• Gastrohepatosplenomesenteric trunk (3%)

The importance of identifying these variants is that any of these replaced or substituted trunks may contribute a significant amount, if not all, of the arterial blood supply to the respective lobe; therefore, preserve them whenever possible. Also, the presence of an aberrant left branch means that the dissection will be more tedious and delicate in order to preserve the left gastric artery, the main origin of this aberrant branch, alongside the lesser gastric curvature. Similarly, a right substituted or replaced branch requires the delicate dissection of the SMA up to the point of its origin in the aorta.

At this point in the operative procedure, a decision is made to either proceed in the usual fashion or resort to the rapid flush technique. This depends on the stability of the donor. For stable donors, the hepatic hilum is dissected systematically, dividing and ligating successively the right gastric artery and the gastroduodenal artery. The other branches of the celiac trunk (ie, the splenic artery on the superior edge of the pancreas and the left gastric artery along the upper lesser curvature of the stomach) are isolated and tied; the ties are cut long for posterior identification.

The free edge of the common bile duct is exposed laterally and isolated, ligating the distal portion and transecting it. This normally allows dissection of the common hepatic artery upward and the pancreatic edge downward, thus bringing into view the anterior surface of the portal vein. Mild blunt dissection is used to separate the anterior portal surface from the pancreas, with care to not injure minor tributaries. This allows visualization of the splenic, superior, and inferior mesenteric veins and cannulation of the splenic vein with the portal cannula for the portal flush afterward. To do this, the size of the cannula is adjusted to the size of the vein (introduced after appropriate venotomy) and is secured with ties.

After the portal cannula is in place, attention is directed to the infrarenal aorta, which is dissected free near its bifurcation; during this step, the inferior mesenteric artery is divided near its origin to obtain a proper segment of aorta for cannulation. Isolation of the supraceliac aorta follows by retracting the esophagus to the left and the previously mobilized left hepatic lobe to the right, thus exposing and dividing the diaphragmatic crura. This is used later as the site for cross-clamping.

The scenario is now set for perfusion of the organs. The donor is heparinized with 20,000-30,000 IU of heparin, the aortic cannula is introduced in the infrarenal aorta, the distal aorta is tied, and the suprarenal aorta is clamped. The organs are then perfused with ice-cold University of Wisconsin (UW) solution, and the suprahepatic vena cava is vented in the pericardial space. At this point, the cold, topical, iced solution is poured in the abdomen for surface cooling. Some surgeons also vent the vena cava via the infrarenal portion.

Removal of the liver then proceeds. The suprahepatic vena cava is taken along with a generous patch of diaphragm. The left gastric artery is dissected back, as is the splenic artery. The duodenum is kocherized, and fingers are placed behind the pancreas; the portal vein is dissected back, and its tributaries are divided. The SMA is felt through the pancreatic parenchyma, is dissected free, and is placed on traction with aid of a clamp. Sharp dissection proceeds to the left of the SMA and is carried down to the aorta; then, dissection from left to right is performed to identify potential right branches. The celiac trunk is then removed along with a generous Carrel patch of aorta.

After the hepatic hilar dissection is completed, the inferior vena cava is divided above the renal veins and is taken along with the bisected right adrenal vein. The remaining attachments of the liver and its hilar structures are carefully divided, and the organ is removed and taken to the back table for an immediate flush.

This general procedure is modified in cases of aberrant vessels to include dissection of the left gastric artery along the lesser curvature of the stomach (for left branches), or the SMA is included in the Carrel patch and is dissected very carefully from left to right to avoid injury to accessory right branches. In unstable donors, the portal system is cannulated first, prior to the hilar dissection, via the superior mesenteric vein in the inframesocolic space; the aortic control and cannulation quickly follow, and, after cross-clamping the supraceliac aorta, cold flushing is performed. Thereafter, hilar dissection and removal of the liver is performed in an asanguinous field. Exquisite care must be exercised to avoid injury to the vessels or biliary structures.

Once removed from the body, the liver is again flushed with 1 L of UW on the back table. After the organ has been properly flushed and packed, the internal iliac arteries and veins of the donor are procured for potential use as grafts. Transportation to the recipient's hospital immediately follows, in close coordination with the recipient's preparation.

For transportation of the liver allograft from the donor hospital to the recipient hospital, static cold storage has been the standard method. However, static cold storage and rapid rewarming can cause significant damage to organs from extended-criteria donors, even those considered to be of good quality, increasing the risk of transplantation complications or failure. ^[27]

During the past decade, continuous mechanical perfusion of livers with blood or preservation solution has been developed as a means of mitigating ischemia-reperfusion injury. Two forms of machine perfusion exist: hypothermic and normothermic. Hypothermic perfusion uses a red blood cell (RBC)–free oxygenated perfusate at 2–10°C. Normothermic perfusion mimics physiologic liver perfusion, using an RBC-based solution at 35.5–037.5°C. ^[27]

Normothermic perfusion can optimize suboptimal organs for successful transplantation, potentially allowing the use of donor livers that would otherwise be discarded. ^{[28, 29]} Amelioration of ischemia-reperfusion injury results in a reduced risk of early allograft dysfunction and biliary complications, including ischemic cholangiopathy. ^[27]

Back-table allograft preparation

Prior to engraftment, the donor liver is removed from ice and prepared for implantation in a back-table procedure. In this procedure, the superfluous tissues that accompany organs removed en bloc are trimmed, and, if any vascular reconstruction is necessary, it is performed.

The aim of the vascular reconstruction procedures, usually arterial, is to provide a single common inflow vessel of sufficient length so that only one anastomosis needs to be performed in the recipient. All vessels are then tested for patency and integrity by flushing with sterile preservation solution. The donor iliac arteries and veins routinely procured at the termination of the donor operation are also prepared for use, if necessary, as venous or arterial grafts in the recipient.

Full liver recipient procedure

The goals of an orthotopic LT operation are to remove the diseased liver (total hepatectomy) and then replace it with a healthy liver in exactly the same location. The recipient hepatectomy could result in massive bleeding; therefore, paying careful attention to the meticulous gentle handling of tissues and having a strict systematic approach to hemostasis at all times are crucial. Proper usage of venovenous bypass and blood products can optimize this part of the operation, thus decreasing morbidity rates.

A bilateral subcostal incision with a midline extension to the xiphoid process is routinely used (ie, "Mercedes-Benz" incision). After mobilizing and dividing the round and falciform ligaments, a large self-retaining upper abdominal retractor is placed. The ligamentous attachments of the liver (ie, left triangular, right triangular, and gastrohepatic ligaments) are then dissected to mobilize the liver in its entirety. See the image below.

Dissection of the hilar structures then proceeds, with systematic ligation of the hepatic artery, cystic duct, and common hepatic duct. The portal vein is then cleaned of surrounding tissue from the level of the head of the pancreas up to its bifurcation into right and left branches. The hepatic artery is now formally dissected proximal to the gastroduodenal artery, exposing the common hepatic artery to allow for subsequent anastomosis. The gastroduodenal artery is left untied to avoid distal thrombosis or dissection, which may happen if this artery is ligated. See the image below.

Venovenous bypass may now be initiated. Whether and when to start bypass depends on the degree of portal hypertension, the extent of previous surgery with vascularized adhesions, and the degree of bleeding within the operative field, notoriously from the retroperitoneum. Thus, initiation of bypass may occur early or late during the hepatectomy phase, as judged by the operating surgeon. See the image below.

Once bypass is initiated, the remaining attachments to the liver can be divided rapidly and the liver can be removed, leaving both upper and lower caval cuffs for later anastomosis. Depending on the degree of bleeding and the size of the donor liver to be implanted, the bare area of the liver may be oversewn. Following this, the vena caval cuffs are shaped for anastomosis.

Implantation and caval techniques

Standard technique

The suprahepatic vena cava is anastomosed first, followed by the infrahepatic cava.

Prior to completion of the latter, the liver is flushed free of preservation solution by infusion of chilled Ringer lactate solution. Alternatively, this may be performed after the portal vein anastomosis is completed, using portal blood (ie, "blood flush"). The recipient portal vein is decannulated and anastomosed to the recipient portal vein. After reperfusion, the caval clamps are opened, restoring normal flow. After a quick hemostatic check, the hepatic artery is anastomosed in an end-to-end fashion. The author has routinely used the common hepatic artery at the level of the gastroduodenal to avoid a steal phenomenon.

To confirm adequacy of the vascular reconstructions, flow is then measured with an ultrasonic or electromagnetic flow meter. If flow is inadequate, the inflow, outflow, and anastomoses are examined to determine the reason and to correct the problem(s).

Piggyback technique

In certain cases, removal of the cava is not necessary. In these cases, the caudate lobe is dissected free by dividing the short hepatic veins individually, leaving the recipient's cava in place. Once the liver is dissected in this fashion, it remains attached solely by the 3 main hepatic veins. These veins are controlled with a clamp, and the liver is removed. A common cuff is then formed from the 3 remaining orifices; this common cuff is then anastomosed to the donor liver's suprahepatic cava. Bypass may be instituted, either total or partial (only portal flow diverted), or omitted altogether. If bypass is omitted, creating a temporary portocaval shunt or simply clamping the portal vein (if the hemodynamic status of the patient allows) accomplishes this. The donor infrahepatic cava is tied or stapled shut. The rest of the procedure proceeds as described above. See the image below.

After achievement of adequate hemostasis, biliary reconstruction can begin. If the recipient bile duct is of normal caliber and is free of intrinsic disease, a donor-to-recipient duct-to-duct reconstruction can be performed without an indwelling T-tube stent.  The use of T-Tubes has fallen into disuse over time; however, if used, the tube is exteriorized through a separate stab wound incision. If the 2 ends of the bile duct can be tailored to meet perfectly without redundancy and are of similar caliber, this end-to-end reconstruction can be performed without a T-tube. If the patient's native bile duct is diseased or if the duct is too small, the bile duct of the donor is anastomosed to a defunctionalized Roux-en-Y loop of jejunum over an internal stent. See the image below.

Cholangiography is performed to confirm a technically sound biliary reconstruction and may be performed through the T-tube or via the cystic duct. With this completed, closing the abdomen after leaving 3 closed suction drains above and below the liver concludes the operation.

Recipient procedure (special cases)

Recipients with preexisting portal vein thrombosis

Techniques for the replacement of the portal vein or for thrombectomy of a recent thrombosis have been described. In essence, these techniques use donor iliac vein grafts from the superior mesenteric vein, tunneled toward the hepatic hilum over the head of the pancreas. Portal vein thrombectomy in cases in which the thrombosis is less well organized (fresh thrombosis) is a simple and effective technique that reserves the proximal portion of the native portal vein for anastomosis.

Intraoperative hepatic artery dissection or inadequate inflow 

If any doubt exists as to the adequacy of the inflow, fashion an aortohepatic graft by using the donor iliac artery and sew it end-to-end to the celiac axis of the donor liver. Grafts can also be used to lengthen the vessels for anastomosis as interposition arterial or venous grafts.

Patients with preexisting TIPS

Migration of these stents can be problematic. Proximal migration can interfere with placement of the upper caval clamp during hepatectomy and can lead to massive bleeding and air embolism if the TIPS is accidentally divided. Similarly, lower migration can result in fibrosis of the portal vein, making dissection difficult. In the former situation, incision of the pericardium and intrapericardial control of the suprahepatic cava may be necessary. In the latter, it is usually not so problematic.

Partial liver recipient procedures

While the number of LTs has grown exponentially, the number of organ donors has not kept pace with the growing number of candidates. This widening gap between supply and demand has led to higher mortality rates among candidates on the waiting list. In attempts to narrow this gap, transplantation centers have broadened their donor selection criteria and have begun to use innovative surgical techniques such as reduced-size LT, split LT, and living-donor LT.

Reduced-size LT was introduced in the mid 1980s to provide size-matched grafts for pediatric patients. In reduced-size LT, a cadaveric liver procured using standard techniques is resected on the back table to create a smaller graft. The liver allograft can be tailored based on the recipient's body size. Right lobe grafts, left lobe grafts, or left lateral segment grafts can be created. The rest of the liver is discarded.

Living-donor LT

In living-donor LT, part of the liver from a living donor is resected and transplanted into a recipient. The technique was first used for pediatric recipients and has now been extended to the adult recipient population because of excellent results and established donor safety. ^[30] In pediatric recipients, either left lateral segments or full left lobes usually suffice. For adults, right lobe grafts are necessary to ensure sufficient liver volume. See the image below.

This new procedure provides many advantages to the recipient because of the elective nature of the procedure (usually before severe hepatic decompensation) and the assurance of a healthy donor organ with a short ischemia time, resulting in better graft quality than with cadaveric liver allografts. Technical problems in the recipient, such as hepatic artery thrombosis and biliary leaks, were observed initially but have decreased dramatically with increasing experience in technique and recipient selection. For the donors, the advantage is mainly psychological.

The operation to implant a right lobe split graft is similar to orthotopic whole LT because the cava is retained. In left lobes or left lateral segments, split grafts, and right lobe living-donor grafts, the allograft lacks the vena cava; therefore, the anastomosis from the upper hepatic vein to the cava (outflow) must be performed end-to-end to the recipient's right hepatic vein stump after oversewing is used to close the middle and left hepatic vein orifices (middle and right in case of left lobe grafts) using 5-0 Prolene running suture.

In this case, removal of the native liver by a piggyback technique is mandatory. The portal vein anastomosis is performed between the allograft portal vein and the recipient portal vein using 6-0 Prolene continuous suture. The hepatic artery anastomosis is performed between the allograft hepatic artery (either right or left) and the recipient right or left hepatic artery using 8-0 Prolene interrupted sutures.

Sometimes, an operating microscope may be needed, especially for small arterial anastomoses. Extension grafts are rarely needed. In most cases, the bile duct anastomosis is accomplished by Roux-en-Y hepaticojejunostomy (although sometimes performing duct-to-duct anastomosis is possible) using interrupted 6-0 polydioxanone sutures.

Split LT

With this technique, a whole adult liver is transected into 2 pieces to provide grafts for 2 recipients. The splitting can be performed through the falciform ligament to provide a small (left lateral segment) graft for a child and a large (extended right lobe) graft for an adult. Splitting a whole liver through the main portal fissure and gallbladder bed to create right and left lobe grafts is also possible. The actual splitting can be performed ex situ (after removal from the donor, on the back table) or in situ (during procurement, before aortic cross-clamping), in a manner analogous to living-donor LT.

In situ splitting has many advantages over ex situ splitting: it avoids cold ischemia, allows evaluation of the viability of segment 4, minimizes bleeding upon reperfusion, and facilitates sharing with other centers. In both in situ and ex situ splitting, vessels can be shared based on both recipients' needs. See the image below.

Not all donors are suitable for split procedures. Donors should be older than 50 years and should be hospitalized for less than 3 days with perfect liver function, minimal pressor support, and no steatosis. The final decision of whether a liver is suitable for splitting should be made in the operating room. Similarly, recipients should be selected carefully. Relatively stable patients in Child class B or C tolerate split-related complications better.

For full discussion of this topic, see Split Liver Transplantation

Intensive care unit care

Following LT, the function of the new liver is monitored closely in an intensive care unit (ICU) setting. Elevations of liver enzymes, notoriously transaminases (ie, aspartate aminotransferase, alanine aminotransferase), early on are reflective of preservation injury (cold preservation). On occasion, these enzyme levels rise sharply. If they are higher than 2000, the overall viability function of the liver should be monitored carefully to assess the need for retransplantation.

Usually, the liver enzyme levels normalize very quickly, typically within a week of transplantation. The bilirubin level follows a similar pattern of early rise and delayed clearing. However, if the preservation injury is severe, this elevation can persist for 2-3 weeks and can be accompanied by a significant rise in alkaline phosphatase levels.

Platelet counts usually decrease in the first week after LT and recover during the second week. This may be caused by platelet sequestration in the liver and spleen due to preservation injury. Once the liver has recovered, as manifested by the return of bilirubin levels to normal, the platelet count increases.

Recovery in a typical patient is rapid, as is discharge to the floor, usually within 2-3 days. However, if the graft has suffered severe preservation injury, return to normality may lag. Treatment is mostly supportive, with the goal of maintaining stable hemodynamics while the liver recovers. In extreme cases, termed primary graft nonfunction, the new liver never recovers and urgent retransplantation is required.

Floor care

After the patient's medical condition and graft function have stabilized, he or she is transferred from the ICU to the floor transplant unit. At this time, tests are performed to assure adequacy of the new connections. A duplex Doppler ultrasound helps check for patency of the vascular anastomoses and the presence of abnormal fluid collections. If a tube is present, a T-tube cholangiogram is performed to assure adequate biliary drainage and to exclude leaks.

During the patient's stay on the floor unit, laboratory studies, medications, nutritional status, and exercise tolerance are monitored. As soon as patients are able, discharge instructions begin to prepare them for going home. Most patients with severe ESLD have a very low albumin level prior to transplantation. After successful LT, the albumin level slowly rises to normal levels. This explains the generalized edema that patients may experience following transplantation, which begins to disappear once albumin levels start to normalize.

At hospital discharge, the patient receives a schedule of follow-up clinic visits for laboratory tests and checkups. The intent is to track clinical progress and to detect potential complications (eg, rejections, infections) as early as possible. Patients are instructed to notify the transplantation team if they have any prolonged illness, fever, nausea, vomiting, or diarrhea or if they experience any unusual symptoms or adverse effects potentially related to the immunosuppressants.

Immunosuppression regimens

Liver transplantation (LT) requires lifelong immunosuppression (IS) unless the patient acquires operational tolerance. Following transplantation, all patients are placed on immunosuppressive drugs to prevent rejection of the new liver. These medications are usually started in the operating room and are continued thereafter. The dose of the immunosuppressive agent needed varies from patient to patient depending on the likelihood of rejection.

Immunosuppression must be balanced carefully against the patient's own immune system. Adjusting the dose specifically for each patient helps avoid the risk of postoperative infections, tumor development, and liver rejection. The dose of immunosuppressive agents varies between patients and may vary with time in a particular patient. This explains the requirement of frequent blood drawing, especially early after transplantation, because absorption, metabolism, and dose requirements of these drugs can vary significantly from day to day in the early posttransplant period.

As time passes, the amount of immunosuppression needed to prevent organ rejection usually decreases. Immunosuppression therapy is not without risk and must be monitored closely. Immunosuppression management is based on the following principles:

• The doses used, adjusted over time, should be the minimum necessary to prevent rejection.

• The risk of rejection is highest (40%) during the first 3-6 months after transplantation and decreases significantly thereafter.

• Immunosuppressive therapy accounts for more than 50% of transplant-related deaths, often due to infections and other risks related to long-term use. ^[31]

• Some disease processes (ie, autoimmune diseases) are more likely to produce rejection; drug levels in these patients should be adjusted accordingly.

• Most medications are metabolized by the liver itself; therefore, graft dysfunction can significantly alter drug levels.

• Other medications added to an immunosuppressive regimen can lead to significant toxicities or to a lack of therapeutic effect and subsequent rejection.

In-depth discussion of the pharmacology of immunosuppressive medications is beyond the scope of this article, although certain points are worth mentioning. Induction immunosuppression is not commonly used after LT, although the introduction of interleukin-2 receptor–blocking antibody preparations (eg, basiliximab [Simulect]), may change this approach in the future.

Liver transplantation centers often have their own immunosuppressive therapy regimen protocols. Nearly all  protocols include a calcineurin inhibitor (eg, cyclosporine, tacrolimus), mycophenolate mofetil (MMF), and corticosteroids. Corticosteroids are often used early after transplantation, but are tapered as quickly as possible. ^[31] Mammalian target of rapamycin (mTOR) inhibitors (eg, sirolimus, everolimus) are increasingly administered as indicated for renal dysfunction or malignancy. 

Immunosuppressive medications can interact with other medications. Because transplant recipients receive multiple medications, primary care physicians should be mindful of polypharmacy when starting new drugs. Because of the extensive list of interactions, particularly with calcineurin inhibitors, changes to any medication should be discussed with the transplant team. ^[31]

Acute rejection

Acute (cellular) hepatic allograft rejection, an attempt by the immune system to attack the transplanted liver and destroy it, can occur in as many as 40% of patients during the first 3 months after transplantation. Acute rejection normally occurs 7-14 days after the operation but can occur earlier or much later. Hyperacute rejection of the liver, comparable to that observed in kidney transplantation, is controversial and difficult to diagnose, but early accelerated rejection certainly occurs. Liver biopsy may be required to distinguish between rejection and viral infection.

Rejection is most commonly manifested by malaise, fever, graft enlargement, and diminished graft function. In patients who have undergone LT, a rise in bilirubin and transaminase levels is observed and T-tube biliary drainage may be thin and lighter in color. Acute rejection most commonly first occurs in the second week after transplantation but can occur earlier. Graft biopsy should be performed, if safe, to document rejection. Adult liver biopsies are routinely performed at the bedside with or without ultrasound guidance.

With early suspicion and detection, most acute rejection episodes can be treated successfully. Characteristic signs and symptoms of rejection include fatigue, fever, abdominal pain or tenderness, jaundice, dark yellow or orange urine, and/or clay-colored stools. In some instances, patients may not have any symptoms, but their liver function test results may be abnormal, suggesting that rejection is occurring. Rejection episodes are managed sequentially by pulse steroids, OKT3, and/or the use of mycophenolate or a tacrolimus switch if the patient was on cyclosporine. Retransplantation is the last resort when therapy fails and hepatic failure develops.

Chronic rejection

The characteristics of chronic rejection in recipients of a liver transplant are progressive bile duct disappearance and obliterative arteriopathy, known as ductopenia, and vanishing bile duct syndrome, which results in progressive jaundice and allograft dysfunction. The ducts suffer direct immunological injury and ischemia from the obliterative arteriopathy caused by antibody-mediated intimal damage of hepatic arterioles. In the late phase of chronic rejection, diffuse hepatic fibrosis occurs. Allograft function deteriorates, marked by cholestasis and, ultimately, loss of synthetic function and portal hypertension.

Heavy immunosuppression with tacrolimus, mycophenolate mofetil, and/or sirolimus may reverse chronic rejection in the early phases. Advanced chronic rejection is an indication for retransplantation.

Diagnostic tools for allograft dysfunction

Posttransplant allograft dysfunction is multifactorial and multietiological. Anything from technical factors to recurrent infections or drug interactions can ultimately cause allograft dysfunction. Thus, establishing the diagnosis accurately is of prime importance because many of these conditions have diametrically opposed management strategies. For example, if the dysfunction is due to infection, appropriate antibiotics should be used and immunosuppression should be decreased. This is the wrong course of action if the diagnosis is acute rejection.

Serial monitoring of liver function test results; pan cultures for bacteria, viruses, and fungi; use of imaging tests (described below); and, ultimately, liver biopsy, are essential for an accurate diagnosis. Radiological imaging that the transplantation team may perform to monitor a patient's transplant may include one or more of the following tests and procedures:

• Ultrasonography: This test is performed to ensure vascular patency of the hepatic artery, portal vein, and caval anastomoses and to exclude stenoses. Additionally, a diagnosis of biliary dilation can be made. This test is also used to check for fluid collections such as blood or bile.

• CT scanning: This allows evaluation of the morphology of the liver and assessment of biliary dilation, fluid collections, and infections or other problems. MRI, in some instances, may be performed in lieu of CT scanning.

• T-tube cholangiography: In patients in whom the T-tube is still in place, a T-tube cholangiogram can be readily obtained. In patients in whom the T-tube has already been removed or in whom a Roux-en-Y reconstruction is performed, a percutaneous transhepatic cholangiogram may be necessary to image the biliary tree. Cholangiography allows diagnosis of leaks, blockages, or other potential problems. In other instances, endoscopic retrograde cholangiography may be preferable. If biliary stenosis is present, a stent can be placed at that time.

• Liver biopsy: A liver biopsy is usually performed to exclude rejection, recurrent hepatitis or other diseases, or drug effect as a cause of allograft dysfunction. This may be performed in the hospital or in the outpatient/short-stay unit.

In uncomplicated cases, recovery from the operation is surprisingly rapid and not unlike that experienced by other general surgical patients. However, early graft dysfunction suggests accelerated rejection, technical complications, or primary graft failure.

In a study of 10,295 adult patients who underwent liver transplantion (LT) in the United States from 2009 through 2012, the 90-day reoperation rate was 29.3%. Risk factors for 90-day reoperation included recipients with a history of hemodialysis, severely ill functional status, government insurance, increasing Model for End-Stage Liver Disease score, and increasing donor risk index. Additionally, patients undergoing reoperation more than 30 days after LT were found to have increased risk of 1-year mortality compared with those undergoing earlier reoperative intervention (odds ratio = 1.96; 95% CI, 1.4-2.7; P < 0.01). ^[32]

Imaging plays an important role in detecting postsurgical complications. For full discussion, see Imaging of Liver Transplantation Complications.

Primary graft failure

Primary graft failure occurs in approximately 3-7% of patients and is a very serious complication. The patient decompensates quickly, and a desperate search for a new graft must be initiated. Patients show markedly abnormal liver function, coagulopathy, oliguria, and severe CNS changes (including seizures and status epilepticus).

Ikegami et al showed that primary graft dysfunction after living-donor LT was associated with delayed functional hyperbilirubinemia levels greater than 20 mg/dL for more than 7 consecutive days after postoperative day seven. ^[33] Among these patients, those with early mortality showed coagulopathy compared with those without mortality. Stage IV coma, alkalosis, hyperkalemia, and hypoglycemia characterize the terminal phase of this acute hepatic decompensation.

In these patients, treatment includes avoiding the administration of any potassium, transfusing fresh frozen plasma (FFP) every 4-6 hours (or as a continuous infusion when necessary), and keeping the gastric pH greater than 5.0. FFP can be administered once the determination of primary nonfunction has been made. A continuous 10% aqueous dextrose solution infusion may be needed to control hypoglycemia. Urgent retransplantation is the solution to this complication if it can be performed before pneumonia or irreversible coma occurs. Prostaglandin infusions may also be used in the setting of primary nonfunction.

Biliary complications

Technical complications usually involve either biliary or arterial reconstruction. Biliary complications are relatively frequent after LT and are thought to be primarily of ischemic origin. Persistent jaundice with or without drainage of bile through the drains warrants study. Ultrasound and/or abdominal CT scans may show ductal dilation or bile collection. If the patient has a T-tube, obtain a cholangiogram, preferably in the radiology suite. Reexploration is required if a bile leak is present. Obstruction may require reexploration if it cannot be dealt with by percutaneous interventional radiology.

Hepatic arterial thrombosis

Hepatic arterial thrombosis should be considered in any patient who has a sudden high fever and elevation in liver function study results. A positive blood culture finding for Klebsiella species, Escherichia coli, Pseudomonas species, or enterococci in this setting is virtually pathognomonic. Doppler ultrasound is an effective noninvasive method for evaluating hepatic artery patency. If the vessel cannot be seen well or if clinical suggestion is high, arteriography is indicated.

Warner et al found that abnormal arterial anatomy in the graft, which required bench reconstruction, and a delay in arterial reperfusion were the main risk factors associated with early hepatic arterial thrombosis. In a multivariate regression model, bench arterial reconstruction increased the risk of early hepatic arterial thrombosis 4-fold, and each 10-minute delay in reperfusion increased the risk by 27%. ^[34]

Hepatic arterial thrombosis has 3 general patterns of presentation. The first is acute hepatic gangrene with sepsis and fulminant liver failure. Urgent retransplantation is required.

The second is delayed bile leak or intrahepatic biloma or bile abscess resulting from ischemic necrosis of the bile ducts. Retransplantation is usually required, especially if the common bile duct is disrupted, but in some patients the problem can be controlled, at least temporarily, with percutaneous drainage of intrahepatic collections and antibiotic coverage.

The third general pattern is relapsing bacteremia. Some patients, especially small children, can be treated successfully with antibiotic therapy. A full course of intravenous antibiotics is administered, followed by a course of oral suppressive therapy. If the patient remains afebrile with good liver function, retransplantation may be necessary only if chronic ischemic strictures of the biliary tree develop. Other patients have persistent bacteremia and develop liver abscesses, requiring eventual transplantation.

Because of the risk of hepatic artery thrombosis, it is dangerous to use evaluated prothrombin times or low platelet counts as a basis for vigorous treatment with FFP and platelet transfusions. Except in patients with active bleeding, platelet counts as low as 50,000/µL and prothrombin times less than 25 seconds are not treated. In addition, at the discretion of the surgeon, patients may be started on aspirin and dipyridamole (Persantine).

Infection and fever

Aggressively evaluate all fever episodes in an immunosuppressed patient. Routine workup tests for feverinclude the following:

• Chest radiographs and, when indicated, abdominal radiographs
• Sputum for Gram stain and culture and sensitivity
• Urinalysis and urine culture
• Throat wash and urine for cytomegalovirus (CMV), herpes simplex virus (HSV), and Epstein-Barr virus (EBV)
• Buffy coat for CMV, HSV, and EBV cultures
• Culturing of all drains, tubes, and open wounds
• Culturing of all long-term indwelling lines
• Doppler ultrasonogram of hepatic vessels

The following tests also may be indicated if the above tests fail to identify the source or if the clinical situation dictates:

• Acute-phase serum sample (including EBV, CMV, and HSV titers)
• Arterial blood cultures for fungus
• Stool for ova and parasites
• Pelvic examination
• Skin tests for tuberculosis, mycoses
• Legionella titer
• Ultrasound, CT scan, or both (especially indicated in patients with worsening jaundice or suspected intra-abdominal fluid collections or abscess)
• Lumbar puncture (including 2 mL for cryptococcal examinations)
• Transhepatic cholangiogram or endoscopic retrograde cholangiography (or T-tube cholangiogram, if T-tube is still in place)
• Hepatitis screen

Even mild infections are a serious threat in immunosuppressed patients. As an adjunct to therapy, immunosuppression must be reduced or even completely stopped temporarily. Bacterial infections are better tolerated with cyclosporine than with azathioprine but still must be treated aggressively. Viral infections account for substantial morbidity and mortality. Herpes infections are treated with a 10- to 14-day course of acyclovir (5-10 mg/kg q8h IV over 1 h). Candidal species in sputum, blood, urine, bile, or drains are an indication for systemic therapy. The presence of candidal species in peritoneal fluid strongly suggests a bile leak or bowel perforation.

Cytomegalovirus ^{[35, 36]}

CMV status (positive or negative) of the donor must be recorded in the recipient's chart, and the CMV titer of the recipient must  be ordered as part of the pretransplantation evaluation so the results are available immediately after transplantation. CMV infection is usually observed 3 or more weeks after transplantation and is one of the most common viral infections. CMV infection is often characterized by fever, leukopenia, and malaise.

Patients with systemic CMV infections are treated with ganciclovir. The drug appears to be most effective when started early in the course of CMV infection and may be useful for CMV hepatitis, enteritis, and CMV pneumonia. A tissue diagnosis of CMV should be sought, either by characteristic histological findings or by biopsy cultures. Endoscopy is often successful in demonstrating CMV infection, even in patients without GI symptoms.

Candidal infections ^[35]

Candidal species (ie, Candida albicans, C tropicalis, C parapsilosis, Torulopsis glabrata) can cause severe locally or systematically invasive infections in heavily immunosuppressed patients. As a rule, if candidal species grow from 2 or more sites, even if not from blood (eg, urine, wound), the condition should be managed as a systemic infection. Traditional treatment for systemic candidiasis has been amphotericin B. Amphotericin must be administered intravenously and has synergistic renal toxicity with cyclosporine.

Ketoconazole is avoided because it can cause a dramatic increase in cyclosporine levels and may be hepatotoxic. Fluconazole appears to be promising. It can be administered intravenously or orally and has less troublesome hepatic or renal toxicity. The usual loading dose in patients with a serum creatinine level less than 2 mg/kg is 400 mg followed by 200 mg/d. In patients with a serum creatinine level of 2-4 mg/dL, the loading dose is 200 mg followed by 100 mg/d. If the serum creatinine level is greater than 4 mg/dL, administer a 100-mg loading dose and 100 mg every other day.

​Aspergillosis ^[35]

Infections with Aspergillus niger, A flavus, or A fumigatus may involve the lungs, the upper respiratory tract, the skin, the soft tissues, and the CNS. The disease more commonly presents as a diffuse pneumonia with patchy infiltrates rather than a fungus ball in the lungs. Development of a brain abscess is insidious, and cure has been rare. Treatment with amphotericin B should be initiated whenever the diagnosis of aspergillosis is considered. A long course of systemic therapy (2-3 g) is indicated if infection is confirmed.

Cryptococcosis ^[35]

Cryptococcus neoformans may cause pulmonary, CNS, and disseminated cutaneous infection in immunosuppressed patients. All patients with pulmonary cryptococcosis should have their spinal fluid examined (lumbar puncture). In addition to the traditional India ink stains, testing for cerebrospinal fluid cryptococcal antigen and peripheral antibody should be performed. Systemic treatment with amphotericin B (1-1.5 g) is indicated.

Phycomycetes

Infections with Mucor and Rhizopus species are rarely encountered but can produce destructive CNS or soft tissue infections that are difficult to eliminate. Treatment includes local excision and a long course of systemic amphotericin B.

Legionella and Pneumocystis 

These infections are more common in immunosuppressed patients and must be treated early. A patient who develops a pulmonary infiltrate of unknown etiology should be started on erythromycin (1 g IV q6h) for Legionella infections and trimethoprim-sulfamethoxazole (20 mg/kg/d in 4 divided doses) for Pneumocystis infections, which commonly manifest as dyspnea and hypoxemia before the chest radiographs show a significant infiltrate. Arterial blood gas measurements should be obtained. Consultation with a pulmonologist for bronchoalveolar lavage should be requested.

Long-term infectious complications

The majority of opportunistic infections with the greatest morbidity and mortality for the liver transplant recipients usually occur within the first year after transplant. However, the permanent immunosuppression of these patients renders them susceptible to infections indefinitely. Studies following long-term infection rates in liver transplant recipients showed that these patients are susceptible to increased rates of cholangitis, pneumonia, and sepsis. The most common bacteria involved in those late infections are Enterococcus species and Escherichiacoli, while the most frequent viruses are CMV and varicella zoster virus. ^[37]

Evidence supports the utility of multiplex real-time polymerase chain reaction (SeptiFast) for the early diagnosis of bloodstream infections after liver transplantation. Specifically, Rath et al found that SeptiFast yielded a significantly higher positivity rate in detecting 25 clinically important pathogens from patients with suspected sepsis after liver transplantation than in patients with suspected sepsis after other major abdominal surgery. ^[38]

Posttransplantation lymphoproliferative disorder

Posttransplantation lymphoproliferative disorders (PTLDs) may develop at any time; these lesions have been observed developing as soon as 1 month and as long as 14 years after transplantation, although most cases have developed within the first year. These lesions are usually associated with EBV infection. PTLDs account for 41% of all tumors developing in immunosuppressed patients on cyclosporine, compared with only 12% of patients treated with earlier regimens. They may reflect the overall increased level of immunosuppression achieved with current regimens including cyclosporine rather than a special property of cyclosporine itself.

The clinical presentation varies, but the head and neck and the GI tract have been the most commonly involved. Presenting symptoms include lymphadenopathy, fever, weight loss, abdominal pain, tonsillitis, night sweats, upper respiratory tract infections, and diarrhea. Patients may present with a clinical syndrome indistinguishable from mononucleosis, with fever and lymphadenopathy. Tonsillar swelling may produce acute upper airway obstruction. An acute abdomen resulting from intestinal obstruction or perforation may occur. Cases involving lymphoid proliferation, mainly in the transplanted liver or kidney, which were detected upon graft biopsy performed to exclude suspected rejection, have also been observed. Other more unusual presentations have included lung lesions, a renal mass, prostatic obstruction, disseminated sepsis, and multiple organ failure.

Most lesions are polyclonal in nature. A fulminant course is uncommon, and the appropriate management is reduction in immunosuppression and treatment with acyclovir. Occasionally, an aggressive monoclonal monomorphous lesion may be encountered that requires antilymphoma therapy. Unfortunately, diagnosis of these lesions is usually made late in the course of the disease when the patients are already moribund. Early recognition of PTLDs with prompt reduction in immunosuppression and antiviral therapy is associated with the best prognosis.

Other long-term complications

Arterial hypertension ^[39]

This may develop as a consequence of the natural aging process and as an adverse effect of the immunosuppressive medications. Patients may need to take additional medications for proper control of hypertensive states. One prospective, multicenter study found that blood pressure is not adequately controlled in a noticeable percentage of liver transplant patients, especially in patients with diabetes or metabolic syndrome. ^[40]

Diabetes mellitus ^[39]

Some of the immunosuppressive medications may cause diabetes in the posttransplant period. This may occur de novo or may be an exacerbation of a preexisting condition. Patients are often placed on a diet and exercise program, oral hypoglycemic agents, and even insulin. Symptoms of diabetes may include increased thirst, increased frequency of urination, blurred vision, and confusion.

Kidney failure ^[39]

According to a large UNOS database study, the cumulative incidence of chronic kidney disease after liver transplant is 18.1% after 5 years. ^[41]

Progressive decline in kidney function is predicted by a decline in renal function over the first 3-12 months after transplant. ^{[42, 43]} Other predictors of chronic renal failure include older recipient age, pretransplant renal failure, female sex, cyclosporine (compared with tacrolimus), pretransplant hepatitis C, and pretransplant diabetes. ^[41] Late toxicity associated with calcineurin inhibitors (CNIs) is associated with typical renal histologic lesions. ^[44] A retrospective review of the first 3 years in more than 1000 liver transplant recipients from 11 US centers showed that prevailing serum creatinine and blood pressure measures were higher in subjects whose principal immunosuppressant was cyclosporine rather than tacrolimus. ^[45]

The consequences of hepatorenal syndrome (HRS) after liver transplantation are not well studied. In a small study of 28 patients, ^[46] the HRS resolved in 58% of patients ^[47] after liver transplantation, including in 8 who were on dialysis prior to undergoing liver transplant alone. Of the 42% with continued renal insufficiency after liver transplant, 7 (58%) remained dependent on dialysis. ^[20] Only alcoholic liver disease (ALD) and need for posttransplant dialysis were negative predictors of posttransplant HRS. Thus, no reliable pretransplant markers of continued HRS after liver transplant were identified that could be used to determine the need for combined liver-kidney transplant.

The first step when managing patients with progressive decline in renal function after liver transplantation is to minimize the dose of CNIs. Combination immunosuppression may be used to achieve this without increasing the risk of rejection. In a controlled study, patients with chronic renal dysfunction randomized to a strategy of mycophenolate mofetil introduction with reduction in CNI (tacrolimus trough < 4 ng/mL or cyclosporine < 50 ng/mL) had significant improvement in renal function compared with a conventional CNI dose, along with improvements in blood pressure and lipid profile. ^[48] Other studies have shown similar results with this strategy of CNI reduction. ^{[49, 50, 51, 52]} Some studies have shown no improvement in biopsy-proven CNI renal dysfunction 6 months after CNI withdrawal and replacement by mycophenolate mofetil in late severe renal dysfunction. ^[44]

The other alternatives are CNI-free regimens. Although mycophenolate monotherapy has produced some success in selected patients, ^{[53, 54]} a high rate of rejection, including graft failure, ^[55] has been seen in other studies. ^[56] Sirolimus monotherapy may be safe, but experience is limited, and adverse effects such as hyperlipidemia must be monitored. In small series, however, renal function has improved in patients for whom CNI was withdrawn and replaced by sirolimus because of progressive nephrotoxicity. ^{[57, 58]} The combination of mycophenolate and sirolimus is being studied after CNI withdrawal early after transplantation.

Posttransplant malignancies

Recipients of solid liver transplants, as all transplant recipients, are at particular risk for increased incidence of some malignant neoplasms after transplantation as a consequence of the effects of immunosuppressive drug therapy. Immunosuppressive therapy does not increase the frequency of most common malignancies, but it does significantly increase the risk of lymphoma; skin cancer; and some rare malignancies, including Kaposi sarcoma and carcinoma of the cervix, external genitalia, and perineum.

These malignancies can be virally induced, such as EBV-associated lymphoproliferative disease (eg, PTLD, recurrence of preexisting cancers in recipients, donor-transmitted neoplasms, or de novo malignancies. Development of de novo and other malignancies is also related to the increased longevity of liver transplant recipients. Certain cancers occur at distinct intervals after transplantation, and immunosuppression facilitates the development of cancers that occur relatively close to the actual transplantation event.

A great deal of the knowledge about malignancy after transplantation comes from the Israel Penn International Transplant Tumor Registry (IPITTR), formerly the Cincinnati Transplant Tumor Registry, founded by Israel Penn, MD, now deceased. Since 1968, the IPITTR has collected and analyzed data on de novo cancers of various organs from transplantation centers worldwide. Much of the data in the IPITTR have been collected on renal transplant recipients. Several reports and analyses of the various incidences of different types of neoplasms have been reported.

Another database in wide use comes from a registry for data from transplant recipients in Australia and New Zealand maintained by A.G. Shell, MD. However, these registries are voluntary and thus may not accurately reflect the true risk of malignancies or cancers in immunocompromised patients compared with the general population because not all neoplasms are uniformly reported. Similarly, follow-up data such as survival after diagnosis and/or therapy are not known. Thus, large data sets compiled from UNOS or large transplantation centers with longer follow-up periods may be preferable to evaluate the true risk of cancer after LT. This is of particular interest in nonlymphoid cancers because they generally manifest much later after LT than lymphoid cancers.

Some malignancies occur more frequently in certain subpopulations of transplant recipients, according to preexisting risk factors or behaviors, such as oropharyngeal cancer and lung cancer in those with alcoholism and those who smoke, or colon cancer in patients with preexisting inflammatory bowel disease who underwent transplantation for primary sclerosing cholangitis (PSC). Directed screening in these patients is thus desirable, with oropharyngeal examinations, chest radiographs, and scheduled colonoscopies.

PTLD is related to infection with EBV. It generally arises from B lymphocytes and is most common in children, recipients who were seronegative for EBV and received seropositive donor organs, and patients who required the use of OKT3. PTLD is frequently extranodal, arising in such sites as the GI tract, lungs, or CNS. Therapy is multifactorial and involves decreasing immunosuppressive medications, use of antiviral medications, and, sometimes, chemotherapy or radiotherapy.

Skin cancer, including squamous cell carcinoma, melanoma, and basal cell carcinoma, occurs up to 20 times more frequently in transplant recipients than in the general population. It tends to run a more aggressive course in transplant recipients. Because of this risk, recipients should avoid sun exposure and undergo routine skin evaluations, with aggressive management of lesions, should they develop. Kaposi sarcoma may manifest as cutaneous lesions or also may affect the oropharynx, lung, or other viscera. Treatment involves decreasing immunosuppression and may also involve chemotherapy or radiotherapy.

Recurrence of hepatocellular carcinoma (HCC) after LT is usually persistence rather than recurrence. The size and number of nodules, the presence of capsular/vascular invasion, and lymph node involvement predict the likelihood of recurrence. Options to treat the cancer prior to or during surgery have had little impact on the rates of recurrence, and careful candidate selection remains the most important tool. Cholangiocarcinomas are very difficult to detect prior to transplantation and are rarely cured, although aggressive multimodality approaches with surgery, chemotherapy, and brachytherapy have been associated with a good outcome in highly selected patients at the Mayo Clinic. The only secondary cancers, which may be indications for LT, are the symptomatic endocrine tumors, for which worthwhile palliation can be achieved.

Recurrent liver disease

Liver transplant recipients may be susceptible to recurrence of their original disease. Liver transplant recipients may develop recurrence of hepatitis C (HCV), hepatitis B (HBV), HCC, alcoholic liver disease, or one of the autoimmune hepatitides. The severity of recurrence varies from mild to the development of progressive allograft failure.

Hepatitis A may recur to infect the graft, but, in the few cases reported, no significant consequences have been described. As for HBV, in the past, positivity for HBV DNA was a contraindication for transplantation. Patients with a history of HBV infection who were negative for HBV DNA were treated with hepatitis B immunoglobulin (HBIg) before transplantai. Currently, patients are treated with lamivudine for 6 weeks prior to transplantation until their HBV DNA is reduced to less than 1 million copies per milliliter.

Follow-up after transplantation is with both lamivudine and HBIg; the dose and duration of HBIg treatment are not firmly established, but some centers aim to maintain levels higher than 100 U/mL lifelong or offer vaccination. Development of resistant mutations is an increasing problem. The role of other antiviral therapies, such as ganciclovir, adefovir, or famciclovir, is uncertain at this time.

HCV recurrence after transplantation is almost universal, but the extent of the graft damage is variable. Survival in the short term is not significantly affected, but concerns exist regarding long-term recurrence because the rate of developing cirrhosis at 5 years can be as high as 8-25%. Several factors have been variably implicated in recurrence, including genotype (1b), viral load, HLA match, degree and type of immunosuppression, quasispecies, and recipient age.

Genotype 1 has also been cited as a marker in more severe recurrent hepatitis C in European studies, but this has not been confirmed by North American centers. An important concern has been whether specific primary immunosuppression with tacrolimus results in more frequent and severe HCV recurrence, in contrast to a cyclosporine-based regimen (as based on retrospective analysis). However, when studied prospectively, no deleterious effect of tacrolimus was noted.

Earlier studies implicated treatment of apparent steroid-resistant rejection with the monoclonal antibody OKT3 in exacerbating the consequences of recurrent HCV infection. Distinguishing graft injury due to recurrent HCV infection from acute rejection may be extremely difficult, even for experienced transplantation pathologists. Justifiable caution is warranted when aggressively treating liver transplant recipients with HCV infection for presumed acute cellular rejection, generally using a strategy of repeated liver biopsy before initiating the typical steroid cycle.

Patients who undergo transplantation because of HCV infection seem to develop graft fibrosis more quickly. The reasons for this are not clear. The role of interferon and/or ribavirin is uncertain; concerns about inducing chronic rejection must be balanced against any therapeutic benefit.

Other complications

In patients with alcoholic liver disease, resumption of alcohol use leads to recurrent alcoholic liver disease in a small proportion of cases. However, overall 1- and 5-year survival rates are no different in this cohort of patients. Pretransplantation abstinence, often necessary to determine whether the liver will recover enough to avoid the need for transplantation, is a relatively poor indicator of future abstinence.

Nonalcoholic steatohepatitis (NASH) occasionally is an indication for transplantation. Recurrence of NASH has been identified after transplantation and may be associated with progressive fibrosis in the graft. This is more common when the underlying cause of NASH (eg, obesity, jejunoileal bypass) has not been altered.

Budd-Chiari syndrome was once a major indication for transplantation. However, this is less common because of the introduction of other methods of treatment. The probability of further thrombosis despite the use of anticoagulation is 30-40%. The presence of an underlying disorder affects the need for transplantation.

In a single-center retrospective cohort study, acute-on-chronic liver failure after liver transplantation was not significantly associated with estimated glomerular filtration rate less than 30 mL/min, death, recurrent cirrhosis, or retransplantation when adjusted for potential cofounders. ^[59]

If the metabolic abnormality is primarily within the liver, transplantation is curative; however, at present, it is indicated only if significant liver disease (eg, hemophilia with end-stage HCV infection from multiple blood transfusions) is present. Such indications include alpha1 antitrypsin deficiency, antithrombin-III deficiency, protein C deficiency, protein S deficiency, Wilson disease, tyrosinosis, Byler disease, galactosemia, hemophilia A and B, and Crigler-Najjar syndrome. If the disease process is extrahepatic, liver replacement is not always indicated, unless with the intention of modifying the effects of the disease, such as in hemochromatosis and erythropoietic porphyria.

Most autoimmune liver diseases recur in the allograft but have little impact in the short and medium term. Primary biliary cirrhosis recurs in the allograft in 20% of patients at 5 years and in 45% at 51 years. Some studies have found that recurrence is greater in those taking tacrolimus compared with cyclosporine. The role of ursodeoxycholic acid in this situation is unclear. Autoimmune hepatitis may recur, especially if corticosteroids are withdrawn, but usually responds rapidly to reintroduction of steroids with no adverse long-term impact.

PSC also may recur in the allograft. Making the diagnosis of recurrence is difficult because differentiation of recurrent primary disease from de novo secondary disease may be challenging. PSC recurs in 18-27% of patients at 5 years and may lead to cirrhosis, requiring retransplantation. Significant risk factors for recurrent PSC include the following ^[60] :

• High MELD scores
• Living-donor liver transplant from a first-degree relative
• Postoperative CMV infection
• Postoperative biliary complications

A possible solution to the chronic shortage of allografts is xenotransplantation, ie, the use of tissue from an animal donor. Most experts believe that the pig will provide the most suitable solid organs for use in human beings. However, animal organs are rapidly rejected by a process called hyperacute rejection. In addition, increasing evidence indicates that other barriers besides hyperacute rejection, both immune and nonimmune, might exist to limit the survival of xenografts. New strategies to overcome these barriers are needed if long-term xenograft survival equivalent to, or better than, that of allografts is ever to be achieved.

Xenografts may also offer potential benefits over allografts because they offer the possibility of manipulating donor organs before transplantation, which would help develop graft-specific immunosuppressive treatments and thus reduce the need for systemic immunosuppressive therapy and its risks.

Other concerns may limit the widespread application of xenotransplantation, notoriously the threat of transmissible zoonosis. These fears have been heightened by data showing that co-culture of porcine and human cell lines allows endogenous porcine retroviruses to begin replication. The potential risks of disease transmission must be examined carefully before clinical trials can proceed. However, addressing every concern will be difficult until after clinical xenotransplantation has begun.

Other future directions under consideration include hepatocyte cell transplantation and use of bioartificial liver devices (ie, extracorporeal liver-assist devices). Although promising, great development in these devices is still needed, as with xenotransplantation, to bring them to the clinical arena.

The future of organ availability ultimately may depend on the cautious development of organ-cloning techniques. Once the realm of science fiction, these are now within reach.

The ongoing expansion of criteria for transplantation for hepatocellular carcinoma

As experience grows with transplantation for small HCC, individual centers have analyzed their data for transplantation of tumors exceeding the Milan criteria. In a retrospective study, Yao et al analyzed the outcome of 70 patients with HCC undergoing transplantation. ^[61] Those who exceed the Milan criteria on pathologic examination of the explants had a 75% 5-year survival if they had a single lesion ≤ 6.5 cm or 2-3 nodules with the largest ≤ 4.5 cm and total tumor diameter ≤ 8 cm. Patients who exceeded these so-called University of California at San Francisco (UCSF) criteria, however, had a 50% 1-year survival rate after transplantation.

Even though these results are encouraging, the jury is still out on the expanded UCSF criteria. In a retrospective study that examined 5-year survival rates in patients with HCC after liver transplant, those patients who met the pretransplant Milan criteria had a 5-year survival rate of 60% as compared with only 45% for those who exceeded the Milan criteria but met the UCSF criteria. ^[62] Although the difference was not statistically different, such a large clinical difference warrants comparison of these criteria in large well-designed prospective studies before they are universally adopted.

The role of neoadjuvant therapy for HCC prior to liver transplant is not well defined. In a systematic review of studies reporting the impact of transarterial chemoembolization (TACE) for HCC prior to transplant from 1990 to 2005, the authors concluded that TACE, as a bridge to orthotopic liver transplantation, does not improve long-term survival, expand current criteria, or decrease dropout rates on the waiting list. ^[63] Most studies were of poor methodological quality, and large well-designed randomized trials are needed to define the role of neoadjuvant therapies such as TACE and radiofrequency ablation as a bridge to transplantation. In another study, no difference in short-term (60-d) or long-term (5-y) survival or cumulative tumor recurrence was found in a group of 36 patients with HCC who underwent transplant after TACE compared to 21 controls with HCC who went to transplant without TACE. ^[64]

In another study that examined the effect of TACE on transplant candidates, ^[65] patients who had complete or partial response to TACE had better 1-, 2-, and 5-y survival rates than patients whose tumors had no response or progressed on TACE. In a subgroup analysis, these benefits were seen only in patients who had met the Milan criteria; they were not seen in patients who exceeded the Milan criteria but met the UCSF criteria. These patients were more likely to drop out because of tumor progression while awaiting transplant and also had higher posttransplant HCC recurrence. Downstaged patients fared worse, with higher dropout rates and worse 5-y survival rates. Thus, the response to TACE for patients meeting the Milan criteria may predict long-term outcome.

Yao et al reported that patients with HCC who were successful downstaged to within Milan/United Network for Organ Sharing T2 criteria had a low rate of HCC recurrence and excellent post-transplant survival, comparable to results in patients who met T2 criteria without downstaging. In their study of 118 patients with HCC who underwent downstaging to within T2 criteria, compared with 488 patients with HCC listed for LT who met T2 criteria at listing in the same period, Kaplan-Meier's 5-year post-transplant survival and recurrence-free probabilities were 77.8% and 90.8%, respectively, in the downstaging group versus 81% and 88%, respectively, in the T2 group (P = 0.69 and P = 0.66, respectively). ^[66]

As of October 2015, patients with HCC who are candidates for LT must wait 6 months after initial application to obtain exception points. Ishaque et al reported that before the policy change, deceased-donor liver transplant (DDLT) rates were 3.6-fold higher in HCC candidates, compared with non-HCC candidates with the same calculated MELD; after the policy change, DDLT rates in HCC candidates fell to 2.2-fold higher than in non-HCC candidates. HCC candidates did not experience a substantial increase in waitlist mortality/dropout after the policy change. ^[67]

Transplantation in patients with HIV

In the 1990s, prior to the era of highly active antiretroviral therapy (HAART), HIV was an absolute contraindication to liver transplantation. ^{[68, 69]} Despite the advent of HAART and documentation of improved outcomes in these patients, most transplant centers still do not perform liver transplantation in HIV-positive recipients. A clinical trial is under way to study kidney and liver transplantation in patients with HIV. Click here for more information.

Current data suggest that posttransplantation survival in HIV-positive recipients does not differ from that of the non-HIV liver transplant population as a whole. ^{[70, 68]} Several small institution-specific studies demonstrated comparable survival between HIV-positive and HIV-negative recipients, particularly those who tolerate HAART and have pretransplantation CD4 counts >200 cells/μL. ^{[68, 69]}

In a prospective study of 11 HIV-infected liver transplant recipients, 1- and 3-y patient (91% and 64%) and graft survival (82% and 64%) rates were similar to the general liver transplant population between 1999 and 2004. ^[71] However, posttransplantation outcomes are also reduced in co-infected patients (HIV and HCV) compared to HCV-negative, HIV-positive patients and HIV-negative, HCV-positive recipients. ^[72] Since most patients who require liver transplantation need transplantation because of HCV progression, not HIV, the controversy continues about whether liver transplant is a viable option for these patients.

One of the major concerns in co-infected patients is the risk for recurrence of cirrhosis and HCV posttransplantation. This subgroup of recipients exhibits earlier and more severe HCV recurrence and higher rates of posttransplantation fibrosis, cirrhosis, and fibrosing cholestatic hepatitis. Finally, the concomitant use of immunosuppressive therapy and HAART raises the issue of pharmacologic interactions. Protease inhibitors interfere with the activity of cytochrome P450 3A (CYP3A). Therefore, the dosing of sirolimus and calcineurin inhibitors such as tacrolimus and cyclosporine should be reduced and drug levels carefully monitored to reduce toxicity. ^[73]