Liver transplantation complications

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Liver trasnsplantation Microchapters
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Historical Perspective
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Pre-surgical management
Choice of donor
Epidemiology and Demographics
Techniques
Complications
Acute rejection
Immune therapy
Post-surgical infection
Prognosis

Post-surgical complications

Vascular Disorders

Hepatic Artery

• Hepatic artery complications include thrombosis, stenosis, and pseudoaneurysm.
• a normal hepatic artery waveform obtained at the porta hepatis does not exclude a hepatic artery obstruction.
• In the early postoperative period (<72 hours after transplantation), increased hepatic artery resistance (resistive index of >0.8) is a frequent finding, but resistance ordinarily returns to a normal level within a few days.

Thrombosis

• The estimated incidence of hepatic artery thrombosis among liver transplant recipients is 4%–12% in adults and 42% in children.
• it may lead to fulminant hepatic necrosis. the mortality rate approaches 30%.
• In addition, in liver grafts, biliary ducts are supplied exclusively by small branches of the hepatic artery; therefore, arterial thrombosis may lead to biliary ischemia and necrosis.
• early intervention may allow graft salvage. However, most patients ultimately require retransplantation.
• Risk factors for hepatic artery thrombosis include a significant difference in hepatic artery caliber between the donor and the recipient.
• A US-based diagnosis of hepatic artery thrombosis is established in the absence of flow in the proper hepatic and intrahepatic artery at color and pulsed Doppler imaging.
• Gadolinium-enhanced MR imaging with three-dimensional spoiled gradient-echo sequences is another accurate and noninvasive method for evaluating the hepatic vessels.

Stenosis

• Hepatic artery stenosis has been reported to occur in 5%–11% of liver transplant recipients.
• This complication usually occurs at the site of anastomosis within 3 months after transplantation.
• Causes of hepatic artery stenosis may include clamp injury, intimal trauma from a perfusion catheter, or disruption of the vasa vasorum with resultant ischemia of the arterial ends.
• Duplex Doppler US is the method of choice for postoperative screening of liver transplant recipients because it is capable of depicting any focal increase (of more than two to three times) in peak systolic velocity at the site of stenosis and any poststenotic turbulent flow.
• Both at contrast-enhanced CT and at MR angiography, this arterial lesion appears enhanced.

Portal Vein

• Portal vein thrombosis occurs in about 1%–2% of cases.
• It most commonly results from technical problems (vessel misalignment, differences in the caliber of the anastomosed vessels, or stretching of the portal vein at the anastomotic site), previous portal vein surgery or previous thrombosis, increased downstream resistance due to a supra-hepatic stricture of the inferior vena cava (IVC), decreased portal inflow, and hypercoagulable states.
• Portal vein stenosis has a reported incidence of 1% after liver transplantation.
• The treatment in symptomatic cases is thrombolysis or surgery (thrombectomy, venous graft)
• CT and MR angiography provide excellent depiction of filling defects and focal narrowing of the portal vein.
• Rarely, transhepatic or transjugular portography may be necessary to achieve a definitive diagnosis.

Inferior Vena Cava

• IVC complications include thrombosis and stenosis, usually at the site of surgical anastomosis.
• The “piggyback” anastomosis (with preservation of the recipient vena cava and cavocaval anastomosis) has gained wide acceptance internationally and is the preferred technique for orthotopic liver transplantation at many institutions.
• However, it is especially vulnerable to two types of complications:
• (a) hemorrhage due to hepatic injury during surgery or due to cavocaval dehiscence (3% of cases) and (b) Budd-Chiari syndrome (0.3%–1.5% of cases) due to inadequate venous drainage.
• An obstruction of hepatic venous outflow may be treated with placement of a balloon-expandable stent.
• Cross-sectional modalities such as CT and MR imaging are commonly used to confirm suspicions aroused by Doppler US findings or to exclude a clinical hypothesis when US results are normal or inconclusive.
• In addition to stricture or thrombosis, CT and MR images may show additional diagnostic features, such as a mosaic pattern of perfusion.

Biliary Disorders

• Biliary complications include stenosis, fistula, obstruction, stone formation, dysfunction of the Oddi sphincter, and recurrent biliary disease.
• MR cholangiography is the best noninvasive technique for evaluation of the biliary tree.
• Multiplanar MR imaging enables accurate analysis of the surgically altered biliary anatomy. Although it does not provide a means of therapeutic intervention, it can be used to plan percutaneous, endoscopic, and surgical treatments. Despite good sensitivity for the detection of strictures, MR cholangiography tends to lead to their overestimation.
• Endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography provide high-quality images of the biliary tree and allow therapeutic intervention. However, the modalities are invasive and are associated with complications, which occur in 3.4% of percutaneous transhepatic cholangiographic examinations and in 5% of endoscopic retrograde cholangiopancreatographic examinations.

Obstruction and Stenosis

• Obstruction is the most common biliary complication both in adults and in pediatric patients and is frequently caused by stenosis at the anastomotic site.
• Anastomotic strictures usually result from fibrotic proliferation with narrowing of the biliary lumen less frequently, they are due to ischemia caused by hepatic artery thrombosis or stenosis.
• The possible causes of nonanastomotic strictures include pretransplantation biliary diseases such as primary sclerosing cholangitis, biliary ischemia, and infection.
• When biliary obstruction is believed to be present in a liver graft, it is of paramount importance that imaging findings be correlated with clinical and laboratory findings. Mild dilatation of the biliary tree may be observed on images in the absence of an actual mechanical obstruction.
• On the other hand, clinical and laboratory evidence of high-grade obstruction may be observed without visible dilatation of the biliary tree.
• Some patients with clinical and biochemical evidence of biliary obstruction may have dilatation of both the donor and the recipient bile ducts. Diffuse ductal dilatation may result from papillary dyskinesia due to devascularization or denervation of the papilla of Vater during transplantation.

Bile Leak

• The approximate incidence of bile leaks in liver transplant recipients is 5%. Bile leaks usually occur in the early posttransplantation period, and more than 70% occur within the 1st postoperative month.
• Leaks occur most often at the T-tube site and rarely at the site of an anastomosis.
• Bile may leak freely into the peritoneal cavity or may form a perihepatic collection.
• Treatment includes stent placement and drainage of collections.

Ductal Ischemia

• Bile duct ischemia is usually a consequence of stenosis or thrombosis of the hepatic artery; the bile ducts are entirely dependent on the hepatic artery for their blood supply.
• The results of ductal ischemia are necrosis and its associated complications: bile leak (fistula), ductal scarring with fibrosis (stenosis), and bile collection.
• A ductal stenosis may be treated with balloon dilation, which frequently is used in drainage procedures.
• However, in most cases, retransplantation ultimately is necessary.

Fluid Collections

• Seromas and hematomas are commonly observed near areas of vascular anastomosis (the hepatic hilum, the IVC) and biliary anastomosis, as well as in the perihepatic spaces. Such collections usually are found during the first days after transplantation and disappear within a few weeks. Rarely, they are large enough to compress the portal vein or the IVC.
• Pleural fluid, especially in the right side, also is a common finding. There is rarely a need for intervention if there is no ventilatory compromise.
• Although US is highly sensitive for the detection of fluid collections, it is not specific. A hematoma or purulent abscess may resemble a particulate ascites on US images.
• However, in most cases, collections of bile, lymph, blood, and pus all have the same appearance of a simple fluid collection.
• As expected, CT and MR imaging (especially the latter) are more useful for differentiating hematomas from seromas and bilomas because blood has higher attenuation at CT than do other fluids and has a characteristic signal intensity at MR imaging. Nevertheless, it is difficult to distinguish a bile leak from a periportal seroma at MR imaging.
• In some cases, the main role of imaging is to pinpoint the amount and location of such collections and, when possible, to guide interventional diagnostic or therapeutic procedures.

COMPLICATIONS OF IMMUNOSUPPRESSION

Infections

• The leading cause of mortality following liver transplantation is infection.
• Serious infections occur most frequently within the first three months post-transplantation, which is the time of greatest immunosuppression.

Metabolic syndrome

• The metabolic syndrome is common among patients who have undergone liver transplantation. It is defined by a combination of hypertension, insulin resistance/diabetes, dyslipidemia, and obesity.
• Liver transplant recipients may meet criteria for the metabolic syndrome prior to transplantation, in which case immunosuppressive medications can exacerbate the problem. In addition, many patients will develop the metabolic syndrome de novo.
• A study of 252 liver transplant patients found that 52 percent had metabolic syndrome following transplantation, compared with only 5 percent prior to transplantation.
• A second study with 455 liver transplant recipients found that the rate of obesity increased from 24 percent four months after transplantation to 41 percent three years after transplantation.

Immunosuppressant use is associated with all aspects of the metabolic syndrome:

• Hypertension: Glucocorticoids, cyclosporine >tacrolimus
• Diabetes mellitus: Glucocorticoids, tacrolimus >cyclosporine
• Obesity: Glucocorticoids, cyclosporine
• Dyslipidemia: Glucocorticoids, cyclosporine >tacrolimus, sirolimus

Hypertension

• Approximately 65 to 70 percent of liver transplant recipients develop hypertension following transplantation.
• In addition, some patients lose the normal circadian blood pressure patterns and develop nocturnal hypertension. Because hypertension is common post-transplantation, we suggest that for the first six months following transplantation, the patient's blood pressure be assessed at home with self-monitoring every week and by a
• The cause of hypertension is multifactorial but is mostly related to the use of calcineurin inhibitors (CNIs; eg, cyclosporine or tacrolimus) and glucocorticoids.
• CNIs act by increasing both systemic vascular resistance and renal vascular resistance (primarily affecting the afferent arterioles).

Diabetes mellitus

• Glucocorticoids, cyclosporine, tacrolimus, and weight gain predispose to the development of diabetes following liver transplantation.
• The risk also appears to be increased in patients transplanted for hepatitis C virus.
• To screen for diabetes we obtain fasting plasma glucose levels or hemoglobin A1C every six months. We also obtain annual eye examinations to look for cataracts or diabetic changes.

Obesity

• Patients with end-stage liver disease frequently have a compromised nutritional status. Despite this, over one-third of patients are obese.
• Following transplantation, improved health and treatment with glucocorticoids or cyclosporinepredispose to weight gain. Approximately one-third of patients who are normal weight at the time of transplantation will become obese following transplantation.
• Body weight tends to increase during the first two years after transplantation and then stabilizes. As an example, in one series of 774 patients, mean body mass index increased from 24.8 kg/m² at baseline to 27.0 kg/m² at year 1, to 28.1 kg/m² at year 2; there was very little change with subsequent observations.

Dyslipidemia

• Dyslipidemia is common after liver transplantation, and patients should have a fasting lipid profile obtained annually.
• Hypercholesterolemia develops in 16 to 43 percent of patients and hypertriglyceridemia in 40 to 47 percent; reduced serum HDL-cholesterol is also common.
• Hypertriglyceridemia usually develops within the first month post-transplantation and then remains stable throughout the first year. By comparison, serum cholesterol increases gradually and plateaus at six months.
• Patients with elevated pretransplantation cholesterol levels are most likely to develop hypercholesterolemia following transplantation.

Cardiovascular risk

• Because of the high rates of hypertension, diabetes, obesity, and dyslipidemia following liver transplantation, it is not surprising that coronary heart disease is also common. A meta-analysis that included 4792 patients following liver transplantation with 28,783 person-years of follow-up found that the 10-year risk of cardiovascular events was 14 percent and was particularly high among those with the metabolic syndrome.
• Factors that have been associated with cardiovascular events include older age at transplantation, male sex, post-transplantation diabetes, post-transplantation hypertension, history of coronary artery disease, and use of mycophenolate mofetil.
• Liver transplant recipients have a greater risk of cardiovascular death and ischemic events than age- and sex-matched nontransplanted patients.
• As an example, one study compared 1312 liver transplant recipients with age- and sex-matched controls.

Acute and chronic renal disease

• Acute and chronic kidney injuries are common in liver transplantation. For the first year following transplantation, we screen patients every two to three months with a urinalysis (including microalbumin assessment) and determination of the glomerular filtration rate (GFR). After the first year, we obtain the tests every six months.
• The cause of kidney injury is multifactorial. Important contributing factors are preexisting chronic kidney disease, renal failure prior to liver transplantation, acute tubular necrosis around the time of transplantation, hypertension, diabetes mellitus, and CNI toxicity.
• CNI-related acute renal failure is due to renal vasoconstriction and improves with dose reduction.
• Chronic renal disease can also be induced by these drugs, warranting continued monitoring of the plasma creatinine concentration and urinalysis. There are conflicting data about whether chronic nephrotoxicity in liver transplant recipients is more common with cyclosporine or tacrolimus.

Metabolic bone disease

• Bone loss is an important source of morbidity in liver transplant recipients (figure 5), and we assess bone mineral density prior to transplantation and every other year after transplantation to assess for osteopenia or osteoporosis.
• The majority of bone loss and fractures occur within the first six months following transplantation, and fractures often involve the spine.
• Patients transplanted for cholestatic liver disease are particularly vulnerable to the development of bone loss before liver transplantation.

Malignancy

• The incidence of malignancy is increased in liver transplant recipients [78]. Because of the increased risk, we pursue more intensive screening than is done in the general population.