Liver transplantation complications: Difference between revisions

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Revision as of 23:09, 16 December 2017

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

Overview

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 (15).

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. (18).

Thrombosis

The estimated incidence of hepatic artery thrombosis among liver transplant recipients is 4%–12% in adults and 42% in children. (12,19).
it may lead to fulminant hepatic necrosis. the mortality rate approaches 30% (3).
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 (4,8,15).
early intervention may allow graft salvage. However, most patients ultimately require retransplantation. (14)
Risk factors for hepatic artery thrombosis include a significant difference in hepatic artery caliber between the donor and the recipient. (12,14,19,20).
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 (Fig 3).
Gadolinium-enhanced MR imaging with three-dimensional spoiled gradient-echo sequences is another accurate and noninvasive method for evaluating the hepatic vessels (2,5,13,25).

Stenosis

Hepatic artery stenosis has been reported to occur in 5%–11% of liver transplant recipients (3,4,12).
This complication usually occurs at the site of anastomosis within 3 months after transplantation (3).
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 (8).
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 (17).
Both at contrast-enhanced CT and at MR angiography, this arterial lesion appears enhanced (4,14).

Portal Vein

Portal vein thrombosis occurs in about 1%–2% of cases (12,19).
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 (3,4).
Portal vein stenosis has a reported incidence of 1% after liver transplantation (12).
The treatment in symptomatic cases is thrombolysis or surgery (thrombectomy, venous graft) (4).
CT and MR angiography provide excellent depiction of filling defects and focal narrowing of the portal vein (Fig 11) (3,13). Rarely, transhepatic or transjugular portography may be necessary to achieve a definitive diagnosis (27). IVC and Hepatic Vein

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 (28).
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 (29). An obstruction of hepatic venous outflow may be treated with placement of a balloon-expandable stent (28).
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 (Fig 13c–13e). In addition to stricture or thrombosis, CT and MR images may show additional diagnostic features, such as a mosaic pattern of perfusion (characteristic of Budd-Chiari syndrome) (Fig 14c, 14d) (3).

Biliary Disorders

Biliary complications include stenosis, fistula, obstruction, stone formation, dysfunction of the Oddi sphincter, and recurrent biliary disease (7).
MR cholangiography is the best noninvasive technique for evaluation of the biliary tree (1,27).
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 (1). Despite good sensitivity for the detection of strictures, MR cholangiography tends to lead to their overestimation (31).
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 (1,27).

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 (1). Anastomotic strictures usually result from fibrotic proliferation with narrowing of the biliary lumen (Fig 15); less frequently, they are due to ischemia caused by hepatic artery thrombosis or stenosis (1). 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 (1). On the other hand, clinical and laboratory evidence of high-grade obstruction may be observed without visible dilatation of the biliary tree (3). 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 (1).

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 (4). Leaks occur most often at the T-tube site and rarely at the site of an anastomosis (3). Bile may leak freely into the peritoneal cavity or may form a perihepatic collection (Fig 16). Treatment includes stent placement and drainage of collections (8).

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 (14,32). 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 (3).

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 (Fig 18). 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 (3).
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 (8).
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 (3) 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 (33).
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. In one autopsy series, infections accounted for 64 percent of 321 deaths [7]. Serious infections occur most frequently within the first three months post-transplantation, which is the time of greatest immunosuppression [7,8]. However, patients with poor graft function who require increased levels of immunosuppression to treat recurrent cellular rejection or chronic rejection continue to be at risk for opportunistic infections [9]. A variety of pathogens can cause infections post-transplantation, including bacteria, fungi, and viruses (figure 2). (See "Infectious complications in liver transplantation".)

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 (table 5). 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 [10]. 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 [11].

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 [13-15]. In addition, some patients lose the normal circadian blood pressure patterns and develop nocturnal hypertension [16]. 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 [17]. CNIs act by increasing both systemic vascular resistance and renal vascular resistance (primarily affecting the afferent arterioles) [18].

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 [25,26]. 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. (See "Screening for type 2 diabetes mellitus".)

Obesity

Patients with end-stage liver disease frequently have a compromised nutritional status. Despite this, over one-third of patients are obese [41,42]. 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 [13,42-44].
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 [43].
The dose of prednisone has been identified as an independent predictor of the development of obesity [43]. However, once obesity is established, tapering of prednisone may not lead to weight loss [13]. In addition, patients treated with cyclosporine are more likely to have weight gain than those who receive tacrolimus (46 versus 27 percent in one study) [45].

Dyslipidemia

Dyslipidemia is common after liver transplantation, and patients should have a fasting lipid profile obtained annually [49]. Hypercholesterolemia develops in 16 to 43 percent of patients and hypertriglyceridemia in 40 to 47 percent; reduced serum HDL-cholesterol is also common [50,51]. 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 [51]. Patients with elevated pretransplantation cholesterol levels are most likely to develop hypercholesterolemia following transplantation [51]. (See "Measurement of blood lipids and lipoproteins".)

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 [59]. 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 (MMF) [11,60].
Liver transplant recipients have a greater risk of cardiovascular death and ischemic events than age- and sex-matched nontransplanted patients [59]. As an example, one study compared 1312 liver transplant recipients with age- and sex-matched controls [61]. The relative risk of death due to cardiovascular disease in liver transplant recipients was 2.6 (95% CI 1.5-4.0) compared with controls. When excluding infection, recurrent disease, graft loss due to technical complications, and de novo malignancy, coronary heart disease represents the most common cause of death following liver transplantation [62]:

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[19,20,66].

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 [77]. 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. (See 'Screening and prevention' below.)

@@ Line 4: / Line 4: @@
 {{Liver transplantation}}
 ==Overview==
-==Liver transplantation complications==
+== Post-surgical complications ==
 === Vascular Disorders ===
@@ Line 11: / Line 12: @@
 Hepatic artery complications include thrombosis, stenosis, and pseudoaneurysm.
-At US, the normal hepatic artery waveform shows a rapid systolic upstroke and a continuous diastolic blood flow.
+a normal hepatic artery waveform obtained at the porta hepatis does not exclude a hepatic artery obstruction (15).
-It is important to evaluate the right and left hepatic artery branches, because a normal hepatic artery waveform obtained at the porta hepatis does not exclude a hepatic artery obstruction (15). Whenever possible, the anastomosis also should be examined.
-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. Increased hepatic artery resistance is associated with older donor age and a prolonged period of ischemia (Fig 2) (18).
-Thrombosis.
-The estimated incidence of hepatic artery thrombosis among liver transplant recipients is 4%–12% in adults and 42% in children (12,19). This is one of the most feared complications, as it may lead to fulminant hepatic necrosis. 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 (4,8,15).
-Prompt diagnosis of hepatic artery thrombosis is extremely important because early intervention (with thrombectomy, hepatic artery reconstruction, or both) may allow graft salvage. However, most patients ultimately require retransplantation (14). Even after retransplantation, the mortality rate approaches 30% (3).
-Risk factors for hepatic artery thrombosis include a significant difference in hepatic artery caliber between the donor and the recipient, an interpositional conduit for the anastomosis, a previous stenotic lesion of the celiac axis, excessive duration of cold ischemia time, ABO blood type incompatibility, cytomegalovirus infection, and acute rejection (12,14,19,20).
-The use of US for routine postoperative monitoring of liver transplant recipients has altered the clinical and imaging manifestations of hepatic artery thrombosis at initial diagnosis: Nowadays, fulminant hepatic necrosis is a rare finding (4). 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 (Fig 3). The duplex Doppler imaging findings allow correct diagnosis in an estimated 92% of cases (21).
-A marked reduction of hepatic artery flow in the presence of hepatic edema, systemic hypotension, or high-grade hepatic artery stenosis may lead to false-positive findings of hepatic artery thrombosis (4,8). False-negative findings, on the other hand, may result from the presence of peri-portal arterial collateral vessels in chronic thrombosis (14). Collateral vessel flow causes a dampened (tardus parvus) hepatic artery waveform similar to that distal to a significant hepatic artery stenosis, with a prolonged acceleration time (>0.08 second) and low flow resistance (resistive index of <0.5) (17).
-The use of a first- or second-generation contrast agent may be helpful when Doppler US findings are inconclusive. Contrast-enhanced US may provide clearer depiction of vascular structures. Using a second-generation perfluorocarbon-based contrast agent at US, Hom et al (6) demonstrated sensitivity, specificity, and accuracy of 100% for the detection of vascular complications after liver transplantation. Results from another study indicate that the use of a first-generation air-based microbubble contrast agent could obviate arteriography in 62.9% of cases in which initial Doppler US findings are inconclusive (11). At our hospital, a second-generation perfluorocarbon-based contrast agent has proved particularly valuable for the characterization of the hepatic artery. Its persistence in the bloodstream exceeds that of air-based microbubble contrast agents (Fig 4) (22). In addition, artifacts due to heart-related movement, respiration, or a lack of patient compliance during Doppler US acquisitions may be avoided with contrast-enhanced US (23).
-CT with standard and angiographic protocols allows the evaluation of parenchymal and vascular structures (3). The use of multidetector CT scanners has led to decreased scanning time and improved overall image quality with thin-section acquisitions. Contrast-enhanced multidetector CT provides a good noninvasive alternative to conventional angiography (Fig 5) (24).
-Gadolinium-enhanced MR imaging with three-dimensional spoiled gradient-echo sequences is another accurate and noninvasive method for evaluating the hepatic vessels (2,5,13,25). Good agreement was observed between findings at angiography and those at gadolinium-enhanced MR imaging for the detection of arterial abnormalities (Fig 3b, 3c) (13,26). Three-dimensional spoiled gradient-echo sequences allow evaluation of the liver parenchyma as well as the hepatic vessels. However, contrast-enhanced MR imaging places greater demands on patients than does US or CT: The examination lasts longer (20 minutes or more), and patients must hold their breath for 20–30 seconds. In hypoxic patients, the image acquisition time can be adapted to a shorter breath hold, but this adjustment may compromise anatomic coverage and spatial resolution (13). The criterion for a diagnosis of hepatic artery thrombosis at both CT and MR angiography is the appearance of an abrupt cutoff of flow in the artery, usually at the site of the anastomosis.
-Stenosis.
-Hepatic artery stenosis has been reported to occur in 5%–11% of liver transplant recipients (3,4,12). This complication usually occurs at the site of anastomosis within 3 months after transplantation (3). If left untreated, it may lead to hepatic artery thrombosis, hepatic ischemia, biliary stricture, sepsis, and graft loss. Early detection of hepatic artery stenosis is crucial to allow treatment either with surgical reconstruction or with balloon angioplasty and avoid the necessity of retransplantation. 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 (8).
-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 (17). Sampled intrahepatic waveforms usually show a tardus parvus pattern, which is characterized by an increased acceleration time of more than 0.08 second and a resistive index of less than 0.5 (16) (Fig 6). Severe aortoiliac atherosclerosis and hepatic artery thrombosis with the formation of intrahepatic collateral vessels are two important pitfalls, because flow through collateral vessels also may demonstrate a dampened arterial waveform .
-Low-grade narrowing of the hepatic artery may be present without causing apparent Doppler waveform abnormalities (8). Therefore, when clinical suspicion is high, normal findings at Doppler US should not preclude follow-up with cross-sectional imaging modalities (Fig 6b, 6c) or angiography, which are more accurate in demonstrating hepatic artery narrowing (4).
-Ischemia and Infarction.
-Hepatic infarction is a rare occurrence in patients who have not undergone liver transplantation; even in cases of hepatic artery occlusion, liver blood flow is maintained via the portal system and collateral vessels. In liver transplant recipients, by contrast, these collateral vessels are usually ligated. As a rule (in 85% of cases), liver infarction in transplant recipients (Fig 8) is associated with hepatic artery complications; less frequently, it results from portal vein occlusion (3). Ischemic lesions have a tendency to undergo liquefaction, which may be complicated by infection. Focal abscesses may be a source of intermittent or remittent sepsis. Calcifications may be observed in long-standing cases.
-Pseudoaneurysm.
-A hepatic artery pseudoaneurysm is an uncommon complication that generally develops at the site of anastomosis or arises as a complication of angioplasty (3). It also may occur in an intrahepatic arterial branch as a consequence of a liver biopsy or after a focal parenchymal infection (8).
-A hepatic artery pseudoaneurysm may be asymptomatic; however, a ruptured pseudoaneurysm may be manifested by acute shock (4). In addition, a fistula may form between the aneurysm and the biliary tree or the gastrointestinal tract (14), with resultant hemobilia or upper gastrointestinal bleeding. Treatment options for an extrahepatic pseudoaneurysm include surgical resection, embolization, and exclusion with stent placement. Intrahepatic pseudoaneurysms may be treated with endovascular coil embolization (3).
-On duplex Doppler US images, a hepatic artery pseudoaneurysm appears as a cystic structure, usually near the course of the hepatic artery; its interior is color-filled, demonstrating a turbulent arterial flow. Both at contrast-enhanced CT and at MR angiography, this arterial lesion appears enhanced (4,14).
-Portal Vein
-Portal vein complications are relatively rare and include thrombosis and stenosis. Portal vein thrombosis occurs in about 1%–2% of cases (12,19). 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 (3,4).
-Portal vein stenosis has a reported incidence of 1% after liver transplantation (12). Focal narrowing of the portal vein, usually at the anastomosis, may occur if there is a significant size discrepancy between the donor and recipient portal veins. This focal narrowing is not indicative of stenosis (4).
-The normal portal vein in a liver graft appears on US images with a regular contour, an anechoic lumen, and smooth walls, with the exception of a mild reduction in vessel caliber at the anastomotic site. Color and pulsed Doppler US images demonstrate a hepatopetal (toward the liver) monophasic flow that varies with respiration. Turbulent flow may be a normal finding in the early postoperative period (Fig 9) (8).
-Signs of stenosis on B-mode US images include poststenotic dilatation and portal hypertension demonstrated by an increase in the number or caliber of collateral vessels. On color and pulsed Doppler images, focal color aliasing occurs in the presence of an increase of more than three-to fourfold in flow velocity at the site of stenosis relative to flow velocity in the prestenotic segment (Fig 10) (14). Patients with symptomatic portal vein stenosis may undergo balloon angioplasty (4).
-When thrombosis has occurred, an echogenic filling defect may be seen in the portal vein. Eventually, an acute thrombus becomes anechoic. Color or power Doppler images and pulsed Doppler waveforms may show a lack of portal venous flow (8). Sometimes portal flow is so minimal that it is not detected at US, and further evaluation is necessary. The treatment in symptomatic cases is thrombolysis or surgery (thrombectomy, venous graft) (4).
-CT and MR angiography provide excellent depiction of filling defects and focal narrowing of the portal vein (Fig 11) (3,13). Rarely, transhepatic or transjugular portography may be necessary to achieve a definitive diagnosis (27).
-IVC and Hepatic Vein
-Complications of the IVC and the hepatic vein have a low combined incidence (<1%) (2,12). IVC complications include thrombosis and stenosis, usually at the site of surgical anastomosis. Technical factors, such as a size discrepancy between donor and recipient vessels or suprahepatic caval kinking from organ rotation, may cause acute IVC stenosis. Delayed caval stenosis may be secondary to fibrosis, a chronic thrombus, or neointimal hyperplasia. Chronic caval stenoses are more common after retransplantation and in children (8).
-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 (28). 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 (29). An obstruction of hepatic venous outflow may be treated with placement of a balloon-expandable stent (28).
-The normal Doppler waveform obtained in the hepatic vein in a liver transplant is triphasic because of the effect of pressure variations determined by the right cardiac chambers during the cardiac cycle (Fig 12) (4).
-A reduction in the caliber of the IVC or hepatic vein, with impaired flow and resultant prestenotic dilatation of the hepatic veins, is an indirect diagnostic finding of stenosis at Doppler US (4). A persistent monophasic waveform is a sensitive finding, but it is not specific for a substantial hepatic vein stenosis (Fig 13). On the other hand, a triphasic or biphasic waveform may help exclude a substantial hepatic vein stenosis (10).
-Direct signs of stenosis include a focal stricture on B-mode US images and turbulent flow with increased velocity on pulsed Doppler images (Fig 13b). Thrombosis of the hepatic vein or IVC may be depicted as an intraluminal echogenic thrombus with no flow on Doppler images (Fig 14) (8).
-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 (Fig 13c–13e). In addition to stricture or thrombosis, CT and MR images may show additional diagnostic features, such as a mosaic pattern of perfusion (characteristic of Budd-Chiari syndrome) (Fig 14c, 14d) (3).
-Biliary Disorders
-Biliary complications occur in an estimated 25% of liver transplant recipients, usually within the first 3 months after transplantation (7). These complications are the second most common cause of graft dysfunction (rejection is the most common) (1). Biliary complications include stenosis, fistula, obstruction, stone formation, dysfunction of the Oddi sphincter, and recurrent biliary disease (7).
-The choledochocholedochostomy is the type of biliary anastomosis that is most frequently employed, usually accompanying a cholecystectomy. With this kind of anastomosis, a T-tube may be left in place for 3 months to provide easy access for cholangiography of the biliary tree (3). A Roux-en-Y choledochojejunostomy may be preferred in some situations, such as in the presence of a discrepancy in donor and recipient duct size or of preexistent disease (biliary atresia, sclerosing cholangitis, or primary biliary cirrhosis) (4).
-US and T-tube cholangiography are the imaging methods most often used to evaluate the biliary tree in the first months after liver transplantation. After the removal of biliary catheters, other imaging methods must be used; these may include MR cholangiography, endoscopic retrograde cholangiopancreatography, and percutaneous transhepatic cholangiography (30).
-MR cholangiography is the best noninvasive technique for evaluation of the biliary tree (1,27). 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 (1). Despite good sensitivity for the detection of strictures, MR cholangiography tends to lead to their overestimation (31).
-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 (1,27).
-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 (1). Anastomotic strictures usually result from fibrotic proliferation with narrowing of the biliary lumen (Fig 15); less frequently, they are due to ischemia caused by hepatic artery thrombosis or stenosis (1). 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 (1). On the other hand, clinical and laboratory evidence of high-grade obstruction may be observed without visible dilatation of the biliary tree (3). 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 (1).
-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 (4). Leaks occur most often at the T-tube site and rarely at the site of an anastomosis (3). Bile may leak freely into the peritoneal cavity or may form a perihepatic collection (Fig 16). Treatment includes stent placement and drainage of collections (8).
-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 (14,32). The results of ductal ischemia are necrosis and its associated complications: bile leak (fistula), ductal scarring with fibrosis (stenosis), and bile collection
+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. (18).
-A ductal stenosis may be treated with balloon dilation, which frequently is used in drainage procedures.
+==== Thrombosis ====
+* The estimated incidence of hepatic artery thrombosis among liver transplant recipients is 4%–12% in adults and 42% in children. (12,19).
+* it may lead to fulminant hepatic necrosis. the mortality rate approaches 30% (3).
+* 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 (4,8,15).
+* early intervention may allow graft salvage. However, most patients ultimately require retransplantation. (14)
+* Risk factors for hepatic artery thrombosis include a significant difference in hepatic artery caliber between the donor and the recipient. (12,14,19,20).
+* 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 (Fig 3).
+* Gadolinium-enhanced MR imaging with three-dimensional spoiled gradient-echo sequences is another accurate and noninvasive method for evaluating the hepatic vessels (2,5,13,25).
-However, in most cases, retransplantation ultimately is necessary (3).
+==== Stenosis ====
+* Hepatic artery stenosis has been reported to occur in 5%–11% of liver transplant recipients (3,4,12).
+* This complication usually occurs at the site of anastomosis within 3 months after transplantation (3).
+* 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 (8).
+* 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 (17).
+* Both at contrast-enhanced CT and at MR angiography, this arterial lesion appears enhanced (4,14).
-Fluid Collections
+==== Portal Vein ====
+* Portal vein thrombosis occurs in about 1%–2% of cases (12,19).
+* 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 (3,4).
+* Portal vein stenosis has a reported incidence of 1% after liver transplantation (12).
+* The treatment in symptomatic cases is thrombolysis or surgery (thrombectomy, venous graft) (4).
+* CT and MR angiography provide excellent depiction of filling defects and focal narrowing of the portal vein (Fig 11) (3,13). Rarely, transhepatic or transjugular portography may be necessary to achieve a definitive diagnosis (27). IVC and Hepatic Vein
-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 (Fig 18). 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 (3). 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 (8). 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 (3) 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 (33). 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.
+==== 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 (28).
+* 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 (29). An obstruction of hepatic venous outflow may be treated with placement of a balloon-expandable stent (28).
+* 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 (Fig 13c–13e). In addition to stricture or thrombosis, CT and MR images may show additional diagnostic features, such as a mosaic pattern of perfusion (characteristic of Budd-Chiari syndrome) (Fig 14c, 14d) (3).
-Neoplasms
+=== Biliary Disorders ===
+* Biliary complications include stenosis, fistula, obstruction, stone formation, dysfunction of the Oddi sphincter, and recurrent biliary disease (7).
+* MR cholangiography is the best noninvasive technique for evaluation of the biliary tree (1,27).
+* 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 (1). Despite good sensitivity for the detection of strictures, MR cholangiography tends to lead to their overestimation (31).
+* 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 (1,27).
-Neoplastic complications after liver transplantation may include recurrent tumors and malignant neoplasms. The most commonly occurring neoplasms in patients who have undergone liver transplantation are skin cancers other than melanoma, Kaposi sarcoma, and non-Hodgkin lymphoma (3,14,34). Risk factors for the development of malignancies in liver transplants include long-term immunosuppression, chronic overconsumption of alcohol before transplantation, previous viral infection (with a hepatitis virus, Epstein-Barr virus, cytomegalovirus, or herpesvirus), and acute rejection episodes (34).
+==== 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 (1). Anastomotic strictures usually result from fibrotic proliferation with narrowing of the biliary lumen (Fig 15); less frequently, they are due to ischemia caused by hepatic artery thrombosis or stenosis (1). 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 (1). On the other hand, clinical and laboratory evidence of high-grade obstruction may be observed without visible dilatation of the biliary tree (3). 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 (1).
-Lymphoma associated with Epstein-Barr viral infection is more common among patients who undergo immunosuppressive therapy with cyclosporine and usually occurs 4–8 months after transplantation (14). Involvement of the liver may be intra- or extrahepatic. Extrahepatic involvement, which is more common, is characterized by a poorly defined hypoechoic soft-tissue mass that encases or constricts hilar structures (35). Lymphomatous involvement of the liver parenchyma may be manifested as multiple hypoechoic lesions at US or multiple hypoattenuating nodules at CT, but it occurs more frequently as a diffuse infiltrative process. Other organs that may be involved include the lymph nodes, spleen, small intestine, stomach, kidneys, mesentery, and adrenal glands. In children, the most frequent sites of involvement are the lymph nodes and the gastrointestinal tract (20).
+==== 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 (4). Leaks occur most often at the T-tube site and rarely at the site of an anastomosis (3). Bile may leak freely into the peritoneal cavity or may form a perihepatic collection (Fig 16). Treatment includes stent placement and drainage of collections (8).
-The most common site of recurrence of hepatocellular carcinoma is the lung, and the second most common site is the liver (36).
+==== 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 (14,32). 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 (3).
-Rejection is the most common cause of graft failure. Clinical and laboratory findings are nonspecific and indistinguishable from those observed in transplant loss from other causes. Imaging likewise plays no role in the diagnosis of rejection, which can be achieved only with histologic analysis of a liver biopsy specimen (14).
+==== 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 (Fig 18). 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 (3).
+* 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 (8).
+* 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 (3) 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 (33).
+* 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. In one autopsy series, infections accounted for 64 percent of 321 deaths [7]. Serious infections occur most frequently within the first three months post-transplantation, which is the time of greatest immunosuppression [7,8]. However, patients with poor graft function who require increased levels of immunosuppression to treat recurrent cellular rejection or chronic rejection continue to be at risk for opportunistic infections [9]. A variety of pathogens can cause infections post-transplantation, including bacteria, fungi, and viruses (figure 2). (See "Infectious complications in liver transplantation".)
+'''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 (table 5). 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 [10]. 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 [11].
+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 [13-15]. In addition, some patients lose the normal circadian blood pressure patterns and develop nocturnal hypertension [16]. 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 [17]. CNIs act by increasing both systemic vascular resistance and renal vascular resistance (primarily affecting the afferent arterioles) [18].
+'''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 [25,26]. 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. (See "Screening for type 2 diabetes mellitus".)
+'''Obesity'''
+* Patients with end-stage liver disease frequently have a compromised nutritional status. Despite this, over one-third of patients are obese [41,42]. 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 [13,42-44].
+* 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/m<sup>2</sup> at baseline to 27.0 kg/m<sup>2</sup> at year 1, to 28.1 kg/m<sup>2</sup> at year 2; there was very little change with subsequent observations [43].
+* The dose of prednisone has been identified as an independent predictor of the development of obesity [43]. However, once obesity is established, tapering of prednisone may not lead to weight loss [13]. In addition, patients treated with cyclosporine are more likely to have weight gain than those who receive tacrolimus (46 versus 27 percent in one study) [45].
+'''Dyslipidemia'''
+* Dyslipidemia is common after liver transplantation, and patients should have a fasting lipid profile obtained annually [49]. Hypercholesterolemia develops in 16 to 43 percent of patients and hypertriglyceridemia in 40 to 47 percent; reduced serum HDL-cholesterol is also common [50,51]. 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 [51]. Patients with elevated pretransplantation cholesterol levels are most likely to develop hypercholesterolemia following transplantation [51]. (See "Measurement of blood lipids and lipoproteins".)
+'''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 [59]. 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 (MMF) [11,60].
+* Liver transplant recipients have a greater risk of cardiovascular death and ischemic events than age- and sex-matched nontransplanted patients [59]. As an example, one study compared 1312 liver transplant recipients with age- and sex-matched controls [61]. The relative risk of death due to cardiovascular disease in liver transplant recipients was 2.6 (95% CI 1.5-4.0) compared with controls. When excluding infection, recurrent disease, graft loss due to technical complications, and de novo malignancy, coronary heart disease represents the most common cause of death following liver transplantation [62]:
+'''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[19,20,66].
+'''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 [77]. 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. (See 'Screening and prevention' below.)
 ==References==