Time period
Common complications
Less likely complications
Perioperative
Donor liver diseases (e.g., steatosis)
Preservation injury
Hyperacute rejection
Primary non-function
Within the first week
Preservation/reperfusion injury
Hyperacute rejection
Hepatic artery thrombosis
Recurrent viral hepatitis
Portal vein thrombosis
Sepsis
Bile duct leak
Acute cellular rejection
1 Week to 2 months
Acute cellular rejection
Chronic rejection
Recurrent viral hepatitis
Opportunistic infections
Preservation/reperfusion injury
Biliary complications
Drug reactions
More than 2 months
Acute cellular rejection
Persistent preservation/reperfusion injury
Chronic rejection
Post-transplant lymphoproliferative disorder
Recurrent liver diseases
De novo liver diseases
Biliary complications
Drug reactions
Evaluation of Donor Biopsies
Histologic evaluation of donor biopsies is not routinely performed in most centers. A liver biopsy is requested when the gross appearance of the liver is of concern (e.g., fatty liver), when the donor is known to have pre-existing disease (e.g., hepatitis C infection), or when an extended criteria donor graft is to be used. Examples of the extended criteria donor include advanced donor age (>60 years), donation after cardiac death (DCD), increased cold ischemia time (>12 h), moderate to severe macrovesicular steatosis (>30 %), hypernatremia, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, and a history of malignancy (Harring et al. 2011).
For frozen section evaluation of the donor liver, at least two tissue core biopsies (one from the right lobe and one from the left lobe) should be collected. A third wedge biopsy from the subcapsular right lobe may also be added in some centers. To avoid preparation and freezing artifacts, the fresh liver tissue should be moistened in preservation solution and transported immediately to the frozen section laboratory. Air drying and storage in physiologic saline should be avoided because they can cause hepatocytes to appear shrunken or necrotic. Absorbent substrates and dry tissue paper should also be avoided because they can cause the extent of steatosis to be underestimated.
Histologic findings that usually disqualify an organ for transplantation include hepatic necrosis involving >10 % of the hepatocytes, significant macrovesicular steatosis (>30 %), moderate or severe atherosclerosis of intrahepatic artery branches, and at least bridging fibrosis. Of these factors, the most commonly assessed is steatosis. There are three types of hepatic steatosis (Fig. 1): macrovesicular steatosis is defined as a single intracytoplasmic fat droplet greater than the nuclear diameter that displaces the nucleus; small droplet steatosis is defined as multiple, small fat droplets less than the nuclear diameter with a centrally placed nucleus; and true microvesicular steatosis is defined as numerous tiny lipid droplets surrounding the nucleus and imparting a foamy appearance to the cytoplasm. Many studies have shown that moderate to severe macrovesicular steatosis (>30 %) is associated with an increased risk of early graft dysfunction and failure (Briceño et al. 2009; Spitzer et al. 2010; Gabrielli et al. 2012; Chu et al. 2015). However, several recent reports question this notion, particularly when other risk factors such as cold ischemia time are absent (McCormack et al. 2007; Westerkamp et al. 2015). Small droplet steatosis is often the result of a short period of warm ischemia or other insults, and does not affect outcome (Fishbein et al. 1997). Oil red O stain may be utilized to evaluate fat content; however, the extent of steatosis can be estimated reliably by hematoxylin and eosin (H&E) stains alone, provided that all care is given to eliminating possible artifacts.
Fig. 1
Three types of steatosis in liver: (a) macrovesicular steatosis; (b) small droplet steatosis; and (c) microvesicular steatosis
Post-Transplant Needle Biopsies
Histologic assessment plays an important role in determining the cause of allograft failure/dysfunction, evaluating disease progression, and assessing the effects of therapy, thereby providing guidance for further clinical management. Similar to the guidelines for native liver provided by the American Association for the Study of Liver Diseases, in order to ensure sufficient tissue for diagnosis, an adequate transplant biopsy is best attained by two passes with a 16-gauge needle. This is especially relevant at later time periods when fibrosis can be present, since small biopsies (much smaller than 20 mm in length or <11 total portal tracts) can be subject to sampling error (Rockey et al. 2009).
Preservation/Reperfusion Injury
Preservation/reperfusion injury is a major cause of primary non-function or dysfunction of the allograft. Preservation injury occurs in two phases. The initial cold ischemia lasts less than 12 h, and occurs when the donor organ is stored in preservation fluid and placed in an ice bath. The second phase, a shorter period of warm ischemia (<120 min), results from suboptimal perfusion of the liver at body temperature before and during harvesting. Studies have demonstrated that cold ischemia mainly affects sinusoidal endothelial cells, whereas warm ischemia primarily damages hepatocytes (Schön et al. 1998). Other cell types, including bile duct cells, Kupffer cells, and Ito cells, are also very sensitive to cold and warm ischemia (Wang et al. 2011). The duration and severity of the ischemia determines the degree and type of injury. Several predisposing factors are especially important in preservation/reperfusion, including macrovesicular steatosis and DCD.
The hallmark of preservation/reperfusion injury is centrilobular (zone 3) hepatocyte ballooning, scattered acidophil bodies, and hepatocyte dropout (Fig. 2). Surgical hepatitis (perivenular sinusoidal neutrophilia without necrosis), perivenular cholestasis, and macrovesicular steatosis may also be evident. Severe preservation/reperfusion injury manifests as confluent hepatocellular necrosis, either centrilobular or panlobular, which usually results in graft failure (Fig. 2). A lack of significant portal or lobular inflammation is also characteristic.
Fig. 2
Preservation/reperfusion injury: (a) centrilobular cholestasis (arrows); (b) centrilobular hepatocyte rounding and dropout (arrow); (c) centrilobular cholestasis and hepatocyte ballooning; and (d) confluent necrosis may be seen in severe cases, causing graft failure. CV central vein, PT portal tract
Repair from preservation/reperfusion injury usually starts in 1–2 days and it is resolved within 2–4 weeks. Histologically, the resolving injury manifests as hepatocyte binucleation and repopulation of the perivenular areas, if dropout has occurred. In grafts with severe injury, brisk mitosis may be seen. Zone 3 hepatocyte ballooning and cholestasis may persist for several weeks. The differential diagnosis of preservation/reperfusion injury includes ischemia as a result of hepatic artery occlusion and hyperacute rejection.
Complications
A recent comprehensive meta-analysis of postoperative complications after liver transplantation reviewed 74 studies published between 2002 and 2012 including a cohort of 29,227 deceased donor liver transplant recipients in western countries (McElroy et al. 2014). The most common complications found include biliary complications (biliary leak and biliary stricture), vascular complications (hepatic artery thrombosis [HAT] and hepatic artery stenosis), and hemorrhage/thrombosis (portal vein thrombosis, hemorrhage, and pulmonary embolus).
Vascular Complications
Although vascular complications following liver transplantation rarely occur, they are the most feared complications due to the associated high incidence of graft loss and mortality (McElroy et al. 2014). The overall incidence of vascular complications in adults is around 7 % in orthotopic liver transplantation (OLT) and 13 % in living donor liver transplants (McElroy et al. 2014). It often occurs within the first several months post-transplantation (Pawlak et al. 2003; Piardi et al. 2016).
Hepatic Artery Thrombosis
HAT is the most common vascular complication of liver transplantation. It is associated with a high rate of graft failure (>50 %) and high mortality rate (>50 %) in the absence of revascularization and retransplantation (Piardi et al. 2016). HAT is classified into two types: early HAT (within 30 days of liver transplantation) and late HAT (30 days or more after liver transplantation). The incidence of early HAT varies from 0 % to 12 % in adults, whereas the incidence of late HAT is around 7.5 % (Piardi et al. 2016). Risk factors for HAT include surgical causes at the anastomosis, a hypercoagulable state, extended cold ischemia time, donor positivity for cytomegalovirus (CMV) in a CMV-negative recipient, retransplantation, etc.
The hepatic artery supplies the biliary tree of the transplant. Therefore, biliary complications are frequently encountered in HAT and manifest as ischemic cholangitis/cholangiopathy. The structures most susceptible to ischemic injury include perihilar soft tissue and large bile ducts, which are most often not sampled in needle biopsies, thereby make these biopsies unreliable. The peripheral biopsies show ischemic injury, such as centrilobular (zone 3) hepatocyte swelling, dropout, and frank necrosis. Ischemic hepatitis is occasionally seen with spotty hepatocyte necrosis/acidophil bodies. Biliary changes, such as ductular reaction and acute cholangitis, may also be present. When a failed explant is examined grossly, hepatic artery thrombus with occlusion is observed and the liver parenchyma shows segmental collapse and necrosis. Other possible findings include bile duct epithelial damage/necrosis, acute cholangitis, and biliary abscesses.
The differential diagnosis includes primary biliary complications alone and acute viral hepatitis (in the case of ischemic cholangitis). Doppler ultrasound and computed tomography (CT) angiogram/angiography are important imaging modalities to confirm a suspected diagnosis of HAT.
Portal Vein Complications
Portal vein complications include thrombosis, stricture, and poor flow. They are relatively uncommon, occurring in 1–3 % of transplants (Piardi et al. 2016). Portal vein complications are associated with high morbidity and graft loss and are more common in split liver, living donor transplantations, and pediatric transplantations. The clinical presentation of these complications depends on the severity of the venous flow compromise, ranging from small infarcts, seeding bacteremia, and recurrent fever to massive necrosis and fulminant hepatic failure. Diagnostic tools include Doppler ultrasound, contrast-enhanced ultrasound, and contrast-enhanced CT.
Pathologically, complete portal vein thrombosis causes massive necrosis. Partial obstruction due to smaller thrombi, strictures, kinks, or persistent collateral circulation can cause periportal or zone 2 hepatocyte atrophy and necrosis. Unexplained panlobular or zonal steatosis or nodular regenerative hyperplasia may occur, and secondary infections may also be seen.
The differential diagnosis includes hepatic vein outflow obstruction, which can also cause hepatocyte necrosis. However, the zonal distribution is different in hepatic vein complications, mainly in the centrilobular and perivenular regions, with characteristic sinusoidal dilatation, red blood cells within the space of Disse, and perivenular fibrosis. Severe cases can lead to Budd-Chiari syndrome with hepatomegaly and ascites.
Biliary Complications
Biliary complications continue to be a major cause of morbidity in liver transplant patients, with a reported incidence of 10–30 % and a mortality rate of up to 10 % (Wojcicki et al. 2008). In a recent meta-analysis following OLT recipients from 2002 to 2012, the mean incidence of the most common biliary complications, namely biliary leak and stricture, was 7.9 % and 12.5 %, respectively (McElroy et al. 2014). Other common biliary complications include sphincter of Oddi dysfunction, hemobilia, biliary obstruction from cystic duct mucocele, stones, sludge, and casts. The majority of biliary complications occur within 6 months after transplantation, one-third occurring within 1 month and two-thirds within 3 months of surgery (Wojcicki et al. 2008). Biliary complications are one of the leading causes of allograft dysfunction within the first 3 months of liver transplantation.
Patients with biliary strictures present with cholestasis and associated abnormal liver function tests (selective elevation of alkaline phosphatase [ALP] and γ-glutamyltransferase [GGT] levels), pyrexia, or septicemia with coexisting cholangitis. Symptoms may be non-specific and are often masked by corticosteroid and immunosuppressive therapy. Biliary tract problems are often first suspected on routine liver biopsies, and cholangiography (magnetic resonance cholangiopancreatography [MRCP], endoscopic retrograde cholangiopancreatography [ERCP], or percutaneous transhepatic cholangiography [PTC]) is needed to confirm the diagnosis.
Pathologically, biliary strictures in liver allograft are identical to those seen in native liver. They show a biliary outflow obstruction pattern of injury: prominent ductular reaction, pericholangitis with neutrophilic infiltration within the bile duct epithelium, or ascending cholangitis with neutrophils within the bile duct lumen (Fig. 3). Hepatocellular and canalicular cholestasis may be seen, both of which are more prominent in the centrilobular region. Portal and periportal edema are seen in the early stages, whereas mixed portal inflammation, bile duct epithelial senescence-type damage, and fibrosis may develop when the condition becomes chronic.
Fig. 3
Biliary outflow impairment. (a) Portal tract with prominent ductular reaction, mixed inflammation with lymphocytes and neutrophils, pericholangitis with associated bile duct/ductular epithelial damage, and cholestasis. Edematous stromal change is seen in the early stage. (b) Lobular inflammation and cholestasis
Rejection
Rejection is a host immune response against foreign donor antigens in the allograft. It has the potential to cause graft damage and graft failure in severe cases. The target cells involved in rejection include the bile duct epithelium and endothelial cells; hepatocytes are usually spared. Rejection is broadly divided into three main categories: humeral (or antibody-mediated) rejection, acute cellular (cell-mediated) rejection, and chronic rejection (Am J Gastroenterol 1994). In most cases, these processes reproducibly follow the time course post-transplantation: hyperacute antibody-mediated rejection occurs in the immediate post-operative period; acute cellular rejection (ACR) occurs within the first several months; and chronic rejection is a much later event. Nevertheless, there are reports that document chronic rejection within the first 3 months and ACR occurring years after transplant.
Humoral (Antibody-Mediated) Rejection
Primary humoral rejection is caused by pre-formed anti-donor antibodies in the recipient and occurs mainly in ABO-incompatible grafts. It may present as a hyperacute form within a few hours of transplantation, or as an acute form within a few days. The liver seems to have relatively high resistance to antibody-mediated injury. Thus, hyperacute rejection is rarely seen in clinical practice and when it does occur, effective therapy regimens usually transform it into a milder and delayed form that has later complications, such as increased acute rejection and late biliary strictures (Wu et al. 2011). Treatment options include plasmapheresis, splenectomy, and more aggressive immunotherapy. The employment of rituximab and mycophenolate therapies have also significantly improved the outcomes of ABO-incompatible grafts (Haberal and Dalgic 2004).
The earliest biopsy changes occur within a few hours and may show only fibrin deposition and neutrophils accumulating within sinusoids and small vessels. If left untreated, the graft may rapidly fail, and the pathologist will encounter a grossly enlarged explant with a hemorrhagic and mottled appearance. Sectioning shows extensive, geographic hemorrhagic necrosis. Microscopically, the liver parenchyma is diffusely congested and hemorrhagic with hepatocellular necrosis. Vascular thrombi and fibrinoid necrosis of blood vessels are also seen. Reperfusion injury and bile duct necrosis can also be present. A characteristic feature in this form of rejection is the lack of significant lymphocytic inflammation. Mild acute humoral rejection presents with portal edema, bile ductular reaction, and neutrophilic infiltration, reminiscent of bile duct obstruction. Deposition of C4d has been shown in sinusoids and portal vessels (Sakashita et al. 2007); however, the significance and the utility of C4d deposition in diagnosis is uncertain. A definitive diagnosis of humoral rejection requires the presence of ABO incompatibility and anti-donor antibodies.
Acute Cellular Rejection
ACR is the most common form of liver allograft rejection. It usually occurs within the first month of transplantation, but is not uncommon in the first 3–6 months. ACR is associated with many risk factors, such as pre-existing autoimmune hepatitis or hepatitis C (Carbone and Neuberger 2014). Acute rejection can also occur months and even years post-transplantation, when it is mainly associated with inadequate immunosuppression. This form of rejection is mediated by inflammatory cells, mainly activated (blastic) lymphocytes, and the target tissue includes portal areas, bile ducts, and vascular structures.
Histologically, a characteristic triad is present during ACR: mixed portal-based inflammation, lymphocytic cholangitis, and endotheliitis (Fig. 4). The portal areas contain mixed inflammatory infiltrates, which include lymphocytes, macrophages, eosinophils, and neutrophils. Rarely, plasma cells may be seen. The lymphocytes are the predominant component of the portal areas; they are composed of activated or blastic lymphocytes as well as small T cells. The activated (blastic) lymphocytes are characterized by a larger cell size and vesicular chromatin with prominent nucleoli. Variable numbers of eosinophils are almost always present, and neutrophils may also be present. The bile duct shows lymphocyte-mediated injury that is manifested by lymphocytic infiltration within the ductal epithelium and associated ductal epithelial changes, including disarray, cytoplasmic vacuolation and eosinophilia, nuclear irregularity, overlapping, pyknosis, and apoptosis. Occasionally, mild ductular reaction and periductal neutrophilic infiltration may be seen and intraluminal neutrophils mimicking ascending cholangitis are observed rarely. Endotheliitis is the third feature of ACR and involves portal and central veins. Morphologically, it is characterized by subendothelial lymphocyte infiltrates lifting up and causing detachment of the endothelial cells.
Fig. 4
Acute cellular rejection: (a) portal-based inflammation without lobular activity; (b) dense inflammation centered in the portal tract without interface activity; and (c, d, e) mixed inflammatory infiltrates are composed of lymphocytes (large, ‘blastic’), eosinophils, neutrophils, and macrophages. Bile duct injury by lymphocytes and endotheliitis (arrows) are also prominent
Two of these three features (portal inflammation, bile duct injury, and endotheliitis) are required to establish a pathologic diagnosis of ACR. A Banff grading scheme is widely used in the transplant community to grade ACR, in the form of either a descriptive grading scheme (Table 2) or a semi-quantitative Rejection Activity Index (RAI) (Table 3). A direct correlation exists between the total RAI score (rejection grade) and the risk of persistent/recurrent rejection, chronic rejection, and graft failure (Demetris et al. 2002). The total RAI scores range from indeterminate (score of 1–2), mild (score of 3–4), and moderate (score of 5–6) to severe (score >6). Most ACRs have a score <6 and respond well to increased immunosuppression. Severe ACR may cause inflammatory, necrotizing arteritis, but because it is usually located within the hilar region, it is generally not sampled on biopsy specimens.
Table 2
Banff working group criteria for acute liver allograft rejection (Adapted from Demetris et al. (1997))
Gradea | Criteria |
|---|---|
Indeterminate | Portal inflammatory infiltrates that fail to meet the criteria for the diagnosis of acute rejection |
Mild | Rejection infiltrate in a minority of the triads, which is generally mild and confined within the portal spaces |
Moderate | Rejection infiltrate, expanding most or all of the triads |
Severe | As above for mild, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and its associated perivenular hepatocyte necrosis |
Category | Criteria | Scorea |
|---|---|---|
Portal | Mostly lymphocytic inflammation involving, but not noticeably expanding, a minority of the triads | 1 |
Expansion of most or all of the triads by a mixed infiltrate containing lymphocytes with occasional blasts, neutrophils, and eosinophils | 2 | |
Marked expansion of most or all of the triads by a mixed infiltrate containing numerous blasts and eosinophils with inflammatory spillover into the periportal parenchyma | 3 | |
Bile duct | A minority of the ducts are cuffed and infiltrated by inflammatory cells and show only mild reactive changes such as increased nuclear cytoplasmic ratio of the epithelial cells | 1 |
Most or all of the ducts infiltrated by inflammatory cells. More than an occasional duct shows degenerative changes such as nuclear pleomorphism, disordered polarity, and cytoplasmic vacuolization of the epithelium | 2 | |
As above, with most or all of the ducts showing degenerative changes or focal luminal disruption | 3 | |
Venous | Subendothelial lymphocytic infiltration involving some, but not most, of the portal and/or hepatic venules | 1 |
Subendothelial infiltration involving most or all of the portal and/or hepatic venules | 2 | |
As above, with moderate or severe perivenular inflammation that extends into the perivenular parenchyma and is associated with perivenular hepatocyte necrosis | 3 |
Late ACRs (usually after 100 days, most often after 1 year) show similar histologic features to the early ACRs. However, they do have slightly different findings, such as fewer activated (blastic) lymphocytes, slightly greater interface activity, less endotheliitis, and slightly more lobular activity, which may mimic recurrent hepatidities (Banff Working Group et al. 2006). Late ACR can also manifest as isolated central perivenulitis (perivenular inflammation and hepatocyte dropout) and may develop into chronic rejection with ductopenia.
Classic ACR cases are usually diagnostically straightforward; it is the indeterminate cases that pose significant diagnostic challenges. The main differential diagnosis is recurrent hepatitis, especially in the setting of recurrent hepatitis C, with the two entities having overlapping histologic features, including portal-based mononuclear inflammation, endotheliitis, and bile duct injury. However, early recurrent hepatitis C shows more prominent interface and lobular necroinflammatory activity, only mild endotheliitis and bile duct injury, and less blastic lymphocytes.
Chronic Rejection
Chronic rejection is an immune-mediated, potentially irreversible damage to the liver allograft, especially the bile ducts, arteries, and veins. It occurs in approximately 3–5 % of patients by 5 years post-transplant (Demetris et al. 2000; Banff Working Group et al. 2006). Histologically, chronic rejection has two main features: progressive bile duct injury with subsequent ductopenia and obliterative vasculopathy involving large- and medium-sized arteries. The latter is not usually seen in biopsy material, and the former is the most commonly identified finding in chronic rejection. Therefore, chronic rejection is also referred to as chronic ductopenic rejection or vanishing bile duct syndrome (Table 4).
Structure | Early chronic rejection | Late chronic rejection |
|---|---|---|
Small bile ducts | Bile duct loss in <50 % of portal tracts Degenerative and atrophic changes in the majority of the ducts (cytoplasmic eosinophilic change, nuclear overlapping, hyperchromasia, uneven nuclear spacing, nuclear loss, with epithelial attenuation) | Bile duct loss in at least 50 % of portal tracts Degenerative changes in remaining ducts |
Central veins and zone 3 hepatocytes | Intimal/luminal inflammation, zone 3 necrosis and dropout, mild perivenular fibrosis | Focal obliteration with variable inflammation, severe fibrosis including bridging fibrosis |
Hepatic arterioles | Loss of hepatic arterioles in <25 % of the portal tracts | Loss of hepatic arterioles in >25 % of the portal tracts |
Large perihilar hepatic artery branches | Intimal inflammation, focal foam cell deposition without luminal compromise | Luminal narrowing by suboptimal foam cells, fibrointimal proliferation |
Large perihilar bile ducts | Periductal inflammation, injury and focal foam cell deposition | Mural fibrosis |
Lobules | Spotty hepatocyte necrosis (‘transitional hepatitis’) | Marked cholestasis, clusters of foamy macrophages |
In a biopsy specimen, the minimum diagnostic criteria for chronic rejection are (1) biliary epithelial senescence or degenerative changes affecting a majority of the bile ducts with or without bile duct loss; or (2) foam cell obliterative arteriopathy; or (3) bile duct loss affecting >50 % of the portal tracts (Banff Working Group et al. 2006). Bile duct epithelial senescence or degenerative-type changes include an eosinophilic cytoplasm with irregular, enlarged, and overlapping nuclei that mimicks a dysplasia-type appearance. Some small bile ducts may be only partially lined by biliary epithelial cells, a finding that is thought to precede frank duct loss. Perivenular hepatocyte dropout and central perivenulitis are typical of early chronic rejection (Fig. 5). When ductopenia (defined as loss of interlobular bile ducts in more than 50 % of the portal tracts) is present, there is usually a lack of inflammation as well as a bile ductular reaction (Fig. 5). In difficult cases, a CK7 immunostain may help delineate the bile ducts and secure the diagnosis. As stated earlier, the obliterative arteriopathy involves medium- to large-sized arteries; however, inflammatory or foam cell lesions may be seen in portal or hepatic venules, causing luminal fibrous obliteration.
Fig. 5
Chronic rejection: (a, b) early chronic rejection with portal inflammation and bile duct injury, without endotheliitis; and (c, d) late chronic rejection with ductopenia (absence of bile duct in a portal tract in d)
Recurrent Diseases
Almost all primary liver diseases recur after transplantation, although the incidence and time course varies according to each disease entity. Recurrence may pose a significant risk for long-term graft dysfunction, even graft loss. Liver biopsy is an important diagnostic tool in the evaluation of disease recurrence and activity (Table 5).
Table 5
Recurrent diseases
Disease | Incidence (%) | Diagnostic tests | Timinga | Histologic similarity to native liver disease |
|---|---|---|---|---|
HCV | 60–100 | Biopsy HCV RNA does not correlate accurately with histology | 6–8 weeks, can be as early as 10 days | Similar to native liver; acute hepatitis more often identified due to careful monitoring |
HBV | <10 | Viral DNA, serology; serum DNA used to monitor recurrence and therapy | 6–8 weeks, can be as early as 10 days | Similar to native liver |
AIH | 30 | Autoantibodies | >6 months | Similar to native liver |
PBC | 20–30 | Biopsy | >1 year | Similar to native liver |
PSC | 30 | Cholangiogram | Usually >1 year | Similar to native liver |
NASH | 20–40 | Biopsy | Similar to native liver | |
ALD | 5–30 | Biopsy, serum carbohydrate deficient transferrin | Similar to native liver |
Hepatitis C Virus Infection
HCV infection recurs universally in liver transplant recipients (deLemos et al. 2014; Dumortier et al. 2014). Although the natural history is variable, 80 % of HCV patients develop recurrence on histologic evaluation within 5 years after liver transplant (Dumortier et al. 2014). In recurrent HCV infection, patients develop cirrhosis more rapidly (20–30 % by 5 years post-transplant), with an accelerated rate of decompensation (>40 % at 1 year and >70 % at 3 years post-transplant vs. <5 % and <10 %, respectively, in immunocompetent patients). There is also an accelerated rate from decompensation to death (3-year survival of <10 % following the first decompression vs. >60 % in immunocompetent patients) (Dumortier et al. 2014). Early (1 year) post-transplant biopsy has been shown to have prognostic value for graft cirrhosis (Gane et al. 1996; Prieto et al. 1999; Firpi et al. 2004) and survival (Neumann et al. 2004). Therefore, a 1-year post-transplant protocol biopsy is essential for every liver transplant recipient.
Risk factors for poor prognosis in the recurrent HCV graft include donor age (over 40–50 years), viral factors (HCV genotype 1, high level of pre-transplant HCV RNA, HCV RNA 4 months post-transplant ≥1 × 109 mEq/mL), concurrent CMV or HIV infections, recipient characteristics (female, African American, metabolic syndrome, IL28B non-CC genotype), and immunosuppression (use of corticosteroids, sirolimus, and OKT3) (Dumortier et al. 2014).
Recurrent hepatitis C can be classified into three categories: early acute hepatitis; late chronic hepatitis; and unusual variants, including fibrosing cholestatic hepatitis (FCH) and the plasma cell-rich variants.
Acute Recurrent Hepatitis C
The onset of acute recurrent hepatitis C is generally within 4–12 weeks after transplant, with the earliest recurrence being detectable between days 9 and 14 post-transplantation (Saraf et al. 2007; Demetris 2009). Acute recurrent hepatitis C shares similar histopathologic findings as those of native livers, including prominent lobular hepatitis with little or no portal tract involvement. Lobular hepatitis features hepatocyte disarray, apoptosis (Councilman bodies or acidophil bodies), Kupffer cell hypertrophy, and mild sinusoidal lymphocytosis. A greater number of the apoptotic bodies are more indicative of recurrent hepatitis C than of ACR (Saxena et al. 2002).
Chronic Hepatitis C
Chronic hepatitis C is usually evident in the 6–12 months post-transplantation and has similar histologic findings as in the native liver, with portal-based lymphocytic inflammation, lymphoid aggregates, interface activity, and lobular necroinflammatory activity. Lymphocyte-mediated bile duct injury, ductular reaction, as well as perivenulitis and endotheliitis may be seen, but are usually mild and affect only a few portal tracts (Fig. 6). Since these features are also present in ACR, the extent and severity are key to making the correct diagnosis. Similar to the native liver, grading for activity and staging for fibrosis is required for recurrent disease, and the Batts and Ludwig grading system is widely used (Batts and Ludwig 1995).
Fig. 6
Recurrent chronic hepatitis C: the usual variant. (a) Portal inflammation with interface activity and mild lobular activity. (b) Portal inflammation composed of predominantly small mature lymphocytes, with no bile duct injury or endotheliitis. (c) Trichrome stain shows bridging fibrosis
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