Role of Histology Following Pediatric Liver Transplantation


This chapter will briefly consider the examination of the recipient’s liver, removed at transplantation, and then focus on the role of the pathologist in the interpretation of the liver allograft biopsy.

Complications following liver transplantation have been described in other chapters of the text, as summarized in Fig. 24.1 . Biopsy manifestations of these complications are comprehensively addressed elsewhere and will be described here with an emphasis on the pediatric setting. It is stressed that biopsy alone is rarely sufficient to identify the precise cause of graft injury. This requires multidisciplinary communication and integration with other diagnostic modalities. It should also be remembered that damage to a graft can be multifactorial, and therefore the biopsy may reflect more than one complication. In cases where more than one etiological factor is present, liver biopsy can help to identify the predominant cause of graft injury.

Fig. 24.1

Overview of post-transplantation complications that may have manifestations in the liver biopsy. Complications are not mutually exclusive.

Practical Considerations

In the context of early post-operative complications, biopsies are taken with a clinical indication rather than as a protocol procedure. The pathologist cannot answer the clinical question if they do not know what the question is! The request form must say more than “abnormal liver function tests post–liver transplant.” Date of, and indication for, transplantation and the reason for the biopsy are minimum requirements if the biopsy is going to contribute to effective management and justify the risk to the patient of taking it. Major complications of biopsy may be less than 1%, but this cannot be ignored. Timing is important; it is very difficult to interpret findings after blind treatment of suspected rejection, for example.

Histopathology of the Recipient Liver

The first role the pathologist has following liver transplantation is the examination of the recipient’s own liver, sometimes referred to as the “explant.” Defining the original disease is important for future management because some conditions can recur in the graft. Discovery of an unsuspected hepatocellular carcinoma (HCC) in a background of cirrhosis is less frequent in pediatric, as compared with adult, practice but remains an important consideration. The liver explant should be finely sliced to discover any dominant nodules. Certain pediatric conditions do predispose to HCC, for example, tyrosinemia and ATPB11 disease (bile salt export pump [BSEP] deficiency/progressive familial intrahepatic cholestasis type 2). Particular care should be taken in these settings to identify and sample all nodules that stand out from the cirrhotic background. Many of these will transpire to be regenerative/dysplastic nodules, but some may be HCCs. The distinction between pre-neoplastic and neoplastic nodules in the cirrhotic liver may be difficult. Among other criteria, features favoring a diagnosis of HCC include reticulin fiber depletion and diffuse CD34 expression on sinusoidal endothelium. Young adults with primary sclerosing cholangitis are occasionally only discovered to have hilar cholangiocarcinoma once the explant is examined after transplantation; the hilum should therefore be extensively sampled in these patients.

Post-Reperfusion Biopsies

In some centers, a post-reperfusion biopsy of the newly implanted liver (also referred to as a “time zero” biopsy) accompanies the explant. Examination of this specimen provides a baseline and may also occasionally reveal an unsuspected liver disease in the donor. Iron deposition related to genetic hemochromatosis and globules of alpha 1 antitrypsin are occasionally seen in this setting. Large-droplet macrovesicular steatosis is a more frequent donor-related lesion and is discussed further in the preservation/reperfusion injury section.

Technical Complications

Under this heading are conditions arising from the logistics and practicalities of transplantation, including procurement, transport and preservation, and the necessity of anastomoses of venous inflow and outflow, hepatic artery, and bile duct. There is an imbalance between the number of children awaiting transplantation and the availability of size-matched donors. Children may therefore be in receipt of a reduced or split graft, the single lobe transplanted in the living related donor setting, for example.

Small-for-Size Syndrome

This occurs when the allograft liver volume is insufficient for the recipient and presents as early dysfunction or non-function of the graft, often with ascites. Small-for-size grafts have an inferior outcome in children. The postulated mechanism is portal venous hyperperfusion and reactive arterial vasospasm. Endothelial denudation of portal veins and hemorrhage into portal areas may be a clue to this in early biopsies. Later changes can occur secondary to arterial compromise, including ischemic cholangiopathy, which may lead to biliary manifestations in the peripheral liver biopsy, or an obliterative portal venopathy may develop with nodular regenerative hyperplasia. At this stage, the pathologist would not be able to implicate “small for size” specifically as the mechanism of damage.

Preservation/Re-Perfusion Injury

The liver graft is subjected to periods of both warm and cold ischemia: warm ischemia occurs during implantation and, for living related and donation after circulatory/cardiac death settings, during retrieval; cold ischemia occurs while the donor liver is “on ice” during transport. These have consequences for hepatocytes and endothelial cells, respectively, and both are further stressed by reperfusion post-implantation. Donor factors, principally large-droplet macrovesicular steatosis, can exacerbate the damage. In general, biopsies at “time zero” after implantation show features of glycogen depletion, canalicular cholestasis, and clustering of neutrophils in sinusoids. Hepatocytes are often pale or “ballooned” ( Fig. 24.2 ). A grading scheme for ischemia-reperfusion injury (IRI), based mainly upon neutrophil numbers and the presence/severity of hepatocyte necrosis, showed that severe IRI (defined by the presence of zonal or confluent hepatocyte loss) was an independent risk factor for graft loss by 1 year, suggesting that the histological assessment of these specimens may be useful for prognosis.

Fig. 24.2

Preservation/reperfusion injury (PRI). This “time zero” postimplantation biopsy shows canalicular cholestasis (examples within boxes). This lesion is not specific to PRI; it can persist for up to 10 days. Early-allograft biopsies often show ballooned hepatocytes, as demonstrated in the inset on the bottom left. In the pediatric setting, large-droplet macrovesicular steatosis as a donor-related lesion is usually very mild (arrows) .

“Marginal” or “extended criteria” donors, where there are known risk factors for subsequent poor graft function, are used less in the pediatric setting. Large-droplet macrovesicular steatosis, where the fat vacuole displaces the hepatocyte nucleus to the periphery of the cell as a donor-related lesion, is a factor related to poor graft outcome. In children, this would be expected to be rarely more than minimal and to quickly resolve. Small-droplet macrovesicular steatosis, where the hepatocyte nucleus is not displaced, does not seem to influence graft function and may even be part of preservation/reperfusion injury. It should be noted that the latter type of fatty change is sometimes referred to as microvesicular in this setting, but this term is best reserved for the rarely observed foamy-type fatty change in hepatocytes seen in metabolic conditions such as mitochondrial cytopathies, for example.

The pathologist can also comment upon any unsuspected disease in the donor at this point in the patient journey.

Primary Non-Function

Various descriptors are used for poor function early posttransplantation defined by clinical/biochemical/coagulation factors. The most severe manifestation is primary non-function (PNF) leading to graft failures and the need for retransplantation. This typically arises during the first 24 to 28 hours following transplantation. PNF should be regarded as a diagnosis of exclusion, and the term should only be used if there are no other identifiable reasons for early graft failure. Preservation/reperfusion injury is high among postulated causes. Liver biopsies are rarely obtained in this setting because of problems with poor blood clotting, and pathological observations are thus largely restricted to failed allografts obtained at re-transplantation. These specimens frequently contain large areas of ischemic-type coagulative necrosis, which have an irregular “geographic” pattern resembling continents on a map.

Vascular Complications

Hepatic artery, portal, and hepatic veins are all subject to manipulation and anastomosis during transplantation. The technical challenges are considerable and, although included here under “technical complications,” it should be remembered that recipient factors are important in some cases. In a series of 46 pediatric liver transplants, all cases of vascular thrombosis were associated with an unsuspected thrombophilic tendency in the recipient.

The most dramatic injury seen when blood flow is compromised is with hepatic artery thrombosis (HAT). This is more common in children than adults, particularly where there is a low graft-to-recipient weight ratio (< 1.1%), and is a focus for dissemination of best practice. Very early HAT gives rise to areas of ischemic necrosis similar to that described in PNF. Because this process is patchy, a peripheral liver biopsy is unlikely to be representative of the whole liver, and the pathologist rather is often presented with the entire graft following retransplantation.

HAT of later onset or longer duration may show a different pattern; as the bile ducts derive their oxygenation entirely from the artery, occlusion causes biliary ischemia (ischemic cholangiopathy). In more severe cases, abscesses form at the location of the ischemic ducts ( Fig. 24.3 ). Some cases may have a more insidious presentation, perhaps because of the development of collaterals. An important pattern for the pathologist to recognize is of biliary features, similar to those expected with large bile duct obstruction. The changes seen can include sclerosing bile duct lesions—a form of secondary sclerosing cholangitis.

Fig. 24.3

Hepatic artery thrombosis. This allograft needed to be replaced early post-transplantation. Abscesses have formed at the site of ischemic bile ducts. Inset panels from different cases on the right show organized thrombus occluding the lumen of a hepatic artery branch above. The lower panel demonstrates an arterial dissection; hemorrhage is seen into the media, internal to the black ring of the external elastic lamina.

Obstruction of venous outflow is associated with characteristic findings in the biopsy of perivenular congestion and red cells pushed into the space of Disse. Affected plates are compressed on a reticulin stain, and there may be perisinusoidal fibrosis. The obstruction to flow can be in small hepatic veins—these may be seen as venoocclusive lesions in biopsies, where they raise the differential diagnosis of a drug reaction, or at the level of the large hepatic veins, where they are anastomosed to the inferior vena cava. Different techniques are employed and debated for this anastomosis; venogram is superior to ultrasound for the detection of outflow obstruction. In some cases of venous outflow obstruction resulting from the “piggyback syndrome,” outflow obstruction is aggravated by an upright posture and may not be detected radiologically when the patient is lying flat—the pathologist may be the first to suggest the diagnosis in this situation.

Portal venous inflow problems give rise to subtle changes in the parenchyma of nodular regenerative hyperplasia; portal vein branches may be either lost or dilated in portal tracts. Changes in the biopsy might be described as “subtle vascular/venous flow related” without it being possible to identify the specific site of abnormality but prompting the team to investigate large vessels.

Biliary Complications

Biliary complications take the form of leaks, strictures—either anastomotic or non-anastomotic and casts (sludge/stones). The risk of developing these complications is higher in children, likely attributed to the frequent use of reduced grafts in this population, and in recipients of a poorer-quality graft—“extended criteria” donors. Incidences of 23% and 14.5% have been described in pediatric recipients, the latter relating specifically to donation from a living donor. Radiologically stenosed and distally dilated ducts may be demonstrated. Dilated ducts on an ultrasound are a fairly late manifestation. Therefore, the pathologist may be in a position to suggest a biliary problem before this time, and more sensitive imaging techniques may be appropriate ( Fig. 24.4 ). The precise nature of the complication affecting large bile ducts—a technical problem with an anastomosis or ischemia, for example—cannot be determined from a peripheral liver biopsy.

Fig. 24.4

Biliary features are illustrated here as can be seen in cases of large bile duct obstruction/anastomotic stenosis and also in ischemic cholangiopathy where the primary disease may have been arterial occlusion. The cellularity in the portal tract, top left, is caused by biliary ductules rather than inflammatory cells. The ductules can be highlighted with immunohistochemistry for cytokeratin 7 ( bottom left ). Identification of periportal copper (as seen top right on a rhodanine stain ) or copper-associated protein is a useful early clue to biliary disease. The biopsy on the bottom right included part of an ulcerated bile duct—most likely of ischemic etiology.

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Feb 23, 2021 | Posted by in HEPATOPANCREATOBILIARY | Comments Off on Role of Histology Following Pediatric Liver Transplantation

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