Biliary Atresia

Portal-based changes of biliary obstruction in biliary atresia are not specific for biliary atresia, and they develop over time. In particular, early biopsies may not demonstrate definitive changes of extrahepatic biliary obstruction. Furthermore, other important causes of biliary obstruction pattern such as choledochal cyst, α1-antitrypsin deficiency, total parenteral nutrition–induced injury, and others are often histologically indistinguishable from biliary atresia. Liver biopsy is >90% sensitive in documenting the obstructive features of biliary atresia; however, because specificity is relatively low, some centers have bypassed preoperative biopsy for the definitive test—intraoperative cholangiogram. This trend of bypassing liver biopsy is likely to continue because treatment outcomes are better with decreasing infant age at the time of surgery; at the same time, histology is less reliable in the youngest patients.

α1-Antitrypsin Deficiency

α1-antitrypsin deficiency (A1ATD) is another cholestatic liver disease that can be a diagnostic challenge in young infants. The histology may be variable, but most commonly demonstrates a portal-based picture of biliary obstruction. Alternatively, A1ATD may also demonstrate a neonatal hepatitis pattern of injury. The pitfall is that the diagnostic A1AT inclusions may not be well developed until the patient is 12 weeks of age or older. The A1AT globules are located in the cytoplasm of the periportal hepatocytes. The globules can be seen on hematoxylin and eosin (H&E)–stained sections as slightly darker cytoplasmic inclusions ( Figure 66-6 ), but are typically nicely accentuated by periodic acid–Schiff stain after diastase digestion (PAS/D; Figure 66-7 ). A1AT globules, thus, are PAS positive and diastase resistant. Diastase is important because glycogen that fills all hepatocytes also stains positively with PAS, but glycogen is diastase sensitive. A1ATD is an autosomal recessive disorder, so patients that are heterozygous for the A1AT mutant allele also may show accumulation of A1AT globules in the cytoplasm of periportal hepatocytes. On a case-by-case basis, homozygous A1ATD cannot be distinguished from heterozygous mutation with use of pathology alone. That said, the heterozygous patients tend to harbor smaller, more granular-appearing globules rather than the larger space-occupying ones seen in homozygous deficiency.

Hematoxylin and eosin–stained section revealing innumerable eosinophilic inclusions in the cytoplasm of hepatocytes.

The same area of liver as in Figure 66-6 with periodic acid–Schiff (PAS) staining after diastase digestion. The cytoplasmic inclusions are PAS-positive and diastase-resistant, consistent with α1-antitrypsin inclusions.

Total Parenteral Nutrition–Induced Liver Injury

Total parenteral nutrition (TPN)–induced liver disease is another cause of cholestatic/obstructive pattern of injury. Accumulation of fat with or without steatohepatitis may be part of the pathologic spectrum of disease. The incidence of TPN-induced liver disease is higher in children (especially infants) than in adults. Most studies in infants tend to report progression of liver disease (i.e., fibrosis) with duration of TPN; however, others have not found severity of disease to depend on the duration of TPN. Cholestasis may occur within 2 weeks, and cirrhosis has been reported in at little as 3 months.

When confronted with a liver biopsy demonstrating cholestasis and features of biliary obstruction, a compatible history is needed to determine that the injury is derived from TPN. That said, a recent series of TPN-related liver disease found that ductopenia and perivenular fibrosis in addition to features of cholestasis/obstruction are characteristic of TPN-related liver disease.

Idiopathic Neonatal Hepatitis

Idiopathic causes used to make up the majority of cases of neonatal cholestasis; however, as the clinical, laboratory, and molecular spectrum of other neonatal cholestatic diseases have been increasingly defined, idiopathic neonatal hepatitis as a diagnosis is a term used less often. Nevertheless, as suggested by a recent series, the most common cause of neonatal giant cell hepatitis pattern on liver biopsy is idiopathic (49% of cases), with hypopituitarism (16%), biliary atresia (8%), Alagille syndrome (6%), and bile salt defects (6%) being other important associations. It is important for the clinician not to assume that the patient has the “idiopathic” form until many other possibilities have been excluded. That said, the most common cause of neonatal giant cell hepatitis remains unknown.

Hypopituitarism

Panhypopituitarism may be the most “diagnosable” form of giant cell hepatitis. Bile duct hypoplasia may be more common in these patients than in other patients with giant cell hepatitis, but there is no ductopenia to suggest a disorder of bile duct paucity as in Alagille syndrome. Follow-up data are limited in these patients, but one series of nine infants found that cholestasis began at a median age of 13 days of age with median age at diagnosis of 1.4 months. γ-Glutamyl transferase (GGT) levels were elevated in only two of nine patients, so pituitary deficiency is in the differential diagnosis of low GGT neonatal cholestasis (see subsequent text). Cholestasis resolved with treatment at a median of 88 days, and no cases of cirrhosis were reported.

Normal/Low GGT Disorders

Progressive Familial Intrahepatic Cholestasis Type 2 (PFIC-2)

Progressive familial intrahepatic cholestasis type 2 (PFIC-2), has been renamed bile salt export pump disease because the disease-causing mutation ( ABCB11 ) encodes a bile salt export pump. The bile salt export pump (BSEP) is expressed only in liver. Patients usually present with cholestasis in the neonatal period with a paradoxically low or normal GGT level. Aminotransferase levels are often quite elevated, and progression to cirrhosis is fairly rapid, usually requiring transplantation. Giant cell hepatitis with little inflammation is the most characteristic pattern in early biopsies of patients with BSEP disease ( Figure 66-10 ). However, a recent study found variable histology beyond hepatocellular cholestasis. Electron micrography reveals characteristic amorphous bile. Immunohistochemistry can be a useful adjunctive in the diagnosis, as there are commercially available antibodies that target the BSEP. Not all mutations cause loss of antigen expression, so loss of BSEP by immunohistochemistry is much more meaningful than intact expression. Disease may recur after liver transplantation.

This biopsy from a patient with progressive familial intrahepatic cholestasis 2 ( ABCB11 disease) reveals canalicular cholestasis (short arrows) as well as scattered giant cell hepatocytes (long arrow) and mild lobular disarray (i.e., cholestatic hepatitis).

Progressive Familial Intrahepatic Cholestasis Type 1 (PFIC-1)

Progressive familial intrahepatic cholestasis type 1 (PFIC-1), formerly Byler disease, has been renamed FIC1 deficiency after the protein (FIC1) that is encoded by the disease-causing mutations in the gene ATP8B1. FIC1 functions as a phospholipid flippase that transfers phosphatidylserine from the outer cell membrane to the inner membrane. There is a disease spectrum under the umbrella of FIC1 deficiency, all of which are inherited in an autosomal recessive manner. Benign recurrent intrahepatic cholestasis (BRIC) is on the indolent side of this spectrum, so it rarely necessitates liver pathology input. Severe forms of FIC1 deficiency tend to present with cholestasis in the first year of life with progressive fibrosis. Cirrhosis occurs at a variable rate. FIC1 protein is also expressed on other organs such as intestines and pancreas, so these patients may also demonstrate other organ-specific problems such as diarrhea, malabsorption, failure to thrive, and sensorineural hearing loss. GGT levels are typically normal or low, whereas bile acids are markedly elevated.

Pre-cirrhotic histologic changes are characterized by so-called “bland” cholestasis, namely lobular cholestasis without any other significant pathologic findings such as features of biliary obstruction, inflammation, or giant cell hepatitis ( Figure 66-11 ). From the time of the original Byler disease descriptions, the unique qualities of bile have been described, and the term “Byler bile” was introduced shortly thereafter. On light microscopy, the bile in FIC1 deficiency is pale gray rather than green-brown as in other cholestatic disorders. On electro­microscopy, the bile has a characteristic coarse granular quality, although this is evident only on tissue that has not undergone formalin fixation with paraffin embedding. If patients require liver transplantation, they are at risk for hepatic steatosis, steatohepatitis, and even cirrhosis.

Wedge biopsy from a patient with progressive familial intrahepatic cholestasis 1 ( ATP8B1 disease) reveals canalicular cholestasis (arrows) that is paler than normal.

Sepsis

About half of neonates with bacterial septicemia will demonstrate liver enzyme abnormalities, most commonly stemming from cholestatic jaundice, but these numbers may be reflective of gram-negative septicemia alone. For instance, one study found that gram-positive septicemia caused liver enzyme abnormalities in only about 13% of neonates, compared to 46% with gram-negative sepsis. Cholestasis usually manifests a few days after onset of sepsis, and, in most surviving patients, the bilirubin normalizes within 1 to 2 months. Rarely, the direct bilirubin goes beyond 15 mg/dL in septic patients. Cholestasis of sepsis with or without hemolysis may manifest as bland cholestasis (lobular or canalicular cholestasis without other specific features), but the classic finding of cholestasis of sepsis is so-called “cholangitis lenta,” whereby the cholestasis is present within periportal areas and bile ductules (without other features of biliary obstruction). This finding is probably more common in the setting of autopsy liver pathology, as it is more often seen in severe systemic disease.

Defining Ductopenia

According to the most thorough study of its kind, the “average” adult portal tract harbors 2.6 hepatic artery profiles, 2.3 bile duct profiles, and 0.7 portal vein profiles. Ninety-three percent of portal tracts (±6%) contain at least one bile duct profile. Using 2 standard deviations (SD) as a convention of “normal,” bile duct loss (i.e., reduced numbers of bile ducts) can be defined as 80% or fewer portal tracts containing a bile duct profile. The literature has arbitrarily defined ductopenia as 50% or less portal tracts harboring a bile duct profile. Similarly, Alagille defined paucity as 40% or less portal tracts containing a bile duct profile. There are some caveats to these definitions, however. First, most authorities have suggested a minimum number of portal tracts that need to be evaluated in order to be confident that the bile duct counts are an accurate representation of the patient’s liver. The problem is that there are numerous opinions as to what constitutes the adequate number, ranging from 5 to 20. In reality, there is no magic number, and the more portal tracts evaluated, the greater chance the pathologist has at making an accurate interpretation. Second, infants of less than 38 weeks gestation have fewer bile ducts, so their bile duct–to–portal tract ratios may be lower.

Alagille Syndrome

Although originally described as a hepatic disease, hepatic involvement by Alagille syndrome is highly variable. That said, 95% of patients with Alagille syndrome have cholestasis in the neonatal period, although this is often mild and not clinically relevant. In severe cases, the cholestasis is accompanied by marked elevations of transaminases and GGT levels. Liver biopsy may show a giant cell hepatitis pattern with lobular cholestasis. Ductopenia is the hallmark of the syndrome ( Figure 66-12 ), but duct loss may not be identified in early biopsies, so additional biopsies may be warranted later in life.

This representative portal tract in a patient with Alagille syndrome lacks an interlobular bile duct. Interlobular bile ducts run in pairs with hepatic arteries (arrows), but in this case, no bile ducts are identified adjacent to the artery profiles.

The distinction between Alagille and biliary atresia is critical, and there may be a mild obstruction-like histologic picture in some biopsies from Alagille patients. It has been shown that Alagille patients undergoing the Kasai procedure do not fare as well as Alagille patients who do not receive a Kasai. Features supporting Alagille include bile duct loss, lack of fibrosis, and patent extrahepatic biliary tree. In addition, identifying other clinical features of Alagille such as cardiac anomalies, posterior embryotoxon of eye, butterfly vertebrae, and renal dysfunction or lesions also supports the diagnosis of Alagille syndrome. Finally, progressive fibrosis occurs only in a minority of Alagille patients, and those who progress to cirrhosis are older children. On the contrary, untreated biliary atresia patients universally progress to cirrhosis and death, usually before 2 years of age.

Nonsyndromic Bile Duct Paucity

A variety of etiologies have been postulated to cause loss of interlobular bile ducts, including infections, metabolic disorders, structural disorders, toxic insults, and chro­mosomal abnormalities; however, most causes remain idiopathic. Duct loss and ductopenia have been asso­ciated with a laundry list of medications, including many common antibiotics such as amoxicillin–clavulanic acid, ampicillin, trimethoprim–sulfamethoxazole, erythromycin, and ciprofloxacin. Ibuprofen and oral contraceptives are also common medications that have been associated with bile duct loss. Usually, the duct loss/injury stops and even reverses upon cessation of the medication, but, on occasion, the changes are irreversible and even progressive.

Chronic Hepatitis

Chronic hepatitis is a pattern of histologic injury characterized by predominantly portal-based chronic inflammation and fibrosis ( Figure 66-13 ). The portal inflammation is usually dominated by lymphocytes and plasma cells and characteristically spills into the periportal hepatocytes (so-called interface activity or interface hepatitis). Lobular inflammation with hepatocyte injury ranging from spotty necrosis (acidophil or apoptotic bodies) to broad zones of hepatocellular collapse also typically is present in chronic hepatitis. Because chronic hepatitis is a pattern of injury, multiple different causes can appear histologically similar, and clinical and serologic features are often required for a more definitive diagnosis.

Low-magnification view of a patient with chronic hepatitis, which could be secondary to autoimmune injury, chronic viral hepatitis, drug, and others. The portal-based inflammation is composed of small blue cells and is centered on the interface between the portal tract and the periportal hepatocytes (i.e., interface activity). The hepatic lobules are only mildly inflamed.

Liver biopsies demonstrating chronic hepatitis usually come to the laboratory for one of two reasons—first, to assess liver enzyme abnormalities of unconfirmed cause and, second, to provide histologic grading and staging of known chronic hepatitis. There are a variety of grading and staging schema for chronic hepatitis, but they all aim to accomplish the same goal via a semiquantitative scale: to convey degree of inflammatory injury (i.e., grade) and amount of fibrosis (i.e., stage). Grade is assessed on two features—interface activity and lobular hepatocyte injury. Stage in chronic hepatitis progresses from the portal tracts, to the periportal regions, to other portal tracts and central veins (i.e., bridging fibrosis), to cirrhosis, which is defined as diffuse fibrosis and regenerative nodule formation.

Autoimmune Hepatitis

Histology remains a major criterion in the diagnosis of autoimmune hepatitis, although on a case-by-case basis it may be impossible to differentiate autoimmune hepatitis from other causes of chronic hepatitis. There are some histologic clues to the diagnosis of autoimmune hepatitis, however ( Figure 66-14 ). First, plasma cell infiltrates may be prominent and form dense sheets in autoimmune hepatitis. Dense plasma cell infiltrates are uncommon in other causes of chronic hepatitis in children, but are also found in entities such as acute hepatitis A infection and primary biliary cirrhosis. Another histologic clue to the diagnosis of autoimmune hepatitis is the presence of advanced fibrosis, even on initial diagnostic biopsy. Autoimmune hepatitis often smolders in the patient for years prior to the discovery of liver enzyme abnormalities or other indicators of chronic liver disease. Finally, autoimmune hepatitis often presents with disease of severe activity, characterized by broad zones of hepatocellular necrosis (i.e., bridging hepatocellular necrosis). In these instances of marked activity, it is often difficult to be certain about the degrees of fibrosis in the patient—it is very easy to “overcall” bridging fibrosis or cirrhosis in the setting of marked reticulin collapse. On trichrome, the areas of collapse tend to stain paler blue than the vibrant blue of collagen fibrosis. Autoimmune hepatitis is often difficult to diagnose posttreatment. Ideally from a pathologist’s standpoint, if clinically appropriate and a promptly peformed biopsy, consideration may be given to delaying initiation of steroid treatment until after diagnostic biopsy unless the patient has an acute presentation. Similarly, autoimmune hepatitis may “burn out” at end stage, and the characteristic histologic features may no longer be present.

Liver biopsy revealing characteristic portal changes in autoimmune hepatitis. The inflammatory infiltrate is centered on the interface between the portal tract and the periportal hepatocytes and is rich in plasma cells. The inflammation typically spares the interlobular bile ducts.

Chronic Viral Hepatitis

Laboratory methods of diagnosis are so robust that rarely, if ever, is a liver biopsy performed to establish a diagnosis of chronic viral hepatitis in the pretransplantation setting. On the other hand, liver biopsies are obtained regularly in patients with chronic viral hepatitis to assess fibrosis stage. Most chronic viral hepatitides are caused by chronic hepatitis B or C virus infection. Biopsies are particularly common in patients with chronic hepatitis C virus infection, when the patient and their hepatologist are considering interferon-based therapy. As in all chronic hepatitides, the usual findings in liver biopsies are not specific. That said, hepatitis C virus infection tends to be associated with portal-based lymphoid aggregates, fat deposition in the lobules (especially genotype 3). In addition, hepatitis C infection may be associated with lymphocyte-mediated injury of the interlobular bile ducts. Chronic (not acute) hepatitis B infection may induce characteristic changes in the cytoplasm, known as “ground glass” hepatocytes ( Figure 66-15 ). Ground glass morphology is not specific for hepatitis B virus infection, however, as immunodeficiency states, drug-induced changes, glycogen storage disease IV, and other conditions may look morphologically identical to hepatitis B–related ground glass change.

Chronic hepatitis B virus infection may demonstrate so-called “ground glass” hepatocytes due to an abundance of hepatitis B virus surface antigen within the cytoplasm/smooth endoplasmic reticulum. This photomicrograph contains many of such hepatocytes, a few of which are demarcated with arrows.

Wilson’s Disease

The pathology of Wilson’s disease has been reported as variable, but can usually be characterized as one of two patterns—steatosis/steatohepatitis or chronic hepatitis. Given that these two patterns are common findings in the setting of all chronic liver disease, Wilson’s disease must be remembered and considered in many pediatric liver biopsies. Ironically, copper staining by histochemical methods plays little role in the workup of a liver sample with suspected Wilson’s disease. Rather, assessment of hepatic copper content by dry weight is a much more sensitive and specific test, and it is the primary job of the pathologist to advise this test in just about any fatty liver or chronic hepatitis biopsy in young patients. However, an important pitfall is that chronic biliary diseases such as primary sclerosing cholangitis may cause increased hepatic copper content. In fact, hepatic copper content in disorders of chronic cholestasis can reach those levels typical of Wilson’s disease.

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis is not a chronic hepatitis, per se, but may induce chronic hepatitis–like changes, particularly in early stage disease. There are two main forms of primary sclerosing cholangitis—large duct and small duct. Large duct primary sclerosing cholangitis rarely comes to the pathology laboratory for a definitive diagnosis, as imaging modalities are the gold standard for diagnosis. However, a subset of primary sclerosing cholangitis affects only the ducts that are not visible on imaging, and liver biopsy may be helpful in establishing the diagnosis. A portion of patients with sclerosing cholangitis will also harbor autoimmune clinical markers and demonstrate histologic features of autoimmune hepatitis—so-called overlap syndrome. The characteristic lesion of primary sclerosing cholangitis (small duct or large duct) is fibroobliteration of the interlobular bile duct. The ducts tend to range from unaffected to injured with periductal fibrosis (“onion skinning;” Figure 66-16 ) to completely destroyed. However, bile injury/destruction occurs only in a minority of liver biopsies—one series found that bile duct destruction occurred in 8% of known primary sclerosing cholangitis patients. Periductal fibrosis was also seen in 8% of cases. More typically, biopsies from patients with primary sclerosing cholangitis demonstrate features of biliary outflow impairment, owing to strictures of the larger bile ducts; these features are certainly not specific for primary sclerosing cholangitis. These features of biliary obstruction are portal-based and include portal edema and bile ductular proliferation with or without lobular cholestasis. The patchy involvement of the liver in primary sclerosing cholangitis may lead to a nondiagnostic liver biopsy, and this should be taken into account when the clinical impression of primary sclerosing cholangitis is strong but the biopsy is nondiagnostic.

Classic “onion skinning” fibrosis and duct injury in a patient with primary sclerosing cholangitis.

Fatty Liver Disease

In children, fatty liver disease usually occurs secondary to metabolic causes such as obesity and insulin-resistant diabetes and is thought to affect at least 10% of children. Fatty liver disease can be broadly categorized into alcoholic and nonalcoholic fatty liver disease, and nonalcoholic fatty liver disease is histologically categorized into nonalcoholic fatty liver steatosis without evidence of lobular injury or steatohepatitis (steatosis with injury). An arbitrary cut-off of 5% of the biopsy surface area has been assigned as the minimum amount of fat to establish a diagnosis of nonalcoholic fatty liver disease. The fat in nonalcoholic fatty liver disease is predominantly large droplet macrovesicular—the hepatocyte cytoplasm is replaced by one or a few large fat vacuoles, and the nucleus is displaced to the periphery. Small droplet macrovesicular steatosis has visible fat vacuoles, but does not displace the nucleus. Microvesicular steatosis, which is characterized by numerous tiny vacuoles that commonly indent, but do not displace the nucleus, rarely may be seen, but is never the exclusive pattern. Microvesicular steatosis is often unrecognizable on H&E-stained sections, requiring special stains or electron microscopy to recognize the fat. There are two types of histologic patterns of steatohepatitis. Type 1, or the adult form of steatohepatitis, will demonstrate steatosis predominantly in zone 3 with ballooning degeneration of hepatocytes, lobular inflammation, and, if present, zone 3 predominant perisinusoidal fibrosis ( Figures 66-17, 66-18, and 66-19 ). In contrast, in type 2, or pediatric form of steatohepatitis, typically there is portal inflammation and fibrosis with abundant azonal steatosis, but a lack of ballooning or perisinusoidal fibrosis. In a survey of childhood nonalcoholic steatohepatitis, most patients had overlapping features of type 1 and type 2 steatohepatitis (82%), whereas 8% were pure type 1 steatohepatitis, and 9% were type 2. Therefore, although type 2 steatohep­atitis is the important and more subtle subtype for pathologists to be aware of, it is, in its pure form, uncommon.

Macrovesicular steatosis (short arrows), as evidenced by many large, clear vacuoles that displace the hepatocytes nucleus to the periphery of the cell. The long arrows highlight a ballooned hepatocyte.

High magnification view centered on a hepatocyte undergoing ballooning degeneration (arrow). Ballooned hepatocytes are typically larger and paler than normal hepatocytes. In addition, the cytoplasmic contents are disrupted.

Trichrome-stained section in a patient with steatohepatitis. The lobular fibrosis is arranged in a perisinusoidal, or “chicken wire,” distribution, and envelops individual hepatocytes.

Assessment of Donor Liver Pretransplantation

Although there are many possible abnormalities in a potential donor liver, pathology is usually used to assess for the degree of macrovesicular steatosis (see definition in the preceding paragraph). Allografts with abundant large droplet steatosis (the cut-offs vary from institution to institution, but often range from 30% to 60%) are at increased risk of primary nonfunction of the allograft, rapid graft loss, and need for retransplantation. These assessments are usually done under suboptimal conditions—characteristically late at night, on frozen section slides, and interpreted by a general pathologist rather than a liver pathologist. There are two major pitfalls in the assessment of donor liver. First, micro­vesicular steatosis has not been associated with poor transplantation outcome, so one must be cautious to avoid “overinterpretation” of microvesicular steatosis as macrovesicular steatosis, particularly when performed by inexperienced hands in the middle of the night. Second, the process of generating a frozen section slide frequently introduces artifactual vacuoles that also mimic steatosis. Both of these pitfalls may eliminate a perfectly acceptable organ from being transplanted.

Assessment of Liver Posttransplantation

Acute Cellular Rejection

Acute cellular rejection is characterized by the histologic features of portal-based inflammation, bile duct injury, and vein endotheliitis ( Figure 66-20 ). The portal inflammation is unique in that it is made up of a mixture of different inflammatory cells, most notable small, mature-appearing lymphocytes and activated, blast-like lymphocytes. Eosinophils are another useful inflammatory cell to identify when considering a diagnosis of acute rejection. The inflammatory infiltrate typically is focused in interlobular bile ducts and portal veins. Rather than round and regular bile duct profiles with evenly distributed nuclei, bile ducts injured in acute cellular rejection become irregular with haphazardly placed nuclei and vacuolated or eosinophilic cytoplasm. Endotheliitis is characterized by lymphocytes undermining and lifting the endothelial cells lining the veins. The endothelial cells undergo reactive changes—they become larger and rounder in response to the inflammatory injury. Although endotheliitis is typically found in the portal tracts, the same changes may occur in central veins.

Portal tract with typical features of acute cellular rejection. The inflammatory infiltrate is composed of a mixture of large and small lymphocytes as well as scattered eosinophils. Portal vein endotheliitis (long arrows) and bile duct injury (short arrows) are also present.

Chronic Rejection

Chronic allograft rejection is typically seen in a patient with repeated episodes of acute cellular rejection. Unlike acute rejection, inflammation or endotheliitis is not characteristically identified in chronic rejection. There are two recognized phases of chronic rejection—early and late. Early chronic rejection is thought to be reversible and is characterized by pervasive injured and attenuated interlobular bile ducts ( Figure 66-21 ). Late rejection is defined by ductopenia, wherein at least 50% of the portal tracts lack an identifiable interlobular bile duct. Chronic rejection is primarily an ischemic phenomenon, so in addition to ischemic-type bile duct injury and loss, the zone 3 hepatocytes may be replaced by scarring. Ischemic-type injury is not surprising, given that larger arteries may undergo luminal obliteration by foam cells ( Figure 66-22 ). Cholestasis and chronic cholestatic changes (i.e., copper accumulation and feathery degeneration of the periportal hepatocytes) may also occur. One must not interpret feathery degeneration as the ballooning degeneration of steatohepatitis. Furthermore, chronic ischemia, recurrent primary sclerosing cholangitis, or even chronic extrahepatic biliary obstruction (i.e., secondary sclerosing cholangitis), may be difficult to separate from chronic rejection based on histology alone.

Senescent/ischemic-type changes to the interlobular bile duct (arrow) in a patient with early chronic rejection. Also, note the characteristic lack of portal inflammation in chronic rejection.

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