Introduction
Assessment of liver architecture is the first step in assessment of a liver biopsy specimen. Unlike other organs that have well-defined anatomic compartments (e.g., glomeruli and tubules in the kidney), the liver consists of sheets of hepatocytes interrupted, at discrete intervals, by portal tracts and central veins of various sizes. Fibrous tissue is especially scarce in normal liver. It is limited to the portal tracts and central veins, and the amount varies according to the size of these structures. Therefore, delineation of normal architecture is challenging.
Preservation of normal architecture is indicated by the presence of portal tracts and central veins occurring at regular intervals. Alteration of architecture is suspected when portal tracts and central veins either are not present in the biopsy specimen or are distorted by fibrous tissue. After assessment of architecture, examination of portal tracts and parenchyma helps identify a dominant pattern of injury. The major patterns of liver injury include predominantly portal inflammation, predominantly lobular injury, ductular reactions, steatosis, and fibrosis. In some instances, histologic changes are minimal or absent. An algorithm to facilitate interpretation of liver biopsies is shown in Figure 42.1 .
Helpful Diagnostic Tips
There is considerable overlap in morphologic patterns of injury among the various types of liver diseases. Therefore, clinical correlation is essential to establishing a correct diagnosis. For example, viral, autoimmune, and drug-induced hepatitis all show portal inflammation, and distinction among these disorders often requires clinical and serologic data (see Evaluation of Clinical and Serologic Information ).
More than one pattern of injury may be present in a single liver biopsy specimen. For instance, a prominent ductular reaction can indicate biliary disease, but a mild ductular reaction can also indicate chronic viral hepatitis. Similarly, significant portal inflammation may be present in patients with lobular hepatitis.
Liver injury caused by drugs or toxins can mimic any type of liver disease. Drugs and toxins are the most frequent cause of a mixed, or “atypical,” pattern of liver injury. Establishing a diagnosis of drug- or toxin-induced liver injury relies heavily on determination of a temporal relationship between liver injury and drug use (including disappearance of symptoms on withdrawal of the drug and reappearance on rechallenge), as well as exclusion of competing causes of liver injury.
Pathognomonic features of certain diseases may be focal and therefore may not be present in a liver biopsy specimen. Examples include granulomatous duct destruction characteristic of primary biliary cirrhosis (PBC) and occluded central veins in patients with sinusoidal obstruction syndrome (formerly termed “veno-occlusive disease”). In such cases, other “soft” findings may be helpful in establishing the diagnosis in the right clinical context.
Some diseases, such as Wilson disease and α 1 -antitrypsin deficiency exhibit several different patterns of liver injury that can mimic other diseases. For example, Wilson disease may manifest as chronic hepatitis or steatohepatitis.
In some disorders, such as focal nodular hyperplasia, the features observed in a liver biopsy specimen depend on the portion of the lesion that was sampled.
Identification of Major Pattern of Injury
Predominantly Portal Inflammation
Inflammation located predominantly in the portal tracts ( Fig. 42.2 ) occurs in a wide variety of liver diseases, such as chronic viral hepatitis, autoimmune hepatitis, drug- or toxin-induced hepatitis, chronic biliary diseases (PBC, primary sclerosing cholangitis [PSC], chronic biliary strictures), metabolic diseases (Wilson disease, α 1 -antitrypsin deficiency), and neoplastic conditions (lymphomas, leukemia).
The infiltrate may be limited to the portal tracts, or it may extend into the periportal parenchyma (“interface hepatitis”). Even in this pattern of injury, there may be some degree of lobular inflammation with hepatocyte injury ( Fig. 42.3 ). The presence of interface hepatitis indicates a chronic disorder that, ultimately, may lead to fibrosis. However, the rate of progression of fibrosis varies among the various disorders, and even among individuals with the same disease.
The type of infiltrate, the pattern of involvement, and the presence or absence of associated findings (e.g., ductular reaction in chronic biliary diseases, intracytoplasmic globules in α 1 -antitrypsin deficiency) provide clues to the correct diagnosis.
Predominantly Lymphocytic Inflammation in Portal Tracts
Chronic Hepatitis C
Lymphoid follicles (lymphoid aggregates with germinal centers) are a characteristic feature of hepatitis C. Although bile ducts may be associated within lymphoid follicles, they are not the primary target of injury. Nevertheless, bile ducts may show evidence of mild epithelial damage, such as loss, overlapping, and irregularity of nuclei. This may be caused by direct infection of cholangiocytes. Although lymphoid aggregates and lymphoid follicles are most often associated with hepatitis C virus (HCV) infection, they are not specific for this disorder. They also may occur in chronic hepatitis B virus (HBV) infection and in autoimmune hepatitis ( Fig. 42.4 ).
Chronic hepatitis C is also characterized by the presence of macrovesicular steatosis, lipogranulomas, or both. Lipid droplets are essential for viral assembly, and the hepatitis C core protein has been shown to be localized to lipid droplets. Also, HCV is able to induce transcription of genes involved in lipid metabolism, most notably sterol regulatory element binding protein 1 (SREBP1) and peroxisome proliferator–activated receptor-γ (PPAR-γ). Chronic HCV infection also induces insulin resistance, which correlates with viral load. HCV infection causes insulin resistance by interfering with the function of the insulin receptor and insulin signaling pathways. Both steatosis and insulin resistance are associated with treatment resistance and progression of fibrosis.
Chronic Hepatitis B
Chronic HBV infection shows predominantly portal mononuclear inflammation. Lymphoid aggregates are not as frequently present as with HCV infection. The presence of ground-glass hepatocytes is suggestive of chronic hepatitis B. However, ground-glass cells have been described in a wide variety of other conditions, such as use of certain drugs, and in patients who have received total parenteral nutrition. For this reason, immunohistochemical staining for the hepatitis B surface antigen (HBsAg) is important to confirm HBV infection ( Fig. 42.5 ).
Autoimmune Hepatitis
Autoimmune hepatitis is characterized by a mixture of portal and periportal inflammation and by marked lobular activity. Although plasma cells are also characteristic, they are not always prominent ( Fig. 42.6 ). Some cases show predominant lymphocytic inflammation without prominent plasma cells. Eosinophils are usually present, albeit in very small numbers. Lymphoid aggregates and lymphoid follicles may be present as well. If follicles or aggregates surround bile ducts that show evidence of epithelial damage, then the possibility of an overlap syndrome with PBC should be considered.
Most patients with autoimmune hepatitis, before treatment, show severe inflammatory activity. This is characterized by the presence of marked interface and lobular activity with hepatocyte necrosis and hepatocyte loss and, in particular, by confluent necrosis ( Fig. 42.7 ). The latter is often localized around the central veins, or may bridge central–portal or portal–portal areas (“bridging necrosis”) or involve entire lobules (“parenchymal collapse”). Regions of confluent necrosis show loss of hepatocytes, cellular debris, macrophages, and extravasated red blood cells. When the areas of confluent necrosis extend to portal tracts, a ductular reaction often becomes prominent. Because bridging necrosis may mimic fibrous septa on hematoxylin and eosin (H&E) staining, a trichrome stain should be used to distinguish between bridging necrosis and bridging fibrous septa.
Acute Hepatitis
Prominent lobular inflammation and hepatocyte necrosis are characteristic features of acute hepatitis. However, this type of infiltrate is usually also accompanied by a variable amount of portal inflammation, which in some cases is quite prominent. The most common etiologic agents of acute hepatitis include hepatotropic viruses (hepatitis A virus [HAV], hepatitis B virus [HBV] with or without hepatitis D virus [HDV], HCV, and hepatitis E virus [HEV]), nonhepatotropic viruses, and drugs or toxins. Although most nonhepatotropic viruses (e.g., cytomegalovirus [CMV], herpes simplex virus [HSV], and adenovirus) can cause acute hepatitis, these organisms are not generally associated with prominent portal inflammation. However, Epstein-Barr virus (EBV) infection is associated with portal mononuclear infiltration to such as degree that it may mimic chronic hepatitis C or B.
Chronic Biliary Diseases
Chronic biliary diseases also demonstrate prominent portal lymphocytic inflammation. For instance, PBC, in its earliest stage (stage I), shows portal lymphocytic inflammation, lymphoid aggregates, and follicles. The latter are often associated with damaged bile ducts. The pathognomonic feature of PBC is the florid duct lesion (non-necrotizing granuloma surrounding a damaged bile duct), but florid duct lesions tend to be focal and therefore may not always be present in biopsy specimens ( Fig. 42.8 ). Similarly, concentric periductal inflammation, or fibrosis, and bile duct scars are diagnostic of PSC ( Fig. 42.9 ) but may not be present in a biopsy specimen. Nonspecific findings such as ductular reaction or copper accumulation in periportal hepatocytes may be observed in chronic biliary diseases, but mild ductular proliferation is also present in late stages of viral hepatitis (e.g., chronic hepatitis C), particularly as fibrous septa become more frequent and cirrhosis begins to develop.
Miscellaneous Conditions
A prominent portal inflammatory infiltrate may be present in patients with α 1 -antitrypsin deficiency or Wilson disease. In the former, eosinophilic globules within periportal hepatocytes provide a clue to the diagnosis (see Fig. 42.2, B and C ). However, globules may also represent an acute phase reaction during concomitant chronic viral hepatitis. Wilson disease may show prominent portal lymphocytes. Accompanying findings are relatively nonspecific and include mild steatosis, binucleated hepatocytes, and clear (glycogenated) nuclei.
Predominantly Plasma Cell Inflammation in Portal Tracts
The main differential diagnoses in patients with abundant plasma cells in portal tracts are autoimmune hepatitis and PBC. Autoimmune hepatitis is more likely to show extensive interface hepatitis and/or confluent necrosis, features that are not common in PBC (see Fig. 42.7 ). In contrast, bile duct centric granulomas and predominant mononuclear infiltration are not features of autoimmune hepatitis. If hepatitic features predominate, autoimmune hepatitis is more likely; if biliary features (e.g., ductular reaction, chronic cholestasis) predominate, PBC is more likely, even in the absence of a duct-destructive lesion. If both sets of features are present and the clinical features of the patient reflect aspects of both diseases, then an autoimmune hepatitis–PBC overlap may be present.
Immunoglobulin G4 (IgG4) disease–associated sclerosing cholangitis may also show a predominance of plasma cells. In liver allografts, a plasma cell–predominant infiltrate is often indicative of recurrent autoimmune hepatitis, recurrent PBC, or late cellular rejection.
Predominantly Mixed Portal Inflammation in Portal Tracts
Acute cellular rejection is the prototype for a mixed portal inflammatory infiltrate that includes lymphocytes neutrophils, macrophages, and eosinophils ( Fig. 42.10 ). Caution should be exercised in patients who have undergone liver transplantation for hepatitis C, because the portal mononuclear infiltrate characteristic of that disease, when recurrent, may be difficult to appreciate in the presence of rejection, particularly when the recurrent hepatitis C is mild.
Other diseases that may reveal a mixed infiltrate include Hodgkin disease. The presence of Reed-Sternberg cells, combined with immunohistochemical typing of the inflammatory infiltrate, helps reveal the malignant nature of the lesion. Extramedullary hemopoiesis may also have a mixed pattern if it occurs within portal tracts.
Predominantly Eosinophilic Inflammation in Portal Tracts
A pure eosinophilic infiltrate does not represent a common pattern of liver injury, but when it occurs, parasitic infection should be suspected. Of these, schistosomiasis targets the portal venous system. Larva migrans can cause eosinophilic abscesses. If the biopsy is obtained from a mass lesion, the presence of numerous eosinophils raises the possibility of an inflammatory myofibroblastic tumor, inflammatory pseudotumor, Langerhans cell histiocytosis, or Hodgkin disease ( Fig. 42.11 ).
Eosinophils are also plentiful, although they are not the predominant cell type, in autoimmune diseases such as autoimmune hepatitis, PBC, and PSC and in drug-induced liver injury (see Figs. 42.4, B and 42.9 ).
Predominantly Granulomatous Inflammation in Portal Tracts
Granulomas may be divided into four basic diagnostic categories, characterized as “see the cause,” “know the cause,” “suspect the cause,” and “don’t know the cause.”
- •
See the cause: Acid-fast or fungal organisms are detected with special stains, or foreign material is identified within the granulomas.
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Know the cause: The patient has a known clinical history of infectious (mycobacterial or fungal) granulomatous disease, sarcoidosis ( Fig. 42.12 ), or other granuloma-associated disease, such as PBC (see Fig. 42.8 ).
FIGURE 42.12
Sarcoidosis with a large, non-necrotizing portal granuloma containing entrapped and damaged bile duct ( arrows ). Notice the numerous eosinophils in this inflammatory infiltrate.
- •
Suspect the cause: Caseous necrosis suspicious for infection but with negative results on special stains (histochemistry is relatively insensitive for diagnosis while cultures or serologic studies are more sensitive); fibrin-ring granulomas that suggest specific etiologies, such as Q fever, allopurinol or griseofulvin toxicity; granulomas of differing ages, cellularity, and sclerosis, often with asteroid bodies, suggest sarcoidosis. Also included in this category are drug- and toxin-induced forms of liver injury of a granulomatous nature. These cases may be simply granulomatous, or they may display features of a “granulomatous hepatitis,” which also includes portal, lobular, and parenchymal hepatitis, around the granuloma as well as away from it. Eosinophils may or may not be prominent.
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Don’t know the cause: In autopsy series, this may be the largest group; a cause of the granulomas cannot be identified.
Atypical Lymphoid Infiltrate in Portal Tracts
The differential diagnosis includes hemopoietic malignancies such as leukemia, lymphoma, and posttransplantation lymphoproliferative disorder ( Fig. 42.13 ). The infiltrate in EBV hepatitis tends to appear atypical.
Evaluation of Clinical and Serologic Information
After a specific pattern of inflammation has been identified in portal tracts, the next step is to obtain the necessary clinical and serologic data. Most patients with this predominantly portal inflammation have chronic hepatitis B or C or autoimmune hepatitis. If these are excluded clinically, then drug- or toxin-induced hepatitis and Wilson disease are important entities to consider.
If the clinical history indicates either chronic viral hepatitis or autoimmune hepatitis, several points are worth emphasizing: There are several grading and staging schemes available, and all have advantages and disadvantages. When a particular grading or staging system is used, the name of the system (e.g., METAVIR, Ishak, Batts-Ludwig, modified Ishak) should be stated in the diagnosis or in a comment.
The presence of confluent necrosis (perivenular necrosis, bridging necrosis, or parenchymal collapse; see Fig. 42.7 ) is typical of autoimmune hepatitis, particularly early in the course of disease. However, in viral hepatitis, it should trigger an evaluation for other, potentially important concomitant diseases, such as super infection with another type of hepatotropic virus or the presence of an immunodeficiency state ( Table 42.1 ).
| Hepatitis B | Hepatitis C |
|---|---|
| Acute flare from HBeAg to HBeAb seroconversion | Acute flare |
| Super-infection with HDV | |
| Immunocompromise (HIV-associated or other) | Immunocompromise (HIV-associated or other) |
| Concomitant autoimmune hepatitis | Concomitant autoimmune hepatitis |
| Concomitant drug/toxin-induced liver injury | Concomitant drug/toxin-induced liver injury |
Chronic Hepatitis C
If the clinical and serologic data confirm chronic hepatitis C, then the biopsy should be graded and staged with the most useful system at each clinician’s institute.
Steatosis and iron accumulation may be present in biopsy specimens from patients with chronic hepatitis C. Steatosis associated with chronic hepatitis C should be distinguished from primary fatty liver disease (alcoholic or nonalcoholic). Although mild hemosiderin may be associated with chronic hepatitis C, marked hemosiderin may indicate concomitant hereditary hemochromatosis. In all cases of chronic hepatitis, the biopsy should also be evaluated for the presence or absence of large cell change, small cell change, and iron-free foci (in an otherwise siderotic biopsy specimen) ( Fig. 42.14 and Table 42.2 ).
| Feature | Implication |
|---|---|
| Steatosis | HCV-associated steatosis vs. concomitant alcoholic or nonalcoholic fatty liver disease |
| Iron | HCV-associated vs. treatment-associated vs. hereditary hemochromatosis |
| Confluent necrosis | Severe activity of viral hepatitis vs. concomitant autoimmune hepatitis vs. concomitant drug/toxin-induced liver injury (see Table 42.1 ) |
| Large cell change | Malignancy-associated lesion indicating increased risk for development of HCC |
| Small cell change | Premalignant lesion indicating increased risk for development of HCC |
| Iron-free foci in siderotic liver | Malignancy-associated lesion indicating increased risk for development of HCC |
Chronic Hepatitis B
The presence of HBV infection can be confirmed by evaluation of a liver biopsy specimen; this is in contrast to the situation in HCV infection, in which the virus cannot be visualized in a histology specimen. In chronic hepatitis B, ground-glass hepatocytes, which indicate accumulation of HBsAg within endoplasmic reticulum of cells that have viral DNA integrated into the host genome, helps confirm the diagnosis. However, ground-glass changes are not always easy to identify, and their appearance is highly variable and dependent on the quality and type of fixation and staining. They are sometimes highlighted by a trichrome stain, but an immunostain for HBsAg is almost always positive, even in cases without overt ground-glass inclusions.
An immunohistochemical stain for nuclear HBV core antigen (HBcAg) provides valuable clinical information. A positive stain confirms the presence of active viral replication and correlates with the presence of HBV DNA in the patient’s serum. A negative stain may be a sampling artifact, but it may also indicate spontaneous clearance of the viral infection (in which case, HBV DNA is absent) or coinfection with HCV or HDV (“delta hepatitis”). Therefore, this finding should be reported, particularly in geographic regions in which HDV infection is endemic. In cases with diffuse expression of HBVcAg, the patient may be immunocompromised, and coinfection with human immunodeficiency virus (HIV) should be considered. Steatosis and iron accumulation are not usually associated with chronic hepatitis B. Therefore, fatty liver disease should always be considered in chronic hepatitis B patients with steatosis. Similarly, concomitant hereditary hemochromatosis should be considered if significant hemosiderin deposition is present, particularly in patients of European descent ( Fig. 42.15 ; see Table 42.2 ).
Autoimmune Hepatitis
In most patients with hepatitis B or C, the disease is confirmed by clinical and serologic correlation; biopsies are used to assess the grade and stage of infection and to rule out associated conditions. In contrast, in autoimmune hepatitis, the goal of the liver biopsy is confirmation of the disease in a patient with elevated serum transaminases and positive autoantibodies that are characteristic of autoimmune hepatitis, such as antinuclear antibodies (ANA), anti–smooth muscle antibody (ASMA), and anti–liver-kidney microsomal antibody type I (anti-LKM1). However, biopsy specimens may reveal features of other diseases, such as fatty liver disease, in which case the autoantibody levels may represent a reflection of some other disorder, such as rheumatologic conditions in other organs. Therefore, establishing a definite diagnosis of autoimmune hepatitis can be challenging. The following points may be helpful.
In chronic viral hepatitis, necroinflammatory activity is typically present at low levels throughout the natural history of the disease. It may diminish in late (“burned out”) stages, and there may occasionally be acute flares (particularly in hepatitis C) ( Fig. 42.16, A ). Fibrosis develops regardless of inflammation. In contrast, patients with autoimmune hepatitis have bouts of severe activity followed by long periods of inactivity (see Fig. 42.16, B ). Fibrosis is a direct result of necrosis, so progression to cirrhosis is swift compared with chronic viral hepatitis. As a result, cases of autoimmune hepatitis may demonstrate any of the following features : (1) cirrhosis with little or no necroinflammatory activity; (2) intermediate-stage disease with moderate to severe activity, combined with scarring and nodularity; or (3) early-stage disease with marked activity (at least focal confluent necrosis), combined with parenchymal collapse. However, patients with autoimmune hepatitis are unlikely to show periods of mild activity combined with mild or absent fibrosis. Therefore, biopsies that reveal both mild activity and mild fibrosis are unlikely to represent autoimmune hepatitis. In such cases, viral hepatitis and drug- or toxin-induced hepatitis should be excluded clinically.
As mentioned earlier, plasma cells are often absent in patients with autoimmune hepatitis. Their absence should not negate the possibility of autoimmune hepatitis if all other histologic and clinical features are compatible with that disorder. Chronic hepatitis caused by drugs or toxins may reveal prominent plasma cells. Therefore, in patients with no positive autoantibodies but with abundant plasma cells in portal tracts, a drug- or toxin-induced injury is more likely than autoimmune hepatitis.
Autoimmune hepatitis may overlap with PBC, which may also show abundant plasma cells. If serologic features typical of PBC and/or markedly elevated serum alkaline phosphatase are also present, the clinician may suspect the presence of both diseases. However, symptoms of both are just as likely to be seen in a biopsy specimen that shows very prominent activity, particularly with confluent necrosis. It is often not possible to be certain unless all clinical and pathologic features indicate the presence of both diseases. If the pathologist recognizes only scattered foci of interface and lobular hepatitis (akin to what one might see in hepatitis C), then it is likely not autoimmune hepatitis. Plasma cells are also not diagnostic of autoimmune hepatitis because they are almost always present in PBC as well. However, confluent necrosis or widespread interface and lobular hepatitis (that is easily recognized at low power), strongly suggest an overlap syndrome.
Ductular Reaction
A ductular reaction is defined by proliferated bile ductules present at the interface of the portal tracts and parenchyma. The term ductular reaction is preferred to “ductular proliferation,” because this phenomenon is associated with stromal, vascular, and inflammatory changes as well as ductular proliferation ( Fig. 42.17 ). Ductular reactions develop as a result of bile duct or hepatocyte injury and are derived from stem cells located in the canals of Hering. A ductular reaction may also develop directly from intralobular bile ducts or even from extrahepatic bone marrow–derived precursor cells. A ductular reaction should be distinguished from biliary metaplasia of hepatocytes. The latter may occur at the portal-parenchymal interface as well. Biliary metaplasia represents a degenerative rather than a regenerative process. Ductular reactions are separated into acute and chronic forms and also by the primary target of injury (whether the injury occurs primarily to hepatocytes or bile ducts).
Acute Bile Duct Obstruction
Except in patients who have undergone liver transplantation, the finding of features of acute bile duct obstruction in a liver biopsy specimen is rare. In most instances, bile duct obstruction is diagnosed clinically, by radiologic tests. Ductular reactions associated with acute bile duct obstruction are typically diffuse, occurring in many or all portal tracts ( Fig. 42.18 ). The ductular reaction may link portal tracts together. The reaction consists of anastomosing ductules associated with edematous stroma and neutrophils. Therefore, the presence of neutrophils is not necessarily indicative of acute (bacterial) ascending cholangitis. Ductular reactions are not normally associated with cholestasis or bile stasis within the lumina of the bile ductules. Their presence, termed cholangitis lenta , often indicates sepsis in the patient ( Fig. 42.19 ). Acute bile duct obstruction is also often associated with bile infarcts, which are caused by the degenerating and detergent action of bile on hepatocytes.
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