Basic Patterns of Injury in Medical Liver Pathology



Basic Patterns of Injury in Medical Liver Pathology


Roger K. Moreira, MD





6.1 THE NORMAL/NEAR-NORMAL LIVER



6.2 HEPATITIS



Nonspecific inflammation (also referred to as “reactive hepatitis”)

This pattern is characterized by a mild, predominantly lymphocytic infiltrate involving portal tracts, hepatic lobules, or both, usually not accompanied by any other abnormalities. As the name implies, this pattern is typically not associated with any primary liver disease, but rather with systemic inflammatory processes (infections, connective tissue disorders, celiac disease,1,2 primary immunodeficiencies,3 etc.). When features of other patterns concomitantly occur (fatty liver, for example), the latter should be regarded as the primary pattern for differential diagnosis purposes.


Acute hepatitis

Acute liver injury can occur either de novo or as a flare of various chronic liver diseases. The term “acute hepatitis” is largely a clinical term, defined by the length of time for liver enzyme elevations. The histological correlates of acute hepatitis include various degrees of lobular inflammation, injury, necrosis, and regeneration, in the absence of features of chronic hepatitis (e.g., well-formed portal lymphoid aggregates, fibrosis). In typical cases of acute hepatitis, therefore, the process is primarily inflammatory and primarily involves the hepatic lobules (Fig. 6.8). Although a fairly long list of etiologies is associated with this histologic appearance (Table 6.3), the etiology of the acute injury is often clinically known or strongly suspected (e.g., acute viral hepatitides, drug reaction) and a liver biopsy may not be indicated. In practice, most biopsied cases showing this pattern will represent either drug-induced liver injury or an unsuspected viral hepatitis, usually by a nonhepatotropic virus, which may not have been included in the prebiopsy clinical evaluation. Other entities in the differential include autoimmune hepatitis and Wilson disease. The features of an acute hepatitis may overlap with those of “chronic hepatitis,” “panlobular hepatitis,” and “cholestatic hepatitis” patterns (see later).









Table 6.1 Most common “easy-to-miss” findings in otherwise normal/nearly normal liver samples









































































Feature


Associated clinical scenario


Comment


Ductopenia


Cholestasis, drug reaction, Allagille syndrome, PSC, BMT/GVHD, liver transplant


Identification of hepatic arteries without associated bile ducts is helpful


Bile duct injury in graft versus host disease


BMT


GVHD may present with minimal bile duct damage and little or no inflammation


Hepatoportal sclerosis


Clinical, laboratory, and imaging findings related to portal hypertension with no cirrhosis


Findings may be rather subtle and may require a high index of suspicion; look for atrophic or absent portal veins; dilated portal veins with herniation into the lobules, NRH


Focal viral inclusions


Immunosuppression, immunodeficiencies, known viral infection


CMV inclusions may be very focal and not apparent on all levels; search should focus on inflammatory foci or microabscesses, if present. Adenovirus inclusions can be very inconspicuous (small samples may not include areas of necrosis)


Amyloid


Plasma cell dyscrasias, paraproteinemia, chronic infections, chronic inflammatory processes


Small amounts of amyloid are notoriously difficult to recognize on H&E; examine arterioles carefully


α-1 antitrypsin globules


Abnormal α-1 antitrypsin levels or phenotype


Small globules, particularly in the neonatal period, are very difficult to recognize; search periportal hepatocytes carefully; immunostain may also be helpful


Focal hepatocanalicular cholestasis


Elevated bilirubin, usually >2


Search should focus on centrilobular areas; look for small canalicular plugs


Other pigments


Dubin-Johnson, PCT, EPP


Dubin-Johnson syndrome shows abundant, coarse, brown pigment similar to lipofuscin; PCT can show needle-shaped crystals within hepatocytes, best seen using unstained paraffin sections under polarized light; EPP pigment may resemble other pigments but shows a typical red-birefringence and a “Maltese cross” configuration under polarized light


Ito/stellate cell hyperplasia


Vitamin A or multivitamin supplements


Ito/stellate cells are small and inconspicuous and can be missed even when present in large numbers. Multivacuolated cytoplasm with nuclear indentation represent the key cytologic features


Hairy cell leukemia


Hematologic abnormalities, known HCL


HCL cells are typically very bland and may mimic Kupffer cells. A high index of suspicion is required


Nodular regenerative hyperplasia


Portal hypertension, certain medications such as azathioprine, collagen-vascular diseases, vascular malformations and hepatic hemangiomas


NRH can be very subtle on H&E stain. Reticulin stain is very helpful


Hepatitis B


Chronic hepatitis B infection


Ground-glass inclusions may be absent or be difficult to recognize in chronic hepatitis B, and the diagnosis may be missed if no clinical history is available; HBV surface antigen immunohistochemistry typically shows strong and diffuse cytoplasmic positivity in spite of the normal/near-normal appearance on H&E


Kupffer cell clusters (resolving hepatitis)


Evidence of significant improvement of liver enzymes previous to biopsy procedure (spontaneous or treatment-related), most commonly in the setting of proven or suspected drug reaction or systemic infections


PAS-D stain is very helpful in highlighting Kupffer cell and portal macrophage clusters in an otherwise relatively unremarkable liver, indicative of recent, resolving injury (resolving hepatitis pattern)


Sickled red blood cells


Sickle cell disease or trait


Sickled red blood cells often form small clusters within sinusoids but sinusoidal dilatation and iron pigment may be absent


Microvesicular steatosis


Mitochondrial injury or dysfunction, drug toxicity (e.g., tetracycline, valproic acid), Reye syndrome, acute fatty liver of pregnancy


“True” microvesicular steatosis presents exclusively as very small fat droplets in the cytoplasm and can be very difficult to recognize. Fat stains such as Sudan and oil-red-O are useful


Vascular thrombi


Hypercoagulability, suspected ischemia


Thrombi can be easily overlooked in the liver, often dismissed as nonspecific fibrinous debris or hyalinized/fibrous areas; endothelial makers and elastic stains (e.g., Verhoeff-Van Gieson) can be useful


Abbreviations: PSC, primary sclerosing cholangitis; BMT, bone marrow transplant; GVHD, graft versus host disease; NRH, nodular regenerative hyperplasia; PCT, porphyria cutanea tarda; EPP, erythropoietic protoporphyria; HCL, hairy cell leukemia.







Figure 6.1 Focal amyloid. Amyloid material focally involving the wall of a hepatic artery branch.



Chronic hepatitis, NOS

This is one of the most common patterns of injury seen in practice and its hallmark is the presence of dense chronic inflammatory infiltrates in the portal tracts, often associated with lymphoid aggregates (occasionally with germinal centers) and with varying degrees of interface activity (Fig. 6.9). Although the associated lobular activity is highly variable, it is typically less pronounced relative to the portal infiltrate. This stands in contrast to the acute hepatitis pattern, where lobular inflammation is the predominant pattern of injury, with relative less portal inflammation and interface activity. The prototype etiology associated with this pattern is chronic viral hepatitis (B and C). Many different etiologies, however, can potentially show a “chronic hepatitis” histology, including drug-induced liver injury, Wilson disease, α-1 antitrypsin deficiency, autoimmune hepatitis, and primary biliary diseases
(especially primary biliary cirrhosis) (Table 6.4). Fatty liver disease, especially in the setting of advanced fibrosis, can also show relatively dense portal infiltrate as a nonspecific finding, mimicking a superimposed chronic hepatitis. Cases with a pronounced plasma cell component are best classified as “plasma cell rich/autoimmune” pattern.






Figure 6.2 Ito (stellate) cell hyperplasia. Several Ito cells, characterized by multiple small clear cytoplasmic vacuoles indenting the nuclei, are present within spaces of Disse.






Figure 6.3 Hairy cell leukemia. A sinusoidal infiltrate by bland cells, mimicking Kupffer cell hyperplasia, is seen in this example of hairy cell leukemia.






Figure 6.4 Nodular regenerative hyperplasia (NRH). Subtle areas of hepatocyte regeneration alternating with slightly compressed/atrophic areas in this example of mild NRH.






Figure 6.5 Hepatitis B. An essentially normal H&E appearance of the liver in this patient with congenital hepatitis B.






Figure 6.6 Hepatitis B. A hepatitis B surface antigen immunostain in a diffuse membranous and focal cytoplasmic pattern in the same case of congenital hepatitis B illustrated in this igure.






Figure 6.7 Sickle cell disease. Focal areas in this biopsy showed dilated sinusoids with clusters of sickled red blood cells, which are also present within the blood vessel in the center of the image.


Plasma cell rich/autoimmune pattern

This pattern is characterized by dense portal infiltrates, with increased plasma cells (which should


be easily recognizable), often forming clusters, typically associated with brisk interface and lobular activity (Fig. 6.10). Cases showing typical histology most commonly represent autoimmune hepatitis, although clinical correlation is required to establish this diagnosis. Occasionally, this pattern in seen in viral hepatitis B and C (rarely in other infections), as well as in drug-induced liver injury (most notably nitrofurantoin, minocycline, halothane, statins, hydralazine, and methyldopa).4








Table 6.2 Diseases and conditions associated with clinical liver dysfunction and normal/nearly normal histology



































Disease/condition


Histology


Drug reaction


Normal/near-normal histology is common in spite of significant laboratory abnormalities; subtle histologic changes include nonspecific portal/lobular inflammation, mild cytoplasmic eosinophilia (endoplasmic reticulum “induction”), pseudoground glass change, megamitochondria, minimal cholestasis


Celiac disease


Mild nonspecific portal/lobular inflammation


Crohn disease


Mild nonspecific portal/lobular inflammation


Intestinal bacterial overgrowth


Mild nonspecific portal/lobular inflammation


Wilson disease


May be normal; mild steatosis, inflammatory changes and glycogenated nuclei are common


Sepsis


Mild nonspecific inflammatory changes and/or minimal cholestasis


Early biliary tract disease


PBC, PSC, cystic fibrosis, and TPN-associated liver disease, in their early phases, can be very patchy, and findings may be absent in a biopsy sample


Hyperviscosity syndromes


Caused by multiple myeloma, Waldenstrom macroglobulinemia, polycythemia vera, and various autoimmune disorders; may present histologically as normal liver, minimal nonspecific inflammatory changes, minimal sinusoidal dilatation, or lobular disarray


Various genetic/metabolic conditions


Storage diseases, cystinosis, urea cycle defects, hereditary intrahepatic cholestasis syndromes, phenylketonuria, aminoacidopathies, etc.


Abbreviations: PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; TPN, total parenteral nutrition.







Figure 6.8 Acute hepatitis pattern. Lobular injury and disarray with apoptotic hepatitis (acidophilic bodies) but no significant lobular inflammation in this example of hepatitis A.






Figure 6.9 Chronic hepatitis pattern. Marked portal inflammation with a lymphoid aggregate and germinal center as well as mild interface activity in this example of chronic viral hepatitis.








Table 6.3 Etiologies associated with the “acute hepatitis” pattern























Etiology


Related findings/comments


Acute infections by hepatotropic viruses (HAV, HBV with or without HDV, less commonly HCV and HEV)


Ground-glass inclusions typically absent in acute HBV infection but may be present in acute flair of chronic HBV infection; “sanded nuclei” in HDV


Nonhepatotropic viruses (CMV, EBV, adenovirus, HSV, VZV, HHV-6, yellow fever, dengue, hemorrhagic fever-associated viruses)


Lobular microabscesses and/or microgranulomas in CMV; prominent (mononucleosis-like or “beaded”) sinusoidal infiltrate in EBV; localized, “punched-out” necrosisin HSV and adenovirus; hemophagocytosis in HHV-6; Zone 2-predominant necrosis in yellow fever; hemorrhagic zonal necrosis in dengue and yellow fever; prominent hemorrhage in hemorrhagic fevers


Other infections (leptospirosis, tick-borne diseases, malaria, visceral leishmaniasis, Q fever)


Travel history to endemic areas; brown-black pigment in Kupffer cells and portal macrophages in malaria; small round 2-3 µm organisms within histiocytes in leishmaniasis; fibrin ring granulomas in Q fever


Drug reaction


Should be suspected when either prominent eosinophils or a mixed pattern (bile duct inflammation/injury, granulomas, and cholestasis) are present


Miscellaneous: hemophagocytic lymphohistiocytosis/macrophage activation syndrome


Hemophagocytosis


Abbreviations: HAV, hepatitis a virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; VZV, varicella-zoster virus; HHV-6, human herpesvirus 6.









Table 6.4 Diseases associated with the “chronic hepatitis” pattern
































Etiology


Related findings/comments


Viral hepatitis (HBV±HDV, HCV, HEV)


Ground-glass hepatocytes in HBV; sanded nuclei in HDV; HEV has only been associated with chronic hepatitis in immunosuppressed patients


Autoimmune hepatitis


Plasma cells can be focal or absent in histologically “atypical” autoimmune hepatitis


Drug reaction


As in acute hepatitis, drug reaction should be suspected when prominent eosinophils or other associated findings such as bile duct inflammation/injury, granulomas, and cholestasis are seen


Chronic biliary tract disease (PBC and less commonly PSC)


Early PBC may lack florid bile duct lesions, granulomas, or features of “biliary tract disease” but portal inflammation may still be prominent. This is less common but also occurs in PSC


Wilson disease


Glycogenated nuclei are common (but nonspecific); chronic hepatitis pattern may become more prominent as disease progresses


α-1 antitrypsin deficiency


A minority of cases shows a chronic hepatitis pattern; α-1 antitrypsin globules may be focal and difficult to visualize on H&E


Late-onset acute cellular rejection


Typical acute rejection-related findings may be minimal or absent


Sarcoidosis


A minority of cases will show a chronic hepatitis pattern in the background; granulomas may be focal and are not always sampled


Abbreviations: HAV, hepatitis a virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.







Figure 6.10 Plasma cell rich/autoimmune pattern. Chronic portal inflammation with numerous plasma cells in this case of autoimmune hepatitis.


Panacinar hepatitis

The term “panacinar hepatitis” (or “panlobular hepatitis”) refers to a lymphocytic or lymphoplasmacytic inflammatory process, usually of at least moderate degree, involving both portal tracts and hepatic lobules in a relatively diffuse and uniform manner (Fig. 6.11). This pattern is typically seen in the setting of significant transaminase elevation and may represent either an acute process or an acute flare of a chronic disease. The main entities that should be considered in the differential diagnosis of panacinar hepatitis include acute viral hepatitis (including nonhepatotropic viruses), chronic viral hepatitis with an acute flare (primarily hepatitis B), drug-induced liver injury, Wilson disease, and autoimmune hepatitis. This pattern may overlap with acute hepatitis (with more prominent portal inflammation), chronic hepatitis (with significant activity), and cholestatic hepatitis (if cholestatic changes are pronounced).


Giant cell hepatitis

This pattern is defined by the presence of large, multinucleated hepatocytes (Fig. 6.12). Focal giant cell transformation may be seen in various settings, and the term “giant cell hepatitis” is generally reserved for cases in which this finding is either pronounced or predominant. Giant cell transformation is most commonly seen in the setting of neonatal cholestasis, either as a dominant finding in cases of “neonatal/giant cell hepatitis” or as a secondary/nonspecific finding in biliary atresia and other forms of cholestatic liver disease (see Chapter 13). When seen in adults, this pattern is usually referred to as postinfantile (or adult)-type giant cell hepatitis and can be associated with various autoimmune conditions, including primary liver diseases such as autoimmune hepatitis and primary biliary cirrhosis, and extrahepatic/systemic
diseases such as lupus erythematosus, immune thrombocytopenic purpura, autoimmune hemolytic anemia, and various infections (CMV, HHV-6, HCV, HEV, EBV, and HIV).5, 6, 7, 8






Figure 6.11 Panacinar/panlobular hepatitis pattern. A moderate or severe hepatitis involving both portal tracts and hepatic lobules in a somewhat diffuse manner, as in this case of drug-induced liver injury.






Figure 6.12 Giant cell hepatitis pattern. Multiple multinucleated hepatocytes throughout the hepatic lobules are seen in this case of neonatal giant cell hepatitis.


Isolated central perivenulitis

This is a somewhat uncommon pattern in which there is inflammation and hepatocyte injury essentially restricted to the areas around the central veins (Fig. 6.13). Outside of the liver transplant setting, this pattern is usually associated with either autoimmune hepatitis (thought to represent an early feature of this disease, occurring before a “chronic hepatitis” histology develops) or drug-induced liver injury. In liver allografts, central perivenulitis is a common acute cellular rejection-related feature, but one usually seen in combination with portal-based findings. Isolated central perivenulitis becomes more common in the late posttransplantation period, as one of the “atypical” histologic presentations of rejection9 (see Chapter 19 for further discussion). Auto/alloimmune phenomena and drug reactions are also in the differential for isolated central perivenulitis in the posttransplant setting, but the presence of associated central vein endotheliitis strongly favors rejection.

Only gold members can continue reading. Log In or Register to continue

Oct 16, 2018 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Basic Patterns of Injury in Medical Liver Pathology
Premium Wordpress Themes by UFO Themes
%d bloggers like this: