Basic Patterns of Injury in Medical Liver Pathology

Roger K. Moreira, MD

A pattern of injury represents individual histologic findings that cluster into a meaningful and recognizable histologic pattern. Identification of basic patterns of injury is the first and most fundamental step in the evaluation of medical liver biopsies because most patterns are associated with fairly well-established differential diagnoses and accompanying pitfalls. Whenever possible, we should try to fit all individual findings into one pattern of injury, always keeping in mind that any given feature is part of a spectrum and may vary, within certain limits, from case to case. Occasionally, more than one pattern is present in the same sample, with one pattern usually predominating. In spite of their importance, no universal consensus exists regarding the precise nomenclature, definition, or characterization of many of the basic patterns of injury in the liver presented here. Nonetheless, there is general agreement on the core elements that make up these patterns of injury and in this chapter we discuss the patterns most commonly seen in our practice, along with their significance.

6.1 THE NORMAL/NEAR-NORMAL LIVER

Definition

In this pattern, a liver sample is either completely normal or only shows minimal, nonspecific changes.

Dealing with a normal/nearly normal liver sample can be frustrating, especially when significant clinical abnormalities have been identified. The obvious concern is that the pathologist is missing something meaningful or not recognizing subtle, yet diagnostic features. Therefore, the first and perhaps most important step in this setting is to ascertain that the basic pattern is truly “normal/near-normal,” rather than a mild form of another pattern. Four steps should be followed before labeling a liver sample as normal/nearly normal: (1) carefully evaluate the adequacy of the biopsy specimen. A specimen with too few portal tracts, marked crush or other artifacts, or severe fragmentation should be considered inadequate or suboptimal and a diagnosis of “normal” should be rendered with caution; (2) thoroughly review the specimen to ascertain that all expected portal and lobular structures are present, show a normal appearance, and that no abnormal elements are present (also refer to Chapter 1, “Normal liver”); (3)
carefully review the “checklist” (Table 6.1) of the most commonly missed histologic findings in this setting (Figs. 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, and 6.7); and (4) correlate with clinical features, specifically searching for subtle changes related to clinically suspected condition and for features of diseases most commonly associated with a normal/near-normal pattern (Table 6.2). Chapter 7 discusses the “normal/near-normal” differential in more detail.

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.

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