Interpretation of nontargeted liver biopsy findings in adults

INTRODUCTION — Histopathologic examination of the liver can provide useful information regarding structural integrity, type and degree of injury, disease activity, response to treatment, disease progression, and degree of fibrosis. A nontargeted liver biopsy (also termed medical liver biopsy) is typically performed for patients with persistently elevated liver enzyme tests without a clear cause identified by clinical features, laboratory studies, or imaging. The clinical history, and results of viral serologies and autoimmune markers should be made available to the pathologist so that the histologic findings can be interpreted within the clinical context. (See "Approach to the patient with abnormal liver biochemical and function tests".)

The histologic interpretation of nontargeted liver biopsy specimens in adults will be reviewed here. The approach to obtaining a liver biopsy, including transjugular liver biopsy, is discussed separately. (See "Approach to liver biopsy" and "Transjugular liver biopsy".)

The pathology and histologic features of focal liver lesions are discussed separately:

●(See "Clinical features and diagnosis of hepatocellular carcinoma".)

●(See "Hepatocellular adenoma".)

●(See "Focal nodular hyperplasia".)

●(See "Hepatic hemangioma".)

LIVER MICROSTRUCTURE — The microscopic structure of liver parenchyma has been commonly conceptualized in two ways: the acinar model and the traditional lobule model (figure 1) [1]:

●Acinar model – The acinus is a unit that contains a small portal tract at the center and terminal hepatic venules at the periphery. The acinar model (also known as the Rappaport classification) is based on the functional microcirculatory pattern. The acinar model is divided into three zones that represent gradients where the nutrient and oxygen content of the hepatic microcirculation differ. The center of the acinus (periportal) is zone 1; the periphery (perivenular) is zone 3; and the region in between is zone 2 [2]. Zone 1 receives blood with the highest levels of oxygen and nutrients compared with zone 3. Thus, zone 3 is particularly vulnerable to circulatory insults.

In the acinar model, blood supply to an area of hepatic parenchyma and the bile duct draining it are located in one portal tract (ie, hepatic arteriole, portal venule, and bile duct). The acinus consists of a cluster of hepatocytes (approximately 2 mm in diameter) that are grouped around terminal branches of a hepatic arteriole and portal venule. Blood flow is from the portal areas to the central veins. More specifically, blood from a branch of the portal vein and hepatic artery enter the acinus in the portal and periportal regions, flow through the hepatic sinusoids, and drain into a terminal hepatic venule. Blood becomes progressively deoxygenated and depleted of nutrients toward central veins.

Hepatocytes within these zones are adapted to their micro-location. Zone 1 hepatocytes have high oxidative activities and contain many large mitochondria. Their dominant processes include gluconeogenesis, beta oxidation of fatty acids, amino acid catabolism, ureagenesis, cholesterol synthesis, and bile acid secretion. By contrast, zone 3 hepatocytes are more involved with glycolysis and lipogenesis.

●Traditional lobule model – In the lobule model, the central structure of microcirculation is the terminal hepatic venule (also referred to as central vein/venule). Thus, this area is known as the centrilobular zone, while the periphery is delineated by portal tracts with the parenchyma surrounding portal zones referred to as periportal.

GENERAL PRINCIPLES

Correlating histology with clinical data — Histologic findings of the liver may often be nonspecific; for example, there is substantial overlap in the cellular and morphologic changes caused by viral infection, autoimmune disease, drug-induced injury, or a metabolic process [3,4]. As a result, most cases require clinical and histologic correlation to arrive at the most accurate final diagnosis.

Data provided to the pathologist by the clinician at the time of liver biopsy should include (see "Approach to the patient with abnormal liver biochemical and function tests"):

●Age and sex of the patient.

●Timing of onset and duration of disease.

●Suspected clinical diagnosis, which will often lead to a more targeted search by the pathologist.

●Laboratory studies (ie, liver biochemical and function tests, viral and autoimmune serologies, if available).

●Radiographic findings, if available.

Assessing adequacy of the specimen — The initial step in evaluating a liver biopsy is a visual inspection of the adequacy of the sample and the type and quality of staining. It is generally agreed that an adequate specimen is at least 15 mm in length and contains six to eight complete portal tracts. Longer specimens (>15 mm) improve reliability for staging fibrosis and grading histologic activity [2,5]. However, a percutaneous or transjugular liver biopsy typically samples about 1/50,000 of the liver and thus is always vulnerable to sampling variability. (See "Approach to liver biopsy", section on 'Limitations'.)

Prior to microscopic examination, a gross examination of the slides can evaluate not only for an adequate specimen but also for the presence of tissue fragmentation. The latter finding suggests advanced fibrosis/cirrhosis. (See 'Recognizing histologic patterns' below.)

Staining the specimen — Staining of liver biopsy specimens typically includes hematoxylin and eosin (H&E) and Masson or Gomori trichrome stains. H&E staining colors the nuclei of cells blue, while other structures appear as various hues of pink or red [6]. Trichrome stain is useful for evaluating the amount of fibrous tissue and assessing the degree of chronic liver injury. The connective tissue (ie, fibrosis or cirrhosis) appears as various shades of blue or purple.  

Special staining may be performed when evaluating for specific disorders [7]. In most institutions, Perls stain for presence of iron is routinely performed. Other histochemical stains include periodic acid-Schiff stain with diastase digestion for identifying alpha-1 anti-trypsin inclusions, oil red O staining performed on fresh frozen specimens for suspected acute fatty liver of pregnancy or Reye syndrome, stains for copper (eg, rhodanine) for suspected Wilson disease, and reticulin stains for type III collagen for evaluating the liver microarchitecture for hepatocyte necrosis and regeneration. Reticulin staining is also used to assess collapse of the reticulin framework that indicates severe hepatocyte loss and to diagnose idiopathic noncirrhotic portal hypertension. (See 'Recognizing histologic patterns' below.)

RECOGNIZING HISTOLOGIC PATTERNS — Histologic patterns of hepatic injury have been generally grouped by the cell or function that is most affected (eg, hepatocyte, bile ducts, vascular).

Hepatocellular injury — Diseases of hepatocellular injury are characterized by damage to hepatocytes (ie, cytotoxic injury) and histologically may be seen as ballooning or feathery degeneration. These diseases are usually associated with elevated levels of serum aminotransferases (aspartate aminotransferase and alanine aminotransferase). Bilirubin levels may be elevated in patients who have extensive damage to hepatocytes.

Viral hepatitis — A liver biopsy is rarely performed for patients with suspected acute viral hepatitis, but when obtained, the biopsy specimen may show severe lobular and portal inflammation. Examples of liver injury related to viral infection include:

●Acute viral hepatitis – Most patients with acute viral hepatitis have elevated serum aminotransferases. The histologic features of acute viral hepatitis may have various degrees of severity ranging from inflammatory infiltrate consisting mostly of lymphocytes that surround hepatocytes (spotty necrosis) to widespread (panlobular) involvement by necroinflammation. In some patients, bridging necrosis that typically links one vascular structure to another (picture 1A-B) and confluent necrosis are present.

●Chronic hepatitis B virus infection (HBV) – Patients with chronic HBV infection may present with chronic portal inflammation and varying degrees of interface and lobular activity. Ground-glass hepatocytes are pathognomonic. Ground-glass cytoplasm is due to the presence of hyperplastic smooth endoplasmic reticulum filled with hepatitis B surface antigen (picture 2).

●Chronic hepatitis C virus infection (HCV) – Patients with chronic HCV infection may be asymptomatic and have elevated serum aminotransferases. The typical histologic features of HCV infection include distinctly nodular lymphocytic aggregates or lymphoid follicles within the portal areas (picture 3A-B). Hepatic injury in patients with chronic HCV infection has been quantified into grades of inflammation and stages of fibrosis. Several scoring systems have been developed, and these are discussed separately. (See "Histologic scoring systems for chronic liver disease".)

●Epstein-Barr virus hepatitis – Epstein-Barr virus (EBV) has been associated with hepatitis and cholestasis, while more typical features of infectious mononucleosis include fever, pharyngitis, adenopathy, fatigue and atypical lymphocytosis. Although liver biopsy is rarely performed for patients with suspected EBV-associated hepatitis, liver histology is characterized by slightly atypical lymphoid cells filling the sinusoids (picture 4 and picture 5). (See "Infectious mononucleosis".)

●Coronavirus disease 2019 (COVID-19)-related liver injury – Liver injury related to COVID-19 has been reported [8]. For patients with severe liver injury related to SARS-CoV-2 virus, liver biopsy has demonstrated many apoptotic bodies and concurrent increased mitotic figures (picture 6). In this regard, the damage has been mostly hepatocellular. Bile duct damage has also been seen, which may be associated with elevated alkaline phosphatase (picture 7). (See "COVID-19: Issues related to liver disease in adults".)

Autoimmune hepatitis — Autoimmune hepatitis is a chronic, inflammatory disease of the liver that may start as acute hepatitis and progress to chronic liver disease and cirrhosis. Autoimmune hepatitis can be characterized histologically by lobular inflammation and portal inflammation with many plasma cells. A portal mononuclear cell infiltrate (generally lymphoplasmacytic with occasional eosinophils) invades the sharply demarcated hepatocyte boundary (limiting plate) surrounding the portal tract and infiltrates into the surrounding lobule (picture 8A-B). The periportal lesion, referred to as interface hepatitis (formerly termed piecemeal necrosis), may involve more of the lobule (picture 9 and picture 10A-B). There may also be zone 3 (centrilobular) necrosis. (See "Overview of autoimmune hepatitis".)

Some degree of fibrosis is usually present in all but the mildest forms or earliest presentations of autoimmune hepatitis. Advanced fibrosis connects portal and central areas (bridging), which ultimately, by architectural distortion of the hepatic lobule and the appearance of regenerating nodules, results in cirrhosis (picture 11A-C).

Drug-induced liver injury — Histologic findings in patients with drug-induced liver injury (DILI) have been categorized by liver histology, resulting in a spectrum ranging from mild lobular inflammation with focal necrosis to severe hepatocellular necrosis (picture 12), and for some patients, cholestasis. Examples of histologic patterns include (see "Drug-induced liver injury"):

●Acute hepatocellular injury – Acute hepatocellular injury related to DILI has been commonly associated with ingestion of acetaminophen. Histologic features of acetaminophen toxicity initially affect centrilobular (zone 3) hepatocytes and will eventually include the entire lobule, depending on the severity. The cytoplasm of the affected hepatocytes is typically eosinophilic (stained dark pink) and may appear mummified. Zonal necrosis is characteristic of drugs such as acetaminophen with predictable, dose-dependent, intrinsic toxicity (picture 13A-B). (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation".)

●Acute cholestatic hepatitis – Acute cholestatic hepatitis is characterized by portal and lobular inflammation, prominent cholestasis resulting in hepatocellular injury in the form of feathery degeneration, and bile duct damage. Bile ductular proliferation may also be seen. Hepatocyte injury is usually localized to the zones of cholestasis. Some of the drugs associated with this type of injury include erythromycin, amoxicillin-clavulanate, and angiotensin-converting enzyme inhibitors (picture 14A-B) [9-11].

Diseases associated with fatty liver — There is an overlap in the histologic features of nonalcoholic fatty liver disease (NAFLD) and alcohol-associated fatty liver disease (eg, fat droplets in hepatocytes). Typically, the etiology of fatty liver disease is determined based on clinical and laboratory features because the histologic features often cannot distinguish between NALFD and alcohol-associated disease.

●NAFLD – For patients with NALFD, hepatic steatosis is characterized by fat droplets in the hepatocytes in association with ballooning degeneration and lobular inflammation (typically occurring in zone 3) (picture 15A-B). Additional histologic findings of nonalcoholic steatohepatitis (NASH) include (see "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults" and "Metabolic dysfunction-associated steatotic liver disease in children and adolescents"):

•Apoptotic (acidophil) bodies.

•Mild chronic portal inflammation.

•Perisinusoidal collagen deposition that may result in zone 3 accentuation in a "chicken wire" pattern (related to the deposition of collagen and other extracellular matrix fibers along the sinusoids of zone 3 and around hepatocytes).

•Portal fibrosis without perisinusoidal or pericellular fibrosis (mainly seen in the pediatric patients).

•Cirrhosis, which is typically macronodular or mixed (picture 16).

•Mallory-Denk hyaline(s) (cytoplasmic hyaline inclusions of hepatocytes [12]) (picture 17A-B).

●Alcohol-associated liver disease — Clinical, laboratory, and imaging features are often adequate for establishing the diagnosis of alcohol-associated liver disease, while some patients require a biopsy if the diagnosis remains uncertain after noninvasive evaluation. (See "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis".)

Histologic features of alcohol-associated liver disease include macrovesicular steatosis that is characterized by a single large vacuole or fat droplet occupying the entire hepatocyte and thereby pushing the nucleus to the edge of the cell (picture 18). Hepatocytes may also contain Mallory-Denk hyalines surrounded by neutrophils (termed Mallory-Denk bodies), which are more characteristic of alcohol-associated steatohepatitis than NASH. In addition, Mallory-Denk hyalines tend to be more numerous and larger in patients with alcohol-associated steatohepatitis than in patients with NASH (picture 19A-E and picture 20A-B). As the alcohol-associated liver disease progresses, the histologic changes may extend to the portal tracts. Central hyaline sclerosis is fibrous tissue that gets deposited around the central venule (picture 21A-B). (See "Pathogenesis of alcohol-associated liver disease".)

Hereditary hemochromatosis — Hereditary hemochromatosis is a disorder in which increased intestinal iron absorption can lead to total-body iron overload. Liver biopsy has been supplanted by magnetic resonance imaging for estimation of iron stores for most patients with suspected hereditary hemochromatosis. However, liver biopsy can be useful for assessing the extent of fibrosis and presence of cirrhosis, as well as other causes of liver disease that may be contributing to liver injury in patients with hereditary hemochromatosis [13]. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

Histologic features of hereditary hemochromatosis include excess iron deposition, and in some patients, uniformly micronodular cirrhosis that is demonstrated by hypocellular fibrous bands (picture 22A-D and picture 23). Tests for determining the tissue hepatic iron content are discussed separately. (See "Methods to determine hepatic iron content".)

Biliary tree injury — Diseases of the biliary tree may result in cholestasis, which is the retention of bilirubin and other solutes eliminated in bile (bile salts and cholesterol). There are numerous potential causes of cholestasis (table 1), and liver biopsy is typically obtained for patients with chronic cholestasis without clear cause identified by laboratory and imaging studies.

Large bile duct obstruction — Some patients with suspected obstruction of the large bile ducts may undergo liver biopsy as part of the diagnostic evaluation. However, the initial evaluation in such patients typically includes imaging studies. (See "Choledocholithiasis: Clinical manifestations, diagnosis, and management".)

Histologic findings of bile duct obstruction have included edema and inflammation of the portal tract, in addition to loose fibrous tissue surrounding the bile duct (periductal fibrosis) (picture 24A-E).

Primary biliary cholangitis — Primary biliary cholangitis (PBC) is characterized by a T-lymphocyte-mediated attack on small intralobular bile ducts. While a liver biopsy is often not required to make the diagnosis of PBC, it may provide useful information for disease staging and prognosis. The florid bile duct lesion that is diagnostic for PBC is seen more often in the early stages of the disease. Florid-duct lesions are identified by a damaged bile duct surrounded by an infiltrate of lymphocytes and histiocytes. Granulomas may be seen in the liver biopsy specimen (picture 25A-D). Inflammatory cells surrounding the bile ducts are a mixture of lymphocytes, plasma cells, histiocytes, and eosinophils. The continuous assault on the bile duct epithelial cells leads to their gradual destruction and eventual disappearance. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis".)

Histologic findings in PBC have been classified by staging from stage 0 to 4 (table 2) (see "Histologic scoring systems for chronic liver disease", section on 'Primary biliary cholangitis'):

●Stage 0 – Normal liver

●Stage 1 – Florid-duct lesion (picture 26)

●Stage 2 – Proliferation of bile ductules (picture 27)

●Stage 3 – Bridging fibrosis and/or significant bile duct loss (picture 28)

●Stage 4 – Cirrhosis (picture 29 and picture 30)

Primary sclerosing cholangitis — Primary sclerosing cholangitis (PSC) is a chronic progressive disorder that is characterized most commonly by inflammation, fibrosis, and stricturing of medium and large ducts in the intrahepatic and/or extrahepatic biliary tree. However, some patients have a variant known as small duct PSC. The most specific histologic finding is fibrous obliteration of small bile ducts, with concentric replacement by connective tissue in an "onion skin" pattern. (See "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

The histologic findings initially involve the portal tracts but expand into the hepatic parenchyma as the disease progresses. As a result, liver biopsy is helpful for staging the disease and determining prognosis. The staging system that is used most commonly in PSC includes (picture 31A-B) [14]:

●Stage 1 – Enlargement, edema, and scarring of the portal triads, and mononuclear cell infiltration with some piecemeal necrosis and damage to isolated bile ducts. Proliferation of interlobular bile ducts with mononuclear and polymorphonuclear cells may also be present (picture 32A-B).

●Stage 2 – Expansion of portal triads with fibrosis extending into the surrounding parenchyma (picture 33).

●Stage 3 – Bridging fibrosis.

●Stage 4 – Cirrhosis (picture 34).

Vascular disorders

Budd-Chiari syndrome — Budd-Chiari syndrome is defined as hepatic venous outflow tract obstruction, independent of the level or mechanism of obstruction, provided the obstruction is not due to cardiac disease, pericardial disease, or sinusoidal obstruction syndrome (veno-occlusive disease). Liver biopsy is rarely needed for diagnosis, while histologic features of Budd-Chiari syndrome include centrizonal congestion, necrosis, and hemorrhage [15]. Large regenerative nodules, obstructive portal venopathy, and fibrosis /cirrhosis may also be found (picture 35A-C). (See "Budd-Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis".)

Congestive hepatopathy — Congestive hepatopathy refers to hepatic manifestations attributable to passive hepatic congestion, as occurs in patients with right-sided heart failure or in patients who had prior Fontan procedure. (See "Overview of the management and prognosis of patients with Fontan circulation".)

Patients may be asymptomatic with abnormal liver biochemical tests or may have symptoms such as jaundice. Microscopic examination shows sinusoidal engorgement, hepatocyte atrophy, variable degrees of hemorrhagic necrosis in zone 3 of the hepatic acinus, and variable degrees of cholestasis with occasional bile thrombi in the canaliculi (picture 36A-B). The clinical features and diagnosis of passive congestion of the liver are discussed separately. (See "Congestive hepatopathy".)

Other disorders

Idiopathic noncirrhotic portal hypertension — Idiopathic noncirrhotic portal hypertension (INCPH) is characterized by signs of portal hypertension without biopsy-proven cirrhosis and without obstruction in the extrahepatic portal vein and hepatic venous outflow tract.

The histologic findings associated with INCPH can be classified into three subtypes that include (see "Noncirrhotic portal hypertension", section on 'Idiopathic noncirrhotic portal hypertension/Porto-sinusoidal vascular disease'):

●Nodular regenerative hyperplasia – Nodular regenerative hyperplasia is demonstrated by micronodular transformation of the liver parenchyma, with nodules composed of hyperplastic hepatocyte plates, atrophic hepatocytes at the borders, and no fibrosis (picture 37A-B).

●Obliterative portal venopathy – Obliterative portal venopathy is demonstrated by phlebosclerosis of the small and medium branches of the portal vein. This is characterized by increased portal connective tissue around the vessels with irregular wall thickening and eccentric narrowing of the vessel lumen (picture 38 and picture 39). Dystrophic vessels are frequently present, usually in the form of herniated portal veins or paraportal shunts.

●Incomplete septal cirrhosis – Incomplete septal cirrhosis is defined by slender, incomplete septal fibrosis that demarcates the liver parenchyma into nodules. The portal tracts are hypoplastic and hepatocytes are hyperplastic. These changes may be seen in patients with regression of cirrhosis.

Hematologic malignancies — Hematologic malignancies with liver involvement include:

●Diffuse large B-cell lymphoma – Patients with diffuse large B-cell lymphoma (DLBCL) typically present with a rapidly enlarging symptomatic mass, most usually nodal enlargement in the neck or abdomen. Histologic features of DLBCL include atypical lymphoid infiltrate within a portal area (picture 40A-B). Staining for pan-B cell markers is performed to establish the diagnosis, and the immunophenotype and genetic features of DLBCL are discussed separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

●Small lymphocytic lymphoma/chronic lymphocytic leukemia – Liver injury in patients with lymphoma has mainly involved the portal tracts. Liver biopsy may show expansion of portal tracts by chronic inflammatory infiltrates and may be mistaken for chronic hepatitis. Close-up view of the cells shows a monomorphic lymphoid population, which should prompt further testing with immunohistochemistry (picture 41).

●Hepatosplenic T cell lymphoma – Most patients with hepatosplenic T-cell lymphoma have hepatosplenomegaly and abnormal liver biochemical tests. Histologic features on liver biopsy include atypical lymphoid cells infiltrating the sinusoids, but the portal tracts are generally uninvolved (picture 42A-B). Immunohistochemical studies and T-cell receptor gene studies are also performed as part of the diagnostic evaluation, and this is discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of hepatosplenic T cell lymphoma".)

SUMMARY AND RECOMMENDATIONS

●Background – Histopathologic examination of the liver can provide useful information regarding structural integrity, type and degree of injury, disease activity, response to treatment, disease progression, and degree of fibrosis. A nontargeted liver biopsy is typically performed in patients with persistently elevated liver biochemical tests without a clear cause identified by clinical features, laboratory studies, or imaging. (See 'Introduction' above.)

●Liver microstructure – The microscopic structure of liver parenchyma has been commonly conceptualized in two ways (figure 1) (see 'Liver microstructure' above):

•Acinar model – The acinus contains a small portal tract at the center and terminal hepatic venules at the periphery. It is divided into zones 1, 2, and 3, wherein zone 1 surrounds the portal tract and zone 3 surrounds the hepatic venule. Blood from the portal tract flows though these zones to the venule with a decreasing oxygen and nutrient gradient.

•Traditional lobule model – In the lobule model, the central structure of microcirculation is the terminal hepatic venule (also referred to as central vein/venule). Thus, this area is known as the centrilobular zone, while the periphery is delineated by portal tracts with the parenchyma surrounding portal zones referred to as periportal.

●Correlating histology with clinical data – Histologic findings of the liver may often be nonspecific, and most cases require clinical and histologic correlation to arrive at the most accurate final diagnosis. Data provided to the pathologist by the clinician at the time of biopsy should include (see 'Correlating histology with clinical data' above):

•Age and sex of the patient

•Timing of onset and duration of liver disease

•Suspected clinical diagnosis, which will often lead to a more targeted search by pathologist

•Laboratory studies (ie, liver biochemical and function tests, viral and autoimmune serologies, if available)

•Radiographic findings

●Assessing the specimen – The initial step in evaluating a liver biopsy is a visual inspection of the adequacy of the sample and the type and quality of staining. It is generally agreed that an adequate specimen is at least 15 mm in length and contains six to eight complete portal tracts. (See 'Assessing adequacy of the specimen' above.)

●Staining the specimen – Standard staining of liver biopsy specimens typically includes hematoxylin and eosin (H&E) and Masson or Gomori trichrome stains. H&E staining colors the nuclei of cells blue, while other structures appear as various hues of pink or red. Trichrome stain is useful for evaluating the amount of fibrous tissue and assessing the degree of chronic liver injury. The connective tissue (ie, fibrosis or cirrhosis) appears as various shades of blue or purple. (See 'Staining the specimen' above.)

●Recognizing histologic patterns – Histologic patterns of hepatic injury have been generally grouped by the cell or function that is most affected (eg, hepatocyte, bile ducts, vascular). Examples of patterns of hepatic injury include (see 'Recognizing histologic patterns' above):

•Hepatocellular injury – Viral hepatitis, autoimmune hepatitis

•Biliary tree injury – Primary biliary cholangitis, primary sclerosing cholangitis

•Vascular disorders – Budd-Chiari syndrome, congestive hepatopathy

The approach to obtaining a liver biopsy is discussed separately. (See "Approach to liver biopsy".)

ACKNOWLEDGMENT — Some of the examples presented in this topic represent Dr. Marshall M. Kaplan's collection of specimens spanning four decades, and have been used in training generations of gastroenterology and hepatology fellows. UpToDate wishes to acknowledge Dr. Kaplan's past work as an author for this content, as well as his work as our Section Editor for Alcohol-associated and Metabolic Liver Disease.