Cirrhosis and portal hypertension

PART 7  Hepatic Disease

SECTION I  Inflammatory, Infective, and Congenital D. Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure

CHAPTER 76  Cirrhosis and portal hypertension: pathologic aspects Elizabeth M. Brunt and Danielle H. Carpenter

OVERVIEW Cirrhosis, the final stage of untreated chronic liver disease, is attributable to alcohol abuse, viral hepatitis C, and, more recently, nonalcoholic steatohepatitis (NASH) in the industrialized world (Tsochatzis et al, 2014) and accounts for the 14th most common cause of death in adults (Hoyert & Xu, 2012). The true prevalence of cirrhosis is unknown; one reason is that in the early stages, the condition is usually asymptomatic. However, in the United States, 33,539 deaths per year are attributed to cirrhosis (Hoyert & Xu, 2012). In autopsy series, cirrhosis is documented in 5% to 10% of cases, but autopsy subjects may not be representative of the general population (Karsan et al, 2004). Currently, there is consideration from clinicians (Garcia-Tsao et al, 2010) and pathologists alike (Kim et al, 2012) to consider cirrhosis as a process with many stages, rather than a single entity; in this conceptual framework, only the end stage requires transplant as definitive treatment, whereas the preceding stages can be managed with more aggressive medical therapies and preventions (Tsochatzis et al, 2014). The cirrhotic liver functions significantly less efficiently than normal liver, but it is the aberration of the portal blood flow with resultant portal hypertension that causes the most significant complications of cirrhosis (Tsochatzis et al, 2014). In addition, cirrhosis itself is a major predisposing condition to hepatocellular carcinoma (HCC), and is increasingly recognized as a predisposing condition for intrahepatic cholangiocarcinoma (CCA) and liver carcinomas of mixed hepatocellular-biliary phenotypes, likely due to the inflammatory microenvironment as well as the plasticity of cell types within the liver (Raggi et al, 2015). Interestingly, the cirrhotic liver is considered to be resistant to metastases from extrahepatic tumors. Recently, a prospective epidemiologic study of more than 162,000 multiethnic Americans during an 18 year period has confirmed smaller studies that caffeinated coffee is protective against mortality from various chronic liver diseases and incident HCC in chronic liver disease (Setiawan et al, 2015). It is also recognized that portal hypertension may occur in the absence of the structural alterations of cirrhosis, a condition 1148

referred to as noncirrhotic portal hypertension. The underlying conditions associated with noncirrhotic portal hypertension may be idiopathic but are broadly subdivided into prehepatic, intrahepatic, or posthepatic in terms of clinical presentation and for management considerations. This chapter focuses on the histopathologic features of both cirrhosis and noncirrhotic portal hypertension.

CIRRHOSIS: HISTOPATHOLOGIC FEATURES Cirrhosis is ultimately characterized as a process of diffuse parenchymal remodeling, including the hepatic vascular architecture. Thin-walled vascular and lymphatic channels proliferate within newly formed septa that separate nodular groups of hepatocytes. Although portal tracts can still be identified within the septa, terminal hepatic venules, the outflow vessels of the liver, are most often either obliterated by the disease process (as in alcoholic liver disease [ALD]), or incorporated into the septa along with necroinflammatory lesions of the parenchyma. Thus the nodules are devoid of draining vessels. The septa typically contain a mixture of chronic inflammatory cells, including macrophages, and may include epithelial cells. The latter may include residual trapped hepatocytes, but these are primarily biliary cells. The process of epithelial-mesenchymalinflammatory interaction at the interface with damaged hepatocytes is referred to as the ductular reaction, a prototypic response that occurs in all forms of chronic liver disease (Gouw et al, 2011; Roskams et al, 2004). Between the septa and the hepatic nodules, a rim of keratin 19–positive ductular cells in strings and small tubules can be appreciated; many appear to merge with the hepatocytes of the nodules. These are progenitor cells within the canals of Hering, the distalmost ramifications of the biliary tree, and at least some of these are considered stem cells (Roskams, 2006). The epithelial component within this rim is progressively attenuated and then lost with progression of the intranodular hepatocytes from cirrhosis to dysplastic nodule to HCC (Lennerz et al, 2011). This can be appreciated by immunohistochemical staining with antibodies to either keratin 7 or 19.



D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 76  Cirrhosis and portal hypertension: pathologic aspects Gut-derived PAMPs

Macrophages

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Hepatocytes Apoptotic bodies

B cells Increased NF-κB activation, chemokine secretion, BAMBI repression

Immunoglobulinindependent mechanism

IL-1 and TNFmediated NF-κB activation and HSC survival; fibrogenic cytokines

IL-33

ILC2

Apoptotic bodies DNA Other DAMPS?? IL-13

???

CXCR4+ LSEC (without fenestrae)

ANTIFIBROGENIC HSC PROFIBROGENIC Nitric oxide MMP-mediated fibrinolysis HSC killing

Macrophages

FasL and Trailmediated HSC killing

NK cells

Met-dependent repression of HSC activation

LSEC (with fenestrae)

Platelets

FIGURE 76.1.  Fibrogenesis: This figure highlights the cell-cell interactions of matrix production and resolution. (From Seki E, Schwabe RF: Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 61:1066-1079, 2015.)

Pathogenesis and Reversibility of Cirrhosis The transformation from normal hepatic architecture through fibrosis (aberrant matrix deposition) to advanced cirrhosis ultimately results from progressive deposition of mixed connective tissue in regions of “extinct” parenchyma, angiogenesis, and vascular remodeling, regardless of the underlying etiology. Fibrogenesis is a dynamic, complex, and highly regulated process, triggered by liver parenchymal injury and mediated by the interplay of cellular necrosis and apoptosis on one hand (see Chapter 7), and inflammatory cascades that include immune cells (see Chapter 10), cytokines, and chemokines (see Chapter 11) on the other hand, which result in activation of specific matrix-producing cells (Hernandez-Gea & Friedman, 2011; Seki & Schwabe, 2015). These cells are resident hepatic stellate cells and portal myofibroblasts. During fibrogenesis, prevention of matrix degradation by metalloproteinases is orchestrated by the release of potent tissue metalloproteinase inhibitors; apoptosis of fibrogenic hepatic stellate cells is also inhibited (Figs. 76.1 and 76.2) Scar formation is the consequence of an imbalance favoring collagen synthesis and deposition versus degradation and resorption. Established cirrhosis has traditionally been considered as an irreversible process, but accumulating evidence from observations by pathologists (Wanless et al, 2000) and from treatment trials with pretreatment and posttreatment biopsies for viral hepatitis B, C, and hereditary hemochromatosis have shown that this is not necessarily the case. A study by Poynard and colleagues (2002) analyzed 3010 patients with chronic hepatitis C virus (HCV) included in four major clinical trials to receive randomized treatment regimens with interferon (IFN) or pegylated IFN, with or without additional ribavirin. Reversal of cirrhosis was reported in 75 (49%) of 153 patients with

HM B Lympho ILC2

Inflammation

Crosstalk and Amplification

Cell death

Hepatocytes

HSC

Fibrosis

FIGURE 76.2.  Links of cell death, various forms of inflammatory responses and fibrosis are shown in this figure. B lympho, B lymphocyte; HM, hepatic macrophage; HSC, hepatic stellate cell; ILC2, type 2 innate lymphoid cell. (From Seki E, Schwabe RF: Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 61:10661079, 2015.)

baseline cirrhosis. Pol and associates (2004) examined 64 immunocompetent patients with HCV-related cirrhosis and found that cirrhosis disappeared in 5 patients (7.8%) on follow-up biopsies at a mean interval of 4.6 years. In addition, 3 of 4 patients undergoing dialysis showed reversal of cirrhosis secondary to HCV infection, and resolution of cirrhosis was shown in 2 patients upon examination of the whole liver explants at the time of transplantation. Falize and colleagues (2006) analyzed 36 patients with hereditary hemochromatosis

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and demonstrated that regression of fibrosis was seen in 69% of those with bridging fibrosis and in 35% of patients with cirrhosis after institution of venosection therapy. Regression of cirrhosis has also been reported in patients with other diseases, including ALD, autoimmune hepatitis (AIH), and primary biliary cirrhosis (Arthur, 2002; Fallowfield & Iredale, 2004; Serpaggi et al, 2006). The proposed mechanisms for breakdown and remodeling of liver fibrosis include loss of activated stellate cells via apoptosis, decreased expression of matrix metalloproteinase inhibitors, and increased production and activity of metalloproteinases or collagenases (Seki & Schwabe, 2014). Currently, the extent to which cirrhosis is truly reversible is the subject of debate, and an important question not often addressed is the extent to which actual parenchymal and vascular architecture can be restored even if scar tissue is resorbed (Desmet & Roskams, 2003). Considerations include sampling differences or interpretation errors in the studies showing reversibility; these questions rely on comparisons with prior biopsies for convincing answers. Regardless, these discussions have important clinical implications. Finally, Lee and Friedman (2014) have recently introduced and discussed the concept that even with viral cure in hepatitis C, a minority of subjects actually do continue with progressive disease (fibrosis) and HCC (see Chapter 91).

Role of Liver Biopsy in Advanced Liver Disease In modern medicine, investigation of patients with chronic liver disease and cirrhosis involves multiple disciplines and clinical tools, including pathology, radiology, clinical chemistry, virology, serologic testing, and most recently, molecular testing. Liver biopsy evaluation is diminishing while more serum markers and imaging tests gain traction in clinical practice (Tsochatzis et al, 2014); however, in cases with unknown clinical diagnoses, liver biopsy can still be considered a primary diagnostic tool, despite the drawback of invasiveness (Ma & Brunt, 2012; Rockey et al, 2009) (see Chapter 22). In fact, liver biopsy can serve several important purposes, such as establishing or confirming cirrhosis; assessing the possible underlying causes of disease; analyzing the grade of ongoing necroinflammatory activity; detecting dysplastic lesions or a clinically occult HCC; and providing tissue for chemical, biochemical, molecular, or ultrastructural studies (Brunt, 2000). Needle biopsy, rather than wedge biopsy, has proved to be the most useful technique to obtain representative liver tissue for most types of analysis. This procedure can be done percutaneously, via the transjugular route when pressure measurements are being taken, or during surgical procedures (see Chapters 22 and 87). A cutting needle or the Menghini aspiration needle may be used, although the former usually generates a better biopsy specimen for histologic evaluation. If cirrhosis is suspected, a cutting needle is the preferred method of biopsy because an aspiration needle often results in a fragmented specimen that makes histologic evaluation difficult. The size (both length and diameter) of the needle is important in avoiding sampling error. Traditionally, it has been recommended that an adequate biopsy specimen should be no smaller than 20 gauge and at least 1.5 cm in length, or it should contain at least five portal tracts (Rockey et al, 2009). For accurate and reliable grading and staging of chronic viral hepatitis, however, studies have shown that a biopsy specimen of 2 cm in length or longer that contains at least 11 complete portal tracts is needed (Guido & Rugge, 2004).

FIGURE 76.3.  Wedge biopsy showing overestimation of fibrosis just beneath the liver capsule (Gomori reticulin stain). Arrows indicate fibrous septa extending into the hepatic parenchyma.

Usually performed during open surgery or laparoscopy, wedge biopsy is discouraged for evaluation of diffuse parenchymal liver diseases, such as cirrhosis, because this technique samples primarily the subcapsular liver parenchyma, which may contain misleading fibrous septa extending from the capsule that could be easily confused or overinterpreted as cirrhosis or bridging fibrosis (Fig. 76.3). A wedge biopsy is most suitable for evaluation of focal lesions present on or immediately below the capsule. Even during open surgery, a needle biopsy to sample deep liver parenchyma is preferable (Guido & Rugge, 2004). Prompt fixation of the liver biopsy specimen in buffered formalin is vital to high-quality histology. Many special stains and analyses, such as iron or copper quantitation, and newer molecular and genomic analyses can be performed on formalinfixed, paraffin-embedded (FFPE) tissue. If an unusual metabolic disorder is suspected and electron microscopic examination is expected, prebiopsy discussion with the pathologist is useful so that additional fresh tissue can be fixed in glutaraldehyde. For final interpretation of any liver tissue, sufficient clinical information is necessary.

Morphologic Findings in Cirrhosis Grossly, the liver with established cirrhosis exhibits a nodular appearance that diffusely involves the entire liver (Fig. 76.4). The cirrhotic liver is firm and may be enlarged or shrunken. The parenchyma may be tan, yellow (when fatty), or dark green when there is hyperbilirubinemia. The nodules’ sizes are discussed in terms of less than or greater than 3 mm; the former, “micronodular,” are prototypic in ALD when predominant, but mixed micromacronodular cirrhosis is most common and can occur with the majority of long-standing liver disease. Large, bulging, and nodules that are notably discolored from background are worrisome for malignancy, particularly HCC. Microscopically, the liver parenchyma is divided by interconnecting, variable-sized fibrous septa that contain profiles of lymphatic and vascular lumina, as well as epithelial-lined ductular structures and diverse inflammatory cell types; the septa divide the parenchyma into the nodules that typically no longer retain an identifiable terminal hepatic venule. However,



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FIGURE 76.4.  Gross appearance of cirrhotic liver showing diffuse involvement of the entire liver by regenerative nodules and fibrous scar.

identifiable portal tracts may be found within the septa. The normal portal-central relationship is lost; the exception to this remodeling is biliary cirrhosis, in which the terminal hepatic venule may retain its central location. The hepatocytes within the nodules may appear morphologically normal, may be undergoing active injury from the disease process, or may show evidence of regeneration. The latter may be characterized by thickened cell plates with as many as two cells across; anisonucleosis; large-cell change with maintenance of nuclear/ cytoplasmic (N/C) ratio; or small, crowded cells with increased N/C ratios. The reticulin stain is useful to show cord thickening. By some immunostudies, it is apparent the cells within some nodules are derived from “newly formed” immature cells of stem cell lineage (Roskams et al, 2003). The presence of increased ductular profiles within connective tissue admixed with inflammation is referred to as a ductular reaction (Roskams et al, 2004). Some septa may retain lymphoid aggregates, and some may have interface hepatitis, indicative of ongoing hepatitic activity. Biliary cirrhosis is caused by disorders such as primary biliary cirrhosis, primary or secondary sclerosing cholangitis, and biliary atresia. This type of cirrhosis exhibits unique morphologic features appreciated microscopically and characterized by a highly irregular “jigsaw puzzle” or “geographic” nodular pattern (Fig. 76.5). As noted, the terminal hepatic venule may be retained, and loss or effacement of native bile ducts by either lymphoid aggregates or scar tissue may be evident. Ductular reaction (proliferation) may be more pronounced than in other types of cirrhosis. A characteristic clue to biliary cirrhosis is the constellation of findings in periseptal hepatocytes referred to as cholate stasis. These findings include periseptal hepatocyte swelling/ballooning, Mallory-Denk bodies (Mallory’s hyaline), and granules of copper deposition. In addition, foam cell aggregates may be seen in the sinusoids of the nodules. Some investigators have attributed abundant large-cell change to chronic cholestasis. Another subtle histologic clue to biliary cirrhosis is the presence of nodular regenerative hyperplasia within the regenerative nodules. Recognition of cirrhosis can be straightforward when an adequate biopsy specimen is examined, even on hematoxylin and eosin–stained sections. It may be helpful to use Masson

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FIGURE 76.5.  Biliary cirrhosis exhibiting a “jigsaw puzzle” pattern (Masson trichrome stain).

FIGURE 76.6.  Cirrhosis visible on a needle biopsy specimen (Masson trichrome stain).

trichrome or another connective tissue stain to highlight the dense perisinusoidal fibrosis of alcoholic hepatitis and cirrhosis, particularly for fragmented needle biopsy specimens (Fig. 76.6). Fragmentation of the specimen noted at the time of biopsy should raise the suspicion of cirrhosis. On histologic sections, a significant clue is the numerous vascular channels within septa that traverse or course across the core biopsy; in addition, a thin layer of collagen, better appreciated on trichrome and reticulin stains, tends to adhere to the rounded surface of the detached nodules. On the other hand, cirrhosis may be difficult to diagnose on needle biopsy specimens, for instance, when a macronodule is sampled or when cirrhosis is incomplete (incomplete septal cirrhosis). In the last case, the complete spectrum of morphologic features of cirrhosis are not exhibited, but vascular relationships are markedly altered, and ectatic, eccentrically located portal veins may be noted. In addition, the septa are thin, and some may be seen to extend into the parenchyma and end blindly. This type of “cirrhosis” is common in HBV-related liver disease.

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Additional stains considered routine by liver pathologists in evaluation of liver biopsies include the iron stain and periodic acid–Schiff stain after diastase digestion (PAS-d). The former is useful in detecting and relaying semiquantification of hepatocellular iron, detecting reticuloendothelial iron, and highlighting intracanalicular bile plugs. PAS-d is useful in detecting the variable-sized periportal eosinophilic “globules” that accumulate in the endoplasmic reticulum when a Z allele is present in subjects with either MZ or ZZ α1-antitrypsin deficiency. PAS-d also is quite helpful in noting bile duct basement membranes, perisinusoidal basement membranes, and PAS-d–laden Kupffer cells and portal and septal macrophages characteristic of recent necroinflammatory activity. Not all larger nodules detected in cirrhotic livers are malignant. A macroregenerative nodule or large regenerative nodule usually measures 0.5 to 1.5 cm and is rarely 5 cm or more in diameter (International Working Party, 1995). It is seen more commonly in macronodular cirrhosis and may be distinct from surrounding cirrhotic nodules on gross examination. Histologically, a macroregenerative nodule may contain portal structures or short fibrovascular septa. The hepatocytes within the nodule are similar to the hepatocytes in smaller cirrhotic nodules but almost always exhibit hyperplastic change, evidenced by thickened plates. The clonal nature of the macroregenerative nodule has been shown, and its malignant potential is low, but unquestioned (Park, 2011). A dysplastic nodule is a premalignant lesion that usually measures more than 0.5 cm (International Working Party, 1995). Evolution to HCC within months or a few years has been well documented (Hytiroglou, 2004). A high-grade dysplastic nodule exhibits more clear-cut architectural or cytologic atypia, such as bulging or maplike clonal growth; pseudoglandular formation; unpaired arteries; and small-cell change characterized by increased cell density, high N/C cell ratio, and nuclear hyperchromasia. These morphologic changes are insufficient, however, for the diagnosis of HCC because a dysplastic nodule does not invade the surrounding stroma or blood vessels, and it maintains cell plates no more than three cells wide (Roncalli, 2004). Distinguishing a high-grade dysplastic nodule from welldifferentiated HCC can be extremely difficult or impossible from a needle biopsy specimen, although it may be less ambiguous when an explant is examined (Fig. 76.7) (Kojiro, 2004). Identification of ductular reaction at the periphery aids in positive identification of cirrhosis or dysplastic nodule (Lennerz et al,

2011; Park et al, 2007). Clinical management of patients with cirrhosis and dysplasia in biopsy specimens is challenging.

Assessment of Underlying Etiology in Cirrhosis Cirrhosis is best classified by its underlying etiology if possible (Box 76.1), which can be determined by clinical history and laboratory investigation in many but not all cases. Morphologic examination may help establish the diagnosis or guide the clinical investigation. In the following discussion, the morphologic features characteristic of many chronic liver diseases that commonly cause cirrhosis are discussed. At end-stage liver disease,

BOX 76.1  Causes of Cirrhosis Drugs and Toxins Alcohol Methotrexate Isoniazid Methyldopa Amiodarone Infections Hepatitis B Hepatits C Hepatitis D Schistosomiasis Autoimmune Disorders Autoimmune hepatitis Primary biliary cirrhosis Primary sclerosing cholangitis Inherited Metabolic Defects Hemochromatosis Wilson disease α1-Antitrypsin deficiency Galactosemia Tyrosinemia Glycogen storage disease Hereditary fructose intolerance Urea cycle disorders α/β Lipoproteinemia Progressive familial intrahepatic cholestasis Cystic fibrosis Acquired Bile Duct Diseases Biliary atresia Gallstone obstruction Common bile duct stricture Vascular Disorders Budd-Chiari syndrome Venoocclusive disease Congestive heart failure Hereditary hemorrhagic telangiectasia

FIGURE 76.7.  Gross photomicrograph of hepatocellular carcinoma (arrow) in a cirrhotic liver. The tumor stands out from the background cirrhosis.

Miscellaneous Nonalcoholic steatohepatitis Total parenteral nutrition Indian childhood cirrhosis Intestinal bypass surgery Hypervitaminosis A Sarcoidosis Cryptogenic Modified from MacSween RNM, et al. Pathology of the liver, 4th ed. London, 2004, Churchill Livingstone.



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however, the histopathologic findings may no longer be evident, even to experienced hepatopathologists. Many cases of “cryptogenic” cirrhosis represent burned-out processes, for which no identifying clinical or morphologic features remain. These cases are frequently due to ALD, AIH, and nonalcoholic fatty liver disease (NAFLD). The possible contribution of as yet unnamed viral agents is not known.

Alcoholic Liver Disease Excessive alcohol consumption is arguably the leading cause of liver disease in the Western World, which encompasses a clinicopathologic spectrum that includes fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. Alcoholic cirrhosis, or Laënnec cirrhosis, is classically micronodular and may retain some of the features of alcoholic hepatitis. The liver may appear pale or yellow, enlarged and greasy, or shrunken on gross examination. Histologically, in the initial stages, lesions predominate in the perivenular region (zone 3) of the acinus and include various combinations of steatosis (fat), ballooning, Mallory-Denk bodies, and satellitosis. Steatosis may be predominantly macrovesicular, defined by the presence of large fat droplets in the cytoplasm of hepatocytes displacing the nuclei. Microvesicular steatosis can also be seen, characterized by fine fat droplets surrounding the centrally-retained nuclei. Alcoholic hepatitis is characterized by an inflammatory infiltrate rich in neutrophils, most frequently distributed in the lobules adjacent to hepatocytes containing Mallory-Denk bodies (i.e., satellitosis), and dense, perisinusoidal fibrosis (Fig. 76.8). Lymphocytes and histiocytes also may be present (Colombat et al, 2002), sometimes in the form of lipogranulomas, and megamitochondria also may be evident. In the portal and periportal regions, ductular reaction with numerous neutrophils may occur. Cholangiolitis and canalicular bile plugs are worrisome lesions for concomitant pancreatitis. The patterns of fibrosis in alcoholic hepatitis are characteristic. Fibrosis usually involves the terminal hepatic venules, leading to the thickening of the wall; luminal occlusion may be seen with necrosis of adjacent hepatocytes and Mallory-Denk bodies within remaining hepatocytes, a lesion referred to as central hyaline necrosis. Subendothelial fibrosis is a venoocclusive

FIGURE 76.8.  Alcoholic hepatitis characterized by macrovesicular steatosis, hepatocyte ballooning, lobular neutrophilic infiltration, and presence of Mallory-Denk bodies.

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lesion of alcoholism that may be noted even in end-stage cirrhotic livers. Fibrosis may extend into the lobules in perisinusoidal spaces as delicate or dense strands, giving rise to a distinctive “chicken wire” pericellular (perisinusoidal) distribution. Trichrome stain is particularly useful in detecting this unique form of fibrosis. With time, the liver may be replaced by micronodular cirrhosis; often, the septa of ALD are quite broad as manifestations of the microvascular obliteration. (Brunt et al, 2012) While alcoholic cirrhosis progresses, the aforementioned morphologic features may become less obvious. The liver may shrink and be nearly replaced by fibrosis, and the cirrhosis may evolve into a macronodular or mixed nodular architecture with characteristic broad septa. Steatosis, ballooning, and Mallory-Denk bodies may not be discernible, especially in patients who have stopped consuming alcohol for several months or years.

Nonalcoholic Fatty Liver Disease NAFLD is the most common cause of liver test elevation in the Western World. Prevalence studies estimate that approximately 20% to 25% of the US population is affected by fatty liver; of these individuals, 15% to 20% are at risk for progression to cirrhosis (Angulo, 2002). The lesions noted in liver tissue may resemble many of the features of alcohol-induced liver damage in individuals who are not heavy drinkers (Brunt et al, 2012). The disease is etiologically attributed primarily to insulin resistance and is considered the hepatic manifestation of the metabolic syndrome, a constellation of risk factors for cardiovascular disease that includes obesity, hypertension, diabetes, and hyperlipidemia (Marchesini et al, 2001) (see Chapter 71). Histopathologic differences and similarities of NASH and ALD are reviewed elsewhere (Brunt et al, 2012). Pertinent to this chapter are the following. Most, but not all, of the histopathologic features described in alcoholic hepatitis can be found in NASH; lesions of injury can be seen in cirrhosis of both ALD and NAFLD. These mainly include steatosis, which is predominantly macrovesicular (large droplet or mixed large and small droplets); hepatocyte ballooning; lobular inflammation, which is usually mild and includes neutrophils; small lipogranulomas; and varying amounts of perisinusoidal fibrosis (Fig. 76.9). The presence of heavy portal inflammation, particularly when accompanied by lymphoid aggregates or abundant plasma cells, should raise the suspicion of overlapping disease, such as chronic viral hepatitis or AIH (Brunt et al, 2003), and extensive portal chronic inflammation in the absence of an overlapping disease has been shown to correlate with advanced NASH and more severe clinical metabolic features (Brunt et al, 2009). In addition, Mallory-Denk bodies may or may not be seen in NASH; if present, they may be poorly formed. In contrast to ALD, in which Mallory-Denk bodies may be present in apoptotic hepatocytes, in NASH they are restricted to ballooned hepatocytes. Recently, an immunohistochemical stain to detect loss of K8/18 in ballooning, as well as presence of clumped K8/18 in Mallory-Denk bodies, has been introduced (Lackner et al, 2008). If numerous MalloryDenk bodies are present in the background of steatohepatitis, an alcoholic origin is more likely (Brunt et al, 2012). Likewise, marked cholestasis is highly unlikely in precirrhotic NASH but can occur in ALD. The broad septa of ALD are rare in NAFLD as well. Fibrosis in NASH begins in the pericentral perisinusoidal spaces; with time, portal and periportal fibrosis develop, and

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FIGURE 76.9.  Zone 3 “chicken wire” perisinusoidal fibrosis; this feature can be seen in nonalcoholic and alcoholic steatohepatitis (Masson trichrome stain).

eventually bridging fibrosis and cirrhosis may occur. This typically does not obliterate the terminal hepatic venules, a feature dissimilar to alcoholic hepatitis. A grading and staging system has been proposed for NASH primarily based on the extent and severity of the constellation of steatosis, ballooning change, the grade of lobular and portal inflammation, and the stage of fibrosis and remodeling (Brunt et al, 1999). Similar to the widespread use of grading and staging in other forms of chronic liver disease, this proposal was made in recognition of the unique features of steatohepatitis to facilitate further reproducible evaluation for clinical and laboratory investigation. A revision of this system by the National Institute of Diabetes and Digestive and Kidney Diseases–sponsored NASH Clinical Research Network is used widely in clinical trials (Kleiner et al, 2005).

Chronic Hepatitis C Before the new IFN-sparing curative therapies for HCV, cirrhosis developed in a high proportion of patients infected with HCV, especially patients with a long duration of infection, concurrent alcohol consumption, coinfection with HBV or human immunodeficiency virus, nonresponse to antiviral therapy, and men (see Chapter 70). Interestingly, even after virologic cure, a small number of individuals from large clinical trials (7% to 13%) continue to have fibrosis progression or even cirrhosis. (Lee et al, 2014) HCV-related cirrhosis is virtually always macronodular or mixed macronodular and micronodular. The fibrovascular septa vary in width and usually are infiltrated by mononuclear cells, predominantly lymphocytes, but also include plasma cells and eosinophils. Lymphoid aggregates, often with well-formed germinal centers, are characteristic, although not pathognomonic (Fig. 76.10). A mild degree of bile duct damage (the Poulsen lesion) also may be seen in some cases, and interface hepatitis may also be present. The lobular inflammation is typically spotty and mild, with or without acidophilic bodies. Subendothelial inflammation in portal veins, identical to endotheliitis, also may occur in HCV infection. No reliable antibody for immunohistochemical detection of HCV proteins has been found.

FIGURE 76.10.  Hepatitis C virus cirrhosis with characteristic septal lymphoid aggregates.

Chronic Hepatitis B Chronic hepatitis secondary to HBV infection is another common cause of cirrhosis (Fattovich, 2003; Ganem & Prince, 2004; Lai et al, 2003) (see Chapter 70). Compared with hepatitis caused by HCV, HBV hepatitis may exhibit more severe portal and lobular necroinflammation, particularly when there is an acute exacerbation. Confluent or multiacinar bridging necrosis with collapse of the lobular framework may be seen. A relatively specific finding in chronic HBV hepatitis is the presence of “ground-glass” inclusions within hepatocytes, which are uniform, pale, or eosinophilic cytoplasmic alterations resulting from enriched smooth endoplasmic reticulum filled with hepatitis B surface antigen (Fig. 76.11). However, changes resembling ground-glass inclusions have been observed in a variety of conditions (Wisell et al, 2006). A definitive diagnosis can be established by histochemical stains (orcein, Victoria blue) or with immunohistochemical detection of hepatitis B surface antigen in the cytoplasm and hepatitis B core antigen in the nucleus. Coinfection or superinfection with hepatitis D virus (HDV) in HBV patients usually causes more severe liver damage and accelerates the development of cirrhosis (Farci, 2003). Immunohistochemical detection of HDV intranuclear antigen is helpful in establishing the diagnosis.

Autoimmune Hepatitis The diagnosis of AIH relies on a constellation of clinical, laboratory, and histopathologic findings; clinically, AIH may include cirrhosis either as an end result or at presentation. Histopathologic examination of liver tissue serves important roles in confirming clinical concern and excluding diseases secondary to other etiologies (Czaja, 2015). Classic AIH exhibits a dense portal, septal, and lobular mononuclear cell infiltrate, with marked periportal or periseptal interface hepatitis enriched in plasma cells. The presence of numerous plasma cells in portal inflammation and within lobular foci of necrosis and the formation of hepatitic “rosettes” are characteristic (Fig. 76.12). In severe cases, confluent or bridging necrosis may be seen, sometimes accompanied by pseudoacinar formation. Predominantly



D.  Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure  Chapter 76  Cirrhosis and portal hypertension: pathologic aspects

FIGURE 76.11.  Ground-glass hepatocytes (arrow) in chronic hepatitis B virus.

FIGURE 76.12.  Autoimmune hepatitis may be characterized by hepatitic “rosettes” and numerous plasma cells (arrows) in the portal tracts and lobules.

centrilobular necrosis with relatively mild portal inflammation also has been described in AIH (Misdraji et al, 2004). Fibrosis may rapidly progress in untreated patients. At the cirrhotic stage, the liver parenchyma is divided by broad, fibrous bands into variable-sized nodules, similar to those caused by alcoholic or chronic viral hepatitis; plasma cells and rosettes may become less prominent. Burned-out AIH may be a cause of “cryptogenic” cirrhosis. Morphologic features do not separate different types of AIH, classified by either autoantibody profiles, plasma proteins, or immunogenetic markers, such as elevated IgG (McFarlane, 2002).

Primary Biliary Cirrhosis Primary biliary cirrhosis (PBC) is an autoimmune disorder that leads to progressive destruction of intrahepatic bile ducts (Imam & Lindor, 2014). In the early stage, the disease is characterized by mixed chronic portal inflammation with lymphocytes, plasma cells, eosinophils, and the pathognomonic “florid duct lesion,” characterized by lymphocytic or granulomatous

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FIGURE 76.13.  Florid duct lesion with granulomatous portal inflammation and damaged bile duct (arrow) in early-stage primary biliary cirrhosis.

bile duct infiltration (Fig. 76.13). Ductular reaction and interface hepatitis may be seen in more advanced cases. In the setting of positive serum antimitochondrial antibody (AMA), the florid duct lesion is essentially diagnostic. The affected duct may rupture, or the duct epithelium may exhibit degenerative change. With disease progression, ductopenia becomes evident. The native ducts may be absent or obscured by lymphoid aggregates or collections of foamy macrophages. Cholate stasis, as previously described, may be an initial clue to the diagnosis. Features of other autoimmune disease processes may occur together in the liver; these include AIH and, less commonly, primary sclerosing cholangitis (PSC) (Abdalian et al, 2008) AMA-positive primary biliary cirrhosis. Any combination is referred to as overlap syndrome, and the pathology evaluation frequently determines the dominant process (Floreani et al, 2014). True cirrhotic remodeling is seen only at the late stage of PBC; it is commonly inhomogeneously distributed and may be micronodular. Florid duct lesions and granulomas may continue to exist where native bile ducts have not been completely destroyed. Canalicular cholestasis with bile plugs may be seen in the late stage and is regarded as a sign of poor prognosis. The term autoimmune cholangiopathy—also known as antinuclear antibody–positive, AMA-negative PBC—has been used to describe the disease seen in a small subset (<5%) of patients who are seen with typical clinical and histopathologic findings of PBC but are seronegative for AMA. These patients may have other autoantibodies, such as antinuclear antibody and anti–smooth muscle antibody, as seen in AIH. Accumulating evidence suggests that autoimmune cholangiopathy and PBC are likely to be a single disease with variations in the type and concentration of autoantibodies (Vierling, 2004) as well as immunophenotypes in portal infiltrates (Jin et al, 2012). HCC may occur in PBC before cirrhosis; surveillance programs have been proposed (Silveira et al, 2008).

Primary Sclerosing Cholangitis PSC, another idiopathic inflammatory and fibrosing process, segmentally affects both the extrahepatic and intrahepatic

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FIGURE 76.14.  Characteristic concentric onion-skin periductal fibrosis in primary sclerosing cholangitis. The residual duct epithelial cells show atrophic and degenerative changes (arrow).

biliary tree, resulting in biliary strictures and biliary cirrhosis (Williamson & Chapman, 2014) (see Chapter 41). PSC is strongly associated with inflammatory bowel disease, particularly ulcerative colitis, and with the development of cholangiocarcinoma (see Chapter 51). The definitive diagnosis of PSC rests on characteristic imaging findings, because liver biopsy is too selective in this inhomogeneous process. Characteristic features include concentric, “onion-skin” periductal fibrosis; however, this merely indicates chronic biliary obstruction of any cause and thus is not pathognomonic. The involved duct epithelium exhibits atrophic and degenerative changes; a characteristic fibroobliterative scar eventually replaces the bile duct (Fig. 76.14). Ductular reaction is either subtle or overt. As in other forms of biliary cirrhosis, cholate stasis is a recognized feature in PSC. Careful evaluation of explant livers for occult cholangiocarcinoma with thorough sampling of all hilar tissue is recommended.

Hereditary Hemochromatosis Hereditary hemochromatosis (HH) is an autosomal recessive disorder that results in iron overload in several organs. Cirrhosis is a recognized complication, if untreated. HH is due to abnormal genetic control and expression by the liver of the master iron regulator hepcidin. There are several genetic mutations that result in metabolic iron overload, but the best known is associated with homozygous C282Y mutations of the HFE gene (Pietrangelo, 2004; Salgia & Brown, 2015). Iron deposition initially occurs in zone 1 (periportal) hepatocytes, with a decreasing gradient toward the centrilobular area. The iron granules are concentrated along the border of the canaliculi; this is best shown by modified Perls’ Prussian blue stain (Fig. 76.15). With progression, untreated HH results in iron deposition throughout the entire lobule, and iron granules are seen not only in hepatocytes but also in Kupffer cells, biliary epithelial cells, and portal macrophages. Kupffer cell clusters, or siderotic nodules, are common, and usually little to no significant portal and/or lobular inflammation is evident. This pattern of iron deposition is not restricted to HH because any form of ineffective erythropoiesis may also result in it; thus, the diagnosis rests with genetic testing.

FIGURE 76.15.  Massive hepatocellular iron deposition in case of hereditary hemochromatosis (C282Y homozygous) illustrates the pericanalicular location in the hepatocytes with a periportal to centrolobular gradient (Perls’ Prussian blue stain).

Fibrosis in HH is portal based. When cirrhosis develops, it is typically micronodular with portal to portal bridging and retention of the terminal hepatic venules. Hepatocytes in cirrhotic nodules also are iron loaded and may exhibit a periseptal distribution pattern. The presence of iron-free nodules or foci are concerning for dysplasia or HCC, because neither retain iron even in iron-loaded livers. The risk of HCC is markedly increased in C282Y homozygous HH, and is most often seen in the setting of cirrhosis (Kew, 2014). Secondary iron overload in the liver is a common finding in a variety of nonbiliary conditions, including hepatic necrosis and cirrhosis (Limdi & Crampton, 2004). Stainable iron may be detected in cirrhosis from chronic HCV and HBV, alcoholic steatohepatitis and NASH, and cirrhosis unrelated to homozygous HH. Iron deposition in these conditions is usually mild and rarely exceeds 2+ when a semiquantitative histologic score of 1 to 4 is used. Iron granules may be found in hepatocytes, Kupffer cells, and endothelial cells of the sinusoids or large vessels. If a higher score is appreciated in hepatocytes (e.g., 3+ or 4+, which is more commonly associated with C282Y homozygous HH), age-adjusted chemical quantitation of iron concentration, the hepatic iron index, or genetic testing for HFE mutations should be performed. Patients with chronic viral hepatitis or steatohepatitis who also have an increased liver iron content have a higher chance of harboring at least one C282Y HFE mutation. It has been suggested that these patients are less likely to respond to venesection therapy and are also more prone to fibrosis and cirrhosis (Bonkovsky et al, 2003).

Wilson Disease Wilson disease is an autosomal recessive inherited metabolic disorder of copper metabolism. Any young to middle-aged patient with unexplained cirrhosis or chronic or fulminant liver disease should be investigated for Wilson disease (Merle et al, 2007), particularly when neuropsychiatric symptoms are involved. Morphologic features in the liver vary as widely as the different clinical stages. At the precirrhotic stage, lymphocytic portal inflammation with interface hepatitis that mimics chronic viral hepatitis or AIH may be evident. Hepatocytes may show



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FIGURE 76.16.  Abundant copper deposition (red granules) in an endstage case of Wilson disease (rhodanine stain).

variable degrees of steatosis, necrosis, anisocytosis, and anisonucleosis. In later stages, atypical lipofuscin, canalicular cholestasis, and Kupffer cell iron accumulation may be noted. Periportal hepatocytes may contain glycogenated nuclei and Mallory-Denk bodies, and cirrhosis is usually micronodular. Copper and copper-binding protein accumulation may be shown on tissue sections by histochemical techniques, such as rhodanine, rubeanic acid, orcein, or Victoria blue stains (Fig. 76.16), and are most likely present in cirrhosis. It is important to recall that copper deposition also may be seen in chronic cholestatic liver diseases, such as PBC or PSC, usually in zone 1, or in periseptal hepatocytes in cirrhosis. Alternatively, the absence of stainable copper in a noncirrhotic liver does not exclude the diagnosis of Wilson disease. Copper quantitation by biochemical assay in hepatic tissue is the diagnostic test, which can be performed reliably on FFPE tissue. A value of greater than 250 µg/g dry hepatic tissue has been used as a cutoff value. Currently, plasma-based genetic testing has not yet become practical for clinical diagnosis due to the number of genetic mutations that may result in this disease.

α1-Antitrypsin Deficiency Liver injury in α1-antitrypsin deficiency, an autosomal co-dominant inherited metabolic disorder, results from retention of mutant α1-antitrypsin protein with at least one Z allele in endoplasmic reticulum of periportal hepatocytes (Chanprasert & Scaglia, 2015). The histopathologic hallmark of the disease is the presence of eosinophilic globules of varying sizes in zone 1 hepatocytes in patients older than infants. These globules are best shown by PAS-d stain (Fig. 76.17), but immunohistochemical stain is confirmatory. The globules can be seen in homozygous (PiZZ) and heterozygous (PiMZ) phenotypes, which may be determined by serum protein electrophoresis; liver disease and cirrhosis develops in only homozygous patients. Heterozygosity is a risk for progression of other liver disease. When chronic hepatitis is seen in α1-antitrypsin deficiency, other causes, such as HCV or alcohol, should be excluded (Ishak, 2002). Cirrhosis developing from α1-antitrypsin deficiency can be micronodular, macronodular, biliary, or mixed in pattern. Dysplasia and HCC may occur in cirrhotic livers.

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FIGURE 76.17.  Varying sizes and shapes of diastase-resistant hyaline globules in periseptal hepatocytes in α1-antitrypsin deficiency (periodic acid–Schiff stain after diastase digestion).

Cryptogenic Cirrhosis In approximately 10% to 15% of patients with cirrhosis, no clinically or pathologically identifiable cause of cirrhosis is identified. However, accumulating evidence suggests that a large proportion of cryptogenic cirrhosis may represent burned-out NAFLD. This suggestion is based on reported biopsy series of diagnosed NASH, followed by subsequent cirrhosis with complete loss of the features of active steatohepatitis. In addition, several authors have shown that many of these patients have type 2 diabetes, obesity, or both, compared with patients with cirrhosis of other etiologies (Caldwell et al, 1999; Poonawala et al, 2000; Sakugawa et al, 2003; Sanjeevi et al, 2003). Development of posttransplant NAFLD also is frequent in this group of patients (Sanjeevi et al, 2003), but whether this represents actual recurrence of NASH or de novo NASH remains an area of discussion (Czaja, 1997). An autoimmune etiology also has been proposed based on clinical and histopathologic findings (Ayata et al, 2002; Kaymakoglu et al, 1998), but autoantibodies may no longer be detectable in these cases (Carpenter & Czaja, 2002). PSC and alcoholic cirrhosis may present as otherwise cryptogenic cirrhosis, and a case report documented prior biopsy-proven Budd-Chiari syndrome presenting as cryptogenic cirrhosis 34 years later (Havlioglu et al, 2003). Finally, the possibility of an as yet unknown viral infection or metabolic condition cannot be excluded in cryptogenic cirrhosis. Evaluation of patients with unexplained cirrhosis should include careful review of all prior liver biopsy specimens, especially those from several years prior.

NONCIRRHOTIC PORTAL HYPERTENSION An increase in the pressure of the portal venous system can be seen in a heterogeneous group of prehepatic, intrahepatic, and posthepatic conditions in the absence of cirrhosis (Box 76.2). The etiopathogenetic mechanisms leading to portal hypertension in these conditions, the clinical presentation, and the prognoses vary widely (Khanna & Sarin, 2014). Portal hypertension

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BOX 76.2  Causes of Noncirrhotic Portal Hypertension Prehepatic Portal or splenic vein thrombosis Arterioportal shunt Tropical splenomegaly Intrahepatic Nodular regenerative hyperplasia Partial nodular transformation Alcoholic hepatitis Drugs and toxins Sarcoidosis Schistosomiasis Venoocclusive disease Hematologic disorders Congenital hepatic fibrosis Hereditary hemorrhagic telangiectasia Idiopathic portal hypertension Posthepatic Budd-Chiari syndrome Congestive heart failure

FIGURE 76.18.  Reticulin stain highlights nodularity of the parenchyma in nodular regenerative hyperplasia; no scar tissue (fibrous septum) is present (Sweet’s reticulin).

Modified from Geller SA, Petrovic LM, 2004: Biopsy Interpretation of the Liver. Philadelphia, Lippincott Williams & Wilkins.

Venous Outflow Obstruction in Budd-Chiari syndrome (see Chapter 88) is secondary to posthepatic vein obstruction and may have an acute or subacute clinical course with liver failure. Portal hypertension associated with infiltrative amyloid or hematologic disorders, such as leukemia, mastocytosis, and Gaucher disease, is believed to occur primarily at the intrahepatic sinusoidal level. Precirrhotic alcoholic hepatitis also may cause portal hypertension because of hepatocyte swelling, sinusoidal fibrosis, and central sclerosis, which may be more insidious clinically. Liver biopsy functions to confirm the absence of cirrhosis and helps establish or suggest an alternative diagnosis (Ma & Brunt, 2012; Roskams TA et al, 2003). The histopathologic features of several selected entities associated with noncirrhotic portal hypertension are discussed briefly.

Nodular Regenerative Hyperplasia Nodular regenerative hyperplasia (NRH) is associated with a wide range of conditions, mainly including hematologic disorders, connective tissue diseases, and medications. Portal hypertension has been reported in approximately half of patients with NRH (Al-Mukhaizeem et al, 2004). The pathogenesis is unclear, but may involve intrahepatic portal venous thrombosis, leading to a microcirculatory disturbance in the liver that causes localized ischemia with atrophy and compensatory hepatocyte hyperplasia. The liver may be normal sized or enlarged when associated with a hematologic disease. On cut surface, the liver is diffusely nodular in appearance, with nodules ranging from 0.1 to 1 cm in diameter. Microscopically, the nodular appearance is best appreciated with reticulin stain (Fig. 76.18), which highlights regenerative nodules with atrophic hepatocytes at the edges; little to no fibrosis is present. Nodular regenerative hyperplasia differs from cirrhosis in that fibrosis, if present, is minimal, and the portal tract architecture is usually unaltered. These characteristic features may be shown more easily on a wedge biopsy specimen and may be difficult to appreciate on a needle biopsy specimen.

Obstruction of hepatic venous outflow (posthepatic obstruction) increases sinusoidal pressure and results in subsequent portal hypertension. Etiologic possibilities include congestive heart failure, narrowing or occlusion of large hepatic veins (Budd-Chiari syndrome; see Chapter 88), or obliteration of the terminal or sublobular hepatic veins. The lesion known as “sinusoidal obstruction syndrome” (or venoocclusive disease) that occurs in bone marrow transplant recipients is not included, however. Liver injury caused by congestive heart failure is characterized by zone 3 sinusoidal dilation (also known as congestion) and, when severe or acute, extravasation of red blood cells into the space of Disse, displacing hepatocytes from the hepatic cords. Hepatocellular necrosis is uncommon unless accompanied by systemic hypotension and hypoperfusion. The portal tracts are typically unremarkable and devoid of significant inflammatory cell infiltration. In long-standing cases, zone 3 hepatocytes exhibit atrophic change and are often no larger than a small nucleus, with markedly attenuated cell plates. Lipofuscin pigment and sinusoidal lining-cell iron may accrue, and perivenular fibrosis and bridging fibrosis also may develop. Rarely septal formation, reverse lobulation, and cardiac cirrhosis occur in refractory cases. Budd-Chiari syndrome results from obstruction at any level of the hepatic venous system between the liver and the inferior vena cava or the right heart atrium. It may result from a variety of thrombotic and nonthrombotic causes, among which hypercoagulable states secondary to myeloproliferative disorders are the most common (Menon et al, 2004). The histopathologic features of Budd-Chiari syndrome are similar to those of congestive heart failure, but acute onset also may give rise to a hemorrhagic appearance within zone 3, with extravasation of red blood cells into the space of Disse replacing hepatocytes within the cords, and significant hepatocyte loss. If unrelieved, Budd-Chiari syndrome results in cord atrophy, replacement by fibrosis, and eventual cirrhosis. Interestingly, a ductular reaction has been reported in as many as 47% of cases (Kakar et al, 2004); this finding, along with elevated alkaline phosphatase,



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FIGURE 76.20.  Congenital hepatic fibrosis. The duct plate abnormality is manifested by remnant ductal profiles along the limiting plate; some of the duct structures contain inspissated bile. FIGURE 76.19.  This connective tissue stain highlights the lesions of venoocclusive disease (sinusoidal obstruction syndrome). The remnants of the wall of the terminal hepatic venule are seen (arrow); necrosis and dropout of the perivenular, zone 3 hepatocytes are demonstrated (Masson trichrome stain).

can result in a mistaken impression of a cholestatic process except for lack of other features of cholestatic disease. In contrast to Budd-Chiari syndrome, venoocclusive disease, now known as sinusoidal obstruction syndrome (SOS), (DeLeve et al , 2002) rarely results in cirrhosis and has variable clinical manifestations that range from elevation of liver function tests to life-threatening ascites and liver failure. This process affects the distal sinusoids, the intrahepatic portion of the hepatic venous system, and the terminal hepatic and sublobular veins. It has been stressed that the injury in this process is to the sinusoidal lining cells and surrounding hepatocytes. SOS is common after bone marrow or hematopoietic stem cell transplantation, is more likely to occur in persons infected with HCV, and is associated with conditioning chemotherapeutic agents and hepatic radiation (Coppell et al, 2003; Kumar et al, 2003; Wadleigh et al, 2003). Oxaliplatin-based chemotherapy is increasingly recognized as a cause of marked damage to the sinusoids, with the subsequent risks of nodular regenerative hyperplasia, perisinusoidal and outflow vein fibrosis, and potentially liver failure (RubbiaBrandt et al, 2004) (see Chapters 71 and 100). Patients usually are seen within 30 days after chemotherapy; however, late-onset venoocclusive disease has been reported (Carreras et al, 2007; Nalbantoglu et al, 2014) (Fig. 76.19). Bridging fibrosis, cirrhosis, or nodular regenerative hyperplasia may ensue in recovery.

Schistosomiasis In endemic areas, infestation by Schistosoma japonicum or Schistosoma mansoni is a frequent cause of portal hypertension (Bica et al, 2000). The mechanism involves ova deposition in the portal venules, which incites a granulomatous inflammatory response and extensive, so-called clay pipe stem fibrosis, leading to hemodynamic disturbance. Definitive diagnosis can be made by showing the presence of schistosomal ova (see Chapter 73).

Congenital Hepatic Fibrosis Congenital hepatic fibrosis is a developmental disorder of the ductal plate predominantly seen in children and only rarely seen in adults. It is inherited in an autosomal recessive or, less commonly, autosomal dominant fashion and may be part of the spectrum of polycystic kidney and liver disease (Kamath & Piccoli, 2003). The affected patient may initially come to medical attention with portal hypertension, and the liver is usually enlarged and firm. Microscopically, the portal tracts are expanded by mature fibrous tissue and may show portal-toportal bridging fibrous bands that do not have the characteristic features of septa described earlier. An increased number of aberrant duct profiles are distributed at the periphery of the portal tracts, which are believed to represent remnants of incompletely remodeled ductal plates (Fig. 76.20). Inspissated bile may be noted in these ductal lumina, and portal vein branches may be hypoplastic or actually decreased in number, but the hepatic artery branches may be hypertrophic and abnormally numerous (Desmet, 1992), suggesting arteriovenous anastomosis.

Drugs and Toxins Chronic liver injury attributable to drugs or toxins may cause extensive fibrosis and cirrhosis, leading to portal hypertension. Well-known examples include methotrexate toxicity, long-term exposure to arsenic or vinyl chloride, and chronic hypervitaminosis A, resulting in hepatic stellate cell hypertrophy, hyperplasia, and activation. Drugs and toxins also induce noncirrhotic portal hypertension via different mechanisms, such as via venoocclusive disease, Budd-Chiari syndrome, and nodular regenerative hyperplasia. Herbal medicines are recognized as hepatotoxic agents in recent years (Stedman, 2002). A classic example found in a variety of herbal medicines is pyrrolizidine alkaloids, which can cause venoocclusive disease and portal hypertension.

Idiopathic Portal Hypertension As the name implies, idiopathic portal hypertension, also known as hepatoportal sclerosis or noncirrhotic portal fibrosis, is a rubric for disorders of unknown etiology, characterized by splenomegaly, long-standing portal hypertension in the absence of cirrhosis, and patent extrahepatic portal veins (Khanna & Sarin, 2014). It is primarily a disorder of middle-aged adults

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and generally has a better prognosis than cirrhotic portal hypertension because liver synthetic function is better preserved. Subtle histologic differences may exist among these terms, however, which may reflect different underlying etiologies. Although the etiology is obscure, there is a common association of idiopathic portal hypertension with other autoimmune disorders; immunologic disturbance is thus thought to be involved in pathogenesis. Bacterial infection leading to repeated stimulation also has been proposed as a candidate mechanism, but this remains speculative. In addition, some authors (Hillaire et al, 2002; Nakanuma et al, 2001) suggest that prothrombotic disorders and thromboembolism play a role in etiopathogenesis. A recent review suggests it is a combination of recurrent infections and thrombotic disorders that results in the condition (Khanna & Sarin, 2014). Idiopathic portal hypertension is essentially a diagnosis of exclusion; thus morphologic examination of liver tissue is imperative to rule out the presence of cirrhosis or other known etiology of portal hypertension, for instance, schistosomiasis. The pathologic changes in idiopathic portal hypertension are believed to represent the effects of long-standing portal venous insufficiency, which may or may not be related to the initiating factors (Nakanuma et al, 2001). They may be subtle, heterogeneous, and may be missed on a needle biopsy specimen. Macroscopically, the liver may have a reduced mass, and the surface may be irregularly undulant or finely wrinkled, owing to subcapsular parenchymal atrophy (Krasinskas et al, 2005). The cut surface may show portal and perivascular fibrosis, dilation and wall thickening of the veins, and unusual distribution and approximation of the portal and outflow vascular structures. Microscopically, the normal relationship between the portal and central areas is distorted. The portal tracts are either abnormally approximated to each other or widely separated. The terminal hepatic vein may be eccentrically located in the lobule adjacent to a portal tract, and sometimes multiple ectatic tributaries (angiomatous lesions) are seen in a single lobule. Conspicuous fibrosis usually is present in the portal tracts, which may extend into the periportal areas and the lobules in a pericellular, perisinusoidal fashion. The portal veins may show loss of the normal muscle coat or marked wall thickening, and luminal narrowing or obliteration may also be evident (Fig. 76.21).

FIGURE 76.21.  Portal fibrosis in hepatoportal sclerosis (idiopathic portal hypertension). The remnant portal vein (arrow) is small and has a narrowed lumen (Masson trichrome stain).

CONCLUSION Long-standing portal hypertension causes serious extrahepatic complications. Common presentations include esophageal varices with variceal bleeding, portal hypertensive gastropathy, congestive splenomegaly with hypersplenism, and ascites with spontaneous bacterial peritonitis. Portal hypertension also contributes to the development of hepatic encephalopathy and hepatorenal syndrome. In general, portal hypertension secondary to a noncirrhotic etiology has a better prognosis than portal hypertension caused by liver cirrhosis because of maintained synthetic function in the former. Pathologic recognition of the characteristic morphologic features of many commonly encountered disorders underlying cirrhosis and noncirrhotic portal hypertension can aid in clinical management of patients with portal hypertension with and without cirrhosis. References are available at expertconsult.com.



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