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Liver diseases

Introduction

INFLAMMATORY DISEASES

Alcoholic liver disease

liver cirrhosis

fulminant hepatic failure

Intrahepatic Biliary Tract Disease

Benign neoplasms

Malignant tumors

Introduction

The liver is vulnerable to a wide variety of metabolic, toxic, microbial, circulatory, and neoplastic insults. The dominant primary diseases of the liver are viral hepatitis, alcoholic liver disease, and hepatocellular carcinoma. More often, hepatic damage is secondary, to some of the most common diseases in humans, such as cardiac decompensation, disseminated cancer, and extrahepatic infections. The enormous functional reserve of the liver masks the clinical impact of early liver damage. However, with progression of diffuse disease or strategic disruption of bile flow, the consequences of deranged liver function become life-threatening. With the rare exception of fulminant hepatic failure, liver disease is an insidious process in which symptoms of hepatic decompensation may occur weeks, months, or even years after the onset of injury. There is often a long time interval between disease onset (or initiation) and detection. Conversely, the liver may be injured and heal without clinical detection. Hence, patients with hepatic abnormalities who are referred to specialists in liver disease most frequently have chronic liver disease.

Objectives:

1. Define the term carrier state as it relates to viral hepatitis infection.

2. List multiple causes, other than viral infections, of subfulminant and fulminant hepatic failure.

3. Classify the various categories of liver disease associated with drug and toxin exposures, and list some of the more important agents responsible for these.

4. List the major etiologic agents of cirrhosis.

5. Define the term cryptogenic cirrhosis.

6. Describe the clinical signs and symptoms of cirrhosis.

7. List the major causes and clinical features of hepatic failure.

8. Know the epidemiology, pathogenesis, pathology, and clinical consequences of the most common malignant liver tumors: hepatocellular carcinoma and cholangiocarcinoma

Key words: hepatitis, macro- micronodular liver cirrhosis, fulminant hepatitis, jaundice, hepatocellular carcinoma, Malory bodies, ground glass hepatocytes.

Clinical objectives:

1. Describe the pathology of the three forms of alcoholic liver disease: fatty liver, hepatitis, and cirrhosis.

2. Compare and contrast the pathology of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) with alcoholic liver disease and hepatitis C infection.

3. Describe the three microscopic features that are characteristic of cirrhosis.

4. Contrast the two gross morphologic variants of cirrhosis, micronodular and macronodular, and understand why such a classification scheme can be clinically misleading.

5. Describe the pathology of cirrhosis due to chronic viral hepatitis, and recognize that the use of the term postnecrotic cirrhosis is clinically misleading.

6. Describe the pathology of acute hepatitis, subfulminant and fulminant hepatitis, and chronic hepatitis.

INFLAMMATORY DISEASES

"…virtually any insult to the liver can kill the hepatocytes and recruit inflammatory cells…"

Infections are a primary cause of inflammatory hepatic diseases, and hepatotropic viruses cause the majority of hepatic infectious disorders.

Viral Disease -- This may be caused by any number of viral agents under appropriate conditions. In general usage; however, the term applies to a group of viruses that are specifically hepatotropic. Among medical personnel, acute viral hepatitis is an occupational hazard and the most common cause of jaundice. It may occur as an inapparent asymptomatic infection, as a mild anicteric disorder of short duration, or as an icteric disorder of variable severity and duration.

Acute Viral Hepatitis - All of the hepatotropic viruses produce similar clinical and morphologic changes. Although the incubation period differ, biochemical evidence of hepatic damage (elevated ALT, AST, LDH) and peak infective periods precede the development of clinical symptoms.  

Clinical expression - If symptoms develop, there is a prodromal period in which the patients develop a flu-like syndrome with malaise, weakness, loss of appetite and nausea. Tobacco and coffee frequently become distasteful. Clinical symptoms may abate (esp. HAV) without the development of increased bilirubin levels (anicteric hepatitis) or they may worsen with the development of fever, chills, headache, myalgias, vomiting, diarrhea, and jaundice. As the bilirubin (primarily conjugated) levels rise, the prodromal symptoms begin to subside although the urine may darken (bilirubinuria) due to the conjugated bilirubin. If the bile canaliculi become obstructed by hepatic edema or inflammation, the stools will become lighter in color and an intense pruritus may develop due to retention of bile acids. The patient may complain of fullness in the right upper quadrant of the abdomen, and on physical examination the liver is slightly enlarged and usually tender, frequently with a blunted edge. Fulminant hepatic necrosis and death is uncommon.

Morphologic expression - During the prodromal period liver biopsies reveal widespread hepatocellular and Kupffer cell swelling and a sparse lymphocytic/monocytic infiltrate in portal areas. Isolated liver cell necrosis, sometimes called cell "dropout", may be present but is difficult to detect at this stage. Characteristic features include:

▪ liver cell injury - injured cells swell and the cytoplasm appears watery and vacuolated (ballooning degeneration). Such changes are most evident in the centrilobular regions.

▪ hepatic necrosis - Individual necrosis cells may disappear leaving no trace while others appear as round eosinophilic bodies (Councilman bodies). Occasionally hepatocellular necrosis is more extensive reaching from one lobule to another and forming so-called bridging necrosis.

▪ reticuloendothelial hypertrophy/hyperplasia - Kupffer cells become more prominent.

▪ portal infiltration - macrophages and lymphocytes can be found in the portal areas as well as in areas of focal liver cell necrosis.

At high magnification, the hypercellularity in acute viral hepatitis is noted to be due to infiltration of the hepatic sinusoids by an acute, as well as chronic, inflammatory cellular infiltrate and Kupffer cell hypertrophy and hyperplasia. The hepatic cords are also disrupted with evidence of both hepatocyte necrosis and ongoing hepatocyte regeneration. Regenerating hepatocytes are large, frequently containing multiple nuclei.

▪ regeneration of liver cells - During recovery, evidence of regeneration of hepatocytes (binucleated cells, increased mitosis) is present.

▪ intrahepatic cholestasis - This may be present to a variable extent and may be manifested as small droplets of bile pigment seen in the hepatocytes and Kupffer cells and inspissated bile within the canaliculi.

▪ lobular disarray - All of the preceding changes alter the normal architecture of the hepatic lobule which may later interfere with normal hepatic function.

Chronic Hepatitis - This may be defined as any hepatitis which persists for more than six months. Although most often the result of hepatotropic viruses (excepting HAV), a variety of other causes including autoimmune mechanisms and drug-induced mechanisms have been identified. Because of this, the older classification scheme of chronic persistent hepatitis, chronic active hepatitis, and chronic lobular hepatitis is being abandoned in favor of the diagnosis of "chronic hepatitis" accompanied by an indication of the severity of the inflammatory response (grading), the degree of fibrosis (staging) and, if possible, a statement as to the likely etiology.

This image is from another patient who has chronic viral hepatitis. In this patient, there is a chronic inflammatory infiltrate in the portal areas of the liver that extends beyond the portal area into the adjacent lobule, where it encircles hepatocytes, many of which are undergoing degeneration and necrosis. This is the morphologic correlate of progressive active liver damage that is present in some patients with chronic viral hepatitis.

On liver biopsy, there is nonspecific portal mononuclear cell infiltrate, sometimes follicular, with preservation of the limiting plates. Intralobular necrosis and inflammation are mild or absent. Most patients recover but a few progress to higher grades characterized by progressive liver destruction and more extensive fibrosis. Liver histology reveals mononuclear inflammation (lymphocytes, macrophages, and plasma cells) spilling out of the portal areas with piecemeal necrosis (destruction of the limiting plates) and, in severe cases, bridging necrosis with extensive fibrosis and cirrhosis.

Hepatotropic viruses

Hepatitis A (HVA) - Often associated with childhood or rural epidemics, outbreaks also occur when conditions are crowded (military installations) or sanitary conditions are poor (mental institutions, developing countries). The incubation period for HAV is two to six weeks and this is the period of peak infectivity since the virus is shed in the feces during this time. A short period of viremia occurs just before the onset of clinical symptoms but transfer of the virus via blood is rare. By the time clinical symptoms appear, however, the virus is no longer being shed. The disease tends to be less severe in children (95% of childhood cases recover completely and less than 1% progress to acute fulminant hepatitis.)

Hepatitis B (HBV) - HBV has also been identified in stool, urine, saliva, sweat, semen, and menstrual blood and may be transmitted by aerosols or by sexual contact. The incubation period for HBV is six weeks to six months and the resulting disease may range in clinical severity from asymptomatic to fulminant.

Hepatitis C (Non-A, Non-B hepatitis; NANBV) - Today the infections are associated with IV drug use, needlestick injuries, multiple sex partners, but most of the "socially acquired" infections are not associated with "high risk" events. About 1/3 of patients infected will develop acute symptoms but there is a greater predilection to develop chronic disease than with HBV. Recent studies indicate that up to 75% or more will develop chronic hepatitis or cirrhosis which may eventuate into hepatocellular carcinoma.

Hepatitis D (HDV) - This is an RNA virus which relies on the HBV outer coat in order to replicate and is therefore dependent on a coexistent HBV infection, either in an active or carrier form. In patients with active HBV infection, coinfection with HDV infection tends to worsen the acute course but chronic disease is unusual. HDV infection of HBV carrier, however, is likely to induce chronic progressive hepatic damage. The virus is probably transmitted much in the same manner as HBV.

Hepatitis E (HEV) - This is a non-A, non-B, non-C virus that is spread by the fecal-oral route, usually by fecally contaminated drinking water, with an incubation period of 2-9 weeks.

Hepatitis G - This hepatotropic virus has recently been described.

Morphology of Acute and Chronic Hepatitis. Tissue alterations caused by acute infection with HAV, HBV, HCV, and HEV are similar, as is the chronic hepatitis caused by HBV, HCV, and HBV + HDV. A few histologic changes may be indicative of a particular type of virus. HBV-infected hepatocytes may exhibit a cytoplasm packed with spheres and tubules of HBsAg, producing a finely granular eosinophilic cytoplasm ("ground glass hepatocytes,". HCV-infected livers frequently show lymphoid aggregates within portal tracts and focal sublobular regions of hepatocyte macrovesicular steatosis, which are to be distinguished from the extensive panlobular microvesicular and macrovesicular steatosis seen in many forms of toxic hepatitis (e.g., alcohol-induced).

Acute Hepatitis. With acute hepatitis hepatocyte injury takes the form of diffuse swelling ("ballooning degeneration"), so the cytoplasm looks empty and contains only scattered eosinophilic remnants of cytoplasmic organelles. An inconstant finding is cholestasis, with bile plugs in canaliculi and brown pigmentation of hepatocytes.

Also noted at high magnification in acute viral hepatitis is bile stasis, which is manifest as orange-brown pigment within the cytoplasm of hepatocytes as well as within dilated bile canaliculi (bile canalicular plugging).

The canalicular bile plugs result from cessation of the contractile activity of the hepatocyte pericanalicular actin microfilament web. Two patterns of hepatocyte cell death are seen. In the first, rupture of cell membranes leads to cytolysis and focal loss of hepatocytes. The sinusoidal collagen reticulin framework collapses where the cells have disappeared, and scavenger macrophage aggregates mark sites of hepatocyte loss. The second pattern of cell death, apoptosis, is more conspicuous. It is caused by anti-viral cytotoxic T cells. Apoptotic hepatocytes shrink, become intensely eosinophilic, and have fragmented nuclei; effector T cells may still be present in the immediate vicinity. Apoptotic cells also are phagocytosed within hours by macrophages and hence might be difficult to find despite a brisk rate of hepatocyte injury. In severe cases of acute hepatitis, confluent necrosis of hepatocytes may lead to bridging necrosis connecting portal-to-portal, central-to-central, or portal-to-central regions of adjacent lobules. Hepatocyte swelling and regeneration compress sinusoids, and the more or less radial array of the parenchyma is lost.

Inflammation is a characteristic and usually prominent feature of acute hepatitis. Kupffer cells undergo hypertrophy and hyperplasia and are often laden with lipofuscin pigment due to phagocytosis of hepatocellular debris. The portal tracts are usually infiltrated with a mixture of inflammatory cells. The inflammatory infiltrate may spill over into the adjacent parenchyma to cause necrosis of periportal hepatocytes; this "interface hepatitis" can occur in both acute and chronic hepatitis. Finally, bile duct epithelia may become reactive and even proliferate to form poorly defined ductular structures (ductular reaction), particularly in cases of HCV hepatitis.

Chronic Hepatitis. Liver architecture is usually well preserved, but smoldering hepatocyte necrosis throughout the lobule may occur in all forms of chronic hepatitis. Even in mild chronic hepatitis due to HCV infection, common findings are lymphoid aggregates and bile duct damage in the portal tracts and focally mild to moderate macrovesicular steatosis.

In this image of liver from a patient with chronic hepatitis due to hepatitis B virus, a chronic inflammatory infiltrate is seen that is limited to the portal area. It does not extend into the adjacent lobule.

In all forms of chronic hepatitis, continued interface hepatitis and bridging necrosis are harbingers of progressive liver damage. The hallmark of irreversible liver damage is the deposition of fibrous tissue. At first, only portal tracts exhibit increased fibrosis, but with time, periportal septal fibrosis occurs, followed by linking of fibrous septa between lobules (bridging fibrosis).

In this patient, there is a chronic inflammatory infiltrate in the portal areas of the liver that extends beyond the portal area into the adjacent lobule, where it encircles hepatocytes, many of which are undergoing degeneration and necrosis. This is the morphologic correlate of progressive active liver damage that is present in some patients with chronic viral hepatitis.

Continued loss of hepatocytes and fibrosis results in cirrhosis, with fibrous septae and hepatocyte regenerative nodules. This pattern of cirrhosis is characterized by irregularly sized nodules separated by variable but mostly broad scars. Historically, this pattern of cirrhosis has been termed postnecrotic cirrhosis, but it should be noted that the term "postnecrotic cirrhosis" has been applied to all forms of cirrhosis in which the liver shows large, irregular-sized nodules with broad scars, regardless of etiology. Autoimmune hepatitis, hepatotoxins (carbon tetrachloride, mushroom poisoning), pharmaceutical drugs and even alcohol (discussed later) may give rise to a cirrhotic liver with irregular-sized large nodules. In some cases that come to autopsy, the inciting cause of the so-called postnecrotic cirrhosis cannot be determined at all ("cryptogenic cirrhosis"). In essence, the morphology of the end-stage cirrhotic liver is neither helpful in determining the basis of the liver injury, nor can it be easily related to any specific set of clinical circumstances.

Fulminant Hepatitis

When hepatic insufficiency progresses from onset of symptoms to hepatic encephalopathy within 2 to 3 weeks, it is termed fulminant hepatic failure. A less rapid course, extending up to 3 months, is called subfulminant failure. Causes of fulminant hepatitis include:

• Sometimes, reactivation of chronic hepatitis B or acute herpesvirus infection is the cause.

• Drug and chemical toxicity acting either as direct hepatotoxins or via idiosyncratic inflammatory reactions.

Much rarer causes, but just as life-threatening, are ischemic hepatic necrosis, obstruction of the hepatic veins, massive malignant infiltration of the liver, Wilson disease, hyperthermia (heat stroke), and microvesicular steatosis syndromes, particularly acute fatty liver of pregnancy. The evolution of hepatic failure is extremely variable and is significantly influenced by the previous status of the liver and patient age (younger patients fare better).

Morphology. All causative agents produce essentially identical morphologic changes that vary with the severity of the necrotizing process. With all, the distribution of liver destruction is extremely capricious: The entire liver may be involved or only random areas. With massive loss of substance, the liver may shrink to as little as 500 to 700 gm. In so doing, it is transformed into a limp, red organ covered by a wrinkled, too-large capsule.

In fulminant hepatitis from any cause, the liver is smaller than normal, due to extensive areas of liver necrosis. The liver is also soft with a wrinkled capsular surface.

On transection, necrotic areas have a muddy red, mushy appearance with blotchy bile staining. Microscopically, complete destruction of hepatocytes in contiguous lobules leaves only a collapsed reticulin framework and preserved portal tracts. There may be surprisingly little inflammatory reaction. Alternatively, with survival for several days, there is a massive influx of inflammatory cells to begin the phagocytic cleanup process.

There is massive necrosis of hepatocytes throughout the lobules in fulminant hepatitis.

Patient survival for more than a week also permits secondary regenerative activity of surviving hepatocytes and bile ducts. The bipotential proliferative compartment linking hepatocytes with the biliary tree-the canal of Hering-also is a major site of the regenerative response, giving rise to poorly formed ductular structures. A dormant stem cell population lying alongside the bile ductules and canals of Hering also proliferates, generating a population of small cells with a high nuclear:cytoplasmic ratio (so-called oval cells) interspersed with surviving hepatocytes. Given sufficient time (i.e., survival of the patient beyond the first several weeks), the liver can recover completely with maturation of all proliferating cell populations into morphologically normal hepatocytes and bile duct epithelial cells. With centrilobular zonal necrosis caused by direct hepatotoxins or ischemia, the parenchymal framework is preserved. Regeneration is directly from hepatocytes, and native liver architecture is restored in time. With more massive destruction of confluent lobules, regeneration is disorderly, yielding nodular masses of liver cells that produce a more irregular liver on healing

Fibrous scarring may occur in patients with a protracted course of submassive or patchy necrosis, representing a route for developing so-called postnecrotic cirrhosis, as noted earlier.

ALCOHOLIC LIVER DISEASE

Of greatest impact, however, are the three distinctive, albeit overlapping, forms of liver disease: (1) hepatic steatosis, (2) alcoholic hepatitis, and (3) cirrhosis, collectively referred to as alcoholic liver disease. Because the first two conditions may develop independently, they do not necessarily represent a continuum of changes. The morphology of the three forms of alcoholic liver disease is presented first, because this facilitates consideration of their pathogenesis

Morphology

Hepatic Steatosis (Fatty Liver). Following even moderate intake of alcohol, small (microvesicular) lipid droplets accumulate in hepatocytes. With chronic intake of alcohol, lipid accumulates to the point of creating large, clear macrovesicular globules, compressing and displacing the nucleus to the periphery of the hepatocyte. This transformation is initially centrilobular, but in severe cases, it may involve the entire lobule. Macroscopically, the fatty liver of chronic alcoholism is a large (up to 4 to 6 kg), soft organ that is yellow and greasy. Although there is little or no fibrosis at the outset, with continued alcohol intake, fibrous tissue develops around the terminal hepatic veins and extends into the adjacent sinusoids. The fatty change is completely reversible if there is abstention from further intake of alcohol.

Alcoholic Hepatitis. Alcoholic hepatitis is characterized by the following:

• Hepatocyte swelling and necrosis: Single or scattered foci of cells undergo swelling (ballooning) and necrosis. The swelling results from the accumulation of fat and water, as well as proteins that normally are exported. In some cases, there is cholestasis in surviving hepatocytes and mild deposition of hemosiderin (iron) in hepatocytes and Kupffer cells.

• Mallory bodies: Scattered hepatocytes accumulate tangled skeins of cytokeratin intermediate filaments and other proteins, visible as eosinophilic cytoplasmic inclusions in degenerating hepatocytes.

These inclusions are a characteristic but not specific feature of alcoholic liver disease, as they also are seen in primary biliary cirrhosis, Wilson disease, chronic cholestatic syndromes, and hepatocellular tumors.

• Neutrophilic reaction: Neutrophils permeate the lobule and accumulate around degenerating hepatocytes, particularly those having Mallory bodies. Lymphocytes and macrophages also enter portal tracts and spill into the parenchyma.

Fibrosis: Alcoholic hepatitis is almost always accompanied by prominent activation of sinusoidal stellate cells and portal tract fibroblasts, giving rise to fibrosis. This is most frequently in the form of sinusoidal and perivenular fibrosis that splits apart the parenchyma; occasionally, periportal fibrosis may predominate, particularly with repeated bouts of heavy alcohol intake.

Although steatotic hepatocytes are present, they are interspersed with the inflammatory cells and activated stellate cells. In macroscopic appearance, the liver is mottled red with bile-stained areas. Although the liver may be of normal or increased size, it often contains visible nodules and fibrosis, indicative of evolution to cirrhosis.

Alcoholic Cirrhosis. The final and irreversible form of alcoholic liver disease usually evolves slowly and insidiously. At first, the cirrhotic liver is yellow-tan, fatty, and enlarged, usually weighing over 2 kg. Over the span of years, it is transformed into a brown, shrunken, nonfatty organ, sometimes less than 1 kg in weight. Cirrhosis may develop more rapidly in the setting of alcoholic hepatitis, within 1 to 2 years. Initially, the developing fibrous septae are delicate and extend through sinusoids from central to portal regions as well as from portal tract to portal tract. Regenerative activity of entrapped parenchymal hepatocytes generates fairly uniformly sized "micronodules." With time, the nodularity becomes more prominent; scattered larger nodules create a "hobnail" appearance on the surface of the liver.

In alcoholic cirrhosis, nodules of regenerating hepatocytes consist of disordered cords of cells of irregular thickness, many of which are two or more cell layers thick. Note the lack of central veins in these regenerative nodules. The nodules are surrounded by fibrous tissue containing variable amounts of chronic inflammatory cells and areas of bile ductular proliferation.

As fibrous septae dissect and surround nodules, the liver becomes more fibrotic, loses fat, and shrinks progressively in size. Parenchymal islands are engulfed by ever wider bands of fibrous tissue, and the liver is converted into a mixed micronodular and macronodular pattern. Ischemic necrosis and fibrous obliteration of nodules eventually create broad expanses of tough, pale scar tissue ("Laennec cirrhosis"). Bile stasis often develops; Mallory bodies are only rarely evident at this stage. Thus, end-stage alcoholic cirrhosis comes to resemble, both macroscopically and microscopically, the cirrhosis developing from viral hepatitis and other causes.

Alcoholic liver disease, thus, is a chronic disorder featuring steatosis, hepatitis, progressive fibrosis, cirrhosis, and marked derangement of vascular perfusion. In essence, alcoholic liver disease can be regarded as a maladaptive state in which cells in the liver respond in an increasingly pathologic manner to a stimulus (alcohol) that originally was only marginally harmful.

CIRRHOSIS - This is a very important clinical disorder because of its prevalence, its disruption of hepatic architecture, and its consequent interference with liver function, but there is no universal classification of cirrhosis on either morphologic or etiologic grounds. Cirrhosis is characterized by hepatic necrosis, regeneration, fibrosis, and architectural distortion. Regeneration probably occurs from preserved hepatic cells of the limiting plate in the portal areas. When hepatic necrosis occurs without collapse of the underlying reticular framework of the liver, the remaining liver cells are able to regenerate the entire lobule with its normal architecture. If the total lobule and its reticulin framework are destroyed, however, adjacent liver cells may proliferate producing nodules of hepatic cells which lack normal canalicular and sinusoidal relationships. Such cells can function in the normal metabolic activities of the liver but cannot normally excrete bile. The patterns of scarring (micronodular vs. macronodular) are not specific but may give a clue as to the underlying etiologic event.

Cirrhosis as the end-stage of chronic liver disease is defined by three characteristics:

• Bridging fibrous septae in the form of delicate bands or broad scars linking portal tracts with one another and portal tracts with terminal hepatic veins

• Parenchymal nodules containing proliferating hepatocytes encircled by fibrosis, with diameters varying from very small ( ................
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