tbl 6 pathology readings

Question 1

What is the viral genome of Hep A-E

Answer 1

Hepatitis A, C, E: ssRNA
Hepatitis B: partially dsDNA
Hepatitis D: circular defective ssRNA

Question 2

What viral family is Hepatitis A from?

Answer 2

Hepatovirus, related to picornavirus

Question 3

What viral family is Hepatitis B from?

Answer 3

Hepadnavirus

Question 4

What viral family is Hepatitis C from?

Answer 4

Flaviviridae

Question 5

What viral family is Hepatitis D from?

Answer 5

Subviral particle in Deltaviridae family

Question 6

What viral family is Hepatitis E from?

Answer 6

Calcivirus

Question 7

Route of transmission for Hepatitis A?

Answer 7

faecal oral (contaminated food or water)

Question 8

Route of transmission for Hepatitis B?

Answer 8

Parenteral, sexual contact, perinatal

Question 9

Route of transmission for Hepatitis C?

Answer 9

Parenteral; intranasal cocaine use is a risk factor

Question 10

Route of transmission for Hepatitis D?

Answer 10

Parenteral

Question 11

Route of transmission for Hepatitis E?

Answer 11

Fecal-oral

Question 12

How to diagnose Hepatitis A?

Answer 12

Detection of serum IgM antibodies

Question 13

How to diagnose Hepatitis B?

Answer 13

Detection of HBsAg or antibody to HBcAg; PCR for HBV DNA

Question 14

How to diagnose Hepatitis C?

Answer 14

ELISA for antibody detection; PCR for HCV RNA

Question 15

How to diagnose Hepatitis D?

Answer 15

Detection of IgM and IgG antibodies, HDV RNA in serum, or HDAg in liver biopsy

Question 16

How to diagnose Hepatitis E?

Answer 16

Detection of serum IgM and IgG antibodies; PCR for HEV RNA

Question 17

[HAV]
HAV usually is a benign self-limited infection that does not cause chronic hepatitis and rarely (in about 0.1% of cases) produces fulminant hepatitis. HAV has an incubation period of ___________. It is typically cleared by the host immune response, so it does not establish a carrier state. The infection occurs throughout the world and is endemic in countries with poor hygiene and sanitation.

Acute HAV tends to cause a ________________ and nonspecific symptoms such as fatigue and loss of appetite. Overall, HAV accounts for about 25% of clinically evident acute hepatitis worldwide.

HAV is a small, _____________ positive-strand RNA picornavirus that occupies its own genus, Hepatovirus . Ultrastructurally, HAV is an icosahedral capsid 27 nm in diameter. The receptor for HAV is HAVcr-1, a membrane glycoprotein that also may serve as a receptor for _______________. HAV is spread by ingestion of contaminated water and food and is shed in the stool for 2 to 3 weeks before and 1 week after the onset of jaundice. Thus, close personal contact with an infected individual or fecal-oral contamination accounts for most cases and explains outbreaks in institutional settings such as schools and nurseries, as well as water-borne epidemics in places where people live in overcrowded, unsanitary conditions. HAV can also be detected in serum and saliva of infected individuals.

In developed countries, sporadic infections may be contracted by the consumption of __________________ that have concentrated the virus from seawater contaminated with human sewage. Infected workers in the food industry are another source of outbreaks. HAV itself does not seem to be cytopathic. The cellular immune response, particularly that involving cytotoxic CD8+ T cells, plays a key role in HAV-mediated hepatocellular injury.

Because HAV viremia is transient, blood-borne transmission is very rare; therefore, donated blood is not specifically screened for this virus. ________________ appears in blood at the onset of symptoms and is a reliable marker of acute infection. Fecal shedding of the virus ends as the IgM titer rises. The IgM response usually declines in a few months followed by the appearance of IgG anti-HAV that persists for years, often conferring lifelong immunity. However, there are no routinely available tests for IgG anti-HAV; the presence of IgG anti-HAV is inferred from the difference between total and IgM anti-HAV. The HAV vaccine, available since 1992, is effective in preventing infection.

Answer 17

3-6 weeks;

febrile illness associated with jaundice;

nonenveloped;

Ebola virus;

IgM antibody against HAV;

raw or steamed shellfish

Question 18

[HBV]
HBV is a member of __________________, a family of DNA viruses that cause hepatitis in multiple animal species. The HBV genome is a partially double-stranded, 3200-nucleotide, circular DNA with four open reading frames, which encode the following proteins:
- _______________ (HBcAg, hepatitis B core antigen) and a longer polypeptide with a precore and core region, designated HBeAg (hepatitis B e antigen). The precore region directs the secretion of the HBeAg polypeptide into blood, whereas HBcAg remains in hepatocytes, where it participates in the assembly of virions.
- Envelope glycoproteins (HBsAg, hepatitis B surface antigen). Infected hepatocytes synthesize and secrete massive quantities of _________________ (mainly small HBsAg).
- A polymerase (Pol) with both ___________ and ____________________, which enables genomic replication to occur through a unique DNA → RNA → DNA cycle via an intermediate RNA template. This unusual polymerase is the target of drugs used to treat hepatitis B infection (described later).
- ______________, which is required for virus replication and which may act as a transcriptional transactivator for viral genes and a wide variety of host genes. It has been implicated in the pathogenesis of HBV-associated liver cancer.

Occasionally, mutated strains of HBV emerge that do not produce HBeAg but are replication competent and express HBcAg. In such patients, the _________ may be low or undetectable despite the presence of serum HBV DNA. A second ominous development is the appearance of HBV mutants in vaccinated individuals that replicate in the presence of normally protective anti-HBs antibodies.

The host immune response is the main determinant of the outcome of the infection. Innate immune mechanisms protect the host during initial phases of the infection, and a strong response by virus-specific CD4+ and CD8+ interferon γ–producing cells is associated with the resolution of acute infection. HBV generally is not directly hepatotoxic, and most hepatocyte injury is caused by _________________

Patient age at the time of infection is the best predictor of chronicity. In general, the younger the age at the time of HBV infection, the higher the chance of chronic infection. Treatment of chronic hepatitis B with viral polymerase inhibitors and interferon can slow disease progression, reduce liver damage, and prevent liver cirrhosis or liver cancer but does not eliminate the infection. As a result, treatment sometimes fails due to emergence of viruses bearing mutations that lead to drug resistance.

Answer 18

Hepadnaviridae;

Nucleocapsid “core” protein;

noninfective envelope glycoproteins;

DNA polymerase activity ; reverse transcriptase activity;

HBx protein;

HBeAg;

CD8+ cytotoxic T cells attacking infected cells.

Question 19

[Hepatitis C virus]
HCV is a major cause of liver disease, with approximately 170 million individuals affected worldwide. Approximately 4.1 million Americans (1.6% of the population) have chronic HCV infection. Notably, there has been a decrease in the annual incidence of infection from a mid-1980s peak of over 230,000 new infections per year to 30,000 new infections per year currently, due primarily to a reduction in transfusion-associated cases as a result of effective screening procedures. Until recently, the number of patients with chronic infection appeared likely to continue to increase, but new therapies (discussed later) are changing the outlook for the better.

According to data from the Centers for Disease Control and Prevention (CDC), the most common risk factors for HCV infection are as follows:

• ______________
• Multiple sex partners
• Having had surgery within the last 6 months
• Needle stick injury
• Multiple contacts with an HCV-infected individual
• Employment in the medical or dental field

Currently, transmission of HCV by blood transfusion is close to zero in the United States; the risk for acquiring HCV by _____________ is about six times higher than that for HIV (1.8 vs. 0.3%). For children, the major route of infection is ______________. Some patients have multiple risk factors, but one-third of individuals have no identifiable risk factors, an enduring mystery.

HCV, discovered in 1989, is a member of the _____________ family. Just as in the case of HIV, an understanding of viral replication and assembly has facilitated the development of highly effective anti-HCV drugs . HCV is a small, enveloped, single-stranded RNA virus with a 9600-base genome encoding a single polyprotein that is processed by several proteases into 10 functional proteins. Included among these viral proteins is a viral protease that is needed for complete processing of the polyprotein; ___________, a protein that is essential for assembly of HCV into mature virions; and a viral RNA polymerase that is necessary for replication of the viral genome. Because of the low fidelity of the HCV RNA polymerase, the viral genome is inherently unstable, giving rise to new genetic variants at a high pace. This has led to the appearance of six major HCV genotypes worldwide, each with one or more “subspecies.” Infections in most individuals are due to a virus of a single genotype, but new genetic variants are generated in the host as long as viral replication persists. As a result, each patient usually comes to be infected with a population of divergent but closely related HCV variants known as quasispecies.

Answer 19

Intravenous drug abuse;

needle stick;

vertical perinatal transmission from the mother;

Flaviviridae;

NS5A;

Question 20

[Hepatitis C virus]
The incubation period for HCV hepatitis ranges from 4 to 26 weeks, with a mean of 9 weeks. In about 85% of individuals, the acute infection is asymptomatic and goes unrecognized. HCV RNA is detectable in blood for 1 to 3 weeks, coincident with elevations in __________ . In symptomatic acute HCV infection, anti-HCV antibodies are detected in only 50% to 70% of patients; in the remaining patients, the anti-HCV antibodies emerge after 3 to 6 weeks. The clinical course of acute HCV hepatitis is milder than that of HBV. It is not known why only a small minority of individuals is capable of clearing HCV infection.

Persistent infection and chronic hepatitis are the hallmarks of HCV infection, despite the generally asymptomatic nature of the acute illness. In contrast to HBV, chronic disease occurs in the majority of HCV-infected individuals (80%–90%), and cirrhosis eventually occurs in as many as one-third. The mechanisms leading to chronicity are not well understood, but it is clear that the virus uses multiple strategies to evade host anti-viral immunity. In addition to rapid generation of genetic variants, which may allow the virus to elude neutralizing antibodies, HCV encodes proteins that inhibit __________________- and interferon signaling in hepatocytes, activites that would otherwise allow hepatocytes to resist viral infection.

In chronic HCV infection, _____________ persists in 90% of patients despite the presence of neutralizing antibodies. Hence, testing for HCV RNA must be done to confirm the diagnosis of chronic HCV infection. A characteristic clinical feature of chronic HCV infection is ___________________ separated by periods of normal or near-normal enzyme levels. However, even HCV-infected patients with normal transaminases are at high risk for developing permanent liver damage, and anyone with detectable serum HCV RNA needs treatment and long-term medical follow-up.

Fortunately, recent years have seen dramatic improvements in treatment of HCV infection that stem from development of drugs that specifically target the viral protease, RNA polymerase, and NS5A protein, all of which are required for production of virus. Combination therapy with these drugs (a strategy akin to triple drug therapy for HIV) has proven to be remarkably effective. The goal of current treatment is to eradicate HCV RNA, which is defined by the ________________________________ and is associated with a high probability of cure. Currently, over 95% of HCV infections are curable, and this can be expected to improve further as new anti-viral drugs become available. The major downside of these advances is their very high cost; a curative course of drug therapy costs over $100,000, and it is estimated that treatment of HCV infections in the United States alone may generate expenses of over $50 billion over the next 5 years.

Answer 20

serum transaminases;

Toll-like receptor;

circulating HCV RNA;

episodic elevations in serum aminotransferases;

absence of detectable HCV RNA in the blood 6 months after treatment is stopped

Question 21

Hepatitis D Virus (HDV)
Also called the delta agent, HDV is a unique RNA virus that is dependent for its life cycle on HBV. Infection with HDV arises in the following settings:

• Coinfection by HDV and HBV. The HBV must become established first to provide the HBsAg, which is necessary for production of complete HDV virions. Coinfection with HBV and HDV is associated with higher rates of ________________________, particularly in intravenous drug abusers, and higher rates of progression to chronic infection, which is often complicated by emergence of liver cancer.
• Superinfection of a chronic HBV carrier by HDV. The superinfection presents 30 to 50 days later as severe acute hepatitis in a previously unrecognized HBV carrier or as an exacerbation of preexisting chronic hepatitis B. Chronic HDV infection occurs in 80% to 90% of such patients. The superinfection may have two phases: an acute phase with ______________ and suppression of HBV with high ______________, followed by a chronic phase in which HDV replication ________, HBV replication _________, ALT levels ____________, and the disease progresses to cirrhosis and hepatocellular cancer.

HDV infection occurs worldwide and affects an estimated 15 million individuals (about 5% of the 300 million individuals infected by HBV). Its prevalence varies, being highest in the Amazon basin, Africa, the Middle East, and Southern Italy, and lowest in Southeast Asia and China. In most western countries, it is largely restricted to intravenous drug abusers and those who have had multiple blood transfusions.

HDV RNA is detectable in the blood and liver at the time of onset of acute symptomatic disease. IgM anti-HDV is a reliable indicator of recent HDV exposure, but is frequently short-lived. Acute coinfection by HDV and HBV is associated with the presence of IgM against __________________ (denoting new infection with hepatitis B). With chronic delta hepatitis arising from HDV superinfection, HBsAg is present in serum, and anti-HDV antibodies (IgG and IgM) persist for months or longer. Because of its dependency on HBV, HDV infection is prevented by vaccination against HBV.

Answer 21

severe acute hepatitis and fulminant liver failure;

active HDV replication; ALT levels;

decreases; increases; fluctuate;

HDAg and HBcAg

Question 22

HEV is an enterically transmitted, water-borne infection that usually produces a self-limiting disease. The virus typically infects young to middle-aged adults. HEV is a zoonotic disease with animal reservoirs that include monkeys, cats, pigs, and dogs. Epidemics have been reported in Asia and the Indian subcontinent, sub-Saharan Africa, and Mexico, and sporadic cases are seen in Western nations, particularly where pig farming is common and in travelers returning from regions of high incidence. Of greater importance, HEV infection accounts for 30% to 60% of cases of sporadic acute hepatitis in India, exceeding the frequency of HAV. A characteristic feature of HEV infection is the high mortality rate among __________________, approaching 20%. In most cases, HEV is not associated with chronic liver disease or persistent viremia. The average incubation period following exposure is 4 to 5 weeks.

Discovered in 1983, HEV is an unenveloped, positive-stranded RNA virus in the Hepevirus genus. Virions are shed in stool during the acute illness. Before the onset of clinical illness, HEV RNA and HEV virions can be detected by _________________. The onset of rising serum aminotransferases, clinical illness, and elevated IgM anti-HEV titers are virtually simultaneous. Symptoms resolve in 2 to 4 weeks, during which time the IgM titers fall and IgG anti-HEV titers rise.

Answer 22

pregnant women;

PCR in stool and serum;

Question 23

As already discussed, infection with hepatitis viruses produces a wide range of outcomes. Acute infection by each of the hepatotropic viruses may be symptomatic or asymptomatic. ________________ do not cause chronic hepatitis, and only a small number of HBV-infected adults develop chronic hepatitis. In contrast, __________ is notorious for producing chronic infections. Fulminant hepatitis is unusual and is seen primarily with HAV, HBV, or HDV infections. Although HBV and HCV are responsible for most cases of chronic hepatitis, there are many other causes of similar clinicopathologic presentations, including autoimmune hepatitis and drug- and toxin-induced hepatitis. Therefore, serologic and molecular studies are essential for the diagnosis of viral hepatitis and for distinguishing between the various types.

Answer 23

HAV and HEV;

HCV ;

Question 24

Acute Asymptomatic Infection With Recovery.
Patients in this group are identified incidentally on the basis of _____________________ or the presence of anti-viral antibodies. HAV and HBV infections, particularly in childhood, are frequently subclinical.

Acute Symptomatic Infection With Recovery.
Whichever virus is involved, acute disease follows a similar course, consisting of: (1) an incubation period of variable length (2) a ____________________; (3) a symptomatic icteric phase; and (4) convalescence. Peak infectivity occurs during the last asymptomatic days of the incubation period and the early days of acute symptoms.

Fulminant Hepatic Failure.
Viral hepatitis is responsible for about 12% of cases of fulminant hepatic failure; of these, two-thirds are caused by __________ and the rest by HAV. Survival for more than 1 week may permit recovery to occur via replication of residual hepatocytes. Activation of the stem/progenitor cells in the ________________ gives rise to very prominent ductular reactions but is usually insufficient to accomplish full restitution. Fulminant hepatic failure that follows acute viral hepatitis is treated supportively. _______________________ is the only option for patients whose disease does not resolve, as death from secondary infections and failure of other organs is otherwise inevitable.

Answer 24

elevated serum transaminases;

symptomatic preicteric phase;

HBV infection;

canals of Hering; Liver transplantation

Question 25

Chronic Hepatitis.
Chronic hepatitis is defined as persistent or relapsing hepatic disease for a period of more than 6 months. The clinical features are extremely variable and are not predictive of outcome. In some patients, the only signs of chronic disease are elevations of serum transaminases. Laboratory studies also may reveal prolongation of the prothrombin time and, in some instances, ____________, ________ and mild elevations in alkaline phosphatase levels. In symptomatic individuals, the most common finding is fatigue; less commonly, there is malaise, loss of appetite, and bouts of mild jaundice. In precirrhotic chronic hepatitis, physical findings are few, the most common being ____________, palmar erythema, mild hepatomegaly, hepatic tenderness, and mild splenomegaly. Occasionally, in cases of HBV and HCV, immune complex disease develops that results in _____________ (subcutaneous or visceral) and _____________. _________________ is found in about 35% of individuals with chronic hepatitis C.

The Carrier State.
A carrier is an individual who is chronically infected with a hepatropic virus and has no or subclinical evidence of liver disease. In both cases, particularly the latter, these individuals constitute reservoirs for infection. In the case of HBV, “healthy carriers” typically have serum studies that show an absence of HBeAg, the presence of anti-HBe, normal aminotransferases, and low or undetectable serum HBV DNA and liver biopsies showing a lack of significant inflammation or parenchymal injury. HBV infection acquired early in life in endemic areas (such as Southeast Asia, China, and sub-Saharan Africa) gives rise to a carrier state in more than 90% of cases, whereas in nonendemic regions the carrier state is rare. By contrast, it has been estimated that HCV infection in the United States produces a carrier state in 10% to 40% of cases.

HIV and Chronic Viral Hepatitis.
Because of their similar transmission modes and overlapping risk factors, coinfection of HIV and hepatitis viruses is a common clinical problem. In the United States, 10% of HIV-infected individuals are coinfected with HBV and 25% with HCV, and, when untreated, chronic HBV and HCV infection are important causes of morbidity and mortality in HIV-infected individuals, even in those who receive effective anti-HIV therapy. Similarly, in individuals who progress to acquired immunodeficiency syndrome (AIDS), liver disease is the second most common cause of death. However, in adequately treated immunocompetent HIV patients, the severity and progression of HBV and HCV infection and response to anti–hepatitis virus therapy resembles that seen in non-HIV–infected individuals.

Answer 25

hyperglobulinemia, hyperbilirubinemia;

spider angiomas;

vasculitis; glomerulonephritis;

Cryoglobulinemia

Question 26

[Acute viral hepatitis- Morphology]

Grossly, livers involved by mild acute hepatitis appear normal or slightly ___________. At the other end of the spectrum, massive hepatic necrosis may produce a greatly shrunken liver. Microscopically, there is considerable morphologic overlap in acute hepatitis caused by various hepatropic viruses. As is typical of many viral infections, _______________ predominate in all phases of viral hepatitis. A subtle difference is that the mononuclear infiltrate in hepatitis A may be especially rich in ____________. Most parenchymal injury is scattered throughout the hepatic lobule as “spotty necrosis” or lobular hepatitis . _____________ in acute hepatitis is minimal or absent.

As discussed earlier, hepatocyte injury may result in necrosis or apoptosis. In the former, the cytoplasm appears empty, with only scattered wisps of cytoplasmic remnants, and eventual rupture of cell membranes leads to “dropout” of hepatocytes. In their place, collapsed sinusoidal collagen reticulin framework remains behind along with ____________. With apoptosis, hepatocytes shrink, becoming intensely ________________, and their nuclei become pyknotic and fragmented; effector T cells may be present in the immediate vicinity.

In severe acute hepatitis, confluent necrosis of hepatocytes is seen around ___________. In these areas, there may be cellular debris, collapsed reticulin fibers, congestion/hemorrhage, and variable inflammation. With increasing severity, there is central-portal bridging necrosis, followed by parenchymal collapse. In its most severe form, massive hepatic necrosis and fulminant liver failure ensue.

Answer 26

mottled;

mononuclear cells;

plasma cells;

Portal inflammation;

scavenger macrophages;

eosinophilic;

central veins

Question 27

[Chronic viral hepatitis morphology]

The defining histologic feature of chronic viral hepatitis is _______________. It may be mild to severe and variable from one portal tract to the other. There is often interface hepatitis as well, in addition to lobular hepatitis, distinguished by its location at the interface between __________________. The hallmark of progressive chronic liver damage is scarring. At first, only portal tracts exhibit fibrosis, but in some patients, with time, ____________ —bands of dense scar—will extend between portal tracts. In the most severe cases, continued scarring and nodule formation leads to the development of cirrhosis, as discussed earlier.

Certain histologic features point to specific viral etiologies in chronic hepatitis. In chronic hepatitis B, ________________ (cells with endoplasmic reticulum swollen by HBsAg) are a diagnostic hallmark, and the presence of viral antigen in these cells can be confirmed by immunostaining. Liver biopsies involved by chronic hepatitis C quite commonly show _________________. Often, hepatitis C, particularly ___________, is associated with fatty change in scattered hepatocytes. Bile duct injury is also prominent in some cases of hepatitis C and may mimic the histologic changes seen in primary biliary cholangitis (see later); clinical parameters distinguish these two diseases easily, however.

Answer 27

mononuclear portal infiltration;

hepatocellular parenchyma and portal tract stroma;

fibrous septa;

“ground-glass” hepatocytes;

large lymphoid aggregates;

genotype 3

Question 28

[Bacterial, Parasitic, and Helminthic Infections]
A multitude of organisms can infect the liver and biliary tree, including bacteria, fungi, helminths and other parasites, and protozoa. Infectious organisms can reach the liver through several pathways:
- Ascending infection , via the ______________ (ascending cholangitis)
- _______________, most often through the portal system via the gastrointestinal tract
- Direct invasion , from an adjacent source (e.g., bacterial cholecystitis)
- Penetrating injury

Bacteria that may establish an infection in the liver via the blood include _____________________ in toxic shock syndrome, _______________ in typhoid fever, and _______________ in secondary or tertiary syphilis. Ascending infections are most common in the setting of partial or complete biliary tract obstruction and are typically caused by gut flora, which may colonize the static bile in the ducts. Whatever the source of the bacteria, with pyogenic organisms intrahepatic abscesses may develop, producing fever, right upper-quadrant pain, and tender hepatomegaly. Although antibiotic therapy may sterilize small abscesses, surgical drainage is often necessary for larger lesions. More commonly, extrahepatic bacterial infections, particularly sepsis, induce mild hepatic inflammation and varying degrees of hepatocellular cholestasis indirectly, without establishing an infectious nidus in the liver.

Other non-viral infectious agents cause liver disease with important or unusual pathogenic features that merit specific comment. These include the following:
___________, most commonly found in Asia, Africa, and South America, is one of the most common causes of noncirrhotic portal hypertension worldwide. Adult worms in the gut produce numerous eggs, some of which find their way into the portal circulation, where they lodge and induce a granulomatous reaction associated with marked fibrosis.

Entamoeba histolytica , an important cause of dysentery, sometimes ascends to the liver through portal circulation and produces secondary foci of infection that can progress to large necrotic areas called amebic liver abscesses. Amebic abscesses are more common in the __________________ The abscess cavity contains necrotic liver cells, but unlike pyogenic abscesses, neutrophils are absent.

Liver fluke infection, most common in Southeast Asia, is associated with a high rate of ________________. Responsible organisms include Fasciola hepatica , Opisthorcis species, and Clonorchis sinensis .

Echinococcal infections may cause the formation of intrahepatic hydatid cysts that produce symptoms due to pressure on surrounding structures or following rupture.

Answer 28

gut and biliary tract;

Vascular seeding ;

Staphylococcus aureus;

Salmonella typhi;

Treponema pallidum;

Schistosomiasis;

right lobe of the liver.;

cholangiocarcinoma

Question 29

[Autoimmune Hepatitis]
Autoimmune hepatitis is a chronic, progressive hepatitis with all the features of autoimmune diseases in general: genetic predisposition, association with other autoimmune diseases, the presence of autoantibodies, and therapeutic response to immunosuppression. Risk for autoimmune hepatitis is associated with certain HLA alleles, such as the ___________ in Caucasians, but as in other autoimmune disorders the mechanistic basis for this relationship is unclear. Triggers for the immune reaction may include viral infections or drug or toxin exposures.

Clinicopathologic Features
The annual incidence is highest among white northern Europeans at 1.9 in 100,000, but all ethnic groups are susceptible. There is a female predominance (78%). Autoimmune hepatitis is classified into two types, based on the patterns of circulating antibodies.

• Type 1, more common in middle-age and older individuals, is characterized by the presence of __________, ____________, ___________, and anti–soluble liver antigen/liver-pancreas antigen (anti-SLA/LP) antibodies.
• Type 2 , usually seen in children and teenagers, is chararc­terized by the presence of ______________ and anti–liver cytosol-1 antibodies.

MORPHOLOGY
Although autoimmune hepatitis shares patterns of injury with acute or chronic viral hepatitis, the time course of histologic progression differs. In viral hepatitis, fibrosis typically follows many years of slowly accumulating parenchymal injury, whereas in autoimmune hepatitis, there is an early phase of severe parenchymal destruction followed rapidly by scarring. For unclear reasons, this early wave of hepatocyte damage is often subclinical. The following features are typical of autoimmune hepatitis:
- Necrosis and inflammation , indicated by extensive interface hepatitis or foci of confluent (perivenular or bridging) necrosis or parenchymal collapse
- Plasma cell predominance in the mononuclear inflammatory infiltrates
- ____________ in areas of marked activity

An acute clinical illness is a common presentation (40%); sometimes the disease is fulminant, progressing to hepatic encephalopathy within 8 weeks of onset. Mortality for patients with severe untreated autoimmune hepatitis is approximately 40% within 6 months of diagnosis, and cirrhosis develops in at least 40% of survivors. Hence, diagnosis and intervention are imperative. ________________ is usually effective, leading to remission in 80% of patients and enabling long-term survival. End-stage disease is an indication for liver transplantation. The 10-year survival rate after liver transplant is 75%, but recurrence in the transplanted organ occurs in 20% of cases.

Answer 29

DRB1;

anti-nuclear (ANA); anti–smooth muscle actin (SMA); anti-mito­chondrial (AMA)

anti–liver kidney microsome-1 antibodies;

Hepatocyte “rosettes”;

Immunosuppressive therapy;

Question 30

As the major drug metabolizing and detoxifying organ in the body, the liver is subject to injury from an enormous array of therapeutic and environmental chemicals. Injury may result from direct toxicity, may occur through hepatic conversion of a xenobiotic compound to an active toxin, or may be produced by immune mechanisms, such as by the drug or a metabolite acting as a hapten to convert a cellular protein into an immunogen. A diagnosis of drug- or toxin-induced liver injury may be made on the basis of a temporal association of liver damage with drug or toxin exposure, recovery (usually) upon removal of the inciting agent, and exclusion of other potential causes. Exposure to a toxin or therapeutic agent should always be included in the differential diagnosis of any form of liver disease.

Drug reactions may be predictable (intrinsic) or unpredictable (idiosyncratic). Predictable drug or toxin reactions affect all individuals in a _________________. Unpredictable reactions depend on idiosyncrasies of the host, particularly the propensity to mount an immune response to the antigenic stimulus or the rate at which the agent can be metabolized. Both classes of injury may be immediate or take weeks to months to develop.

A classic, predictable hepatotoxin is acetaminophen, now the most common cause of acute liver failure necessitating transplantation in the United States. The toxic agent is not acetaminophen itself but rather toxic metabolites produced by the cytochrome P-450 system. The damage begins in ______________ but extends to encompass entire lobules in the most severe cases.

Examples of drugs that can cause idiosyncratic reactions include _________________, an agent that causes cholestasis in patients who are slow to metabolize it, and ___________ and its derivatives, which can cause a fatal immune-mediated hepatitis after repeated exposure.

Answer 30

dose-dependent fashion;

centrilobular hepatocytes;

chlorpromazine;

halothane

Question 31

Alcoholic and Nonalcoholic Fatty Liver Disease
Since the morphologic changes of alcoholic and NAFLD are indistinguishable, they are discussed together, followed by the pathogenesis and distinctive clinical features of each entity.

MORPHOLOGY
Three types of liver alterations are observed in fatty liver disease: steatosis (fatty change), hepatitis (alcoholic or steatohepatitis), and fibrosis.

Hepatocellular steatosis. Hepatocellular fat accumulation typically begins in ________________. The lipid droplets range from small (microvesicular) to large (macrovesicular), the largest filling and expanding the cell and displacing the nucleus. As steatosis becomes more extensive, the lipid accumulation spreads outward from the central vein to hepatocytes in the midlobule and then the ________________. Macroscopically, fatty livers with widespread steatosis are large (weighing 4–6 kg or more), soft, yellow, and greasy.

Steatohepatitis. These changes typically are more pronounced with alcohol use than in NAFLD, but can be seen in either:

• _______________. Single or scattered foci of cells undergo swelling and necrosis; as with steatosis, these features are most prominent in the centrilobular regions
• Mallory-Denk bodies. These consist of tangled skeins of intermediate filaments (including ubiquitinylated _______________) and are visible as eosinophilic cytoplasmic inclusions in degenerating hepatocytes ).
• Neutrophil infiltration. Predominantly neutrophilic infiltration may permeate the lobule and accumulate around degenerating hepatocytes, particularly those containing Mallory-Denk bodies. Lymphocytes and macrophages also may be seen in portal tracts or parenchyma.
• Steatofibrosis. Fatty liver disease of all kinds has a distinctive pattern of scarring. Like other changes, fibrosis appears first in the centrilobular region as central vein sclerosis. _______________ appears next in the space of Disse of the centrilobular region and then spreads outward, encircling individual or small clusters of hepatocytes in a chicken wire fence pattern. Tendrils of fibrosis eventually link to portal tracts and then condense to create central portal fibrous septa. As these become more prominent, the liver takes on a nodular, cirrhotic appearance. Because in most cases the underlying cause persists, the continual subdivision of established nodules by new, perisinusoidal scarring leads to a classic micronodular or Laennec cirrhosis.

Early in the course, the liver is yellow-tan, fatty, and enlarged, but with persistent damage over the course of years the liver is transformed into a brown, shrunken, nonfatty organ composed of cirrhotic nodules that are usually less than 0.3 cm in diameter—smaller than is typical for most chronic viral hepatitis. The end-stage cirrhotic liver may enter into a “burned-out” phase devoid of fatty change and other typical features. A majority of cases of cryptogenic cirrhosis, without clear etiology, are now recognized as “burned-out” NAFLD.

Answer 31

centrilobular hepatocytes;

periportal regions;

Hepatocyte ballooning;

keratins 8 and 18;

Perisinusoidal scarring;

Question 32

[Alcoholic Liver Disease]
Excessive ethanol consumption causes more than 60% of chronic liver disease in Western countries and accounts for 40% to 50% of deaths due to cirrhosis. Among the most important adverse effects of chronic alcohol consumption are the overlapping forms of alcohol-related fatty liver disease already discussed: (1) _________, (2) ____________, and (3) fibrosis and cirrhosis, collectively referred to as alcoholic liver disease.

Between 90% and 100% of heavy drinkers develop fatty liver (i.e., hepatic steatosis), and of those, 10% to 35% develop alcoholic hepatitis, whereas only 8% to 20% of chronic alcoholics develop cirrhosis. Steatosis, alcoholic hepatitis, and fibrosis may develop sequentially or independently, so they do not necessarily represent a sequential continuum of changes. _______________ arises in 10% to 20% of patients with alcoholic cirrhosis.

Answer 32

hepatic steatosis; alcoholic hepatitis;

Hepatocellular carcinoma;

Question 33

[Alcoholic liver disease- Pathogenesis]
Short-term ingestion of as much as 80 g of ethanol per day (5–6 beers or 8–9 ounces of 80-proof liquor) generally produces mild reversible hepatic changes, such as fatty liver. Chronic intake of 40 to 80 g/day is considered a borderline risk factor for severe injury. For reasons that may relate to decreased gastric metabolism of ethanol and differences in body composition, women are more susceptible than men to hepatic injury. It seems that how often and what one drinks may affect the risk for liver disease development. For example, binge drinking causes more liver injury than that associated with steady, lower-level consumption. Since not everyone who drinks gets all the listed complications, individual, possibly genetic, risk factors must exist, but no reliable markers of susceptibility are known. In the absence of a clear understanding of the factors that influence liver damage, it is difficult to state what constitutes a safe level of alcohol consumption.

Hepatocellular steatosis is caused by alcohol through several mechanisms. First, metabolism of ethanol by alcohol dehydrogenase and acetaldehyde dehydrogenase generates large amounts of ______________________, which increases shunting of substrates away from catabolism and toward ______________. Second, ethanol impairs the assembly and secretion of _____________. The net effect is to cause the accumulation of intracellular lipids.

The cause of alcoholic hepatitis is uncertain, but it may stem from one or more of the following toxic byproducts of ethanol and its metabolites:

• Acetaldehyde (a major metabolite of ethanol) induces lipid peroxidation and acetaldehyde-protein adduct formation, which may disrupt ________________ function.
• Alcohol directly affects _________________________.
• Reactive oxygen species generated during oxidation of ethanol by the microsomal ethanol oxidizing system react with and damage membranes and proteins. Reactive oxygen species also are produced by neutrophils, which infiltrate areas of hepatocyte necrosis.

Because generation of acetaldehyde and free radicals is maximal in the centrilobular region, this region is most susceptible to toxic injury. Pericellular and sinusoidal fibrosis develop first in this area of the lobule. Concurrent viral hepatitis, particularly hepatitis C, is a major accelerator of liver disease in alcoholics. The prevalence of hepatitis C among individuals with alcoholic liver disease is about 30% (and vice versa).

For unknown reasons, cirrhosis develops in only a small fraction of chronic alcoholics. With complete abstinence, at least partial regression of scarring occurs, and the micronodular liver transforms though parenchymal regeneration into a macronodular cirrhotic organ ; rarely, there is regression of cirrhosis altogether.

Answer 33

nicotinamide-adenine dinucleotide (NADH);

lipid biosynthesis;

lipoproteins;

cytoskeleton and membrane;

mitochondrial function and membrane fluidity;

Question 34

[Acoholic Liver disease- clinical features]
Alcoholic steatosis may be innocuous or give rise to hepatomegaly with mild elevations of serum bilirubin and alkaline phosphatase. Severe hepatic compromise is unusual. Alcohol withdrawal and the provision of an adequate diet are sufficient treatment.

It is estimated that 15 to 20 years of excessive drinking are necessary to develop alcoholic cirrhosis, but _____________ can occur after just weeks or months of alcohol abuse. The onset is typically acute and often follows a bout of particularly heavy drinking. Symptoms and laboratory abnormalities range from minimal to severe. Most patients present with malaise, anorexia, weight loss, upper-abdominal discomfort, tender hepatomegaly, and fever. Typical findings include hyperbilirubinemia, elevated serum alkaline phosphatase levels, and ________________. Serum alanine and aspartate aminotransferases are elevated but usually remain below __________. The outlook is unpredictable; each bout of alcoholic hepatitis carries a 10% to 20% risk for death. With repeated bouts, cirrhosis appears in about one-third of patients within a few years.

The manifestations of alcoholic cirrhosis are similar to those of other forms of cirrhosis. In chronic alcoholics, ethanol may be the major source of calories in the diet, displacing other nutrients and leading to malnutrition and vitamin deficiencies (e.g., thiamine, vitamin B 12 ). Compounding these effects is impaired digestive function, primarily related to chronic gastric and intestinal mucosal damage and _____________.

The long-term outlook for alcoholic patients with liver disease is variable. The most important aspect of treatment is abstinence from alcohol. The 5-year survival rate approaches 90% in abstainers who are free of jaundice, ascites, and hematemesis, but drops to 50% to 60% in individuals who continue to imbibe.

Among those with end-stage alcoholic liver disease, the immediate causes of death are as follows:

• Hepatic failure
• Massive gastrointestinal hemorrhage
• _____________ (to which affected individuals are predisposed)
• Hepatorenal syndrome
• ______________ (3%–6% of cases)

Answer 34

alcoholic hepatitis;

neutrophilic leukocytosis;

500 U/mL;

pancreatitis;

Intercurrent infection ;

Hepatocellular carcinoma

Question 35

[Nonalcoholic Fatty Liver Disease]
NAFLD is a common condition in which fatty liver disease develops in individuals who do not drink alcohol. The liver can show any of the three types of changes discussed earlier (steatosis, steatohepatitis, and cirrhosis), though on average inflammation is less prominent than in alcoholic liver disease. The term nonalcoholic steatohepatitis (NASH) is used to describe overt clinical features of liver injury, such as _________________, and the histologic features of hepatitis already discussed. NAFLD is consistently associated with _______________ and the metabolic syndrome. Other commonly associated abnormalities are as follows:
- Type 2 diabetes (or family history of the condition)
- Obesity, primarily ___________ (body mass index >30 kg/m 2 in whites and >25 kg/m 2 in Asians)
- Dyslipidemia (hypertriglyceridemia, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol)
- Hypertension

Pathogenesis
The key initiating events in NAFLD appear to be the development of obesity and insulin resistance, the latter within both adipose tissue and the liver. These factors combine to increase the mobilization of free fatty acids from ____________ which are taken up by hepatocytes, and to stimulate the synthesis of fatty acids within hepatocytes. It is estimated that over half of the lipid found in hepatocytes in NAFLD is derived from adipose tissue, with most of the remainder coming from de novo synthesis in liver cells. Precisely how the accumulation of lipid in hepatocytes predisposes to the development of NASH is not known and may involve several interrelated mechanisms. Excessive intrahepatic lipids and their metabolic intermediates enhance insulin resistance in the liver and sensitize hepatocytes to the toxic effects of inflammatory cytokines, which are produced in increased amounts in the setting of the metabolic syndrome. In addition, hepatocytes in patients with NASH show evidence of inflammasome activation, possibly due to direct or indirect effects of particular lipids, leading to local release of the _____________________. Other products of lipid metabolism appear to be directly toxic to hepatocytes; proposed mechanisms include increased production of reactive oxygen species, induction of ER stress, and disruption of mitochondrial function. Liver injury resulting from these various insults causes stellate cell activation, collagen deposition, and hepatic fibrosis, which along with ongoing hepatocyte damage lead to full-blown NASH.

Clinical Features
NAFLD is the most common cause of incidental elevation of serum transaminases. Most individuals with steatosis are asymptomatic; patients with active steatohepatitis or fibrosis may also be asymptomatic, but some may have fatigue, malaise, right upper-quadrant discomfort, or more severe symptoms of chronic liver disease. Liver biopsy is required to identify NASH and distinguish it from uncomplicated NAFLD. Fortunately, the frequency of progression from steatosis to active steatohepatitis and then from active steatohepatitis to cirrhosis is low. Nevertheless, NAFLD is considered to be a significant contributor to the pathogenesis of ___________________. Because they share common risk factors, the incidence of coronary artery disease also is increased in patients with NAFLD.

Current therapy is directed toward obesity reduction and reversal of insulin resistance. Lifestyle modifications that lead to _____________ (diet and exercise) appear to be the most effective form of treatment.

Pediatric NAFLD is becoming an increasing problem as obesity and metabolic syndrome approach epidemic proportions. In children, the appearance of the histologic lesions is somewhat different, as inflammation and scarring tend to be more prominent in the portal tracts and periportal regions, and mononuclear infiltrates rather than neutrophilic infiltrates predominate.

Answer 35

elevated transaminases;

insulin resistance;

central obesity;

adipose tissue;

pro-inflammatory cytokine IL-1;

“cryptogenic” cirrhosis

weight loss;

Question 36

[Hemochromatosis]

Hemochromatosis is caused by __________________, which is primarily deposited in parenchymal organs such as the liver and pancreas, as well as in the heart, joints, and endocrine organs. It results most commonly from an inherited disorder, hereditary hemochromatosis . When iron accumulation occurs as a consequence of parenteral administration of iron, usually in the form of transfusions, it is called acquired hemochromatosis. Secondary iron overload also can complicate diseases that are associated with persistent ineffective erythropoiesis, particularly thalassemia and myelodysplastic syndromes.

As discussed in Chapter 12 , the total body iron pool ranges from 2 to 6 gm in normal adults; about 0.5 gm is stored in hepatocytes. In severe hemochromatosis, total iron may exceed 50 gm, one-third of which accumulates in the liver. Fully developed cases exhibit (1) ______________ (2) __________ (up to 80% of patients); and (3) abnormal skin pigmentation (up to 80% of patients).

Pathogenesis
Because there is no regulated iron excretion from the body, the total body content of iron is tightly regulated by intestinal absorption. _____________ is a circulating peptide hormone that acts as a key negative regulator of intestinal iron uptake. Diverse mutations in several genes have been described in hereditary hemochromatosis, all of which lower hepcidin levels or diminish hepcidin function. Whatever the underlying defect, the net result is an increase in intestinal absorption of dietary iron, leading to an accumulation of 0.5 to 1 gm of iron per year.

The most frequently mutated gene in patients with hereditary hemochromatosis is HFE, which is located on _____________ close to the HLA gene cluster. HFE encodes an HLA class I–like molecule that regulates the synthesis of hepcidin in hepatocytes. The most common HFE mutation is a ________________. This mutation, which inactivates the HFE protein, is present in over 70% of patients diagnosed with hereditary hemochromatosis and is most common in European populations. Several other mutations can also give rise to hemochromatosis, including other mutations in HFE as well as mutations in transferrin receptor 2 and in hepcidin itself. The associated clinical condition is milder with some of these alternative mutations and more severe with others, sometimes manifesting in young adults or even during childhood.

Whatever the underlying cause, the onset of disease typically occurs after 20 gm of stored iron have accumulated. Excessive iron appears to be directly toxic to host tissues. Mechanisms of liver injury include the following:

• Lipid peroxidation via _______________
• Stimulation of collagen formation by activation of _______________
• DNA damage by reactive oxygen species, leading to lethal cell injury or predisposition to HCC

The deleterious effects of iron on cells that are not fatally injured are reversible, and removal of excess iron with therapy promotes recovery of tissue function.

Answer 36

excessive absorption of iron;

micronodular cirrhosis;;

diabetes mellitus;

hepcidin;

chromosome 6;

cysteine-to-tyrosine substitution at amino acid 282 (C282Y)

iron-catalyzed free radical reactions;

hepatic stellate cells

Question 37

[Hemotochromatosis]
MORPHOLOGY
The morphologic changes in severe hemochromatosis are characterized principally by (1) tissue deposition of hemosiderin in the following organs (in decreasing order of severity): liver, pancreas, ___________, ___________, adrenal gland, thyroid and parathyroid glands, joints, and skin; (2) cirrhosis ; and (3) pancreatic fibrosis . In the liver, iron becomes evident first as ____________________ in the cytoplasm of periportal hepatocytes, which can be histochemically stained with ____________. With increasing iron load, there is progressive deposition in the rest of the lobule, the bile duct epithelium, and Kupffer cells. At this stage, the liver typically is slightly enlarged and chocolate brown. Fibrous septa develop slowly, linking portal tracts to each other and leading ultimately to cirrhosis in an intensely pigmented (very dark brown to black) liver.

The pancreas also becomes pigmented, acquires ________________, and may show parenchymal atrophy. Hemosiderin is found in the acinar and the islet cells and sometimes in the interstitial fibrous stroma. The heart often is enlarged, with hemosiderin granules within the myocardial fibers. The pigmentation may induce a striking brown coloration of the myocardium. A delicate interstitial fibrosis may appear. Although skin pigmentation is partially attributable to hemosiderin deposition in dermal macrophages and fibroblasts, most of the coloration results from increased __________________. The combination of these pigments renders the skin slate-gray. With hemosiderin deposition in the joint synovial linings, an acute synovitis may develop. There is also excessive deposition of __________________, which damages the articular cartilage and sometimes produces disabling polyarthritis, referred to as pseudogout. With the onset of cirrhosis, the testes may become atrophic.

Clinical Features
Symptoms usually appear earlier in men than in women since menstrual bleeding limits the accumulation of iron until menopause. This results in a male-to-female ratio of clinically significant iron overload of approximately 5 : 1 to 7 : 1. In the most common form caused by HFE mutations, symptoms usually appear in the fifth and sixth decades of life in men and later in women. With population screening, it has become clear that homozygosity for the most common HFE mutation (C282Y) shows variable penetrance; thus disease development is not inevitable, presumably because other genetic and environmental factors influence the rate of iron accumulation.

The principal manifestations include ___________, abdominal pain, skin pigmentation (particularly in sun-exposed areas), deranged glucose homeostasis or frank diabetes mellitus due to destruction of pancreatic islets, cardiac dysfunction (arrhythmias, cardiomyopathy), and atypical arthritis. In some patients, the presenting complaint is___________(e.g., amenorrhea in the female, impotence and loss of libido in the male). As noted, clinically apparent disease is more common in males and rarely becomes evident before 40 years of age. Death may result from cirrhosis or cardiac disease. In those with untreated disease, the risk for HCC is increased 200-fold, presumably because of ongoing liver damage and the genotoxic effects of oxidants generated by iron in the liver.

Fortunately, hemochromatosis can be diagnosed long before irreversible tissue damage has occurred. Screening of family members of probands is important. Heterozygotes also accumulate excessive iron, but not to a level that causes significant tissue damage. Currently most patients with hemochromatosis are diagnosed in the subclinical, precirrhotic stage due to routine serum iron measurements (as part of another diagnostic workup). _____________ results in steady removal of excess tissue iron, and with this simple treatment life expectancy is normal.

Answer 37

myocardium; pituitary gland;

golden-yellow hemosiderin granules;

Prussian blue

diffuse interstitial fibrosis;

epidermal melanin production;

calcium pyrophosphate;

hepatomegaly;

hypogonadism ;

Regular phlebotomy

Question 38

[Wilson Disease]

Wilson disease is an autosomal recessive disorder caused by mutation of the ____________, which results in impaired copper excretion into bile and a failure to incorporate copper into ceruloplasmin. This disorder is marked by the accumulation of toxic levels of copper in many tissues and organs, principally the liver, brain, and eye. Normally, 40% to 60% of ingested copper (2–5 mg/day) is absorbed in the _________________, from where it is transported complexed with ____________ to the liver. Here, free copper dissociates and is taken up by hepatocytes, where copper is incorporated into enzymes and α 2 -globulin (apoceruloplasmin) to form __________, which is secreted into the blood. Ceruloplasmin carries 90% to 95% of plasma copper. Circulating ceruloplasmin is eventually desialylated, endocytosed by the liver, and degraded within lysosomes, after which the released copper is excreted into bile. This degradation/excretion pathway is the primary route for copper elimination.

The ATP7B gene, located on chromosome 13, encodes a transmembrane copper-transporting ATPase that is expressed on the ____________________. The overwhelming majority of patients with Wilson disease are compound heterozygotes with different loss-of-function mutations affecting each ATP7B allele. The overall frequency of mutated alleles is 1 : 100, and the prevalence of the disease is approximately 1 : 30,000 to 1 : 50,000. Loss of ATP7B protein function impairs the transport of copper into the bile and the incorporation of copper into ceruloplasmin, which is not secreted in its __________________ form. These abnormalities lead to copper accumulation in the liver and a decrease in plasma ceruloplasmin. Accumulating copper causes liver injury through the production of reactive oxygen species by the ________________. Eventually, non-ceruloplasmin–bound copper is released from injured hepatocytes into the circulation, causing red cell hemolysis and allowing copper to deposit in other tissues, such as the brain, corneas, kidneys, bones, joints, and parathyroid glands. Concomitantly, urinary excretion of copper increases markedly from its normal minuscule levels.

Answer 38

ATP7B gene;

duodenum and proximal small intestine;

albumin and histidine;

ceruloplasmin;

hepatocyte canalicular membrane;

apoceruloplasmin;

Fenton reaction;

Question 39

[Wilson disease]
MORPHOLOGY
The liver often bears the brunt of injury. The hepatic changes are variable, ranging from relatively minor to massive and mimic many other disease processes. There may be mild to moderate fatty change (steatosis) associated with focal hepatocyte necrosis. Acute, fulminant hepatitis can mimic acute viral hepatitis. Chronic hepatitis in Wilson disease exhibits moderate to severe inflammation and hepatocyte necrosis, areas of fatty change, and features of steatohepatitis (hepatocyte ballooning with ___________ bodies). In advanced cases, cirrhosis may be seen. Copper deposition in hepatocytes can be demonstrated by special stains (__________ stain for copper, _________ stain for copper-associated protein).

Toxic injury to the brain primarily affects the basal ganglia. Nearly all patients with neurologic involvement develop eye lesions called _______________, green to brown deposits of copper in Desçemet membrane in the limbus of the cornea.

Clinical features
The age at onset and the clinical presentation of Wilson disease are extremely variable. Symptoms usually appear between 6 and 40 years of age. Acute or chronic liver disease are common presenting features. Neuropsychiatric manifestations are the initial features in most of the remaining cases and stem from deposition of copper in the __________ .

The diagnosis of Wilson disease is based on low levels of serum ceruloplasmin, an ________________ (the most sensitive test), and increased urinary excretion of copper (the most specific test). Hepatic copper content in excess of 250 µg per gram dry weight of liver is taken to be diagnostic, but is only about 80% sensitive. In those with lower liver copper levels, the diagnosis depends on other abnormalities, such as elevated urinary copper, low serum ceruloplasmin, and the presence of Kayser-Fleischer rings. Unlike hereditary hemochromatosis, where the limited number of genetic variants makes genetic testing fairly simple, the large number of different causative mutations in ATP7B7 complicates the use of DNA sequencing as a diagnostic test. Serum copper levels also are of no diagnostic value, as they may be low, normal, or elevated, depending on the stage of the liver disease.

Early recognition and long-term copper chelation therapy (with ______________ or Trientine) or zinc-based therapy (which inhibits copper uptake in the gut) has dramatically altered the usual progressive downhill course. Individuals with hepatitis or advanced cirrhosis require liver transplantation, which can be curative.

Answer 39

prominent Mallory-Denk ;

rhodamine;

orcein ;

Kayser-Fleischer rings;

basal ganglia;

increase in hepatic copper content;

d -penicillamine

Question 40

‘α 1 -Anti-Trypsin Deficiency]
α 1 -Anti-trypsin deficiency is an autosomal recessive disorder marked by very low levels of circulating α 1 -anti-trypsin (α 1 AT) that is caused by mutations that lead to misfolding of α 1 AT. The major function of α 1 AT is to inhibit proteases, particularly _______________________________ which are released from neutrophils at sites of inflammation. α 1 AT deficiency leads to the development of pulmonary emphysema because the activity of destructive proteases is not inhibited. It also causes liver disease as a consequence of hepatocellular accumulation of the misfolded α 1 AT protein.

α 1 AT is a small 394–amino acid plasma glycoprotein synthesized predominantly by hepatocytes. The gene, located on chromosome 14, is very polymorphic. At least 75 α 1 AT variants have been identified, denoted alphabetically by their relative migration on an isoelectric gel. The most common genotype is PiMM, occurring in 90% of individuals (the “wild-type”).

The most common clinically significant mutation is PiZ; PiZZ homozygotes have circulating α 1 AT levels that are only 10% of normal. These individuals are at high risk for developing clinical disease. Variant alleles are codominant, and, consequently, PiMZ heterozygotes have intermediate plasma levels of α 1 AT. Among individuals of northern European descent, the PiZZ state affects 1 in 1800 live births. Because of the early presentation of the liver disease, α 1 AT deficiency is the most commonly diagnosed genetic hepatic disorder in infants and children.

Pathogenesis
The PiZ polypeptide is prone to misfolding and aggregation due to a single amino acid glutamine-to-lysine substitution at residue 342 (E342K). This in turn creates ________________ and triggers the unfolded protein response, which ultimately leads to apoptosis. It is worth emphasizing that the liver damage is caused by protein misfolding, whereas lung damage leading to emphysema stems from the loss of α 1 AT function and excessive protease activity. Although all individuals with the PiZZ genotype accumulate α 1 AT-Z in the endoplasmic reticulum of hepatocytes, only 10% to 15% develop overt clinical liver disease; thus, other genetic factors or environmental factors must also play a role in the development of liver disease.

MORPHOLOGY
α 1 -Anti-trypsin deficiency is characterized by the presence of round-to-oval ______________________ in hepatocytes that are strongly periodic acid–Schiff (PAS) positive and diastase resistant. _______________ are most affected in early and in mild forms of the disease, with central lobular hepatocytes being affected later or in more severe disease. Other pathologic features vary, ranging from hepatitis to fibrosis to full-blown cirrhosis.

Clinical Features
Neonatal hepatitis with cholestatic jaundice appears in 10% to 20% of newborns with α 1 AT deficiency. In adolescence, presenting symptoms may be related to hepatitis or cirrhosis. Attacks of hepatitis may subside with apparent complete recovery, or they may become chronic and lead progressively to cirrhosis. Alternatively, the disease may remain silent until cirrhosis appears in middle to later adult life. HCC develops in 2% to 3% of PiZZ adults, usually in the setting of cirrhosis. The definitive treatment, for severe hepatic disease is liver transplantation. In patients with pulmonary disease, avoidance of cigarette smoking is crucial, because smoking results in accumulation of neutrophils and release of elastase in the lung that is not inactivated because of lack of α 1 AT. The unopposed action of neutrophil derived proteases destroys elastic fibers in alveolar walls, leading to ______________ .

Answer 40

neutrophil elastase, cathepsin G, and proteinase 3;

endoplasmic reticulum stress ;

cytoplasmic globular inclusions;

Periportal hepatocytes;

emphysema

Question 41

Hepatic bile serves two major functions: (1) the _________________ in the lumen of the gut through the detergent action of bile salts, and (2) the elimination of ___________, excess cholesterol, xenobiotics, and other waste products that are insufficiently water-soluble to be excreted into urine. Processes that interfere with excretion of bile lead to jaundice and icterus due to retention of bilirubin, and to cholestasis (discussed later).

Jaundice may occur in settings of increase bilirubin production (e.g., extravascular red cell hemolysis), hepatocyte dysfunction (e.g., hepatitis), or obstruction of the flow of bile (e.g., an impacted gallstone), any of which can disturb the equilibrium between bilirubin production and clearance (summarized in Table 16.4 ). The metabolism of bilirubin by the liver occurs in four steps: uptake from the circulation; intracellular storage; conjugation with glucuronic acid; and biliary excretion.

Answer 41

emulsification of dietary fat;

bilirubin

Question 42

[Bilirubin and Bile Formation]
Bilirubin is the end product of heme degradation ( Fig. 16.22 ). Approximately 85% of daily production (0.2–0.3 gm) is derived from the breakdown of senescent red cells by macrophages in the spleen, liver, and bone marrow. The remainder is derived from the turnover of hepatic heme or hemoproteins (e.g., the P-450 cytochromes) and from destruction of red cell precursors in the bone marrow. Whatever the source, intracellular heme oxygenase oxidizes heme to __________ (step 1), which is immediately reduced to bilirubin by _______________. Bilirubin thus formed is released and binds to _____________ (step 2), which is critical since bilirubin is virtually insoluble in aqueous solutions at physiologic pH and also highly toxic to tissues. Albumin carries bilirubin to the liver, where bilirubin is taken up into hepatocytes (step 3) and conjugated with one or two molecules of glucuronic acid by ______________________ (UGT1A1, step 4) in the endoplasmic reticulum. Water-soluble, nontoxic bilirubin glucuronides are then excreted into the bile. Most bilirubin glucuronides are deconjugated in the gut lumen by bacterial β-glucuronidases and degraded to ______________ (step 5). The urobilinogens and the residue of intact pigment are largely excreted in feces. Approximately 20% of the urobilinogens formed are reabsorbed in the ileum and colon, returned to the liver, and reexcreted into bile. A small amount of reabsorbed urobilinogen is excreted in the urine.

Two-thirds of the organic materials in bile are bile salts, which are formed by the conjugation of bile acids with ______________. Bile acids, the major catabolic products of cholesterol, are a family of water-soluble sterols with carboxylated side chains. The primary human bile acids are ____________________. Bile acids are highly effective detergents. Their primary physiologic role is to solubilize water-insoluble lipids secreted by hepatocytes into bile, and also to solubilize dietary lipids in the gut lumen. Ninety-five percent of secreted bile acids, conjugated or unconjugated, are reabsorbed from the gut lumen and recirculate to the liver (enterohepatic circulation), thus helping to maintain a large endogenous pool of bile acids for digestive and excretory purposes.

Pathophysiology of Jaundice
Both unconjugated bilirubin and conjugated bilirubin (bilirubin glucuronides) may accumulate systemically. As discussed earlier, unconjugated bilirubin is virtually insoluble and tightly bound to albumin. As a result, it cannot be excreted in the urine, even when blood levels are high. Normally, a very small amount of unconjugated bilirubin is present as a free anion in plasma. If unconjugated bilirubin levels rise, this unbound fraction may diffuse into tissues, particularly the brain in infants, and produce toxic injury. The unbound plasma fraction increases in severe hemolytic disease or when protein-binding drugs displace bilirubin from albumin. Hence, hemolytic disease of the newborn (erythroblastosis fetalis) may lead to accumulation of unconjugated bilirubin in the brain, which can cause severe neurologic damage, referred to as _____________. In contrast, conjugated bilirubin is water-soluble, nontoxic, and only loosely bound to albumin. Because of its solubility and weak association with albumin, excess conjugated bilirubin in plasma can be excreted in urine.

Serum bilirubin levels in the normal adult vary between 0.3 and 1.2 mg/dL. Jaundice becomes evident when the serum bilirubin levels rise above 2 to 2.5 mg/dL; levels as high as 30 to 40 mg/dL can occur with severe disease. Causes of conjugated and unconjugated hyperbilirubinemia differ, and so measurement of both forms is of value in evaluating a patient with jaundice.

Answer 42

biliverdin;

biliverdin reductase;

serum albumin;

bilirubin uridine diphosphate (UDP) glucuronyltransferase;

colorless urobilinogens;

taurine or glycine

cholic acid and chenodeoxycholic acid;

kernicterus;

Question 43

[Defects in Hepatocellular Bilirubin Metabolism]

Neonatal Jaundice
Because the hepatic machinery for conjugating and excreting bilirubin does not fully mature until about 2 weeks of age, almost every newborn develops transient and mild unconjugated hyperbilirubinemia, termed neonatal jaundice or physiologic jaundice of the newborn . This may be exacerbated by breastfeeding, due to the action of __________________- in breast milk. Nevertheless, sustained jaundice in the newborn is abnormal.

Hereditary Hyperbilirubinemias
Jaundice also may result from inborn errors of metabolism, including the following:
Gilbert syndrome is a common (7% of the population) inherited condition that manifests as fluctuating unconjugated hyperbilirubinemia of variable severity. The primary cause is mildly decreased hepatic levels of ________________ attributed to a mutation in the encoding gene, UGT1A1; polymorphisms in the gene may play a role in the variable expression of this disorder. Gilbert syndrome is not associated with any morbidity. By contrast, severe glucuronosyltransferase deficiency causes a rare disorder called __________________ that is fatal in infancy.

________________ results from an autosomal recessive defect in the transport protein responsible for hepatocellular excretion of bilirubin glucuronides across the canalicular membrane. Affected individuals exhibit conjugated hyperbilirubinemia. Other than having a darkly pigmented liver (from polymerized epinephrine metabolites, not bilirubin) and hepatomegaly, patients are normal.

Answer 43

bilirubin-deconjugating enzymes;

glucuronosyltransferase;

Crigler-Najjar Syndrome Type 1;

Dubin-Johnson syndrome

Question 44

[Cholestasis]
Cholestasis is a condition caused by extrahepatic or intrahepatic obstruction of bile channels or by defects in hepatocyte bile secretion. Patients may have jaundice, pruritus, skin xanthomas (focal accumulation of cholesterol), or symptoms related to intestinal malabsorption, including nutritional deficiencies of the fat-soluble vitamins A, D, or K. A characteristic laboratory finding is elevated ______________________________ enzymes that are present on the apical membranes of hepatocytes and cholangiocytes.

MORPHOLOGY
The morphologic features of cholestasis depend on its severity, duration, and underlying cause. Common to both obstructive and nonobstructive cholestasis is the accumulation of bile pigment within the hepatic parenchyma. Elongated __________________ are visible in dilated bile canaliculi. Rupture of canaliculi leads to extravasation of bile, which is quickly phagocytosed by Kupffer cells. Droplets of bile pigment also accumulate within hepatocytes, which can take on a fine, foamy appearance referred to as feathery degeneration . Occasional apoptotic hepatocytes also may be seen.

Answer 44

serum alkaline phosphatase and γ-glutamyl transpeptidase (GGT),

green-brown plugs of bile

Question 45

[Bile Duct Obstruction and Ascending Cholangitis]
The most common cause of bile duct obstruction in adults is _______________, followed by malignant obstructions, and postsurgical strictures. Obstructive conditions in children include biliary atresia, cystic fibrosis, choledochal cysts (a cystic anomaly of the extrahepatic biliary tree), and syndromes in which there are insufficient intrahepatic bile ducts (paucity of bile duct syndromes). The initial morphologic features of cholestasis have been discussed and are entirely reversible with correction of the obstruction. Prolonged obstruction can lead to biliary cirrhosis, discussed later.

Ascending cholangitis, secondary bacterial infection of the biliary tree, may complicate duct obstruction. Enteric organisms such as _______________ are common culprits. Cholangitis usually presents with fever, chills, abdominal pain, and jaundice. The most severe form of cholangitis is __________________, in which purulent bile fills and distends bile ducts. Since sepsis rather than cholestasis tends to dominate this potentially grave process, prompt diagnostic evaluation and intervention are imperative.

Since extrahepatic biliary obstruction is frequently amenable to surgical treatment, correct and prompt diagnosis is imperative. In contrast, cholestasis due to diseases of the intrahepatic biliary tree or hepatocellular secretory failure (collectively termed intrahepatic cholestasis ) is not benefited by surgery (short of transplantation), and the patient’s condition may be worsened by an operative procedure. It is thus important to establish the underlying basis for jaundice and cholestasis.

MORPHOLOGY
Acute biliary obstruction, either intrahepatic or extrahepatic, causes distention of upstream bile ducts, which often become dilated. In addition, ductular reactions appear at the portal-parenchymal interface along with_______________ . The hallmark of superimposed infection (ascending cholangitis) is the influx of periductular neutrophils into the bile duct epithelium and lumen.

Left uncorrected, the inflammation and ductular reactions resulting from chronic biliary obstruction initiate periportal fibrosis, eventually generating ___________________ . Cholestatic features in the parenchyma may be prominent. These take the form of extensive feathery degeneration of periportal hepatocytes , a type of cytoplasmic swelling often associated with Mallory-Denk bodies and bile infarcts caused by the detergent effects of extravasated bile

Answer 45

extrahepatic cholelithiasis (gallstones);

coliforms and enterococci;

suppurative cholangitis;

stromal edema and neutrophils;

secondary or obstructive biliary cirrhosis

Question 46

[Neonatal Cholestasis]
Prolonged conjugated hyperbilirubinemia in the neonate, termed neonatal cholestasis (as opposed to the already discussed neonatal jaundice) affects approximately 1 in 2500 live births. The major conditions causing it are (1) cholangiopathies, primarily biliary atresia (discussed later), and (2) a variety of disorders causing conjugated hyperbilirubinemia in the neonate, collectively referred to as neonatal hepatitis .

Neonatal hepatitis is not a specific entity, nor does it necessarily have an inflammatory basis. Rather it is an indication to conduct a diligent search for recognizable toxic, metabolic, and infectious liver diseases, as greater than 85% of cases have identifiable causes.

Differentiation of biliary atresia from nonobstructive neonatal cholestasis is very important, since definitive treatment of biliary atresia requires surgical intervention (___________________), whereas surgery may adversely affect a child with other disorders. Fortunately, discrimination can be made on the basis of clinical data in about 90% of cases. In 10% of cases, liver biopsy may be necessary to distinguish neonatal hepatitis from an identifiable cholangiopathy. Affected infants have jaundice, dark urine, light or acholic stools, and hepatomegaly. Variable degrees of hepatic synthetic dysfunction may be identified, such as hypoprothrombinemia.

MORPHOLOGY
The morphologic features of neonatal hepatitis include striking _______________________, associated with lobular disarray, focal liver cell apoptosis and prominent hepatocellular and canalicular cholestasis. In some cases, this parenchymal pattern of injury also is accompanied by ductular reaction and fibrosis of portal tracts.

Answer 46

Kasai procedure;

giant-cell transformation of hepatocytes

Question 47

Biliary Atresia
Biliary atresia is defined as a complete or partial obstruction of the extrahepatic biliary tree that occurs within the first 3 months of life. It underlies approximately one-third of cases of neonatal cholestasis and is the single most frequent cause of death from liver disease in early childhood. Approximately 50% to 60% of children referred for liver transplantation have biliary atresia.

Pathogenesis
Two major forms of biliary atresia are recognized; these are based on the presumed timing of luminal obliteration.
- The fetal form accounts for as many as 20% of cases and is commonly associated with other developmental anomalies involving the thoracic and abdominal organs, including malrotation of abdominal viscera, interrupted inferior vena cava, polysplenia, and congenital heart disease.
- Much more common is the perinatal form of biliary atresia, in which an apparently normally developed biliary tree is injured and obstructed following birth. The etiology of perinatal biliary atresia is unknown; viral infection and toxic exposures are considered prime suspects.

MORPHOLOGY
The salient features of biliary atresia include ______________________ of the hepatic or common bile ducts; in some individuals, periductular inflammation also extends into the intrahepatic bile ducts, leading to progressive destruction of the intrahepatic biliary tree as well. When biliary atresia is unrecognized or uncorrected, cirrhosis develops within 3 to 6 months of birth.

There is considerable variability in the pattern of biliary atresia. When the disease is limited to the common duct or right and/or left hepatic bile ducts with patent intrahepatic branches, the disease is surgically correctable ( Kasai procedure ). Unfortunately, in 90% of patients the obstruction also involves bile ducts at or ___________________. These cases are not correctable, since there are no patent bile ducts amenable to surgical anastomosis.

Clinical Features
Infants with biliary atresia present with neonatal cholestasis, but exhibit normal birth weight and postnatal weight gain. There is a slight female predominance. Initially stools are normal, but they become __________ as the disease progresses. Ascending cholangitis and/or intrahepatic progression of the disease may impede attempts at surgical resection of the obstruction and bypass of the biliary tree. ____________________ is the primary hope for saving these young patients. Without surgical intervention, death usually occurs within 2 years of birth.

Answer 47

inflammation and fibrosing stricture;

above the porta hepatis;

acholic;

Transplantation of a donor liver and its accompanying bile ducts

Question 48

Primary Biliary Cholangitis
Primary biliary cholangitis (PBC) is an autoimmune disease whose primary feature is nonsuppurative, inflammatory destruction of ______________________ bile ducts. Large intrahepatic ducts and the extrahepatic biliary tree are not involved. Previously, this disease was known as primary biliary cirrhosis, but most patients do not progress to this stage, and the name primary biliary cholangitis is now preferred.

PBC is primarily a disease of middle-age women, with a female-to-male ratio of 6:1. Its peak incidence is between 40 and 50 years of age. The disease is most prevalent in Northern European countries (England and Scotland) and the Northern United States (Minnesota), where the prevalence is as high as 400 per 1 million cases. Recent increases in incidence and prevalence along with geographic clustering suggest that both environmental and genetic factors are important in its pathogenesis. Family members of PBC patients have an increased risk for developing the disease.

Pathogenesis
PBC is thought to be an autoimmune disorder, but as with other autoimmune diseases the triggers that initiate PBC are unknown. ___________________ are the most characteristic finding in PBC. T cells specific for certain mitochondrial enzymes are another feature of the disease, supporting the notion of an immune-mediated process. Other findings suggestive of altered immunity include __________ molecules on bile duct epithelial cells, accumulation of autoreactive T cells around bile ducts, and the frequent presence of other autoantibodies against nuclear pore proteins centromeric proteins, and other cellular components.

MORPHOLOGY
Interlobular bile ducts are actively destroyed by lymphoplasmacytic inflammation with or without granulomas (the florid duct lesion. Some biopsy specimens, however, do not have active lesions and only show the absence of bile ducts in portal tracts. The disease is quite patchy in distribution; it is common to see a single bile duct under immune attack in one level of a biopsy specimen, while other nearby ducts, are unaffected. Ductular reactions follow on this duct injury, and these in turn participate in the development of portal-portal septal fibrosis.

In the absence of treatment, the disease follows one of two paths to end-stage disease. In the first, most classic pathway, there is increasingly ___________, slowly leading to established cirrhosis and eventually to profound cholestasis. Alternatively, some patients eventually developed __________________ rather than severe cholestasis. Fortunately, both of these outcomes are now rarely seen.

Answer 48

small- and medium-sized intrahepatic;

Anti-mitochondrial antibodies;

aberrant expression of MHC class II;

widespread duct loss;

prominent portal hypertension

Question 49

[Primary Biliary cholangitis]
Clinical Features
Most patients are diagnosed while asymptomatic following a workup triggered by the identification of an ________________ or severe itching. _______________ is common. _______________ are present in 90% to 95% of patients. They are highly characteristic of PBC, although other autoantibodies may be seen in a small number of cases. The disease is confirmed by liver biopsy, which is considered diagnostic if a _________________ is present. When symptoms appear, their onset is insidious, with patients typically complaining of slowly increasing fatigue and pruritus.

In recent years, early treatment with oral __________________ has dramatically improved outcomes by slowing disease progression. Its mechanism of action remains unclear, but is presumably related to the ability of ursodeoxycholate to enter the bile acid pool and alter the biochemical composition of bile.

With time, even with treatment, secondary features may emerge, including skin hyperpigmentation, ____________, steatorrhea, and vitamin D malabsorption–related osteomalacia and/or osteoporosis. Individuals with PBC may also have extrahepatic manifestations of autoimmunity, including the sicca complex of dry eyes and mouth (Sjögren syndrome), systemic sclerosis, thyroiditis, rheumatoid arthritis, Raynaud phenomenon, and celiac disease. Liver transplantation is the best treatment for individuals with advanced liver disease.

Answer 49

elevated serum alkaline phosphatase level;

Hypercholesterolemia;

Anti-mitochondrial antibodies

florid duct lesion;

ursodeoxycholic acid;

xanthelasmas;

Question 50

Primary Sclerosing Cholangitis
Primary sclerosing cholangitis (PSC) is characterized by inflammation and obliterative fibrosis of intrahepatic and extrahepatic bile ducts, leading to dilation of preserved segments. Irregular biliary strictures and dilations cause the characteristic “beading” of the intrahepatic and extrahepatic biliary tree seen by MRI. _____________________, coexists in approximately 70% of individuals with PSC. Conversely, the prevalence of PSC in individuals with ulcerative colitis is about 4%. Like inflammatory bowel disease, PSC tends to occur in the third through fifth decades of life and has a 2 : 1 male predominance.

Pathogenesis
Several features of PSC suggest immunologically mediated injury to bile ducts. T cells in the periductal stroma, the presence of autoantibodies, an association with HLA-B8 and other MHC alleles, and clinical linkage to ulcerative colitis all support an underlying, immunologic process. First-degree relatives of patients with PSC are at increased risk for developing the disease, suggesting that genetic factors also contribute.

In one model, it is proposed that T cells activated in the damaged mucosa of patients with ulcerative colitis migrate to the liver, where they recognize a cross-reacting bile duct antigen and initiate an autoimmune assault on bile ducts. Autoantibody profiles in PSC are not as characteristic as in PBC, but ______________________ that recognize a nuclear envelope protein are found in up to 80% of patients. The pathogenic relationship of pANCA to PSC is unknown.

MORPHOLOGY
Morphologic changes differ between large ducts (intrahepatic and extrahepatic) and smaller intrahepatic ducts. Large duct inflammation resembles that seen in ulcerative colitis, taking the form of neutrophils infiltrating into the epithelium superimposed on a chronic inflammatory background. Inflamed areas develop strictures as scarring narrows the lumen. The smaller ducts, however, often have little inflammation and show a striking circumferential, _______________ around an atrophic duct lumen, which eventually is obliterated, leaving a _________________. Because the likelihood of sampling small-duct lesions on a random needle biopsy is small, diagnosis depends on radiologic imaging of the extrahepatic and large intrahepatic ducts. As the disease progresses, the liver becomes markedly cholestatic, culminating in cirrhosis. Biliary intraepithelial neoplasia often appear in the setting of chronic inflammation and cholangiocarcinoma develops in up to 7% of patients, usually with a fatal outcome.

Clinical Features
Patients may come to attention only because of ______________________, particularly in those with ulcerative colitis who are being routinely screened. Alternatively, progressive fatigue, pruritus, and jaundice may develop. Acute bouts of ascending cholangitis may also signal the presence or progression of PSC. Chronic pancreatitis and chronic cholecystitis due to involvement of the pancreatic ducts and gallbladder are also seen. In some patients, sclerosing cholangitis is associated with _______________. In such cases PSC may be one manifestation of IgG4 related chronic disease

PSC follows a protracted course of 5 to 17 years, and severely afflicted patients have symptoms typical of chronic cholestatic liver disease, including steatorrhea. Unlike with PBC, there is no satisfactory medical treatment. A variety of immunosuppressive agents have been tried, but none has been proven to alter the disease course. Endoscopic dilation with sphincterotomy or stenting is used to relieve obstruction. Liver transplantation is the only definitive treatment for individuals with end-stage liver disease.

Answer 50

Inflammatory bowel disease, most commonly ulcerative colitis;

atypical perinuclear anti-neutrophil cytoplasmic antibodies (pANCA)

“onion skin” fibrosis; “tombstone” scar

persistent elevation of serum alkaline phosphatase;

autoimmune pancreatitis

Question 51

Focal Nodular Hyperplasia
Solitary or multiple hyperplastic hepatocellular nodules that may develop in the noncirrhotic liver are called focal nodular hyperplasias. These lesions arise from ________________________, such as arterio-venous malformations or inflammatory or posttraumatic obliteration of portal vein radicles and compensatory augmentation of arterial blood supply.

Focal nodular hyperplasia appears as a _______________________ ranging up to many centimeters in diameter. It presents as a mass lesion in an otherwise normal liver, most frequently in young to middle-age adults. Typically, there is a central ____________________ scar from which fibrous septa radiate to the periphery.

Microscopically, the central scar contains large abnormal vessels and ductular reactions along the spokes of scar. A vascular lesion is probably the initiating insult, as it is believed that hypoperfused parenchyma collapses to produce the septa, whereas hyperperfused regions undergo hyperplasia. The hyperplastic regions are composed of normal hepatocytes separated by thickened sinusoidal plates.

Answer 51

local alterations in hepatic parenchymal blood supply;

well-demarcated, poorly encapsulated nodule;

gray-white, depressed stellate

Question 52

Benign Neoplasms
_________________ are the most common benign liver tumors. The chief clinical significance of cavernous hemangiomas is that they must be distinguished radiographically or intraoperatively from metastatic tumors.

Hepatocellular Adenomas
Benign neoplasms developing from hepatocytes are called hepatocellular adenomas. They may be detected incidentally as a hepatic mass on abdominal imaging or when they cause symptoms. The most common symptom is pain, which may be caused by ________________________ or hemorrhagic necrosis of the tumor as it outstrips its blood supply. Hepatocellular adenomas occasionally rupture, an event that may lead to life-threatening intraabdominal bleeding.

Hepatic adenomas can be subclassified molecularly into tumors at low, intermediate, and high risk for malignant transformation. ____________________ (e.g., oral contraceptive pills, anabolic steroids) markedly increases the frequency of all types of hepatic adenoma, and cessation of exposure to sex hormones often—but not always—leads to tumor regression, clearly linking sex hormones to the growth and survival of tumor cells in some cases.

Answer 52

Cavernous hemangiomas;

pressure placed on the liver capsule by the expanding mass;

Sex hormone exposure;

Question 53

[Hepatocellular Carcinoma (HCC)]
Globally, HCC, also erroneously known as hepatoma, accounts for approximately 5.4% of all cancers, but its incidence varies widely in different parts of the world. More than 85% of cases occur in countries with high rates of ______________ . The incidence of HCC is highest in Asia (southeast China, Korea, Taiwan) and sub-Saharan Africa, areas in which HBV is transmitted vertically and, as already discussed, the carrier state starts in infancy. Moreover, many of these populations are exposed to ________, which when combined with HBV infection increases the risk for HCC dramatically. The peak incidence of HCC in these areas is between 20 and 40 years of age and, in almost 50% of cases, the tumor appears in the absence of cirrhosis.

In Western counties, the incidence of HCC is rapidly rising, largely owing to the increased prevalence of _______. The number of new HCC cases tripled in the United States in recent decades, but its incidence is still 8-fold to 30-fold lower than in some Asian countries. It is hoped that new, effective treatments for hepatitis C infection will stem the rising tide of HCC in the United States. In Western populations, HCC rarely manifests before 60 years of age, and in almost 90% of cases the malignancy emerges after cirrhosis becomes established. There is a pronounced male predominance throughout the world, about 3 : 1 in low-incidence areas and as high as 8 : 1 in high-incidence areas.

Answer 53

chronic HBV infection;

aflatoxin;

hepatitis C

Question 54

[Hepatocellular Carcinoma (HCC)]

Pathogenesis
Chronic liver diseases are the most common setting for emergence of HCC. While usually identified in a background of cirrhosis, cirrhosis is not required for hepatocarcinogenesis. Rather, progression to cirrhosis and to hepatocellular cancer take place in parallel over many years to decades.

The most important underlying factors in hepatocarcinogenesis are viral infections (HBV, HCV) and toxic injuries (aflatoxin, alcohol). Thus, where HBV and HCV are endemic, there is a very high incidence of HCC. Coinfection further increases risk. Aflatoxin is a mycotoxin produced by Aspergillus species that contaminates staple food crops in Africa and Asia. Aflatoxin metabolites are present in the urine of individuals who consume these foods, as are aflatoxin-albumin adducts in serum. These biomarkers identify populations at risk and have helped to confirm the importance of aflatoxin in hepatocarcinogenesis. As discussed earlier, aflatoxin synergizes with HBV (and perhaps also with HCV) to increase risk further.

Other HCC risk factors all share the ability to cause chronic liver injury associated with varying degrees of inflammation. These factors include:

• ________________, which synergistically increases risk with HBV, HCV, and possibly even cigarette smoking.
• Inherited disorders, particularly_________________, and to a lesser degree Wilson disease
• Metabolic syndrome and its attendant obesity, diabetes mellitus, and NAFLD, all of which increase the risk for HCC.

As with all cancers, HCC is induced by acquired driver mutations in oncogenes and tumor suppressor genes. No single, universal sequence of molecular or genetic alterations leads to emergence of HCC. Gain of function mutations in ________________ and loss of function mutations in p53 are the two most common driver mutations. Beta-catenin mutations are identified in up to 40% of HCCs. These tumors are more likely to be unrelated to HBV and to demonstrate genomic instability. Inactivation of TP53 is present in up to 60% of HCCs. These tumors are strongly associated with __________________, which appears in many cases to be directly responsible for the causative TP53 mutations.

HCC often appears to arise from premalignant precursors lesions. Hepatic adenoma has already been discussed, some of which carry beta-catenin–activating mutations. Chronic liver disease is associated with cellular dysplasias called large-cell change and small-cell change . These may be found at any stage of chronic liver disease, before or after development of cirrhosis, and serve to indicate which patients need more aggressive cancer surveillance. Dysplastic nodules are usually found in cirrhosis, either radiologically or in resected specimens (including explants). Low-grade dysplastic nodules may or may not undergo transformation to higher-grade lesions, but they indicate a higher risk for HCC. High-grade dysplastic nodules are probably the most important precursor of HCC in viral hepatitis and alcoholic liver disease. Overt HCC is often found in high-grade dysplastic nodules in biopsy or resection specimens.

Answer 54

alcohol consumption;

hereditary hemochromatosis and α 1 AT deficiency;

beta-catenin;

exposure to aflatoxin

Question 55

[Hepatocellular Carcinoma (HCC)]

MORPHOLOGY
HCC may appear grossly as (1) a unifocal (usually large) mass ; (2) multifocal, widely distributed nodules of variable size; or (3) a diffusely infiltrative cancer, permeating widely and sometimes involving the entire liver. Sometimes HCCs arise within dysplastic nodules , eventually overgrowing these precursor lesions. Intrahepatic metastases by either vascular invasion or direct extension become more likely once tumors reach ____________. These metastases are usually small, satellite tumor nodules around a larger primary mass. ________________ is also the most likely route for extrahepatic metastasis, especially by the hepatic venous system, usually only in advanced cases. Occasionally, long, snakelike masses of tumor invade the portal vein (causing portal hypertension) or inferior vena cava; in the latter instance, the tumor may extend all the way up into the right ventricle. Lymph node metastases are less common.

HCCs range from well differentiated to highly anaplastic lesions. Well-differentiated HCCs are composed of cells that look like normal hepatocytes and grow as ___________ (recapitulating liver cell plates) or in pseudoglandular patterns that recapitulate poorly formed, ectatic bile canaliculi .

Answer 55

3 cm in size;

Vascular invasion;

thick trabeculae

Question 56

[Hepatocellular Carcinoma (HCC)]
Clinical Features
The clinical manifestations of HCC are varied and in Western populations are often masked by symptoms related to underlying cirrhosis or chronic hepatitis. In areas of high incidence, such as tropical Africa where aflatoxin exposure is common, patients usually have no clinical history of liver disease (although cirrhosis may be detected at autopsy). In both populations, most patients have ill-defined upper-abdominal pain, malaise, fatigue, weight loss, and sometimes awareness of an abdominal mass or abdominal fullness. Jaundice, fever, and gastrointestinal or esophageal variceal bleeding are inconstant findings.

Laboratory studies may provide clues but are rarely conclusive. Elevated serum levels of _________________ are found in 50% of individuals with advanced HCC, but this is neither a sensitive nor specific marker for premalignant or early well-differentiated cancers. Better tests for detection of small tumors are imaging studies, such as ultrasonography, computed tomography, and magnetic resonance imaging. _________________ during the development and progression of HCC can be identified by imaging and is so characteristic that its detection can be diagnostic, precluding the need for tissue biopsy.

The natural history of HCC involves the progressive enlargement of the primary mass until it disturbs hepatic function or metastasizes, most commonly to the lungs. Death usually occurs from (1) _____, (2) ___________________, (3) liver failure with hepatic coma, or rarely (4) rupture of the tumor with fatal hemorrhage. The 5-year survival of large tumors is dismal, and the majority of patients die within 2 years of diagnosis.

With implementation of screening procedures and advances in imaging, the detection of HCCs less than 2 cm in diameter has increased in countries where such facilities are available. These small tumors can be removed surgically or ablated (e.g., through embolization, microwave radiation, or freezing) with good outcomes. If relatively small HCCs arise in the setting of advanced stage (cirrhotic) chronic liver disease, liver transplantation is a better option and may be curative. Radiofrequency ablation and chemoembolization are used for ________________________. The kinase inhibitor ___________ can prolong the life of individuals with advanced-stage HCC.

Answer 56

α-fetoprotein;

Increasing arterialization;

cachexia;

gastrointestinal or esophageal variceal bleeding;

local control of unresectable tumors;

sorafenib

Question 57

Cholangiocarcinoma
Cholangiocarcinoma (CCA), the second most common primary malignant tumor of the liver after HCC, arises from intrahepatic and extrahepatic bile ducts. It accounts for 3% of gastrointestinal cancers in the United States, where there are approximately 2000 to 3000 new cases each year. However, in some regions of southeast Asia such as northeastern Thailand, Laos, and Cambodia where \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ is endemic, cholangiocarcinoma is much more common, occurring at rates 30 to 40 times higher than in areas of Asia without liver fluke infestation.

All risk factors for cholangiocarcinoma cause chronic inflammation and cholestasis, which presumably promote occurrence of somatic mutations or epigenetic alterations in cholangiocytes. The risk factors include infestation by liver flukes (particularly __________________), chronic inflammatory disease of the large bile ducts (such as primary sclerosing cholangitis), hepatolithiasis, and fibropolycystic liver disease. As with HCC, rates of cholangiocarcinoma also are elevated in patients with hepatitis B and C and NAFLD.

MORPHOLOGY
Extrahepatic cholangiocarcinomas are generally small lesions at the time of diagnosis, as they cause obstruction of the biliary tract early in their course. Most tumors appear as firm, gray nodules within the bile duct wall; some may be diffusely infiltrative, while others are papillary or polypoid. Intrahepatic cholangiocarcinomas occur in noncirrhotic livers and may track along the intrahepatic portal tract system or produce a single massive tumor.

Cholangiocarcinomas are typical ___________________. Most are well to moderately differentiated, growing as glandular/tubular structures lined by malignant epithelial cells . They typically incite marked desmoplasia. Lymphovascular invasion and perineural invasion are both common and often lead to extensive intrahepatic and extrahepatic metastases.

Answer 57

infestation with liver flukes;

Opisthorchis and Clonorchis species;

mucin-producing adenocarcinomas;