The Nature of Disease: Pathology for the Health Professions_2 pot

BACK TO BASICS • Liver Anatomy • Liver Function THE LIVER RESPONSE TO INJURY • Anatomic Patterns of Liver Injury • Functional Patterns of Liver Injury CIRRHOSIS • Anatomic Types of Cirrh

C H A P T E R

389

Diseases of the Liver and Biliary Tract

This chapter begins with a review of the normal anatomy and physiology of the liver and biliary tract.

Diseases and disorders discussed include cirrhosis, hepatitis, alcoholic and metabolic liver disease, gallstones and other gallbladder disease, and cancers of the liver and biliary tract.

BACK TO BASICS

• Liver Anatomy

• Liver Function

THE LIVER RESPONSE TO INJURY

• Anatomic Patterns of Liver Injury

• Functional Patterns of Liver Injury

CIRRHOSIS

• Anatomic Types of Cirrhosis

• The Pathophysiology of Cirrhosis

• Clinical Features of Cirrhosis

VIRAL HEPATITIS

• Clinicopathologic Syndromes

• Hepatitis A Virus (HAV) Infection

• Hepatitis B Virus (HBV) Infection

• Hepatitis C Virus (HCV) Infection

• Hepatitis D Virus (HDV) Infection

• Hepatitis E Virus (HEV) Infection

• The Anatomic Pathology of Hepatitis

AUTOIMMUNE HEPATITIS

LIVER ABSCESS

TOXIC LIVER INJURY

ALCOHOLIC LIVER DISEASE

• Fatty Liver

• Alcoholic Hepatitis

• Alcoholic Cirrhosis INHERITED METABOLIC AND PEDIATRIC LIVER DISEASE

• Hemochromatosis

• Wilson Disease

• Hereditary Alpha-1 Antitrypsin Deficiency

• Neonatal Cholestasis, Biliary Atresia, and Hepatitis

• Reye Syndrome DISEASE OF INTRAHEPATIC BILE DUCTS

• Primary Biliary Cirrhosis

• Primary Sclerosing Cholangitis CIRCULATORY DISORDERS TUMORS OF THE LIVER

• Primary Carcinomas of the Liver

• Cholangiocarcinoma DISEASES OF THE GALLBLADDER AND EXTRAHEPATIC BILE DUCTS

• Diseases of the Gallbladder

• Diseases of Extrahepatic Bile Ducts

After studying this chapter you should be able to:

1. Trace the flow of blood through the liver

2. Name the major functions of the liver

3. Explain the enterohepatic circulation

4. Name the major functional reactions of the liver to injury

5. Explain the difference between conjugated and unconjugated bilirubin

6. Name one cause of unconjugated hyperbilirubinemia and one of conjugated hyperbilirubinemia

7. Define cirrhosis, and name the two most common causes

8. Explain why cirrhosis causes portal hypertension

9. Name two hemodynamic consequences of portal hypertension

10. Outline the main clinical manifestations of cirrhosis

11. Name several clinicopathologic syndromes associated with viral hepatitis

12. Contrast the mode of transmission and clinical course of hepatitis A and hepatitis B infection

Learning Objectives

Key Terms and Concepts

The liver regulates the composition of blood by disposing

of waste products (bilirubin, for example),

convert-ing substances from one form into another (glycogen

into glucose and vice versa), secreting substances into the

intestines (bile and cholesterol), and producing plasma

proteins (albumin, coagulation factors, and others)

The anatomy of the liver, portal venous system, and

bile ducts is illustrated in Figure 16-1 Nutrients

ab-sorbed by the intestine do not enter the general

circula-tion directly; instead they flow first to the liver via the

portal vein The vein gains its name from the fact that

the liver is a gate (a portal or doorway) through whichblood must pass before entering the general circulation.This “gate” effect is unique in human anatomy: venousblood goes from one capillary system (the intestine), iscollected into a large vein (portal), and passes through

a second capillary system (the liver) before entering the

general circulation The liver also receives arterial bloodfrom the hepatic artery, which merges with portal bloodbefore flowing through the hepatic vein into the inferiorvena cava

Two of every three deaths are premature; they are related to the loafer’s heart,

smoker’s lung and drinker’s liver.

DR THOMAS J BASSLER, PATHOLOGIST; QUOTED BY JAMES FIXX (1932–1984),

IN THE COMPLETE BOOK OF RUNNING (Random House, 1977)

390 Part 2 • Diseases of Organ Systems

13. Name the most important epidemiologic fact about hepatitis C, and name the most common serious quences of hepatitis C infection

conse-14. Name one common acute and one common chronic change induced in the liver by alcohol abuse

15. Explain the difference between primary biliary cirrhosis and sclerosing cholangitis

16. Name the liver condition most commonly associated with hepatocellular carcinoma

17. Name the two major categories of gallstones, and know which is the most common

18. Name several risk factors that favor the formation of gallstones

19. Discuss some of the most common causes of extrahepatic bile duct obstruction

• chronic viral hepatitis

• hepatitis A virus (HAV)

DISEASE OF INTRAHEPATIC BILE DUCTS

• primary biliary cirrhosis

TUMORS OF THE LIVER

Chapter 16 • Diseases of the Liver and Biliary Tract

A

B

Inferior vena cava

Left hepatic vein

Hepatic duct

Common bile duct

Hepatic artery Portal vein Cystic duct

Liver

Right hepatic vein

Central vein To hepatic vein,

then to inferior vena cava

Portal

triad

Plates of hepatocytes

Hepatic artery from aorta

Blood mixes

in sinusoids

Bile duct Portal vein from bowel

Bile canaliculi

Figure 16-1The liver, portal venous system, and bile ducts A A,, The liver and biliary system B B,, The hepatic lobule Blood flows into the central

vein from branches of the portal vein and hepatic artery clustered in portal triads at the edge of the lobule Bile flows in the opposite direction— from the interior of the lobule to bile ducts in the portal triads.

392 Part 2 • Diseases of Organ Systems

LIVER ANATOMY

Upon entering the portal circulation, blood and freshly

absorbed nutrients are brought into close contact with

the main functional cells (parenchyma) of the liver

(he-patocytes) Liver cells are formed into plates one or two

cells thick that are sandwiched between large venous

capillaries (hepatic sinusoids) Hepatic sinusoids have

no basement membrane and are therefore much more

permeable than other capillaries are, so that even large

protein and lipid molecules cross freely Venous

sinu-soid walls contain fixed macrophages known as Kupffer

cells, which, unlike other macrophages, do not move

about but remain in place to filter portal blood

The plates of hepatic cells are arranged into a hepatic

lobule In the middle of each lobule is a central vein

sur-rounded by hepatocytes The corners of each lobule are

defined by several portal triads consisting of 1) a

branch of the hepatic artery bringing blood from the

aorta, 2) a portal vein carrying blood from the GI tract,

and 3) a small bile duct that carries bile out of the liver.

Blood entering the lobule from the hepatic artery and

portal vein flows into venous sinusoids, percolates

through hepatic plates, and is collected in the central

vein for delivery to the general circulation

The liver is a large gland that secretes bile into the

in-testines Bile is a mixture of metabolic waste and bile

acids, which emulsify (make water soluble) dietary fat

so it can be absorbed by the intestinal mucosa Bile is

excreted by hepatocytes into a network of small

intra-hepatic bile ducts that carry it out of the liver and into

the common bile duct (hepatic duct), which connects to

the intestine at the ampulla of Vater in the duodenum A

reserve of bile is held in the gallbladder and discharged

after meals Figure 16-2 illustrates that much of the bile

acid excreted into the intestine is reabsorbed by the

small bowel and sent back to the liver for reuse, a

process known as the enterohepatic circulation Only a

small amount of bile acid finds its way into feces

LIVER FUNCTION

As is outlined in Table 16-1, the liver has five main

functions: 1) detoxification and excretion of metabolic

waste, drugs, and hormones; 2) lipid and carbohydrate

metabolism; 3) protein synthesis; 4) conjugation and

excretion of bilirubin; and 5) synthesis and excretion ofbile acids

The liver clears blood of endogenous metabolic waste (especially bilirubin and ammonia), chemicals and toxins (especially drugs), and hormones (especially estrogen) It

does so by excreting them into bile, as it does withbilirubin, or converting them into something not harm-ful, as it does by converting ammonia to urea

The liver modulates blood glucose concentration by storing glucose as glycogen and reconverts and excretes it

on demand Additionally, the liver synthesizes

triglyc-erides and cholesterol and, when necessary, burns fat

and excretes the ketones produced by the process.

Ketones are an acidic by-product of fat metabolism thataccounts for the acidosis (ketosis) that occurs when di-abetic patients are without insulin and cannot burn glu-cose, and the liver must burn fat to produce energy(Chapter 17)

The liver produces virtually all plasma proteins except antibodies (immunoglobulins), which are made by B

lymphocytes of the immune system Plasma proteinconsists of albumin, alpha and beta globulins—all made

by the liver—and gamma globulins (immunoglobulins,

or antibodies, made by lymphocytes of the immune tem, Chapter 8) The most abundant liver protein is al-bumin, which forms about three fourths of plasma pro-tein and provides most of the osmotic pressure ofplasma (Chapter 5) that holds water in blood Otherproteins produced by the liver include clotting factors

sys-(Chapter 11) and specialized proteins for fat (and

trans-port of fat, hormones, iron, and other substances

The liver excretes bilirubin into bile ducts, which

carry it to the bowel Bilirubin is an intensely yellow

pigment, most of which is produced in the spleen fromthe hemoglobin of old red blood cells the spleen has re-moved from the circulation This new bilirubin is notwater soluble and must be attached to a protein fortransport to the liver, where it is made water solubleand excreted in bile In the liver, bilirubin is joined

(conjugated) to glucuronide to make conjugated bin, which is water soluble and can be excreted in bile.

biliru-Before reaching the liver, the water-insoluble bilirubin

is called unconjugated bilirubin Increased blood

bilirubin (of either type) causes jaundice (icterus), a

yellow discoloration of skin and sclera that is a hallmark

of increased blood bilirubin

Bacteria in the bowel convert bilirubin into bilinogen, a compound that gives feces its brown color.

uro-Patients with jaundice usually have pale stools owing to

a lack of urobilinogen However, some urobilinogen isproduced directly by the liver, secreted into blood, and

The circulation of blood through the intestines and liver is unique in human anatomy: blood from one capillary system, the intestinal, flows into another capillary system, the hepatic, be- fore returning to the heart.

Portal vein

Small intestine

Feces

Figure 16-2The enterohepatic circulation Bile acids

are secreted into bile, absorbed back into blood by the

in-testine, and recirculated via the portal vein for

remetabo-lism by the liver.

M

Me etta abolliicc T Ta assk k H He epatto occy ytte e A Accttiio on nss

Detoxification and drug metabolism • Chemical alteration and excretion of hormones and drugs

• Production and excretion of urea and other compounds that are less toxic than the parent compound

Lipid and carbohydrate metabolism • Conversion of glucose to glycogen and fat

• Production of glucose from glycogen and other compounds

• Secretion of glucose into blood

• Synthesis and secretion of triglyceride and cholesterol into blood

• Excretion of cholesterol into bile

• Production of ketones from fatty acid Protein synthesis • Synthesis and secretion into blood of albumin, transport proteins and blood

coagulation (clotting) factors Conjugation and excretion of bilirubin • Conjugation of bilirubin with glucuronide and excretion of it into bile ducts Synthesis and excretion of bile acids • Synthesis of bile acids by liver cells and secretion of them into bile ducts

Liver Functions

Table 16-1

394 Part 2 • Diseases of Organ Systems

excreted into urine, giving urine its faint amber color

Jaundiced patients may have dark urine because of

in-creased urobilinogen

The liver produces and excretes bile acids Bile acids,

the main constituent of bile, emulsify fat like soap does

grease, solubilizing it for absorption Bile acids are

pro-duced by the liver from cholesterol, and bile acid

excre-tion is the main way by which the body rids itself of

cholesterol However, most bile acids and the

choles-terol they contain are reabsorbed by the intestinal

mu-cosa and returned to blood (enterohepatic circulation).

The enterohepatic circulation is, therefore, very tant in cholesterol metabolism Most cholesterol ab-sorbed from the intestine is not from diet but from re-absorption of bile acids New drugs lower bloodcholesterol by blocking intestinal absorption of choles-terol Obstruction of bile excretion is referred to as

impor-cholestasis.

The Liver Response to Injury

The liver responds remarkably well to injury—it has

enormous functional reserve and must suffer a marked

decline of capacity before becoming symptomatic

However, because normal liver function is so crucial in

metabolism, liver disease looms large in human illness

Laboratory evaluation of blood is critical in the

diagno-sis and management of liver disease The nearby Lab

Tools box lists and describes the most common lab

tests

ANATOMIC PATTERNS OF LIVER INJURY

The injury to liver prompts one of four consequences:inflammation, degeneration, necrosis, and fibrosis

• Inflammation: Inflammation of the liver is termed

hepatitis, most of which is caused by virus

infec-tions

• Degeneration: Hepatocytes may undergo hydropic

(watery) or fatty degeneration (Chapter 2) in sponse to toxic or autoimmune injury For example,alcohol abuse typically causes fatty degeneration,which can proceed to injury that is more serious if al-cohol abuse continues

re-• Necrosis: Liver cells may die as blocks of tissue

(in-farcts, Chapter 2) or as single cells In some types ofdiffuse hepatic injuries, such as viral hepatitis andchronic alcohol injury, individual liver cells die one

by one, becoming shrunken, dead cells known as

Councilman bodies.

• Fibrosis: Scarring can occur as a result of severe

he-patic injury Cirrhosis (discussed in detail below) is

a patterned, permanent scarring (fibrosis) of the tire liver from long-standing, severe injury that de-stroys the normal architecture and replaces it withscar tissue

en-FUNCTIONAL PATTERNS OF LIVER INJURY

The direct metabolic consequences of hepatic injury are:

• Jaundice: a yellow discoloration of skin and sclerae

(Fig 16-3) caused by an excess of blood bilirubin

• Cholestasis: an accumulation of bile acids and

cho-lesterol in blood when there is obstruction of bileflow inside or outside of the liver

• Hepatic failure: the loss of hepatic metabolic

func-tion severe enough to cause clinical symptoms.Each of these consequences may be associated withwidespread ill effect on the body

MAJOR DETERMINANTS OF DISEASE

• The metabolic consequences of liver disease

are serious and include:

– Toxic accumulations of:

䊏 metabolic waste (especially ammoniaand bilirubin)

䊏 drugs and toxins

䊏 endogenous hormones (especially gen)

estro-– Bleeding, associated with a deficiency ofcoagulation factors

– Edema, associated with a deficiency ofplasma albumin

– Failure to absorb intestinal fat because of adeficiency of bile acids

• Viral hepatitis is a common contagious

dis-ease

• Cirrhosis is the final endpoint for many liver

diseases

• Portal hypertension is the most important

consequence of cirrhosis and can be ated with liver failure and severe hemorrhage

associ-• Stones often form in the gallbladder and may

pass into and obstruct the bile duct

Chapter 16 • Diseases of the Liver and Biliary Tract

Jaundice and Cholestasis

Jaundice usually becomes visible when blood bilirubin

level is ⬎2 mg/dL (normal ⬍1.2 mg/dL) As is

illus-trated in Figure 16-4, jaundice can be caused by three

conditions:

• the presence of excessive amounts of bilirubin

(pre-hepatic jaundice), such as accompanies red cell

de-struction in hemolytic anemia

• defective liver functioning (hepatic jaundice), such

as occurs with viral hepatitis, drug interference withliver function, or cirrhosis

• biliary obstruction (posthepatic jaundice), such as

occurs when pancreatic cancer occludes the commonbile duct

Prehepatic jaundice causes an increase in blood of

wa-ter-insoluble unconjugated bilirubin The most

com-mon serious cause of increased amounts of gated bilirubin in blood is hemolytic anemia, such assickle cell disease (Chapter 11)

unconju-Increased unconjugated bilirubin can also occur

when there is hepatic malfunction For newborns

un-conjugated hyperbilirubinemia is especially dangerous,because it is toxic to the underdeveloped brain Becausethe immature livers of premature infants are unable toconjugate bilirubin effectively, during the first severalweeks of life a marked increase of unconjugated biliru-

bin may cause kernicterus (from German: kern, nucleus, and icterus, jaundice), a severe neurologic condition re-

sulting from toxic deposits of water-insoluble, jugated bilirubin in the brain (Chapter 7)

uncon-However, the most common cause of increased

un-conjugated bilirubin in blood is Gilbert syndrome

(pronounced jeel-bear), a very common and harmless condition associated with a mild increase of unconju- gated bilirubin that is the result of a genetic enzyme defi-

Figure 16-3Scleral icterus of jaundice.

Liver Function Tests

The most useful laboratory tests for liver function are:

• Enzymes: The liver is packed with enzymes In liver ease these enzymes are washed into blood, where they are easily measured Even mild liver-cell injury can cause minor increases in levels of liver enzymes Elevation of lactic dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) suggests he- patic cellular damage Alkaline phosphatase levels also may be increased in liver disease, but they tend to rise highest in bile duct diseases Red blood cells contain some of these enzymes, and in vitro damage (hemolysis)

dis-to red cells during specimen collection or handling can cause misleading enzyme level increases.

• Bilirubin: The liver metabolizes and excretes bilirubin into the bile ducts If hemolytic disease has been excluded, in- creased levels of blood bilirubin usually indicate at least moderate liver disease or bile duct disease.

• Proteins: The liver makes albumin and many other plasma proteins Low levels of plasma albumin and blood coag- ulation factors are characteristic of moderate to serious liver disease.

• Coagulation tests: The liver makes most of the tion proteins (factors), and liver disease can cause abnor- mal (prolonged) prothrombin time and partial thrombo- plastin time.

coagula-• Hepatitis virus antigens and antibodies: Each type of atitis virus is distinguished by characteristic patterns of virus antigens and antibodies in blood.

hep-• Autoimmune antibodies: Antimitochondrial antibodies in blood are characteristic of primary biliary cirrhosis; anti- smooth muscle antibodies are characteristic of chronic autoimmune hepatitis.

LAB TOOLS

396 Part 2 • Diseases of Organ Systems

ciency, which is usually detected accidentally while the

patient is being seen for an unrelated illness or when thepatient has been fasting for 12 hours or more A similar

genetic syndrome causing increased conjugated bin is the Dubin-Johnson syndrome.

biliru-Jaundice associated with hepatic disorders (hepaticjaundice) may cause an increase in blood of either un-conjugated or conjugated bilirubin, because interferencecan occur either before or after conjugation in the liver.Jaundice resulting from bile duct obstruction (pos-thepatic jaundice) is characterized by increased water-

soluble, conjugated bilirubin in blood because by the

time bilirubin enters hepatic ducts all of it is conjugated,and obstruction forces conjugated bilirubin out of theducts and into blood Gallstones and pancreatic cancerare the two most common causes of duct obstruction

Cholestasis is usually accompanied by jaundice and

sometimes by severe pruritus (itching) because of thedeposition of bile acids in the skin Cholestasis may re-sult from primary liver disease, drug interference withbile secretion, pregnancy, and a variety of other condi-tions Because bile is the means by which the body ridsitself of excess cholesterol, blood cholesterol levels maybecome markedly elevated and associated with yellow

deposits of cholesterol in skin (xanthomas) Because bile

duct epithelium is rich in alkaline phosphatase, a acteristic laboratory finding is marked increase of bloodalkaline phosphatase levels, whereas levels of other liverenzymes are usually normal or only mildly increased

char-Hepatic Failure Hepatic failure is the most severe consequence of liver

disease—most patients die within a few weeks ormonths It may follow sudden injury, as in sudden, se-vere viral hepatitis (fulminant hepatitis), or it may bethe result of chronic injury, as with chronic hepatitis orchronic alcoholism About 90% of hepatic functionmust be destroyed before failure occurs

The clinical features of hepatic failure are:

• Jaundice because of failure to excrete bilirubin

• Ascites because of increased portal pressure and low

blood osmotic pressure

• Fetor hepaticus, literally “liver breath,” because of an

accumulation of volatile waste products such as monia

am-A Prehepatic jaundice (unconjugated hyperbilirubinemia)

B Hepatic jaundice (unconjugated or conjugated

Figure 16-4Three types of jaundice A A,, Prehepatic jaundice causes

increased levels of unconjugated bilirubin in blood B B,, Hepatic jaundice

may be caused by interference with the liver’s ability to conjugate bin or to secrete it after conjugation; increased levels of blood bilirubin

biliru-may be of either conjugated or unconjugated type C C,, Posthepatic

jaun-dice is caused by obstruction of bile flow inside or outside of the liver; increased levels of blood bilirubin are of conjugated type.

Chapter 16 • Diseases of the Liver and Biliary Tract

• Hypoalbuminemia because of diminished hepatic

production of protein

• Hypoglycemia because of lack of liver glycogen stores

• Hyperammonemia because of failure of the liver to

convert ammonia to urea

• Palmar erythema (redness of the palms of the hands),

spider angiomata (small skin hemangiomas), testicular atrophy, balding, and gynecomastia (enlarged male breasts) because of increases in blood estrogen from

impaired liver metabolism of estrogen

• Bleeding disorders because of deficiency of blood

clot-ting factors made by the liverMoreover, kidney and brain function can be seri-ously impaired by liver failure (A summary of the clin-

ical features of hepatic failure can also be found later in

the chapter in Figure 16-10, which appears with the

dis-cussion of cirrhosis.)

Hepatorenal syndrome is renal failure owing to

acute hepatic failure The cause is not completely

clear—it appears to result from renal vasoconstriction

and low renal blood flow, but the kidney is

pathologi-cally normal Hepatic encephalopathy, an especially

se-rious complication of hepatic failure, occurs when

ac-cumulated ammonia and other unmetabolized waste

products exert a toxic effect on the brain Neurologic

signs include rigidity, hyperreflexia, and, rarely,

seizures Fatal coma may occur A particularly

charac-teristic sign is asterixis, a rapid extension-flexion

mo-tion of the head and extremities that can be

demon-strated by testing for “hepatic flap”—the arms are held

extended and the hands dorsiflexed A pulsating,

flap-ping, or hand waving motion constitutes a positive test

Cirrhosis

Cirrhosis is the final, common end-stage for a variety of

chronic liver diseases As is illustrated in Figures 16-5

and 16-6, cirrhosis is a patterned fibrosis of the entire

liver characterized pathologically by a

three-dimen-sional web of interconnecting bands of scar tissue,

di-viding the liver into small nodules separated from one

another by dense fibrous tissue, an architecture that

makes cirrhotic livers tense and hard Cirrhosis is

pro-gressive, irreversible, and incurable

Cirrhosis can be classified by cause, such as alcoholic

or hepatitic, but regardless of cause there are only two

anatomic types of cirrhosis:

• portal cirrhosis, caused by diffuse liver cell injury

• biliary cirrhosis, caused by chronic disease of the

Fibrous tissue

Figure 16-5Cirrhosis A A,, Normal liver B B,, Cirrhosis Note the small size

of the cirrhotic liver.

Figure 16-6Cirrhosis A A,, Gross section B B,, Microscopic study Note

the nodular pattern in both specimens The liver is divided into nodules

by a web of fibrous (scar) tissue Dark discoloration of some nodules is caused by the accumulation of bile pigment in lobules The cause of cir- rhosis in this patient is unknown.

398 Part 2 • Diseases of Organ Systems

In early cases, portal and biliary cirrhosis are easy to

distinguish by microscopic examination, but as disease

progresses the distinctions disappear In the end the

cause of most cases of cirrhosis cannot be determined

by study of the liver: clinical findings and history are of

paramount importance However, a few rare types of

cirrhosis have highly characteristic microscopic

find-ings For example, in hemochromatosis (discussed

be-low), the body is overloaded with iron, much of which

is deposited in the liver A second example is hereditary

alpha-1 antitrypsin deficiency, which is associated with

early emphysema (Chapter 14) and distinctive

micro-scopic findings in the liver

Table 16-2 lists the causes of cirrhosis and the

mi-croscopic pattern associated with each Cirrhosis is

among the top 10 causes of death in the western

hemi-sphere, two thirds of it resulting from alcoholism and

chronic viral hepatitis Less common causes are genetic

hemochromatosis, and diseases of bile ducts In about

one third of cases, the cause is unknown (cryptogenic

cirrhosis)

ANATOMIC TYPES OF CIRRHOSIS

The term portal cirrhosis is assigned to cirrhosis

oc-curring with repeated episodes of liver cell necrosis that

are followed by hepatocyte regeneration and growth of

fibrous tissue from the area of the portal triad Portal

cirrhosis is by far the most common type of cirrhosis

and includes all forms of cirrhosis other than those

de-scribed immediately below as biliary cirrhosis The

ma-jority of portal cirrhosis results from alcoholic liver ease and chronic viral hepatitis

dis-Far less common is biliary cirrhosis, which results

from chronic inflammation of bile ducts Primary

bil-iary cirrhosis is an autoimmune disease (Chapter 8) of

intrahepatic bile ducts Secondary biliary cirrhosis

de-velops as a consequence of prolonged inflammation ofbile ducts, usually associated with obstruction of bileflow because of gallstones lodged in the common bileduct Another cause of bile duct inflammation and fi-

brosis that causes biliary cirrhosis is sclerosing tis, which is associated with chronic ulcerative colitis

cholangi-(Chapter 15)

THE PATHOPHYSIOLOGY OF CIRRHOSIS

Cirrhosis obstructs free flow of portal blood through

the liver and causes portal hypertension; that is, high

blood pressure in the portal venous system This struction of portal blood flow through the liver diverts(shunts) blood around the liver through alternative(collateral) vessels in the GI tract, spleen, and skin, as isdepicted in Figure 16-7

ob-The hemodynamic consequences of portal

hyperten-sion are ascites, congestive splenomegaly (Fig 16-8),

and various types of prominent veins that result from

the shunting of blood around the liver: esophageal varices (see Fig 15-8, Chapter 15), hemorrhoids, and

prominent veins radiating outward from the umbilicus,

known as caput medusa—literally snake-head—so

named because of its likeness to the female haired monster, Medusa, from Greek mythology

serpent-Ascites (from Greek, askos, for bag) is an

intraperi-toneal accumulation of watery (serous) fluid This fluidseeps from portal venules as a result of high portalblood pressure and low blood osmotic pressure caused

by low blood albumin owing to low output of albumin

by the liver Ascites becomes clinically evident whenabout 500 ml of intraperitoneal fluid have accumulated;however, as is depicted in Figure 16-9, fluid accumula-tion may be massive

CLINICAL FEATURES OF CIRRHOSIS

The clinical features of cirrhosis are summarized inFigure 16-10 and result from four phenomena:

• Failure to metabolize estrogen and ammonia Failing

hepatic metabolism of estrogen results in high levels

C

Causse e M Miiccrro osscco op piicc T Ty ype

Chronic viral hepatitis B or C Portal

Biliary obstruction Biliary

Gallstones

Cystic fibrosis

Autoimmune disease

Primary biliary cirrhosis Biliary

Sclerosing cholangitis Biliary

Autoimmune hepatitis Portal

Inherited metabolic disease Portal

Hemochromatosis

Alpha-1 antitrypsin deficiency

Wilson disease

Cryptogenic (unknown) Portal

Causes and Microscopic Types of Cirrhosis

Table 16-2

Cirrhosis is always associated with portal pertension.

Chapter 16 • Diseases of the Liver and Biliary Tract

of blood estrogen, which in men accounts for ning scalp and genital hair, enlarged breasts (gy-necomastia), red palms (palmar erythema), atrophictestes, and spider angiomas—small vascular malfor-mations of skin that feature a tiny central vessel fromwhich spider-like vessels radiate outward Womenmay have abnormal menstrual bleeding Failing he-patic metabolism of ammonia and other waste prod-ucts accounts for hepatic coma and fetor hepaticus(liver breath)

thin-• Protein synthesis failure Failing hepatic protein

syn-thesis causes decreased plasma albumin, which tributes to ascites and peripheral edema (Chapter 5),and decreased production of blood coagulation fac-tors, which accounts for bleeding tendencies, usuallyevident as easy bruising (skin purpura)

con-Portal circulation Systemic circulation

DiaphragmLiver

Stomach

Cirrhosis obstructsportal blood flowSuperior

epigastricvein

Umbilical vein

Inferiorepigastricvein

Superior mesenteric veinInferior mesenteric vein

Anus

Inferior vena cava

Splenic veinSpleen

Veins ofabdominalwall

Portal veinEsophageal and gastric varices

Hemorrhoids

Caput medusa(periumbilical varices)

Splenomegaly

Figure 16-7Portal hypertension The hemodynamic consequences of obstructed portal blood flow.

Figure 16-8Congestive splenomegaly in cirrhosis Both specimens

are from the same patient Note that the spleen (Top) is much larger

than the liver is; normally the opposite is true.

400 Part 2 • Diseases of Organ Systems

• Excretory failure Failing hepatic excretion of

biliru-bin causes jaundice

• Portal hypertension Portal hypertension causes

hem-orrhoids, esophageal varices, splenomegaly, and put medusa veins radiating from the umbilicus, andcontributes to the formation of ascites

ca-Patients with cirrhosis also lose muscle mass (muscle wasting); however, the cause is not clear In early cir-

rhosis the liver may be large, but as scarring progresses

it always shrinks to less than normal size

Cirrhosis may go undetected for years Sometimesthe delay is so great that when symptoms appear theoriginal cause may not be apparent Initial symptomsmay be nothing more than anorexia, fatigue, and weightloss But hepatic symptoms, jaundice especially, areusually present and may appear quite suddenly, mim-

2 3 1

1

2 3 4

1 2

Failure to metabolize estrogen and ammonia

Edema (low albumin)

3

Protein synthesis failure

2 Collateral veins (caput medusae) Ascites

icking acute liver disease The most common causes of

death from cirrhosis are hepatic failure, gastrointestinal

hemorrhage from esophageal varices, and

hepatocellu-lar carcinoma (discussed below)

Viral Hepatitis

Viral hepatitis is infection by one of the several viruses

that preferentially infect the liver: hepatitis viruses A, B,

C, D, and E, which are designated HAV (for hepatitis A

virus), HBV, and so on Other viruses can incidentally

infect the liver and cause hepatitis, most notably the

cy-tomegalovirus or the Epstein-Barr virus of infectious

mononucleosis

Hepatitis viruses are distinguished from one anotheraccording to the following clinical characteristics (sum-

marized in Table 16-3):

• Mode of transmission: Is the virus transmitted by

oral-fecal contamination, close personal contact,

contam-inated water, or blood contamination (needlestick ortransfusion)?

• Length of incubation period: What is the length of time

from infection to symptomatic disease?

• Carrier state: After recovery from acute infection,

does the virus linger, so that an apparently healthyperson continues to infect others?

• Chronic hepatitis: Can the virus cause chronic

hepa-titis?

• Fulminant hepatitis: Can the virus cause a sudden,

catastrophic hepatitis?

• Hepatocellular carcinoma: Is the virus associated with

increased risk of hepatocellular carcinoma?

Charra acctte erriissttiicc H He epattiittiiss A A H He epattiittiiss B B H He epattiittiiss C C

States (2001)

Transmission

Route Fecal-oral Parenteral or close contact Parenteral or close contact

Incubation period 3–6 weeks 2 weeks to 6 months 2 weeks to 6 months

carcinoma

anti-HBs anti-HBc (IgM) anti-HBc (IgG) anti-HBe

Characteristics of Major Hepatitis Viruses

Table 16-3

• Hepatitis A is a mild, epidemic disease spread

by contaminated food and water; it does not cause chronic hepatitis or cirrhosis.

• Hepatitis B and hepatitis C are spread from individual to individual by needles or sexual contact; both can cause chronic hepatitis and cirrhosis.

402 Part 2 • Diseases of Organ Systems

• acute viral hepatitis

• chronic viral hepatitis

• fulminant hepatic failure

• hepatocellular carcinoma

However, not every virus can produce each of these;

and some of these disorders can be caused by diseases

other than viral hepatitis

Asymptomatic hepatitis may produce no lasting

liver injury and be detected only by accident The usual

circumstance is unexpected abnormal blood

tests—ab-normally elevated liver enzymes, for

example—ob-tained as part of an annual physical exam or in the

course of attention to an unrelated condition

The carrier state exists in a patient who despite

be-ing asymptomatic harbors the virus and is therefore

ca-pable of transmitting the virus to others The

percent-age of infected people who become carriers varies

greatly from one type of viral hepatitis to another For

example, few patients infected with hepatitis B virus

(HBV) become carriers; conversely, many of those with

hepatitis C virus (HCV) develop asymptomatic chronic

infection and, therefore, fit the definition of carrier

Acute viral hepatitis is an acute illness that typically

progresses through four clinical phases:

• Incubation usually lasts a few weeks Peak infectivity

occurs about the time symptoms appear

• The symptomatic prejaundice phase is usually marked

by constitutional symptoms, including malaise,

fati-gability, nausea, and anorexia However, right

upper-quadrant pain, low-grade fever, headache, skin rash,

vomiting, diarrhea, or muscle and joint aches may

occur

• The symptomatic jaundice phase begins as jaundice

(icterus) appears and other symptoms fade The

jaun-dice reflects a rise in conjugated bilirubin Because

conjugated bilirubin is water soluble, it is excreted in

urine, causing a brown discoloration Because less

bilirubin is getting into the gut, stools may be pale

With HAV infection, most adults become jaundiced,

but most children do not About half of patients with

HBV infection become jaundiced, but patients with

HCV infection are rarely jaundiced

• Convalescence begins as jaundice fades, infectivity

disappears, and antibodies appear in blood to confer

immunity

Chronic viral hepatitis is defined as viral hepatitis

proven by liver biopsy, with six months or more of oratory or clinical evidence of disease activity Not allpatients with chronic hepatitis have chronic viral hepa-titis—autoimmune hepatitis and alcoholic hepatitis,discussed below, are examples About 10% of patientswith hepatitis B infections develop chronic hepatitis,whereas more than 50% of patients with hepatitis C do

lab-so Most patients with chronic hepatitis show few cific clinical signs and symptoms, and the extent of dis-ease is revealed only by laboratory tests

spe-On the other hand, some patients may be very ill andexhibit a variety of laboratory and clinical abnormali-ties Laboratory coagulation tests are often abnormalbecause liver impairment affects the production of co-agulation factors Increased levels of enzymes bynecrotic liver cells are detected in blood Impairedbilirubin excretion causes increased levels of bilirubin.The immune system (Chapter 8) reacts to the virus in-fection by producing large amounts of immunoglobu-lin, appearing in blood as hypergammaglobulinemia.Moreover, about 10% of patients with hepatitis B orhepatitis C infection develop autoimmune disease, usu-ally kidney disease (glomerulonephritis, Chapter 19) orvasculitis (Chapter 12)

Patients with chronic hepatitis may have an larged, tender liver because of liver inflammation, andthey may have an enlarged spleen (splenomegaly) re-sulting from portal hypertension and reaction of the im-mune system to the infection Appearance of palmarerythema or spider angiomas (owing to failure of theliver to metabolize estrogen) or other signs of liver fail-ure is evidence of severe chronic viral hepatitis

en-Fulminant hepatic failure denotes explosively acute

liver disease that progresses to hepatic failure and cephalopathy in a very short time, usually a few weeks

en-Fulminant hepatitis (Fig 16-11) accounts for more than

half of cases, most of which are associated with tis A or B infections Other causes include suicidal doses

hepati-of acetaminophen, heat stroke, acute fatty liver hepati-of nancy, wild mushroom poisoning, and adverse reac-tions to drugs

preg-Finally, patients with hepatitis B and C infections are

at substantially increased risk for development of tocellular carcinoma.

hepa-HEPATITIS A VIRUS (HAV) INFECTION

HAV is the cause of epidemic hepatitis, which is

prima-rily spread by oral-fecal contamination of water or food,for instance, contaminated shellfish (oysters, shrimp).Shared food utensils, kissing, handshaking, and sexualactivity are less common modes of transmission HAV

Chapter 16 • Diseases of the Liver and Biliary Tract

infection is benign and self-limited (it resolves

sponta-neously), with an incubation period of 2–6 weeks It is

the most common type of hepatitis infection in the

world Infection is much more common than actual

dis-ease is; by mid adult life about half of people in

devel-oped countries have blood anti-HAV antibodies as

evi-dence of infection, but few recall being ill Rates arehigher in developing nations, where most children haveevidence of infection (anti-hepatitis antibodies inblood) by age ten About 10,000 new clinical cases arereported each year in the United States; however, be-cause the great majority of cases are asymptomatic, it islikely that hundreds of thousands of unreported infec-tions occur each year Fatalities are very rare HAV in-fection has no carrier state, does not cause chronic hep-atitis, and very rarely causes fulminant hepatitis ordeath It is most common in poor countries withoutmodern sanitation and hygiene A vaccine is available

As is depicted in Figure 16-12A, the virus infects theliver and quickly begins to be shed in feces It appearstransiently in blood (viremia), but the viremia is soshort that risk of blood-borne transmission—by trans-fusion of infected donor blood or accidental needle-stick by health care personnel—is very low

As is illustrated in Figure 16-12B, jaundice, creased liver enzymes in blood, and the appearance ofIgM type anti-HAV antibodies are clinical markers ofdisease progress Recall from Chapter 8 that IgM anti-bodies are acute phase antibodies, and IgG antibodies

in-Figure 16-11Hepatitis with massive hepatic necrosis Dark spots

are hemorrhagic necrosis around central veins; red areas are

Figure 16-12Hepatitis A: clinical phases and blood markers of infection A A,, Infection of the liver is followed quickly by the appearance of

virus in blood and feces B B,, Jaundice or other symptoms of acute infection are accompanied by the appearance of IgM-type acute phase antibodies

in blood The appearance of IgG-type antibodies signals recovery and immunity against reinfection.

404 Part 2 • Diseases of Organ Systems

appear later and confer immunity Anti-HAV (IgM)

an-tibodies are a valuable diagnostic tool to confirm the

di-agnosis of HAV infection Vaccination produces

immu-nity by stimulating the production of IgG anti-HAV

antibodies

HEPATITIS B VIRUS (HBV) INFECTION

HBV is a much more serious disease than hepatitis A is.

Unlike hepatitis A, it is not spread by food, water, or

ca-sual contact—it spreads by needlestick or sexual

con-tact, and it infects hundreds of millions of people

world-wide The incubation period varies greatly: from a few

weeks to six months Outcomes of infection are

illus-trated in Figure 16-13 In the United States new cases

have fallen dramatically to near 10,000 annually

be-cause of improved public awareness and vaccination

However, about two thirds of infections are

asympto-matic, so the number of actual infections is about three

times the number of reported cases Most symptomatic

infections appear as a syndrome of acute hepatitis that

resolves quickly with supportive care A carrier state

evolves in less than 10% of infections, most likely in

neonates and people with impaired immunity

As is depicted in Figure 16-14A, the viremia of acute

infection is indicated by detection in blood of a

particu-lar hepatitis B antigen, hepatitis B surface antigen,

des-ignated HBsAg Hepatitis B viremia may last for many

weeks in acute infection, or for years in chronic infection

(Fig 16-14B) or in asymptomatic carriers (Fig 16-14C),

a critical fact in its infectivity It is transmitted in blood,saliva, and semen and can be spread by heterosexual orhomosexual contact, blood transfusion, renal dialysis,and needlestick accidents among health care workersand intravenous drug users Some infected mothers in-fect the fetus in utero or during vaginal delivery In onethird of cases, the method of infection is not known.Laboratory tests for hepatitis markers (antigens andantibodies) are critical in the diagnosis and manage-

ment of hepatitis B HBV antigens usually appear first.

HBsAg is the first marker to appear and is an indicator

of viremia and, therefore, of infectivity

Anti-hepatitis B antibodies are also important markers

of disease and the state of patient immunity to tion Significant variation occurs in the type of antibody(acute phase IgM or late phase IgG, Chapter 8), the time

reinfec-at which they appear, and whether or not they disappear

or persist, features that reveal much about the state of the

infection and patient immunity Antibody to hepatitis B core antigen (anti-HBc) is the first to appear and is use-

ful as an early indicator of HBV infection (Fig 16-14A).The appearance of antibodies to hepatitis B surface anti-

gen—anti-HBs—marks the beginning of recovery and is

not usually detectable until viremia (HBsAg in blood)has disappeared Anti-HBs confers immunity and is theantibody created by vaccination Anti-HBs does not ap-pear in patients who develop chronic hepatitis B (Fig.16-14B) or hepatitis B carrier state (Fig 16-14C)

35%

Symptomaticacute hepatitis

70-90%

Asymptomaticcarrier state

1%

1%

10 - 30%

2-6% annually 90%

ACUTE LIVER FAILURE AND DEATH

HEPATOCELLULAR CARCINOMA

CHRONIC HEPATITIS AND CIRRHOSIS

RECOVERY

100%

Figure 16-13Outcomes of hepatitis B infection.

Chapter 16 • Diseases of the Liver and Biliary Tract

A Acute hepatitis B with recovery

C Hepatitis B carrier state

YearsMonths

Virus inblood

• Increased bilirubin in blood

Figure 16-14Hepatitis B: clinical phases and blood markers of infection A A,, Acute infection is characterized by rapid appearance of the virus

in blood before symptoms appear, disappearance of the virus from blood, and the appearance in blood of antibodies to hepatitis B surface antigen

(HBsAg) B B,, Chronic hepatitis is signaled by continuing jaundice or clinical symptoms, or the continued presence of virus in blood (as is indicated by

the detection in blood of HBsAg) C C,, The carrier state is indicated by disappearance of clinical symptoms and the persistence of virus in blood (as is

indicated by the detection in blood of HBsAg).

406 Part 2 • Diseases of Organ Systems

HEPATITIS C VIRUS (HCV) INFECTION

HCV is a major cause of chronic liver disease (chronic

hepatitis, cirrhosis, and hepatocellular carcinoma) The

incubation period varies from a few weeks to six

months, similar to hepatitis B About 40,000 new cases

are reported each year Nearly 2% of the United States

population has blood antibodies, indicating previous

infection In more half of these cases, virus is detectable

in the blood, indicating a chronic carrier state HCV is

responsible for half of all chronic liver disease in the

United States

Over half of new HCV infections are a consequence

of intravenous drug abuse—the great majority of IV

drug users are infected About 15% of cases can be

ac-counted for by transmission through sexual activity and

by infected health care workers, and by neonatal

trans-mission However, in about one third of cases the

man-ner of infection cannot be determined because the

ini-tial infection is usually asymptomatic, and years later,

when chronic infection is detected, the patient has no

recollection of having had hepatitis Outcomes of

infec-tion are depicted in Figure 16-15 About 3 million

peo-ple in the United States are chronically infected

Viremia is marked by detection in blood of virus

RNA (HCV-RNA) In acute infection (Fig 16-16A),

anti-HCV appears promptly as a marker of acute

im-mune response but does not confer immunity Over half

of patients with HCV progress to chronic infection (Fig

16-16B) Many of these patients remain asymptomatic,

but others have relapsing symptoms marked by

reap-pearance of detectable HCV-RNA and elevated levels of

liver enzymes and bilirubin in blood After 20 years

about 25%–35% of those with chronic hepatitis develop

cirrhosis Of those developing cirrhosis a few percentdevelop hepatocellular carcinoma each year HCV is amutating RNA virus with dozens of subtypes, which hasfrustrated hope for a vaccine Case Study 16.1 at the end

of this chapter focuses on a patient with hepatitis C

HEPATITIS D VIRUS (HDV) INFECTION HDV (delta virus) is peculiar—it cannot exist without

HBV It can co-infect at the same time HBV is acquired,

in which case the infection takes on characteristics ofthe usual HBV infection In most instances of co-infec-tion, the immune system successfully overcomes both

of the viruses, and the patient recovers On the otherhand, HDV can infect someone who is already a carrier

of HBV, in which case the asymptomatic HBV carrierdevelops acute hepatitis syndrome, or chronic hepatitisevolves Most such infections occur among patientswho inject illegal drugs, and in patients with hemo-philia Patients in both of these groups have multipleopportunities for infection—first by HBV infection,then by HDV infection on a subsequent injection ortransfusion

HEPATITIS E VIRUS (HEV) INFECTION HEV infection is rare in the United States, but it is the

most common form of epidemic hepatitis in India,where it is more common even than hepatitis A Likehepatitis A it is transmitted by food and water andcauses epidemics from time to time in Asia and Africa.The disease usually is mild and self-limiting, but it is ex-ceptionally dangerous in pregnant women—20% ofcases are fatal It does not appear to have a carrier stateand does not cause chronic hepatitis

65-75%

Chronic hepatitiswithout cirrhosis

Chronic hepatitis

HEPATOCELLULAR CARCINOMA

Figure 16-15Outcomes of hepatitis C infection.

Chapter 16 • Diseases of the Liver and Biliary Tract

A Acute hepatitis C with recovery

Anti-HCVantibody in blood

Exposure

Months

Virus in blood(HCV RNA)

B Chronic hepatitis C with chronic hepatitis or carrier state

Symptomaticrelapses

Months

Virus in blood(HCV RNA)

Anti-HCVantibody

• Increased bilirubin

in blood

• Clinical symptoms

• Increased liver enzymes in blood

• Increased bilirubin

in blood

THE ANATOMIC PATHOLOGY OF HEPATITIS

A liver biopsy from a patient in the carrier state of

hep-atitis is usually normal, with two exceptions: hephep-atitis C

carriers usually have microscopic evidence of low-grade

inflammation, and in hepatitis B carriers the virus

par-ticles may be seen as a “ground glass” appearance of

he-patocyte cytoplasm

The microscopic changes seen in acute hepatitis are

similar among the various types Hepatocytes show

hy-dropic (watery) degeneration (Chapter 2), and chronic

inflammation is present Necrosis occurs, most often

af-fecting scattered individual cells rather than entire

blocks of tissue Tiny plugs of bile appear between liver

cells, indicating that bile flow is obstructed in the

small-est bile ducts In fulminant hepatitis or hepatic failure

the inflammatory reaction is overshadowed by

exten-sive blocks of cell necrosis

In chronic hepatitis all of the above changes of

hepa-titis are present, but the damage is more severe and liverarchitecture shows considerable disorganization Theinflammatory reaction is more intense, and necrosis ismore extensive A network of scar tissue appears thatcan evolve into cirrhosis if inflammation persists

Autoimmune Hepatitis

Autoimmune hepatitis, accounting for about 20% of all

cases of chronic hepatitis, is a syndrome of chronic atitis not associated with a viral infection, although itsmicroscopic features are indistinguishable from those

hep-of chronic viral hepatitis The clinical picture variesfrom mild to severe hepatitis, and most patients areyoung women As a rule no blood markers of viral hep-atitis are present, but a few patients may have false-pos-

Figure 16-16Hepatitis C: clinical phases and blood markers of infection A A,, Acute infection with recovery is characterized by permanent

dis-appearance of clinical symptoms and disdis-appearance of the virus from blood (as is indicated by inability to detect hepatitis C virus RNA—HCV RNA—

in blood) B B,, Chronic hepatitis is characterized by reappearance of jaundice or clinical symptoms and persistent evidence of the virus in blood, as is

indicated by detection in blood of hepatitis C virus RNA (HCV RNA) The carrier state is indicated by asymptomatic persistent evidence of the virus

in blood.

408 Part 2 • Diseases of Organ Systems

itive anti-HCV antibody test results Most patients have

high titers of autoantibodies—such as antinuclear,

anti-smooth muscle, or anti-mitochondrial antibodies—and

in more than half of patients some other autoimmune

disease is present, such as ulcerative colitis, Sjögren

syndrome, thyroiditis, systemic lupus erythematosus,

or rheumatoid arthritis As with many autoimmune

dis-eases (Chapter 8), there is an increased frequency of

as-sociation with certain HLA genotypes Most patients

re-spond well to immunosuppressive therapy, but a few

patients progress to cirrhosis

Liver Abscess

Anatomically, a liver abscess is similar to any other

ab-scess (Chapter 3)—it is a focal collection of necrotic

and acute inflammatory debris and fluid Liver abscess

is rare in industrialized countries, but when it occurs it

is most often caused by bacteria or fungi that reach the

liver by direct ascent up the biliary tree, as in ascending

cholangitis (discussed below), hematogenous spread

from another infected site, or penetrating injury Liver

abscess most often occurs in patients who are

immu-nodeficient or on cancer chemotherapy or who are very

old or severely debilitated from chronic disease

Diagnosis is often missed or delayed because symptoms

of the abscess are obscured by other serious clinical

problems or the patient is too dulled by disability or

de-mentia to respond Antibiotic therapy may control

smaller lesions, but surgical drainage usually is required

for larger ones

On the other hand, in nations with poor sanitary

sys-tems, most liver abscesses are caused by infection with

Entamoeba histolytica, a protozoan parasite that is

spread by fecal contamination of unwashed food

Organisms burrow into the intestinal wall and spread

up the portal vein to infect the liver

Toxic Liver Injury

Injury from toxins or drugs should always be suspected

in liver disease because the liver metabolizes and

ex-cretes most drugs and other exogenous compounds,

al-most any of which in sufficiently large amounts can

cause liver damage Symptoms of acute toxic injury

span the continuum of liver injury from almost

imper-ceptible to fatal, and onset ranges from instantaneous to

weeks after exposure Mild injury may be asymptomatic

and detectable only by modest elevations of liver

en-zymes in blood, whereas severe injury can cause hepatic

failure or hepatic coma and death Patients with

drug-induced or toxin-drug-induced liver disease usually recoverupon withdrawal of the agent

There are two types of liver reactions to drugs and

toxins First are those that are dose related; that is, liver

damage is certain if enough chemical is present.(Historically most cases of liver toxicity were industrial,but improved occupational safety regulations havenearly eliminated the problem.) Today acute, dose-related liver injury is uncommon When it happens, it isusually the result of large doses of chemotherapy agents

or of suicidal doses of drugs such as acetaminophen(Tylenol ©)

Second, and much more common, is unpredictable

toxic injury, where the damage is out of proportion to the dose These reactions, called “idiosyncratic,” occur

when people cannot metabolize a chemical as well asothers can The chemical may initiate autoimmune hep-atitis Although microscopically, idiosyncratic reactionsare indistinguishable from chronic viral hepatitis, labo-ratory markers of virus infection are present in patientswith viral hepatitis Idiosyncratic reactions have beenattributed to a very long list of drugs, among them sul-fonamide antibiotics, isoniazid (an antituberculosisdrug), halothane (a gas anesthetic), and chlorpro-mazine (a tranquilizer)

Drugs or toxins may incite neoplastic growth For stance, oral contraceptives can stimulate the develop-ment of large benign liver tumors (adenomas), andchronic industrial exposure to vinyl chloride can cause

in-hepatocellular carcinoma Reye syndrome (discussed in

detail below) is a potentially fatal liver and brain drome caused by aspirin use in children in some situa-tions

syn-However, the most important drug affecting the liver

is one not mentioned above—alcohol (ethanol)

Alcoholic Liver Disease

They never taste who always drink;

They always talk who never think.

MATTHEW PRIOR (1664–1721), ENGLISH POET AND DIPLOMATAlcohol abuse is a fact of antiquity It is no less truetoday: alcoholism is the leading cause of liver disease inindustrialized countries About 20 million Americansabuse alcohol (about 10% of adults) and about 25% ofhospitalized patients have some alcohol-related prob-lem

The best evidence linking alcohol to liver disease isepidemiologic: 1) Evidence shows a direct relationshipbetween the amount of alcohol consumed and the de-velopment of cirrhosis; and 2) during prolonged short-

Chapter 16 • Diseases of the Liver and Biliary Tract

ages of alcohol there is less cirrhosis—in the United

States during Prohibition (1919–1933) and in France

during World War II (1939–1945) deaths from

cirrho-sis declined As a rule, the amount of alcohol necessary

to produce cirrhosis is about 200 grams of ethanol per

day—the approximate amount in one pint (near 500

ml) of whiskey, gin, or vodka or two bottles of wine—

and consumed regularly for 10–16 years Even so, only

about 16% of alcoholics develop cirrhosis Women are

more prone to develop alcoholic cirrhosis than men are

Alcohol directly damages hepatocytes, producingthree distinct lesions: fatty liver, alcoholic hepatitis, and

cirrhosis, which usually occur in sequence

FATTY LIVER

All alcoholics develop fatty livers The first sign of

alco-hol injury is fatty degeneration (Chapter 2) of

hepato-cytes, also known as steatosis, or fatty liver, as is

de-picted in Figure 10-10 (Chapter 10) and Figure 16-17

In severe cases the liver is large (sometimes two or three

times normal), yellow, and greasy Exactly how alcohol

causes fatty liver is unclear, but there is no doubt thatalcohol itself is the cause: withdrawal produces com-plete reversal For example, a week at the beach down-ing 8–10 beers a day is likely to produce a fatty liver to

go along with the sunburn But the fat disappears withreturn to normal habits at home

Patients with fatty liver are usually asymptomatic,though they may have mild elevations of liver enzymelevels in blood Elevations of liver enzyme levels indi-cate that even though fatty liver is fully reversible, he-patocytes are being damaged Continued damage maylead to increasingly severe liver disease Evidence ofdamaged hepatocytes is present in Figure 16-17: Dyinghepatocytes appear as small, round, dark cells

(Councilman bodies), and clumps of damaged protein appear as irregular reddish deposits (Mallory’s alcoholic hyaline, or Mallory bodies).

Not to be forgotten in this discussion is the otherdamage done by alcohol abuse—social disruption, can-cers of the oral cavity and esophagus, pancreatitis, car-diomyopathy, fetal alcohol syndrome, brain damage,and accidents of every kind

Historical people who were alcoholic include literary titans Edgar Allen Poe (1809–1849), F Scott Fitzgerald (1896–1940), Dylan Thomas (1914–1953), and athlete Jim Thorpe (1888–1953) Alcoholism takes nothing from their accomplishments; if anything it makes them all the more re- markable that they triumphed despite the burden.

Poe, most famous for his haunting poem, The Raven, died at age 40 Fitzgerald, author of the classic American novel The Great Gatsby, died at age 44 Thomas, the Welsh poet most famous for his poem Do Not Go Gentle into That Good Night, may have been anticipating his own death at age 39 when he wrote these immortal lines:

Do not go gentle into that good night, Old age should burn and rave at close of day;

Rage, rage against the dying of the light.

Jim Thorpe, however, lived to age 64 At the 2000 Olympics in Sydney, Australia, Thorpe, a Native American, was voted the greatest athlete of the 20 th century, a fact that astonished legions of sports-crazed Americans who had never heard of him In the 1912 Olympics Thorpe won Gold Medals in the decathlon and pentathlon (which to- gether encompass 16 sports); he played professional base- ball, hitting for a lifetime average of 252 in six seasons

with the Giants, Braves, and Reds; he played professional football, playing on both offense and defense and scoring

25 touchdowns in one season for the Canton Bulldogs, ter which he became president of what would later be- come the National Football League; in 1950 he was named

af-by the Associated Press as the greatest football sional ever He was formidable at every sport he tried: bas- ketball, lacrosse, hockey, archery, handball, tennis, boxing, wrestling, bowling, billiards, darts, shooting, golf, gymnas- tics, and swimming He even won first place in a school dance contest while a student at Carlisle (Pennsylvania) In- dian School In 1941 on a return trip to Carlisle, Thorpe stood at midfield and drop-kicked a football over the goal.

profes-He then turned and placekicked a second ball for a cessful field goal at the other end of the field—both at the age of 52 and wearing street shoes.

suc-In a triumph of legalism over justice, Thorpe’s Olympic Medals were stripped from him in 1913 because it was found he had played semi-professional baseball, something

he did not hide like others, who played under false names.

He battled alcoholism the last twenty years of his life and died penniless in 1953.

Thorpe’s Olympic medals were restored by the tional Olympic Committee in 1983.

Interna-History of Medicine FAMOUS PEOPLE WITH ALCOHOLISM

410 Part 2 • Diseases of Organ Systems

ALCOHOLIC HEPATITIS

Alcoholic hepatitis is a subacute or chronic form of

al-cohol liver injury characterized by inflammation,

hepa-tocyte necrosis, and early fibrosis, which can progress

to cirrhosis if alcohol abuse continues Why some

pa-tients progress from fatty liver to alcoholic hepatitis is a

mystery—a patient may have fatty liver for many years

without a change in drinking habits but suddenly

de-velop alcoholic hepatitis that eventually progresses to

cirrhosis

Clinical features depend on the degree of liver injury

Occasionally alcoholic hepatitis may appear so

sud-denly that bile duct obstruction or viral hepatitis is

sus-pected Malaise, anorexia, right upper quadrant pain,

and jaundice are common Leukocytosis and fever may

be present, depending upon the extent of liver cell

necrosis Blood enzyme levels are moderately elevated

Each bout of alcoholic hepatitis carries a 10–20%

chance of death, not merely from liver disease, but also

from intestinal hemorrhage, pancreatitis, and other cohol-related problems Abnormal clotting tests, lowblood albumin, or clinical signs of hepatic failure are abad prognostic sign because they do not become abnor-mal until the liver is severely damaged

al-Established alcoholic hepatitis may not be reversibleeven with complete abstention from alcohol Amongthose who quit drinking completely, one in five will nev-ertheless progress to cirrhosis Patients who continue todrink usually develop cirrhosis within a few years

ALCOHOLIC CIRRHOSIS Alcoholic cirrhosis is the final and irreversible stage of

alcoholic liver disease and is similar clinically andanatomically to other forms of cirrhosis discussed ear-lier (Fig 16-5 through Fig.16-10) It is worth repeatingthat despite monumental alcohol intake, most alco-holics do not develop cirrhosis—only about 15% do.Alcoholics suffer from the usual consequences of he-patic failure and portal hypertension upon which ispiled the train wreck of social ruin, gastric ulcers, can-cers of the mouth, throat, and esophagus, encephalopa-thy, accidents, and pancreatitis It’s enough to kill you

It should be no surprise that alcoholic cirrhosis is one ofthe leading causes (with chronic viral hepatitis B and C)for adult liver transplantation in the United States

Inherited Metabolic and Pediatric Liver Disease

Discussed here are diverse and rather uncommon herited and sporadic liver diseases that primarily affectchildren

in-HEMOCHROMATOSIS

The small intestine avidly absorbs iron, but there is noexcretory pathway, especially in men (women regularlyshed iron with the blood they lose with each menstrualperiod) Virtually all body iron reserves are stored in theliver, which therefore is directly affected by iron over-

load Hemochromatosis is the toxic accumulation of an

excessive amount of iron in cells, especially in liver,heart, and pancreas

Primary (inherited) hemochromatosis is an

autoso-mal recessive disorder caused by abnorautoso-mally high ironabsorption from the intestine It is surprisingly com-mon: among people of northern European ancestry—about 1 in 10 persons are heterozygous carriers of thefaulty gene, and about 1 in 200 persons is diseased (ho-mozygous), making hemochromatosis one of the most

Dying hepatocyte(Councilman body)

Figure 16-17Alcoholic liver Fatty liver (steatosis) and alcoholic

hep-atitis Large clear areas are hepatocytes filled with fat Hepatitis is

indi-cated by necrotic liver cells (Councilman bodies), intracellular

degener-ative inclusions (Mallory alcoholic hyaline), and fibrosis.

Chapter 16 • Diseases of the Liver and Biliary Tract

common inborn errors of metabolism in the United

States Secondary (acquired) hemochromatosis is

usu-ally the result of repeated blood transfusions given as

treatment for sickle cell anemia, thalassemia, or aplastic

anemia In such cases, iron can be converted to an

ex-cretable form by intravenous infusion of chemicals that

bind (chelate) iron

Hemochromatosis usually does not become matic until adulthood because it takes many years to ac-

sympto-cumulate enough iron to cause damage Men are

af-fected 10 times more often than women are As is

depicted in Figure 16-18, in fully developed cases iron

deposits in the liver cause cirrhosis; in the pancreas,

di-abetes; in cardiac muscle, heart failure; in skin, brown

pigmentation; in joints, arthritis; and in the pituitary,

pituitary failure (Chapter 18)

The pathology features excessive amounts of iron posited in the liver, pancreas, heart (Fig 16-19), en-

de-docrine glands, joints, and skin Cirrhosis is universal

in untreated cases In some patients the first complaint

is hypogonadism, the origins of which, in these tients, is not well understood Presumably, it is related

pa-to iron deposition in the endocrine glands, including inthe pituitary (Chapter 17)

Diagnosis depends on finding clinical features ormarkedly increased levels of blood iron, ferritin, andtransferrin (Chapter 11) in the absence of anotherknown cause Diagnosis is confirmed by liver biopsyshowing marked iron overload Screening family mem-bers of the patient is very important If the diagnosis ofprimary hemochromatosis is made early, most patientscan expect to live normal lives if the excessive accumu-lation of iron is removed by periodic bleeding (phle-botomy) Patients with transfusion hemochromatosiswho continue to need blood because of their underlyinganemia can be treated effectively with injectable chem-icals that bind (chelate) iron in a form that allows ironexcretion in urine

Hypopituitarism

Skin

pigmentation

Cardiacfailure

412 Part 2 • Diseases of Organ Systems

WILSON DISEASE

Wilson disease is a rare autosomal recessive inherited

disorder of copper metabolism that results in toxic

ac-cumulation of copper, mainly in the brain and liver

Copper is absorbed in the gut and excreted in bile

Absorbed copper is carried by albumin to the liver,

where it is bound to a copper-bearing protein,

cerulo-plasmin, and secreted back into blood for metabolic

dis-tribution In Wilson disease biliary excretion of copper

is decreased, and copper accumulates, with toxic effect,

primarily in the liver and brain Blood levels of copper

and ceruloplasmin are low in Wilson disease

First symptoms may occur at any age but are usually

manifest by young adult years Earliest signs are

neuro-logic—behavioral oddities, psychosis, or tremors and

abnormal gait The liver may show fatty change and

chronic hepatitis or cirrhosis, changes that combined

with the neurologic symptoms may result in

misdiag-nosis of alcoholic liver disease The diagmisdiag-nosis of Wilson

disease can be confirmed by liver biopsy slides stained

for copper Copper deposits in the eye also occur in

Wilson disease, demonstrated as a brown-green arc

(Kayser-Fleischer ring) where the sclera meets the

cornea Early diagnosis is critical Although many

pa-tients given long-term copper chelation therapy do

well, in some liver disease is relentless, and liver

trans-plantation offers the only hope

HEREDITARY ALPHA-1 ANTITRYPSIN

DEFICIENCY

Alpha-1 antitrypsin (AAT), a protein made by the liver,

inhibits the action of trypsin and other

protein-digest-ing enzymes that are released by neutrophils in acute

inflammatory reactions AAT was discussed in Chapter

14 because of its importance in the pathogenesis of

em-physema caused by smoking AAT deficiency is an

in-herited disorder that results in low levels of AAT

activ-ity in the lungs and accumulation of excessive amounts

of defective AAT in the liver, which appear in liver cells

as distinctive protein globules and damage liver cells by

an unknown mechanism

Only about 10% of patients with AAT deficiency

de-velop clinically significant liver disease In a minority of

patients AAT deficiency appears initially as neonatal

cholestasis (discussed below) However, in most

pa-tients liver disease does not appear until hepatitis or

cir-rhosis is diagnosed in adolescence or adult life The

lungs are not severely affected unless the patient

smokes, in which case early and severe emphysema

oc-curs Smoking causes inflammation, which results in

re-lease of protein-digesting enzymes that are not opposed

by AAT, and the diminished AAT activity in the lungsallows the inflammatory enzymes to dissolve alveolarsepta to produce emphysema

In patients with liver or lung disease, the diagnosis ismade by finding low levels of blood AAT activity andcharacteristic microscopic evidence of AAT accumula-tion in hepatocytes

NEONATAL CHOLESTASIS, BILIARY ATRESIA, AND HEPATITIS

Almost all newborns, premature infants in particular,

have physiologic jaundice because of increased gated bilirubin for a week or two after birth, until the

unconju-liver matures enough to produce the glucuronide essary to conjugate bilirubin Jaundice associated with

nec-other causes usually demonstrates an increase of

conju-gated bilirubin and is termed neonatal cholestasis until

a definitive cause can be determined Neonatal sis results from one of two main types of defects: bile

cholesta-duct obstruction, usually termed primary biliary sia, and neonatal hepatitis, a collective term for every-

atre-thing else It is important to realize that these are cal terms of convenience and not specific diagnoses, nor

clini-are the diseases necessarily inflammatory The finding

of increased neonatal conjugated bilirubin should ulate a search for identifiable infectious, toxic, or meta-bolic disease (of which alpha-1 antitrypsin deficiency isthe most common) Affected neonates typically havejaundice, dark urine, light stools, and an enlarged liver.Differential diagnosis is difficult but important becauseextrahepatic bile duct obstruction is sometimes surgi-cally correctible, and prolonged obstruction can causesevere liver disease or death

stim-Most cases prove to be idiopathic hepatitis or biliarystenosis, which together probably represent a contin-uum of diseases from diffuse hepatic inflammation onthe one hand to fibrous scarring of bile ducts on theother This suggests that neonatal hepatitis and biliaryatresia result from a common inflammatory process thatmight better be termed “infantile obstructive cholan-giopathy.”

REYE SYNDROME Reye syndrome is a combination of fatty liver and acute

brain dysfunction (encephalopathy) in children thatmost often develops a few days after an acute viral ill-ness treated with aspirin Onset is heralded by severevomiting, lethargy, irritability, and hepatomegaly.Jaundice is usually absent initially About 25% of theseyoungsters progress to coma Death may be attributable

to liver or to neurologic disease The cause is unknown,

Chapter 16 • Diseases of the Liver and Biliary Tract

but epidemiologic evidence links it to aspirin

adminis-tration for viral illness in persons less than 18 years of

age The disease is more complex than simple aspirin

toxicity because the doses consumed are far too small to

be toxic Aspirin is now rarely used in the United States

to treat childhood fevers, and Reye syndrome is

there-fore uncommon in the United States

Disease of Intrahepatic Bile Ducts

Prolonged obstruction in the extrahepatic biliary tree

results in severe intrahepatic damage The most

com-mon cause of obstruction is cholelithiasis (gallstones),

discussed below Other causes of obstruction include

biliary stenosis, malignancy in the head of the pancreas,

and fibrous strictures (scars) from surgical procedures

Extrahepatic obstruction leads to nonbacterial

inflam-mation in small, intrahepatic bile ducts, which if

pro-longed leads to a special type of cirrhosis, secondary

bil-iary cirrhosis Obstruction also encourages ascending

bacterial infection from the GI tract (ascending

cholan-gitis).

PRIMARY BILIARY CIRRHOSIS

Primary biliary cirrhosis is an autoimmune disease that

evolves from inflammatory destruction of intrahepatic

bile ducts Nearly 90% of patients also have another

au-toimmune disease (Chapter 8) such as systemic lupus

or Sjögren syndrome, and virtually all have high titers

of antimitochondrial antibody As is illustrated in Figure

16-20, biopsy in early disease reveals accumulations of

lymphocytes surrounding bile ducts Later, bile duct

scarring occurs and progresses to cirrhosis

Nearly all patients are middle-aged women who sent with cholestasis They have itchy skin (pruritus) and

pre-increased levels of blood cholesterol because of retained

bile acids, and their blood alkaline phosphatase level is

markedly elevated because of damage to the bile duct

ep-ithelium Jaundice appears late and usually signals that

hepatic failure is near Impaired bile excretion may cause

malabsorption syndrome (Chapter 15) Death results

from hepatic failure and portal hypertension The only

effective treatment is liver transplantation

PRIMARY SCLEROSING CHOLANGITIS

Primary sclerosing cholangitis is a chronic liver disease

caused by inflammation and fibrosis of intrahepatic and

extrahepatic bile ducts Two thirds of patients have

ul-cerative colitis (Chapter 15) Less often, other

inflam-matory bowel disease is present; however, in most of

the other third no underlying disease can be found The

pathology of sclerosing cholangitis is characterized byscarring of bile ducts inside and outside of the liver.Microscopically, findings in the liver are distinctive—onionskin fibrosis that encircles and eventually de-stroys the ducts

Although most patients with ulcerative colitis arewomen, most patients with primary sclerosing cholan-gitis are men under age 40 The typical patient is anadult male with long-standing ulcerative colitis whoslowly develops signs and symptoms of liver disease.Few patients have blood autoimmune antibodies.Biliary cirrhosis is the end point Liver transplantation

is the definitive treatment

Circulatory Disorders

Blood flow may be obstructed in the portal vein as itflows into the liver, as it flows through the liver, or inthe hepatic vein as it flows out of the liver

The portal vein can become obstructed and producechanges similar to the portal hypertension caused bycirrhosis Obstruction is usually attributable to throm-bosis (Chapter 5) associated with intra-abdominal in-

Normal liver

ChronicinflammationBile duct

Figure 16-20Primary biliary cirrhosis Microscopic study of early

stage showing a collar of chronic inflammatory cells (lymphocytes) around small bile duct.

414 Part 2 • Diseases of Organ Systems

flammation, such as pancreatitis, abdominal surgery, or

peritonitis (Chapter 15)

The most common cause of obstructed blood flow

through the liver is chronic passive congestion, which is

usually associated with right heart failure (Chapter 13),

as blood “dams up” trying to enter the heart Sluggish

flow in the liver usually causes minor liver cell damage

detectable only by an increase of liver enzyme levels in

blood Cirrhosis with portal hypertension (discussed

above) is the most serious cause of obstructed blood

flow through the liver

Blood flowing out of the liver can be obstructed in

dis-eases that involve the hepatic vein The most common of

these is hepatic vein thrombosis (Budd-Chiari

syn-drome), which is usually attributable to diseases

associ-ated with an increased tendency for intravascular

coag-ulation and thrombosis—polycythemia vera (Chapter

11), pregnancy, and oral contraceptive use (Chapter

21) Hepatic vein obstruction causes severe congestion

and liver cell necrosis The mortality rate is high

Liver infarcts are uncommon because the liver has a

dual blood supply However, when they occur they are

rarely detected because dead cells are quickly replaced

by new ones, thanks to the liver’s remarkable power of

regeneration

Tumors of the Liver

The most common neoplasm in (not of ) the liver is

metastatic carcinoma (Fig 16-21), usually from a

pri-mary malignancy in the colon, lung, or breast

The most common benign tumor of the liver is

cav-ernous hemangioma, a vascular mass that is not

neoplas-tic and is composed of dilated blood vessels Cavernous

hemangiomas are usually small and located

immedi-ately beneath the fibrous capsule of the liver Liver cell

adenoma is a benign neoplasm of hepatocytes and is

en-countered most often in young women taking oral traceptives It may become quite large and may rupture,especially during pregnancy, to cause life-threateningintra-abdominal hemorrhage

con-PRIMARY CARCINOMAS OF THE LIVER Hepatocellular carcinoma is a malignant neoplasm of

hepatocytes that is usually related to chronic hepatitisvirus B and C infections—chronic hepatitis or the car-rier state confers a 200⫻ increased risk of hepatocellu-lar carcinoma Despite the relative rarity of hepatocellu-lar carcinoma in the United States, its incidence in Africaand Asia, where hepatitis B is exceedingly common,makes it arguably the most common malignant tumor ofhumans Chronic hepatitis C with cirrhosis is the majorcause in industrialized nations Hepatocellular carci-noma also occurs in association with cirrhosis caused byhemochromatosis and alpha-1 antitrypsin deficiency.Hepatocellular carcinoma usually grows as a singlemassive neoplasm (Fig 16-22) It has a marked ten-dency to invade hepatic veins and may snake its way upthe hepatic vein and far into the vena cava.Hematogenous (blood borne) metastases are common.The usual patient has preexisting liver disease.Hepatocellular carcinoma may be heralded by a suddenincrease of liver size, sudden worsening of ascites, ap-pearance of bloody ascites, or intense abdominal pain

Most patients have increased levels of alpha-fetoprotein

in their blood, although this is not a specific marker cause increases are seen in cirrhosis, other liver dis-

be-Figure 16-21Metastatic carcinoma in liver This patient had colon

cancer, which metastasized up the portal vein to the liver.

Figure 16-22Hepatocellular carcinoma The primary tumor is a

sin-gle, large mass, which can be seen invading an intrahepatic branch of the hepatic vein The liver is cirrhotic; cirrhosis is a major cause of he- patocellular carcinoma.

Chapter 16 • Diseases of the Liver and Biliary Tract

eases, pregnancy, and other conditions Marked

eleva-tions, however, are rarely seen in any disease other than

hepatocellular carcinoma The prognosis for patients

with hepatocellular carcinoma is grim; most patients

die of tumor in a short period of time Death usually

fol-lows profound wasting (cachexia), hepatic coma, or GI

bleeding HBV vaccinations have proven effective in

lowering the incidence of hepatocellular carcinoma in

areas where hepatitis B is acquired early in life

CHOLANGIOCARCINOMA

Cholangiocarcinoma is a malignancy of bile duct

ep-ithelium; that is, the cells that line bile ducts In many

aspects, cholangiocarcinoma is very different from

he-patocellular carcinoma Most cases arise without

known preexisting risk factors, but known

predisposi-tion is associated with two specific condipredisposi-tions: primary

sclerosing cholangitis and chronic liver infection with

schistosomiasis (parasites seen in Africa, Asia, and

South America) Cholangiocarcinoma tends to be more

aggressive than hepatocellular carcinoma—patients

quickly develop severe cachexia, hepatic coma, and

esophageal varices with fatal hemorrhage, and very few

survive five years Legendary American football

run-ning back Walter Payton developed

cholangiocarci-noma as a consequence of chronic sclerosing

cholangi-tis, and he died when he was but 45 years old

Diseases of the Gallbladder and

Extrahepatic Bile Ducts

Recall that the biliary tree begins as tiny ducts that

grad-ually grow larger as they merge, like rivers leading to

the sea, until they form the common bile duct that exits

the liver to connect with the duodenum at the ampulla

of Vater The gallbladder, attached to one side of the

common bile duct, holds a reserve of bile that is

dis-charged into the common bile duct after meals

DISEASES OF THE GALLBLADDER

Diseases of the gallbladder are not complicated, and

they are very common Almost all gallbladder and

bil-iary tract disease occurs as a result of inflammation,

closely related to the presence of gallstones There are

two major varieties of gallstones: cholesterol stones and

pigment stones

Cholelithiasis (Gallstones)

Stones in the gallbladder or biliary tree are referred to

collectively as cholelithiasis Stones in the bile ducts are

referred to as choledocholithiasis The great majority of

gallstones form in the gallbladder Most patients havemultiple stones, sometimes several dozen In the UnitedStates about one million new cases are diagnosed eachyear, half requiring surgery The surgical mortality rate

is less than 1%

Most gallstones (80%) are cholesterol gallstones,

which form when bile becomes oversaturated with lesterol Why some people develop gallstones and oth-ers do not is a mystery; however, there are certain well-known conditions associated with the development ofcholesterol stones:

cho-• Age and gender: Older people have more gallstones

than younger ones do In their reproductive years,women are three times more likely than men to havegallstones

• Weight: Obese people are much more likely to

de-velop cholesterol stones

• Ethnic, hereditary, and geographic factors: Cholesterol

gallstones occur in about 75% of Pima, Hopi, andNavajo Native Americans A family history of gall-stones imparts increased risk Gallstones are morecommon in industrialized countries than in develop-ing ones

• Drugs: Oral contraceptives and estrogen therapy

in-crease hepatic uptake and secretion of cholesterol

• Acquired conditions: Any condition that causes

de-creased gallbladder motility (for instance, nancy, rapid weight loss, and spinal cord injury) pre-disposes to gallstones

preg-Figure 16-23 illustrates pure cholesterol stones, which

are semi-translucent, yellowish, and egg shaped.Cholesterol stones arise only in the gallbladder, but pig-ment stones may arise in the biliary tree as well

Pigment gallstones, accounting for the remaining

20% of gallstones, are composed of bilirubin and bilesubstances other than cholesterol The greatest risk fac-tor for pigment gallstones is hemolysis of red bloodcells, as occurs with sickle cell anemia (Chapter 11),which increases the amount of bilirubin delivered to theliver to be excreted in bile Other risk factors for pig-ment gallstones are not so well understood As is de-picted in Figure 16-24, pigment stones are dark brown

or black and have multiple flat surfaces

Gallstones usually do not cause symptoms until theybegin to move through bile ducts, and a majority of gall-

About 10–20% of people develop gallstones The rate is much higher in Hispanics, and in Native Americans in the southwestern United States.

416 Part 2 • Diseases of Organ Systems

stones can exist for decades or a lifetime without

symp-toms Big stones are usually found in the gallbladder

and remain there silently Very small stones can be

passed from the gallbladder or from intrahepatic ducts

without symptoms However, mid-sized stones create

most problems because they are small enough to pass

from the gallbladder or intrahepatic duct, but are toobig to pass out smoothly Passage of a stone may cause

extraordinarily painful cramps—biliary colic—in the

right upper quadrant or upper abdomen, which is ally accompanied by nausea and vomiting Fever, whichdoes not occur in uncomplicated cholelithiasis, shouldarouse suspicion of ascending bacterial infection (as-cending cholangitis), which is a threat when stones arepassed or become lodged in bile ducts Other complica-tions include cholecystitis, pancreatitis, perforation,and empyema of the gallbladder

usu-Because gallstones are often discovered during uation of other medical problems, finding asympto-matic stones forces a decision to leave it alone or to dosurgery Individual situations differ and stone behavior

eval-is unpredictable—about 2% of silent stones becomesymptomatic each year Most patients elect to avoid sur-gery until symptoms occur

Cholecystitis Cholecystitis is inflammation of the gallbladder Acute cholecystitis is the most common major complication

of gallstones: more than 90% of cases are associatedwith stone obstruction of the neck of the gallbladder.Most patients have multiple stones Bacterial infectionusually isn’t present but may occur later and cause the

lumen of the gallbladder to fill with pus (empyema), as

is depicted in Figure 16-25 On the other hand, acute

Pure cholesterolgallstones

Gallbladder mucosawith heavy deposits

of cholesterol (yellow)

Figure 16-23Cholelithiasis (cholesterol gallstones) and chronic

cholecystitis Normally gallbladder mucosa is green because of

stain-ing by normal bile In this patient cholesterol deposits caused a bright

yellow coloration Microscopic study of the gallbladder wall revealed

chronic inflammation.

Cholesterol stonelodged in neck ofgallbladder

Figure 16-24Cholelithiasis (pigment stones) and chronic

chole-cystitis Normally gallbladder mucosa is green because of staining by

normal bile When opened, the lumen contained mucus only; no bile

was present, indicating that stones had blocked the cystic duct

Micro-scopic study of the gallbladder wall revealed chronic inflammation.

Figure 16-25 Acute cholecystitis with empyema Gallbladder is

filled with blood and pus Note a pure cholesterol stone lodged in the gallbladder neck where the cystic duct arises.

Chapter 16 • Diseases of the Liver and Biliary Tract

cholecystitis can occur without stones—about 5–10%

of gallbladders removed for acute cholecystitis contain

no stones Most of these patients have other important

conditions, such as pregnancy, burns, sepsis, or recent

major surgery In acute cholecystitis the gallbladder is

enlarged, tense, and inflamed and in some instances

may be necrotic or filled with pus

Clinically the presentation of acute cholecystitis canvary from persistent, rather mild right upper abdominal

pain to severe, crampy pain (colic) associated with

fever, nausea, vomiting, prostration, and leukocytosis

(increased granulocytes in the peripheral blood,

Chapter 3) Jaundice (because of increased conjugated

bilirubin) suggests obstruction by a stone in the

com-mon bile duct Mild attacks usually resolve in a few days

or a week, but about 25% require immediate surgery

As is depicted in Figure 16-26, chronic cholecystitis

may develop after numerous episodes of acute

chole-cystitis, but most often it occurs without a history of

acute attacks Most cases are nonbacterial: in only a

third of cases can bacteria be cultured from the bile

Chronic cholecystitis is almost always associated with

gallstones, but the exact role stones play is unclear

Obstruction is not necessary Stones may be the result,

not the cause, of the inflammation At the very least it

appears that stones and inflammation coexist in

gall-bladders for many years

Clinically, chronic cholecystitis is not as dramatic as

an acute attack and is usually characterized by episodes

of mild to moderate right upper quadrant pain with

nau-sea, vomiting, and intolerance for fatty foods (becausefatty foods stimulate the gallbladder to contract and sendbile into the intestine to emulsify the fat) Most caseswarrant surgery because complications can be severe—ascending cholangitis, gallbladder perforation with peri-tonitis, or septicemia (bacterial infection of blood)

Tumors of the Gallbladder

Tumors of the gallbladder are uncommon Most mon are small benign mucosal papillary growths thatoccur with gallstones Carcinomas of the gallbladder areadenocarcinomas and are also associated with gall-stones At the time of discovery most are beyond hope

com-of cure, and five-year survival is less than 5%

DISEASES OF EXTRAHEPATIC BILE DUCTS

Obstruction is the most important problem of the

extra-hepatic bile ducts Figure 16-27 depicts the majorcauses Gallstones are by far the most common cause ofobstruction Other causes include cancer of the head ofthe pancreas, pancreatitis, inflammatory disease of theducts, and postoperative scarring In industrialized na-tions, most gallstones form in the gallbladder, but inAsia there is a much higher prevalence of primary stone

formation in ducts Stones in the bile ducts

(choledo-cholithiasis) are the main cause of ascending

cholangi-tis, a bacterial infection of the biliary tree caused by

in-testinal bacteria that travel up the common bile ductinto the liver Not every patient with ductal stones de-velops ascending cholangitis, but ascending cholangitisalmost never occurs without obstruction Sepsis (blood-stream infection) is the most important clinical compli-cation, far outweighing cholestasis In its most severeform it may cause general sepsis and intrahepatic ab-scesses Other acute complications of ductal stones andobstruction include acute pancreatitis and acute chole-cystitis Chronic obstruction may cause chronic liverdisease with secondary biliary cirrhosis

Extrahepatic biliary atresia is an obstruction of

ex-trahepatic bile ducts discussed above in conjunction

with neonatal cholestasis Biliary atresia is a pediatric

disease (Chapter 7) and, strictly speaking, is not atresia(failure to develop) because most affected infants areborn with patent bile ducts that become obstructed andscarred The cause is unknown It accounts for over half

of children referred for liver transplantation

Cholangiocarcinomas of the extrahepatic bile ducts

are rare and usually fatal, but associated with a what longer survival than hepatic cholangiocarcinomasbecause they cause obstructive signs and symptoms ear-lier and are detected earlier ■

some-Pigment stonesand mucus

Thick, fibrotic gallbladder wall

Figure 16-26Chronic cholecystitis and cholelithiasis Gallbladder

contains mucus and numerous pigment stones No normal bile is

pres-ent Note thick gallbladder wall, caused by chronic inflammation and

fibrosis.

418 Part 2 • Diseases of Organ Systems

Sclerosing cholangitis,postoperative stricture

Congenitalbiliary atresia

Duodenum

Carcinoma of

ampulla of Vater

Pancreaticcarcinoma

Pancreas

GallstonesCommon bile duct

Figure 16-27Extrahepatic biliary struction The illustration shows the

ob-sites and causes of obstruction.

TOPIC

Hepatitis C infection

THE CASE

Setting:You are employed in the office of a liver disease

specialist, where one of your tasks is to obtain medical

his-tories and do physical examinations on new patients.

Clinical history:A 48-year-old banker is referred to the

of-fice of a liver disease specialist The entry on her

appoint-ment sheet says “hepatitis C?”

The patient is currently asymptomatic, but when she was

22 years old, she underwent a caesarian section that quired transfusion of two units of packed red blood cells About 2 months following this, she experienced an episode

re-of jaundice, dark urine, pale stools, anorexia, nausea, and vomiting with vague right upper abdominal discomfort An infectious disease specialist told her that she had “non-A, non-B” hepatitis She was ill for several weeks, but after

3 months was told she was completely recovered and charged from care.

dis-“I didn’t give it a second thought,” she adds “After it was all over, I felt completely normal.” 

CASE STUDY 16-1 “I DIDN’T GIVE IT A SECOND THOUGHT”

Chapter 16 • Diseases of the Liver and Biliary Tract

[Case 16-1, continued]

She is in the office now because during a recent change

of employment she took an insurance physical examination that revealed mildly increased levels of liver enzymes in her blood Complete blood count, urinalysis, and other blood chemistries were unremarkable.

Your questioning reveals that she is employed full time and has occasional episodes of fatigue and “the blues.”

Otherwise, she is in excellent health and has not needed to see a physician except for her annual gynecologic exam and pap smear She denies having sex with anyone but her hus- band She usually drinks a glass of wine with dinner She has never smoked In college she “experimented” with mari- juana but never injected drugs She is not taking prescription drugs and denies current illegal drug use of any kind.

Physical examination and other data:She appears her stated age and is articulate and cooperative She is very anx- ious about what might be wrong Vital signs and physical ex- amination are unremarkable Neither liver nor spleen can be palpated No jaundice is noted Her skin shows no evidence

of spider angiomata, palmar erythema, or bruises She does not have hemorrhoids A vaginal examination is not done.

Clinical course:The blood studies you order show mild creases of liver enzymes and the presence of HCV-RNA She refuses the offer of liver biopsy but agrees to alpha-2a inter- feron therapy, which is administered intravenously three times a week for a year under your supervision At the con- clusion of therapy, liver enzymes are normal, and HCV-RNA

in-is no longer detectable Follow up laboratory studies remain normal for 2 years after therapy, and she is discharged back

to the care of her usual physician.

DISCUSSION

This patient became infected with hepatitis C virus from a blood transfusion before the discovery of hepatitis C virus and, therefore, before a way existed to screen blood donors and blood products for infection from what was called at that time “non-A, non-B hepatitis.” Modern screening is ef- fective and has reduced the chance of blood product infec- tion to about one case in 2 million transfusions Although most newly infected patients give no history of transfusion

or illicit drug use, among those new HCV infections for which a cause can be determined, most are associated with intravenous drug use.

This patient was unusual in that she developed an acute hepatitis syndrome with the initial infection, whereas most new HCV infections are asymptomatic At your initial meet- ing with this patient, her history and lab studies were enough to convince her physicians to treat her without the definitive proof of chronic hepatitis that could have been provided by a liver biopsy.

She had an excellent response to therapy Only about one fourth of patients are so lucky; most do not respond to therapy However, of those who do respond well, most do not relapse She may have been permanently cured; only time will tell.

• Blood testing is essential in the diagnosis of viral hepatitis.

1. Trace the flow of blood through the liver : Venous

blood flows from intestinal veins up the portal vein, which divides into progressively smaller ves- sels to form a second capillary network in the liver.

From these hepatic capillaries blood flows into the hepatic vein and then into the inferior vena cava and the main systemic circulation Arterial blood flows through a second set of capillaries that branch from the hepatic artery, and then mixes with portal blood to flow through the hepatic vein and into the vena cava.

2. Name the major functions of the liver: The liver 1)

clears blood of toxins, metabolic waste, and mones; 2) converts glucose into glycogen for en- ergy storage and reconverts it to glucose on de- mand; 3) produces most plasma proteins, with the

hor-exception of antibodies; 4) excretes bilirubin into bile; and 5) produces bile acids and excretes them into bile.

3. Explain the enterohepatic circulation: Enterohepatic

circulation refers to excretion of bile acids (made from cholesterol) from the liver into the intestine and the reabsorption of most of the bile acids (and their cholesterol) by the intestine for recirculation through the portal system and reuse by the liver Most cholesterol absorbed by the intestine comes from reabsorbed bile acids, not dietary cholesterol.

4. Name the major functional reactions of the liver to injury: Jaundice, cholestasis, and hepatic failure.

5. Explain the difference between conjugated and unconjugated bilirubin: Unconjugated bilirubin is

not water soluble and is attached to albumin for

Objectives Recap

420 Part 2 • Diseases of Organ Systems

transport to the liver, where it is conjugated

(joined) to glucuronide and becomes water soluble

and can be excreted in bile.

6. Name one cause of unconjugated

hyperbilirubine-mia and one of conjugated hyperbilirubinehyperbilirubine-mia:

Unconjugated hyperbilirubinemia can occur with

hemolytic anemia, such as sickle cell disease, which

can cause increased production of unconjugated

bilirubin Conjugated hyperbilirubinemia occurs

when bile flow is obstructed after bilirubin has

been conjugated by the liver, such as with bile duct

obstruction.

7. Define cirrhosis and name the two most common

causes: Cirrhosis is a progressive, patterned fibrosis

of the entire liver The most common causes are

al-coholism and chronic hepatitis.

8. Explain why cirrhosis causes portal hypertension:

Portal hypertension occurs when there is

obstruc-tion of portal blood flow caused by the choking

ac-tion of the dense fibrous bands of cirrhosis, which

scar and shrink the liver.

9. Name two hemodynamic consequences of portal

hypertension: The hemodynamic consequences of

portal hypertension are ascites, congestive

splenomegaly, esophageal varices, hemorrhoids,

and radiating prominent periumbilical veins known

as caput medusa.

10. Outline the main clinical manifestations of

cirrhosis: 1) Portal hypertension causes

hemor-rhoids, esophageal varices, splenomegaly, and

ca-put medusa veins radiating from the umbilicus,

and contributes to the formation of ascites 2)

Failing hepatic metabolism of estrogen results in

high blood estrogen, which in men accounts for

thinning scalp and genital hair, female-like breasts

(gynecomastia), red palms (palmar erythema),

at-rophic testes, and spider angiomas—small vascular

malformations of skin that feature tiny central

ves-sels from which spider-like vesves-sels radiate outward.

Women may have abnormal menstrual bleeding 3)

Failing hepatic metabolism of ammonia and other

waste products accounts for hepatic coma and

fe-tor hepaticus (liver breath) 4) Failing hepatic

ex-cretion of bilirubin causes jaundice 5) Failing

he-patic protein synthesis causes a decrease in plasma

albumin, which contributes to ascites and

periph-eral edema (Chapter 5), and decreased levels of

blood coagulation factors accounts for bleeding

tendencies, usually evident as easy bruising (skin

purpura).

11. Name several clinicopathologic syndromes associated

with viral hepatitis: Asymptomatic hepatitis, carrier

state, acute viral hepatitis, chronic viral hepatitis,

ful-minant hepatic failure, hepatocellular carcinoma.

12. Contrast the mode of transmission and clinical

course of hepatitis A and hepatitis B: Hepatitis A

is transmitted by personal contact and oral-fecal contamination of food and water; hepatitis B by transfusion, injection of blood products, renal dialysis, needlestick accidents among health care workers, intravenous drug use, and sexual activity Hepatitis A is a benign, self-limited disease with

no carrier state or chronic hepatitis; hepatitis B is much more serious and may cause symptomatic acute hepatitis, fulminant hepatitis with massive liver necrosis, or chronic hepatitis that may ad- vance to cirrhosis; a small percentage of patients becomes carriers.

13. Name the most important epidemiologic fact about hepatitis C, and name the most common serious consequences of hepatitis C infection:

Hepatitis C infection is largely the consequence of intravenous drug abuse It has a high rate of pro- gression to chronic hepatitis and cirrhosis.

14. Name one common acute and one common chronic change induced in the liver due to alcohol abuse:

The most common acute change is fatty phosis (steatosis); the most common serious chronic change is cirrhosis.

metamor-15. Explain the difference between primary biliary rhosis and sclerosing cholangitis: Primary biliary cir-

cir-rhosis is an autoimmune disease of intrahepatic bile ducts Most patients have other autoimmune disease and antimitochondrial antibody in their blood Primary sclerosing cholangitis is a chronic in- flammatory disease of intrahepatic and extrahep- atic bile ducts usually associated with ulcerative co- litis.

16. Name the liver condition most commonly ated with hepatocellular carcinoma: Chronic hepa-

associ-titis, caused by hepatitis B or hepatitis C infection.

17. Name the two major categories of gallstones, and know which is the most common: Cholesterol

stones (most common) and pigment stones.

18. Name several risk factors that favor the formation

of gallstones: Age, gender, and ethnicity The old

have more stones than young, women more than men, Native Americans and Hispanics more than Anglos Also associated with gallstones are oral contraceptives and estrogen replacement therapy, obesity, hemolytic anemia, and rapid weight loss.

19. Discuss some of the most common causes of hepatic bile duct obstruction : Gallstones are the

extra-most common cause of extrahepatic biliary struction Other causes include biliary atresia in newborn infants, cancer of the head of the pan- creas, pancreatitis, inflammatory disease of the ducts, and postoperative scarring A serious compli- cation of biliary obstruction is ascending cholangi- tis, a bacterial infection that enters the biliary tree from the intestine.

Chapter 16 • Diseases of the Liver and Biliary Tract

1. The enterohepatic circulation refers to

A Blood flow through hepatic sinusoids

B Circulation of bile within the liver

C Bile acid absorption from the intestine

D Distribution of blood between liver arteries and veins

2. Hepatitis B infection

A Is the most common viral hepatitis in the United States

B Causes epidemics of infection

C Of all hepatitis viruses is most likely to cause chronic hepatitis and cirrhosis

D Is transmitted parenterally or by sexual contact

3. Which of the following statements about cirrhosis

is false?

A It is irreversible

B Portal cirrhosis is more common than biliary rhosis

cir-C Alcoholism produces biliary cirrhosis

D The pattern and size of hepatic nodules are not useful in determining etiology

4. Concerning cholelithiasis and cholecystitis, which of

the following is false?

A Bacterial infection causes most cholecystitis

B Cholesterol stones are more common than ment stones

pig-C Ascending cholangitis is closely linked to docholithiasis

chole-D Most patients with chronic cholecystitis have gallstones in the gallbladder

5. Which of the following is false?

A Most liver abscesses worldwide are caused by amebiasis

B Most patients with autoimmune hepatitis have anti-mitochondrial antibody

C The first stage of alcoholic liver disease is fatty liver

D Genetic hemochromatosis can be treated tively by phlebotomy

effec-6. True or false? Biliary obstruction causes increased conjugated bilirubin.

7. True or false? Esophageal varices are a direct sequence of portal hypertension.

con-8. True or false? Hepatitis A is usually transmitted by blood transfusion or needlestick.

9. True or false? Cirrhosis is the most common cause

C H A P T E R

422

Diseases of the Pancreas

This chapter begins with a review of the normal pancreas and its digestive and endocrine functions Major eases and disorders discussed include diabetes, pancreatitis, and pancreatic cancer.

dis-BACK TO BASICS

• The Digestive (Exocrine) Pancreas

• The Hormonal (Endocrine) Pancreas

DISEASES OF THE DIGESTIVE (EXOCRINE) PANCREAS

• Pancreatitis

• Carcinoma of the Pancreas

DISEASES OF THE HORMONAL (ENDOCRINE) PANCREAS

• Diabetes Mellitus

• Pancreatic Endocrine Neoplasms

After studying this chapter you should be able to:

1. Discuss the anatomy of the pancreas, and make a clear distinction between the digestive and the hormonal creas

pan-2. Explain the relationship of glucose, glucagon, and insulin to one another and to stored glycogen

3. Name the two most common causes of acute pancreatitis

4. Explain autodigestion in acute pancreatitis

5. Explain why a patient with acute hemorrhagic pancreatitis may develop hypovolemic shock or hypocalcemia

6. Contrast acute and chronic pancreatitis, and describe their relationship to one another

7. Name the most common cause of chronic pancreatitis

8. Discuss the clinical presentation and complications of adenocarcinoma of the pancreas, and give a reasonable timate of the five-year survival rate

es-9. Explain the pathogenesis of type 1 diabetes

10. Explain the pathogenesis of type 2 diabetes

11. Name the most important factor in the development of type 2 diabetes

12. Name the two types of diabetic coma and the pathogenesis of each

13. Explain the importance in diabetes of hyperglycemia and glycosylation

14. Explain diabetic microvascular disease

15. Name the leading causes of death in diabetes

16. Name some criteria for the diagnosis of diabetes

Learning Objectives

• carcinoma of the pancreas

DISEASES OF THE HORMONAL (ENDOCRINE) PANCREAS

Key Terms and Concepts

Anatomically the pancreas is a single organ; however,

functionally it is two: an exocrine organ that secretes

juice into ducts that carry it to the intestine, and an

en-docrine (without ducts) organ that secretes hormones

directly into blood

As is depicted in Figures 17-1 and 17-2, the pancreas

is a tadpole-shaped organ about 5–6 inches (12–15 cm)

long that is embedded in retroperitoneal fat of the mid

abdomen and lies across the front of the aorta just

be-low the stomach The head is nestled in the duodenal

loop, and the tail rests near the spleen Ducts lead from

individual pancreatic glands (acini) and join to form the

pancreatic duct In most people the pancreatic duct

merges with the common bile duct, and together they

pass through the head of the pancreas before emptying

into the duodenum at the ampulla of Vater

The pancreas is exceptional in two respects First, it

is the most inaccessible organ in the body, hidden

among soft organs and structures that yield to a

pancre-atic mass, making pancrepancre-atic tumors very difficult to

di-agnose early Second, the pancreas has large functional

reserves, which means it is also a difficult task to make

an early diagnosis of lost pancreatic function

THE DIGESTIVE (EXOCRINE) PANCREAS

The digestive (exocrine) pancreas, which constitutes

the bulk of the organ, is composed of acini and ducts.Epithelial cells of the acini excrete about 2–3 liters of al-kaline pancreatic juice each day This juice, a mix ofabout 20 digestive agents, water, bicarbonate, and mu-cus, is carried to the duodenum by the ducts Protein-

digesting enzymes (proteases) are secreted in inactive

form as zymogens (otherwise the digestive juices would

digest the organ before getting to the duodenum, apoint to remember when reading below about pancre-

atitis) However, lipase, which digests fat, and amylase,

which digests carbohydrate, are secreted in active formbecause the walls of the pancreatic ducts are composed

of protein and thus are impervious to the action of thesetwo enzymes As additional insurance against self di-gestion, while still in the pancreas, pancreatic juice con-tains protease inhibitors, which become inactive in theintestine Table 17-1 lists some of the more importantpancreatic enzymes

I’m tired of all this nonsense about beauty being only skin-deep That’s deep

enough What do you want—an adorable pancreas?

JEAN KERR (1923–2003), U.S AUTHOR AND PLAYWRIGHT, MIRROR, MIRROR ON THE WALL

BACK TO BASICS

424 Part 2 • Diseases of Organ Systems

THE HORMONAL (ENDOCRINE) PANCREAS

The hormonal (endocrine) pancreas constitutes a small

fraction of pancreatic mass and is composed of

thou-sands of tiny islets of Langerhans scattered throughout

the gland The islets are clusters of cells not connected

to the ductal system, and they secrete hormones

di-rectly into blood Hormones are chemical compounds

made in organs or tissues that act on other organs or

tis-sues to stimulate or suppress them The most important

cells in the islets are:

• Alpha cells: secrete glucagon, a hormone whose main

function is to stimulate liver output of glucose by

converting glycogen to glucose and forming glucose

from amino acids; at very high concentrations it also

stimulates breakdown of fat for energy

• Beta cells: secrete insulin, a hormone that stimulates

cell uptake of glucose from blood, thereby lowering

blood glucose levels

• Delta cells: secrete somatostatin, a hormone that

in-hibits glucagon and insulin secretion and slows

peri-stalsis in the gastrointestinal and biliary systems

As is illustrated in Figure 17-3, the level of blood

glu-cose is controlled by the opposing effects of insulin and glucagon, the two most important islet hormones.

The most important pancreatic hormone is insulin, a

“gatekeeper” hormone that acts on muscle and othercell membranes to allow glucose to enter cells, wherethey can be burned for energy A mutual push-pull re-lationship exists between insulin and glucose—a highblood level of glucose causes increased pancreatic se-cretion of insulin; a low level of blood glucose causes adecrease in insulin secretion For example, an injection

of insulin forces blood glucose levels down because itallows glucose to leave blood and enter cells Likewise,

as blood glucose level rises after a meal, the pancreas cretes more insulin to lower it Moreover, vigorous ex-ercise burns glucose, lowering blood glucose levels anddecreasing beta-cell release of insulin

se-A similar but less strong push-pull relationship exists

between blood glucose and glucagon It is convenient to

think of glucagon as a “backup” system that releases ergy from body stores First, glucagon stimulates theliver to convert stored glycogen (Chapter 16) to glucose

en-Portal vein Splenic vein

Stomach

Peritoneal cavityPeritoneum

Superior mesentericartery

Aorta

SpleenPancreas

Left kidney

Renal vein

Inferiorvena cava

Right kidneyDuodenum

Retroperitoneal fat

Liver

Commonbile ductPancreatic duct

IntestineIntestine

Figure 17-1The pancreas and its anatomic relationships Cross-section of the upper abdomen.

Chapter 17 • Diseases of the Pancreas

and to form glucose from amino acids For example, in

starvation or prolonged fasting, a drop in blood glucose

level forces the pancreas to secrete glucagon, which

causes liver glycogen to be turned into blood glucose

Second, at high levels glucagon stimulates the

break-down of fat to be used as an energy source if glucose isnot available, as occurs with starvation or fasting, orwith insulin deficiency (diabetes), when cells cannotburn glucose because glucose cannot get into cells to beburned

Duodenum

Bile ductsfrom liverCystic ductCommonbile duct

Pancreas

Gallbladder

Ampulla of Vater

Islet of Langerhans(endocrine)

Pancreatic acinus(exocrine)

Alpha cell,secretesglucagon

Pancreatic duct

Pancreatic islet(of Langerhans)

Pancreatic juice

Zymogen granules(inactive protease enzymes

To pancreatic duct and duodenum

Glucagon Insulin

Bloodvessel

AmylaseLipase

Inactiveprotease

Beta cell,secretesinsulin

Figure 17-2Anatomic detail of the pancreas.

426 Part 2 • Diseases of Organ Systems

Skeletalmuscle

Glucose stored as liver and muscle glycogen

Alpha cells

of islets ofLangerhans

Increased output of glucose from liver

Energy (food) intake

Blood glucoseBlood glucose

The Relationship of Blood Glucose to Insulin, Glycogen, and Glucagon

E

En nz zy yme Z Zy ym mo ogen n

((A Accttiiv ve e F Fo orrm m)) ((IInaccttiiv ve e F Fo orrm m)) A Accttiio on n

Trypsin Trypsinogen

Chymotrypsin Chymotrypsinogen

Elastase Proelastase

carbohydrates

Enzymes in Pancreatic Juice

Table 17-1

Figure 17-3Glucose, glycogen, insulin, and glucagon metabolism.

Of lesser importance is somatostatin, which inhibits

the secretion of insulin and glucagon and slows stalsis in the gastrointestinal and biliary systems.These inhibitory actions guarantee that food is ab-sorbed slower rather than faster, and ensure that glu-cose derived from food is not used too quickly by tis-sues and is available for use over a longer period oftime Somatostatin is also secreted by the pituitarygland (Chapter 18) and inhibits the activity of growthhormone

Chapter 17 • Diseases of the Pancreas

Diseases of the Digestive

(Exocrine) Pancreas

A few congenital conditions affect the pancreas and are

mentioned here because the digestive pancreas

consti-tutes most of the pancreatic mass In about 5% of

peo-ple, the pancreas has two ducts instead of one In these

people, one of the ducts usually drains only a small part

of the pancreas and empties directly into the

duode-num The other duct drains most of the pancreas but is

often too small for the job, predisposing to duct

ob-struction and chronic pancreatitis

Annular pancreas is a congenital deformity in which

the head of the pancreas encircles the duodenum and

may cause duodenal obstruction

Ectopic pancreas is embryologically misplaced but

histologically normal pancreas that has come to rest in

an abnormal place These “rests” occur in about 2% of

people and are usually less than a centimeter in

diame-ter They occur most often in the submucosa of the

stomach and bowel and are rarely symptomatic

PANCREATITIS

Acute pancreatitis is acute inflammation of the

pan-creas Chronic pancreatitis is repeated episodes of

acute pancreatitis that destroys and scars the pancreas

Figure 17-4 depicts the causes and mechanisms of

in-jury in acute pancreatitis

Acute Pancreatitis

In Annals of Surgery in 1925, in elegantly descriptive

language missing from modern medical literature, Dr

B Moynihan wrote of acute pancreatitis as

the most terrible of all calamities that occur in connection with the abdominal viscera The sudden- ness of its onset, the illimitable agony which accompa- nies it, and the mortality attendant upon it render it the most formidable of catastrophes.

Normally pancreatic juice flows smoothly out of theductal system and into the duodenum Along the way avery small amount, not enough to do damage, diffusesinto interstitial fluid and into blood If more than asmall amount of pancreatic juice finds its way fromducts into the substance of the gland, self-digestion ofglands, nerves, and blood vessels can occur, causingpain, bleeding, and release of additional enzymes thatdigest additional tissue in a vicious circle

Conditions known to be associated with acute creatitis are listed below in order of frequency (see alsothe nearby History of Medicine box, as well as CaseStudy 17-1 at the end of this chapter):

pan-• Gallstones About half of patients with acute atitis have gallstones (Fig 17-5), and half of these pa-

pancre-tients suffer a second attack of pancreatitis if thestones are not removed

• Alcoholism About two thirds of cases are associated

with chronic alcohol abuse It appears that alcoholicshave long-standing, smoldering subclinical pancre-atitis that may suddenly flare into acute pancreatitisfor uncertain reasons

• Unknown (idiopathic) About 10% of cases have no

known underlying cause

• Other causes The list is long and includes virus

in-fections of the pancreas (mumps, for example), blunttrauma to the upper abdomen, thiazide diuretics andother therapeutic drugs, high blood levels of lipids(especially high levels of triglycerides), and high lev-els of blood calcium (hypercalcemia)

The initial lesion of acute pancreatitis is composed ofmultiple areas of edema, congestion, and acute inflam-mation As autodigestion progresses, these foci becomeprogressively inflamed, begin to bleed, and becomenecrotic and painful (Fig 17-6) In its most severe

form—acute hemorrhagic pancreatitis—bleeding is

extensive, and the entire pancreas can be destroyed Acommon outcome in survivors is the formation of a cyst

MAJOR DETERMINANTS OF DISEASE

• The pancreas is an integral part of the tive process, especially fat digestion

diges-• Disease affecting the digestive function of thepancreas usually does not affect the insulin-producing capacity of the pancreas

• Normally, pancreatic digestive enzymes arenot activated until they reach the duodenum

Premature activation of enzymes causes thepancreas to self-digest, which is a major factor

in the development of acute pancreatitis

• The common bile duct from the liver passesthrough the head of the pancreas and may beobstructed by disease in the pancreas

• The pancreas is isolated from other tures; pancreatic malignancies can grow formany years without causing symptoms

struc-Of patients with acute pancreatitis, half have gallstones and two thirds abuse alcohol.

428 Part 2 • Diseases of Organ Systems

LipaseAmylase

Protease

Pancreatic acinus

Pancreatic duct

Increased bloodamylase and lipase

Enzyme leakage

ProteaseLipase

Acinar cell injury

• Gallstones in common bile duct

• Thick mucus of cystic fibrosis

Figure 17-4The pathogenesis of acute

pancre-atitis Acinar injury or duct obstruction releases

en-zymes into tissue, where the enen-zymes digest fat and

Figure 17-5Acute pancreatitis Dissection of esophagus, stomach,

duodenum, gallbladder, and pancreas The gallbladder is full of stones, and the surface of the pancreas is covered with an acute in- flammatory exudate Gallstones are an important cause of pancreatitis.

gall-by the fibrous “walling off” of inflammatory fluid andedema Such cysts can be quite large and are termed

pancreatic pseudocyst (“pseudo” because the cyst has

no lining epithelium)

A typical patient with acute pancreatitis presentswith severe upper abdominal pain radiating through tothe back The disease may progress rapidly to cata-strophic vascular collapse and shock, caused by pooling

of blood and edema in the abdomen Renal failure(Chapter 19) and acute respiratory distress syndrome(Chapter 14) often develop In half of patients, thebloody mass of necrotic tissue becomes infected by in-testinal bacteria, increasing mortality