Chapter 4

DISEASES OF THE LIVER, GALL BLADDER AND EXOCRINE PANCREAS

CONTENTS

DISEASES OF LIVER Normal histology Necrosis . (Inflammation (hepatitis Cirrhosis Portal hypertension Jaundice Suppuration Tumors .Hepatomegaly Hepatic failure DISEASES OF GALL BLADDER Cholcystitis (acute & chronic) Mucocele (hydrops) Cholesterlosis Gall bladder stones (cholelithiasis) Tumors DISEASES OF EXOCRINE PANCREAS Pancreatitis (acute & chronic pancreatitis) Cancer of exocrine pancreas

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Diseases of the Liver, Gall Bladder and Exocrine Pancreas

DISEASES OF THE LIVER

BACKGROUND: NORMAL HISTOLOGY 1. Hepatic lobule: A hexagonal lobule centered around the central vein (CV or terminal hepatic venule). At the periphery portal tracts(PT) are seen occupying three of the lobule apices.The hepatic lobule is divided into regions according to their proximity to CV or PT. these are: known as the "periportal, midzonal and centrilobular" regions. 2. The hepatic acinus: is a triangle of hepatic lobule the base of which reveals branches of the portal vein penetrating hepatic parenchyma. Acini are divided into three zones according to their distance from the blood source: zone 1 closest to vascular supply followed by 2 and 3 (closest to the central vein).

Acinar Zones 3 2 1

M -z n l id oa

C n b la e trilo u r

P rip rta e o l
M g aA s f ad sa

Figure (4.1) : Diagrammatic representation of hepatic lobule and hepatic acinus

HEPATIC INJURY
It is a spectrum of changes that starts by hepatocyte degeneration followed by necrosis and eventually fibrosis

HEPATIC DEGENERATION and CELLULAR ACCUMULATION: 1. Ballooning degeneration 2. Intracellular accumulation: of substances in viable hepatocytes, like: a. Steatosis "microvesicles or macrovesicles of fat" (e.g. HCV, Alcoholic hepatitis,..) b. Iron : as in hemochromatosis c. Retained biliary material (cholestasis): as in biliary cirrhosis HEPATIC CELL DEATH: any significant hepatic injury might cause:
1. Apoptosis 2. Coagulative (ischemic) necrosis

1- APOPTOSIS: isolated hepatocytes become shrunken, eosinophilic with either absent or

pyknotic nuclei. These apoptotic cells are known under several terms including " apoptotic bodies, acidophil bodies or councilman bodies" (revise General pathology) 2- COAGULATIVE NECROSIS: Definition: It is coagulative (ischemic) necrosis of hepatic tissue. Types: Hepatic necrosis is classified, according to the extent and distribution of necrosis into: a- Focal necrosis: Affects small groups of hepatocytes of some lobules. e.g Typhoid fever and phenylbutazone drug b- Zonal necrosis: Affects a particular zone in most hepatic lobules, either: a- Central (Centrilobular): Affects central zones (e.g. C.V.C and viral hepatitis). b- Middle (Midzonal): Affects mid zones (e.g. Yellow fever) c- Peripheral (Periportal): Affects periportal zones (Eclampsia & phosphorous poisoning). 110

Diseases of the Liver, Gall Bladder and Exocrine Pancreas

c- Diffuse necrosis: Affects wide areas of hepatic tissue including many lobules (e.g Fulminant viral hepatitis [acute yellow atrophy], carbon tetrachloride and arsenic poisoning) .

FEATURES OF NECROSIS: Focal and zonal necrosis a- Show post-necrotic changes followed by removal of debris. b- Reticulin framework of necrotic area does not collapse. Hepatocytes regenerate and the
normal pattern is restored within 2-3 weeks.

Diffuse necrosis
Massive necrosis with collapse of the supporting reticulin framework Table (4.1) : SUMMARY OF HEPATOCYTE NECROSIS Type of necrosis Focal necrosis Zonal necrosis Affected area Small foci in some lobules a. Central zone b. Middle zone c. Peripheral zone 3 Diffuse necrosis Wide areas of many hepatic lobules Examples Typhoid fever CVC, viral hepatitis Yellow fever Eclampsia, phosphorus poisoning Fulminant viral hepatitis Effect Nonsignificant +/- toxic jaundice

1 2

Toxic jaundice, hepatic failure, death

ACUTE YELLOW ATROPHY

Definition: Diffuse hepatic necrosis. Causes: 1. Infection: Fulminated viral hepatitis 2. Poisoning: Carbon- tetrachloride, chloroform, halothane, arsenical drugs and
insecticides. 3. Nutritional deficiency: Deficiency of methionine, cystine and cysteine in diet.

Pathology: Gross picture: 1. Size &weight: Reduced

2. Consistency: Soft (massive necrosis) 3. Capsule: Wrinkled capsule and subcapsular hemorrhages. 4. Cut section: Yellow degenerative areas stained with bile and red areas of hemorrhage.

Microscopic picture: 1-Hepatic lobules: Massive necrosis in most lobules, some lobules show peripheral
intact hepatocytes.

2-Sinusoids: - Dilated and congested. 3-Portal tracts: - Infiltrated by mononuclear inflammatory cells.
Effects: Mainly death within days or development of post-necrotic cirrhosis.

HEPATITIS
Definition: Inflammation and injury of liver. Causes: a. Infections:
-Bacterial: T.B., typhoid fever, syphilis. -Viral: Hepatotropic viruses(A,B,C,D,E), cytomegalovirus, Epstein Barr virus, herpes and rubella Viruses 111

Diseases of the Liver, Gall Bladder and Exocrine Pancreas

-Fungal: actinomycosis and candidiasis. -Parasitic: Bilharziasis, amoebiasis, hydatid disease b. Other causes: e.g. drugs, irradiation, ..etc.

ACUTE VIRAL HEPATITIS Definition: Acute infectious necro-inflammatory disease ,caused by hepatotropic viruses ,
and presented with necrosis more than inflammation .All produce similar clinical and morphological changes in acute hepatitis but they vary in their potential to produce a carrier state ,chronicity or fulminant disease. Types: It is either Epidemic or sporadic Etiological types: 1-Infectious hepatitis :-Infection occurs by ingestion of contaminated food or water .Incubation period is 3-6 weeks 2-Serum hepatitis :- Virus is transmitted by blood transfusion or contaminated needles of syringe . Incubation period is 3-4 months. The hepatitis viruses involved are: HAV, HBV, HCV, HDV, HEV (HGV is not pathogenic that is why it will not be included) A comparison is presented in the table where the type of virus (DNA or RNA), mode of disease transmission (Fecal- oral or parentral), the incubation period (IP) of the disease, the presence or absence of a carrier state, the possibility of chronicity on top of acute viral infection and the possible malignant potential. The main characteristic features of these viruses are presented in Table (4.2). Table ( 4.2) : HEPATITIS VIRUSES VIRUS Hepati B tis A Type RNA DNA Transmis FecalParenter sion oral al, Sexual Mean IP 2-4 1-4 weeks months Carrier none 0.1-1% state Chronicity None 10% C RNA Parent eral 7-8 weeks 0.2-1% About 80% D RNA Parenteral 1-4 months 1-10% 5% coinfection <70% superinfecti on +/IgM or IgG Ab HDV RNA serum HDV AG liver E RNA Fecaloral 4-5 weeks ? None

Cancer Diagnosis

No Serum IgM Ab

Yes HBs Ag or Ab to HBc Ag

Yes PCR for HCV RNA

? PCR for HEV RNA Serum IgM& IgG Ab

Ab= antibody, Ag= Antigen, HBc Ag= hepatitis B core Antigen, HBs Ag= Hepatitis B surface antigen

PATHOLOGICAL FEATURES OF VIRAL HEPATITIS:

I-EARLY STAGE: Grossly: examination of the liver reveals: 2. Size and weight : Increased 112

Diseases of the Liver, Gall Bladder and Exocrine Pancreas 3. 4. 5. 6. 7.

Surface : Smooth Capsule : Tense Consistency : Firm Borders : Sharp Color : Greenish

Microscopically: 1-Hepatocytes: 1. Degeneration: hydropic &ballooning degeneration of hepatocytes in central zones.

Fatty change is seen in HCV infections 2. Necrosis, either in the form of: - Focal hepatocyte necrosis, - Massive centrizonal necrosis, or - Extensive necrosis reaching the portal tract 3. Apoptosis: Some hepatocytes form apoptotic (councilman) bodies. 2-Inflammatory infiltrate: composed of Lymphocytes, plasma cells, macrophages and eosinophils. The inflammatory cells are found in portal tracts and around necrotic cells. 3-Cholestasis: within both hepatocytes and bile canaliculi. II-LATE STAGE:

Grossly:
The liver becomes smaller than normal and yellowish.

Microscopically: 1. Evidence of hepatocytes regeneration as revealed by double or even multinucleation

with increased mitotic activities. 2. Kupffer cells: Are hyperplastic and contain bile and lipofuscin granules. 3. Inflammatory cells: Lymphocytes, plasma and macrophages in portal tracts. III-HEALING STAGE: Commonly, there is restoration of the normal state or fibrosis if the stroma is collapsed.

CLINICAL MANIFESTATIONS OF VIRAL HEPATITIS:

1-PRE-ICTERIC STAGE:a. Fever, anorexia, nausea and vomiting. b. Pain in epigastrium, muscles and joints c. Sometimes skin rashes d. Hepatomegaly and tenderness 2-ICTERIC STAGE:Presented by jaundice

FATE AND COMPLICATIONS: 1. Complete recovery in 95% of cases within 4-6 weeks 2. Acute fulminating hepatitis and death within 10 days (acute yellow atrophy) 3. Chronic hepatitis and cirrhosis especially with HBV and HCV
4.

5.
6.

Carrier state. Aplastic anemia Hepatocellular carcinoma

FULMINANT HEPATITIS (Syn.: Acute massive liver necrosis or Yellow atrophy) Definition: Acute fulminant hepatic failure, rapidly progressing to hepatic encephalopathy in 23 weeks.

Etiology: 1. Viral hepatitis 2. Drugs: large doses of acetaminophen, anti- TB drugs and others
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Diseases of the Liver, Gall Bladder and Exocrine Pancreas 3. Ischemic hepatic necrosis, hepatic vein obstruction or malignant infiltration Morphology:
Gross: red, shrunken liver with wrinkled capsule. Cut Section: Necrotic red foci with bile stained areas. Microscopy: Early: preserved framework and portal tracts with mild inflammation. Later: massive destruction (massive necrosis) with influx of inflammatory cells to clean up the necrotic areas

Fate: -Intact reticulin framework: regeneration and orderly arranged architecture -Massive destruction: disorder regeneration and scar with possible macro-nodular cirrhosis.

CHRONIC HEPATITIS
Definition:
Symptomatic, biochemical or serologic evidence of continuing hepatic disease for more than six months with histologically documented inflammation and necrosis.

Causes of chronic hepatitis:

1. Cryptogenic (unknown cause) 2. Viral infection (HBV&HCV infections) 3. Metabolic disorders: e.g Wilson`s disease and Alpha-1 antitrypsin deficiency 4. Chronic alcoholism 5. Drug reaction 6. Auto-immune (lipoid) hepatitis: These patients also have other autoimmune diseases as auto-immune thyroiditis

Microscopically: a- Hepatocytes:
-Ballooning degeneration and steatosis (esp. in HCV and alcoholic hepatitis) -Cholestasis

b- Inflammatory reactions:
-Portal tracts are expanded by lymphocytes, plasma cells and macrophages ,that may extend into the lobules. -Walls of bile ducts may be inflammed.

c- Necrosis:
Patterns of necrosis in chronic hepatitis are: 1. Apoptosis: detected in the form of councilman bodies (acidophil bodies) 2. Confluent necrosis: Necrosis ranging from perivenular hepatocyte necrosis (Hepatocytes around the central vein are replaced by mononuclear cells), to bridging necrosis (bridging between two portal tracts or between a portal tract and a central vein), to complete parenchymal collapse. 3. Piece meal necrosis (Interface hepatitis): this is necrosis at the interface between inflammatory portal tract and the periportal parenchyma (limiting plate).

C n l -c n l e tra e tra

P rta -p rta o l o l
M g aA s f a d sa

C n l -p rta e tra o l

M g aA s f a d sa

Fig. 4.2: Types of bridging fibrosis 114

Diseases of the Liver, Gall Bladder and Exocrine Pancreas

.d- Fibrosis: It is an Irreversible event in response to inflammation 1st it is limited, then it progresses to bridging fibrosis. Stages of fibrosis are: 1- Portal fibrosis: Portal tracts are expanded by excessive fibrosis. 2- Bridging fibrosis: Fibrous bridges between portal tracts or portal tracts and central veins 3- Bridging fibrosis (Fig. 4.2) 4- Cirrhosis: Regenerating nodules surrounded by scar tissue.

Cirrhotic nodules

Bridging fibrosis

Figure (4.3): Bridging fibrosis and Cirrhotic nodules GRADING AND STAGING OF CHRONIC HEPATITIS Grading: It refers to the degree of necrosis and inflammation in hepatic lobules (activity) Staging : It refers to the extent of fibrosis in portal tracts (fibrosis) There are several scoring systems adopted to grade and stage a hepatic biopsy. The SCHEUER classification was formerly used. Nowadays there are two more commonly used systems, namely: METAVIR SCORING SYSTEM and THE MODIFIED ISHAK SYSTEM

Figure (4.4):BattsLudwig diagrams of necroinflammatory activity. All grades of activity contain portal inflammation (a defining feature of chronic hepatitis and not

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Diseases of the Liver, Gall Bladder and Exocrine Pancreas

assessed separately from other necroinflammatory lesions) (ac) Activity grades 1 through 3. Confluent necrosis, in the form of bridging necrosis, is present only in activity grade 4 (d)

Figure (4.5):BattsLudwig diagrams of progression of fibrosis in chronic hepatitis The panels portray stage of disease with (a) portal tract fibrosis, (b) fibrotic septa extending from portal tracts and focally linking them, (c) a transition to cirrhosis where some of the tissue shows regenerating nodularity completely bounded by scar, and (d) fully established cirrhosis. In a needle biopsy specimen, (c) may translate to a portion of the needle core with such nodularity, but other areas without this change Table (4.3):Scheuer classification for grading of chronic hepatitis

S h u r c s ific tio fo ga in a ds g go c r n h p titis c e e la s a n r r d g n ta in f h o ic e a e o tiv L b la a tiv o u r c ity G d P rtal/ p rip rtal ac ity ra e o
0 1 2 3 4 N one Porta infla m tion l m a Mild pie ea ne is cem l cros Mod ra pie e te cem a ne is e l cros S v re pie m l ne is ee ce ea cros N one Infla m tion b no necros m a ut is F a ne is or a op b oc l cros cid hil odie s S v foca cell d m g e ere l a ae D m g includ brid ing ne is a ae es g cros

Sa e tg
0 1 2 3 4

F rs ib o is
None E rg , fibroticporta tra nla ed l cts Pe riporta or porta -porta s pta but in ct a l l l e , ta rchite cture Fib is w a ros ith rchitectura dis l tortion, b no obv ut ious cirrhosis Prob bleor d finite cirrhos a e is
Ma daAssaf g 30

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Diseases of the Liver, Gall Bladder and Exocrine Pancreas

CIRRHOSIS
Definition:
A chronic, diffuse, progressive and irreversible liver disease, characterized by: 1. Degeneration and necrosis of hepatocytes 2. Repair by regeneration with formation of nodules that lack normal pattern. 3. Fibrosis and chronic inflammation . 4. Disturbed vascularity of the liver.

CLASSIFICATIONS OF CIRRHOSIS A. ETIOLOGICAL CLASSIFICATION(According to the cause): 1-Primary (cryptogenic) cirrhosis 2-Secondary cirrhosis:a. Portal cirrhosis: Laennecs cirrhosis (nutritional, alcoholic) Post- hepatitic cirrhosis Post- necrotic cirrhosis Biliary cirrhosis (primary & secondary) Cardiac cirrhosis Cirrhosis on top of metabolic disorders: Hemochromatosis ( Bronzed diabetes) Wilsons disease -1 antitrypsin deficiency Syphilitic cirrhosis

b.
c.

d.

e.

B. MORPHOLOGICAL CLASSIFICATION (According to the size of the regenerating nodules): 1-Micronodular cirrhosis: The size of nodules ranges from 1-2mm in diameter .It is usually
seen in Laennec`s and biliary cirrhosis . 2-Macronodular cirrhosis:The nodules are larger and their diameters range from 3-5 mm in diameter .It seen in post -hepatitic and post-necrotic cirrhosis. 3-Mixed micro and macronodular cirrhosis: It contains mixed micro-and macronodules.

MORPHOLOGY: Gross picture: the liver reveals: Size: Reduced (possibly enlarged in biliary cirrhosis) Weight: Decreased (can be increased in biliary cirrhosis). Consistency: Firm. Borders: Sharp Outer surface and cut section: Shows variable sized nodules, with different colors. - Green in biliary cirrhosis - Dark brown in hemachromatosis - Pale in alcoholic cirrhosis. - Nodules are separated by whitish, fibrous bands with variable thickness (thin in
micronodular cirrhosis and thick in macronodular cirrhosis). Microscopic picture: 1-Normal Liver architecture is lost 2-Liver cells: diffuse degeneration and necrosis of hepatocytes 3- Regenerating nodules: - Variable in size and shape - Eccentric or absent central veins - Surrounded by fibrous tissue infiltrated by lymphocytes of variable intensity

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Diseases of the Liver, Gall Bladder and Exocrine Pancreas

4-Portal tracts: Show chronic inflammatory cells, expanded by fibrosis with proliferating bile ducts.

PATHOGENESIS:
The development of hepatic fibrosis reflects an alteration in normal balance between extracellular matrix production and degradation. Extracellular matrix is composed of collagens (types I&III), glycoproteins, and proteoglycans. Stellate cells (Ito cells), located in the peri-sinusoidal space of Disse (the space between hepatocytes and sinusoids), are essential for the production of extracellular matrix. These cells become activated into myofibroblasts (collagen-forming cells) by a variety of factors released by hepatocytes, Kupffer cells, and sinusoidal endothelium following liver injury. These factors include TGF-, IL-1 and TNF. Increased collagen deposition in the space of Disse with diminution of the size of endothelial fenestrae leads to capillarization of sinusoids. Activated stellate cells also have contractile properties leading to constriction of sinusoids. Both capillarization and constriction of sinusoids by stellate cells contribute to the development of portal hypertension, as well as, to more hepatic necrosis and fibrosis .

TYPES OF CIRRHOSIS:
LAENNEC`S CIRRHOSIS: [Synonyms: Nutritional Cirrhosis, Alcoholic Cirrhosis]

Causes: Severe prolonged malnutrition, or alcoholism. Pathogenesis:

1. Severe choline deficiency in malnutrition Steatosis & hepatocyte injury necrosis of hepatocytes 2. Ethanol, its toxic metabolites and O2 free radicals cause steatosis & hepatocyte injury.

Gross:
Shrunken liver, yellowish in color and shows the picture of micronodular cirrhosis

Microscopic:
Hepatocytes in micronodular cirrhotic nodules showing ballooning degeneration ,steatosis and Mallory bodies . Hepatocytes necrosis ,excite neutrophilic infiltrate . This picture progress to pericellular fibrosis. Fibrosis also centered around central veins obliterate it and fibrous bridges between hepatic venules occurs.

BILIARY CIRRHOSIS
A- PRIMARY BILIARY CIRRHOSIS (Intra-hepatic biliary obstruction): -It commonly affects middle aged women (Female: Male = 9:1).

Etiology and pathogenesis:

- An autoimmune disorder (commonly associated with other autoimmune diseases). - Over 90% of patients have anti-mitochondrial antibodies in their serum; 5% of cases have antinuclear and anti-smooth muscle antibodies. - A continuous destruction of small and medium sized bile ducts occurs, which is mediated by activated CD4 and CD8 T- lymphocytes. Subsequent to the loss of the intra-hepatic bile ducts, a disruption of the normal bile flow occurs with retention and deposition of toxic substances, which are normally excreted into bile. The retention of toxic substances, such as bile acids and copper, can cause a further secondary destruction of bile ducts and hepatocytes.

Pathology:
Gross: Liver is enlarged and dark green in color (bile stasis). Regenerating nodules are micronodules. Microscopic: 1-The early changes are chronic granulomatous inflammation in portal tracts centered around bile ducts, destroying them and the limiting plates. 118

Diseases of the Liver, Gall Bladder and Exocrine Pancreas

2-Progressive inflammation and fibrosis spreads from portal tracts to the liver parenchyma. 3-Bile stasis is concentrated in the peripheral zonal hepatocytes (peripheral cholestasis). Ruptured hepatocytes and bile canaliculi which are distended with bile add to the inflammation and fibrosis. 4-Fibrosis is regular, interconnecting portal triads and may encircle single or multiple lobules forming cirrhosis.

Prim ary biliary cirrhosis

Destroy bile ducts ed Lm y pho& plasm cells a around bile ducts Periportal fibrosis

M Assaf .

Extend to hepatocy tes A ccumof bile In canaliculi

O bstruction of bile flow

Peripheral cholestasis

Figure (4.6): PRIMARY BILIARY CIRRHOSIS

Clinical manifestations:
1- Patients, typically, present with fatigue 2-Itching (due to bile salts retention) 3-Jaundice 4-Hyperlipidemia

Effects:
1-Obstructive jaundice 2-Malabsorption 3-Later on portal hypertension B. SECONDARY BILIARY CIRRHOSIS (Extra-hepatic biliary obstruction) Etiology: causes of extra-hepatic biliary obstruction include: 1-Choledocal cyst 2-Gall stone impacted in common bile duct 3-Congenital stenosis of bile duct 4-Pressure by enlarged lymph node 5-Cancer head of pancreas 6-Cancer of common bile duct or ampulla of Vater

Pathology
Gross picture: as primary biliary cirrhosis Microscopic picture: 1-Extra-and intra-hepatic bile ducts cholestasis 2-Neutrophilic infiltration of bile ducts followed by bile duct proliferation 3-Picture of cirrhosis

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Diseases of the Liver, Gall Bladder and Exocrine Pancreas

D

S econ ary d

b iliary

cirrh sis o
B du h perp ile ct y lasia M ixed p ortal in filtrate

C tral cho en lestasis S readin o tw p g u ards

N ecro bile tic, -lad en hepato tes cy fib siscirrh ro osis

Figure (4.7): SECONDARY BILIARY CIRRHOSIS

Clinically: As in obstructive jaundice. Complications of liver cirrhosis:

1-Liver cell failure 2-Portal hypertension 3-Ascites 4-Hepatocellular carcinoma

PORTAL HYPERTENSION
Definition:
Increased blood pressure in portal circulation due to increased resistance to portal blood flow

Etiology: Portal hypertension is caused by: 1. Prehepatic causes:a. Obstruction of portal vein by thrombus. b. Increased splenic venous blood flow to the liver.

2. Hepatic causes:a. Cirrhosis: Hepatic veins are compressed by regenerating nodules b. Anastomotic channels between portal veins and hepatic arteries ,raise intravenous
blood pressure c. Hepatic fibrosis, due to bilharziasis ,sarcoidosis or T.B. d. Massive fatty change e. Veno-occlusive disease, that cause obstruction of hepatic venules

3. Post-hepatic causes:a. Budd-Chiari syndrome :Obstruction of both hepatic veins b. Right sided heart failure.

Effects and complications:1-Spenomegaly: Due to CVC of spleen and hypersplenism with subsequent pancytopenia 2-Opening of normally closed collaterals: Between portal and systemic circulation as compensatory mechanisms to overcome portal obstruction, leading to: -Esophageal varices -Hemorrhoides (Piles) -Caput medusa (varicosities around umbilicus)

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Diseases of the Liver, Gall Bladder and Exocrine Pancreas

Figure (4.7): Opening of collateral circulation

3- Ascites: It develops terminally due to:- Portal hypertension causing increased lymphatic ooze from liver surface "weeping of liver" - Hypoproteinemia (hypoalbuminemia) - Sodium and water retention due to hyperaldosteronism.

4- Chronic venous congestion of the GIT: leading to dyspepsia and malabsorption.

JAUNDICE
BACKGROUND: Bilirubin metabolism and hyperbilirubinemia 1-The released hemoglobin from old RBCs gives rise to hem and globin. Globin fraction is reused in synthesis of new RBCs. while hem is oxidized into biliverdin which is reduced into bilirubin. 2-Bilirubin is bound to albumin forming (hembilirubin or unconjugated bilirubin) and is transported into the liver. 3-Bilirubin is conjugated with glucouronic acid by help of glucouronyl transferase enzyme to form conjugated bilirubin (cholebilirubin) . 4-Cholebilirubin is excreted through bile canaliculi to intestines and is excreted in stool as stercobilinogen which is reduced in the air giving rise to stercobilin, responsible for normal color of stool. 6-Cholebilirubin is reduced into urobilinogen by the help of intestinal bacteria. 7- 10- 20% of urobilinogen returns to the liver through portal vein to be excreted into the bile (entero-hepatic circulation).A small fraction escaping this circulation is excreted in urine and reduced forming urobilin, responsible for normal color of urine.

121

Diseases of the Liver, Gall Bladder and Exocrine Pancreas Causes of hyperbilirubinemia:
1-Causes of unconjugated hyperbilirubinemia: Excess production of bilirubin: e.g hemolytic anemias & hemolysis of RBCs in large sized internal hematoma. Reduced hepatic uptake of bilirubin: e.g drugs , some cases of Gilbert`s syndrome Impaired bilirubin conjugation: e.g Gilbert`s syndrome, Crigler-Najjar syndrome and cirrhosis. 2-Causes of conjugated hyperbilirubinemia: Decreased intrahepatic excretion: e.g Dubin Johnson syndrome, Rotter`s syndrome oral pills, biliary cirrhosis and sclerosing cholangitis. Extrahepatic biliary obstruction: Gall stones ,cancer head of pancreas or cancer ampulla or biliary atresia

JAUNDICE:
Definition:
It means yellowish discoloration of the skin and mucus membranes, due to hyperbilirubinemia where serum bilirubin is more than 2 mg/dl (N. up to 1.2 mg/dl).

Causes and types of jaundice: Causes: 1. Increased destruction of RBCs 2. Hepatic causes 3. Obstructive causes Types:
1-Hemolytic jaundice: caused by: -Increased hemolysis and excess production of bilirubin. 2-Hepatocellular jaundice: caused by: - Reduced uptake - Impaired conjugation - Decreased intra-hepatic excretion 3-Obstructive jaundice: It is caused by intra- and extra-hepatic biliary obstruction. Parameter Urine Color Bilirubin Van den Berg reaction Stool Blood Cholesterol Alk.phosphatas e Proth.time Transaminases Others Hemolytic jaundice Normal Absent Indirect Dark Normal Normal Normal Normal Enlarged spleen Anemia Reticulocytosis Hepatocellular jaundice Dark Increased Biphasic Paler than normal Decreased Increased Increased Raised Manifestations of liver cell failure Obstructive jaundice Dark Increased Direct Pale(clay colored) Increased Increased Increased Normal

Bradycardia Itching Steatorrhea Xanthoma Cholangitis Biliary cirrhosis Table (4.4): Clinical differences between different types of jaundice

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Diseases of the Liver, Gall Bladder and Exocrine Pancreas

Figure (4.9): Types of jaundice

HEPATIC SUPPURATIONS
LIVER ABSCESSES Types:1-Solitary liver abscess 2-Multiple liver abscesses

Solitary liver abscess

Causes: 1. Infected hydatid cyst 2. Amebic abscess 3. Penetrating wound 4. Extension of infection from empyema, subphrenic abscess and ascending cholangitis .

Multiple liver abscess 1. Actinomycotic abscess 2. Pyemic abscesses secondary to:a. Portal pyemia: - Infected hemorrhoids (piles) - Acute suppurative appendicitis - Diverticulitis b. Systemic pyemia 3. Suppurative cholangitis

HEPATIC CYSTS
Causes:1-Hydatid cyst 2-Congenital cyst. 3-Cyst in bile duct (choledecal cyst) 4-Congenital polycystic liver . 5-Bile duct cystadenoma 6-Retention cyst.

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Diseases of the Liver, Gall Bladder and Exocrine Pancreas

HEPATIC TUMORS
CLASSIFICATION: I-Primary tumors:
1-Benign tumors: a. Cavernous hemangioma (common) b. Adenoma from (liver cell & bile duct epithelium) 2-Malignant tumors:a. Hepatocellular carcinoma (Hepatoma). b. Bile duct carcinoma (cholangiocarcinoma) c. Hepatoblastoma d. Angiosarcoma. II-Secondary tumors:- Commoner than primary tumors.

HEPATOCELLULAR CARCINOMA Incidence: Etiology: Predisposing factors:

-It constitutes 90% of primary liver cancers. -It is common in males (40-60 Y) than in females.

1-Cirrhosis : post-necrotic or pigmented cirrhosis 2-Chronic hepatitis B & C 3-Alcoholic liver disease 3-Contaminated food with Aflatoxin (Aspergillus flavus toxin). Gross picture: The tumor mass is either: - Single, non capsulated with foci of necrosis, bile staining and hemorrhage. or - Multicenteric with multiple tumor nodules or - Large diffuse mass occupying the whole liver.
H p to a e a m,
M. Assaf

Pathology:

G s ro s

S lita , la e o ry rg

N d la ou r

D s iffu e

+h m rrh g &n c ss is e o a e e.A sf M roa

Figure (4.10): Gross pictures of HCC Microscopic picture:1-Well differentiated tumors consists of polyhedral malignant hepatocytes arranged in cord, groups or acini (pseudo-glandular pattern) and separated by little stroma. 2-Poorly differentiated tumor consists of undifferentiated cells, spindle cells or large anaplastic cells and multinucleated giant cells. 3-Bile secretion is a pathognomonic feature of hepatoma. FIBROLAMELLAR VARIANT: It is an uncommon variant (< 5%) especially occurring in children and young adults. It is of better prognosis after surgical removal. Microscopically: It composed of large polygonal malignant cells with hyaline and PAS positive cytoplasmic inclusions,forming trabeculae separated by dense fibrous stroma . It differs from conventional HCC by: 1. Usually no cirrhosis 124

Diseases of the Liver, Gall Bladder and Exocrine Pancreas 2. AFP is not raised 3. Commoner in females 4. HB infection is rare
Spread:

1. Intrahepatic spread within the liver: by branches of portal vein

2. Direct spread: To the ribs 3. Lymphatic spread 4. Blood spread: Through hepatic veins to the lungs. Effects :1. Enlarged, nodular liver 2. Hepatic failure and jaundice 3. Portal vein thrombosis 4. Inferior vena caval obstruction causing edema of lower limbs. Diagnosis:1. Liver biopsy is required. 2. High level of alpha-fetoprotein Note that increased levels of fetoprotein are also found in: 1-Certain gonadal tumors (teratoma and yolk sac tumors) 2-Liver damage (chronic hepatitis and cirrhosis, yet the level is not so highly raised)

HEPATOBLASTOMA
Rare malignant tumor of infancy and childhood Gross picture: Large tumor mass with extensive hemorrhage and necrosis. Microscopic picture: It contains mixture of immature hepatocytes with stroma showing mesenchymal differentiation (bone, cartilage, fibrous tissue, etc.). There is a high serum level of alpha-fetoprotein

SECONDARY TUMORS (LIVER METASTASES)

They are more common than primary tumors.

Sources:
1-Direct extension from carcinoma of gall bladder, stomach and colon 2-Through portal vein: From cancer stomach, intestine and pancreas. 3-Through hepatic artery: From cancer breast, malignant melanoma, lymphoma &renal cell Ca. 4-Through lymphatics: from the lung and breast.

Gross picture:
The liver is enlarged and shows multiple whitish nodules, variable in size and circumscribed. The superficial nodules show central depressions due to necrosis (umbilication).

Microscopic features: similar to the primary tumor Effects:1-Hepatomegaly 2-Ascites 3-Obstructive jaundice 4-Portal or inferior vena cava obstruction 5-Later on liver cell failure

HEPATOMEGALY
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Diseases of the Liver, Gall Bladder and Exocrine Pancreas Definition:

Enlargement of liver size

Causes:
1-Inflammation: a. Viral infection (hepatitis) b. Granulomas: T.B. syphilis, sarcoidosis and actinomycosis c. Parasitic diseases: Bilharziasis,leishmaniasis, malaria and hydatid disease d. Pyogenic infection :liver abscess. 2-Degenerative:a. Cloudy swelling and hydropic degeneration b. Fatty change c. Hemochromatosis d. Amyloidosis 3-Vascular disorders:a. Right sided heart failure b. Inferior vena cava obstruction, c. Budd-chiari syndrome d. Veno-occlusive disease 4-Metabolic disorders:a. Diabetes mellitus b. Glycogen and lipid storage diseases 5-Blood diseases: a. Polycythemia b. Leukemia 6-Malignant diseases:a- Primary malignant tumors b- lymphomas c -Secondaries

HEPATIC FAILURE
Definition:
Failure of liver to do its function " impaired liver function"

Etiology:
1. 2. 3. 4. Viral hepatitis (acute or chronic) Necrosis (zonal and diffuse) Liver cirrhosis Biliary obstruction Specific granuloma (military T.B.) Tumors (primary or secondary)

5.
6.

Manifestations: 1. Hypovitaminosis of:Vitamin A Night blindness Vitamin D Osteomalacia Vitamin K hypoprothrombinemia bleeding tendency Vitamins B12 & folic acid Megaloblastic anemia 2. Reduced liver glycogen storage Hypoglycemia 3. Reduced protein synthesis Hypoalbuminemia., hypofibrinogenemia and deficiency of clotting factors V,VII,XI and X Bleeding tendency 4. Fetor hepaticus: Rotten apple smell of the mouth due to methyl mercaptan derived from unmetabolized methionine 5. Hepatocellular jaundice (failure of bilirubin conjugation) 6. Hyperaldosteronism :- Salt and water retention edema &ascites. 7. Hyperestrogenemia: due to inability of liver to inactivate estrogen with the following effects: Male effects - Gynaecomastia - Atrophy of testes 126 - Feminine hair distribution

Diseases of the Liver, Gall Bladder and Exocrine Pancreas

Female effects - Atrophy of female breasts - Atrophy of ovaries Both sexes - Loss of libido - Infertility

- Menstrual disturbances - Spider nevi and plamar erythema

8-Hepatic encephalopathy: Ammonia produced in intestines by the action of bacteria on proteins, bypasses detoxification in liver and reaches the brain and causes degeneration of nerve cells. It is manifested by tremors, apathy, disorientation and finally coma. 9-Renal failure: Hepato-renal syndrome; caused by vasoconstriction in the renal cortex as a result of gut derived bacterial toxins, also increased thromboxane A2 by activated platelets and increased rennin and aldosterone secretions. 10-Anemia: due to -loss of blood as a result of bleeding piles and esophageal varices -Deficiency of vitamin B12 and folic acid -Hypersplenism 11- Ascites; (mentioned before)

---------------------------------------------THE GALL BLADDER

CHOLECYSTITIS
I- ACUTE CHOLECYSTITIS: Definition:
Acute inflammation of the gall bladder

Incidence:
It is common in middle aged females.

Etiology: 1. Chemical irritation: 90% of cases are caused by abnormal concentrated bile or gall
bladder stone obstructing the cystic duct or common bile duct .The chemical (sterile) inflammation opens the way to bacterial infection. 2. Bacterial infection: E.coli, streptococcus fecalis, staphylococcus aureus and typhoid bacilli reach the gall bladder through blood or common bile duct (ascending cholangitis). 3. Reflux of pancreatic enzymes: In some cases. 4. Ischemia: Inflammation arises in ischemic areas.

Pathology:
Gross picture: Gall bladder is swollen with hyperemic surface. The wall: Is thickened and edematous. The cavity: Is distended with turbid bile that contains pus and blood. Microscopic picture: acute inflammation can be: Catarrhal - suppurative or - gangrenous

Complications: 1. Empyema: If the neck of the bladder is obstructed 2. Necrosis and gangrene: Due to ischemia of the distended bladder and superadded
saprophytic infection. 3. Ruptured gall bladder: a. Septic peritonitis b. Enteric fistula c. Liver abscess 4. Ascending cholangitis 127

Diseases of the Liver, Gall Bladder and Exocrine Pancreas 5. 6.

Adhesions with the surroundings Chronicity: Chronic cholecystitis

II-CHRONIC CHOLECYSTITIS: Definition:

Chronic inflammation of the gall bladder

Etiology:
1-Follows acute cholecystitis 2- It commonly starts as a slow chronic process

Pathology:
Gross picture 1. Gall bladder is either small, fibrotic and contracted with exaggerated mucosal folds (if it is obstructed by a stone) or healthy and enlarged in size with absent mucosal folds (if it is obstructed by cancer head pancreas). 2. Wall is thickened and fibrotic with or without calcifications. 3. Lumen: Either distended with clear bile (hydrops) or mucus (mucocele) or contains stones 4. Surface: Fibrous adhesions Microscopic picture: 1- The mucosa: can present by one or more of the following pictures a. Flat and ulcerated b. Hyperplastic c. Squamous metaplasia 2- Submucosa and muscle layer: a. Infiltrated by chronic inflammatory cells. b. Marked histiocytic infiltration is called "xanthogranulomatous cholecystitis" c. Mucosal folds extend into the wall forming sinuses "Aschoff Rokitansky sinus" 3-Wall: reveals fibrosis

Complications: 1. Recurrent acute attacks on top of chronic cholecystits 2. Formation of gall bladder stones in 80-90% of the cases 3. Squamous metaplasia predisposes to development of carcinoma of the gall bladder.

MUCOCELE OF GALL BLADDER (HYDROPS)

-Bile in gall bladder is gradually absorbed and replaced by a clear, watery, mucinous excretion which distends the lumen. -Cause: Cystic duct is completely obstructed by a stone or kink or tumor

CHOLESTEROLOSIS
Grossly: The gall bladder mucosa shows numerous, small, yellow deposits simulating the
picture of "yellow seeds on the surface of strawberry" Microscopically: The mucosa contains aggregates of macrophages laden with cholesterol deposits and distending mucosal folds. - It may be accompanied with cholesterol stones (the detached distended mucosal folds may form a nucleus for stone formation).There is no hypercholesterolemia.

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Diseases of the Liver, Gall Bladder and Exocrine Pancreas

GALL STONES (CHOLELITHIASIS)

Incidence: - Gall stones are 2-5 times more common in fatty, filthy, fertile, females, round age of forty {5f} - Site: gall bladder and bile ducts Etiology: 1-Abnormal bile composition (cholesterol & bilirubin): a. Increased cholesterol concentration in blood or bile (e.g pregnancy, excess dietary
intake or familial). Bile salts become unable to keep cholesterol in solution and some will precipitate b. Increased bilirubin (bile pigment) in blood and bile in cases of hemolytic anemias.

2-Hpercalcemia:
Predisposes to formation of calcium carbonate stone

3-Infection of gall bladder (cholecystitis): a. Inflammation decreases bile salts formation and causes decreased motility of gall
bladder, leading to cholesterol precipitation and stone formation. b. Shed epithelial cells and pus cells act as nuclei upon which bile constituents will precipitate. 4-Bile stasis: this is caused by: a. Organic obstruction by stone b. Hormonal hypomotility of gall bladder in pregnancy Effects: Precipitation of bile constituents Stone formation Infection stone stasis (vicious circle)

Types of gall stones:

1. Metabolic (pure) stones a- Cholesterol stones b- Pigment stones 2. Calcium carbonate stones 3. Mixed stones 4. Combined stones Table (4.5): Characteristics of the different gall bladder stones
TYPE OF STONE % 7%

NUMBE R
Solitary

SIZE
1-5 cm

SURFACE & SHAPE

Mammillated, oval or round Irregular & oval Smooth, round or oval Faceted Irregular & round or oval

COLOR& CUT SECTION

Pale yellow, radiating glistening Dark core Homogenous Black or green Grayish white Mixture of colors. Laminated CS Mixture of colors, cholesterol nucleus, bile ppt

CONSIS TENCY
hard Soft& friable Hard Hard Firm

Cholesterol

Pigment

3%

Multiple Single or Multiple Always multiple Single or Multiple

>1cm small 1-2 cm 1-5 cm

Ca carbonate 10% Mixed Combined

70% 10%

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Diseases of the Liver, Gall Bladder and Exocrine Pancreas

Complications of gall stones:

1- Gall bladder affection: a. Acute or chronic cholecystitis. b. Fistula formation due to perforation of acutely inflamed gall bladder into adherent duodenum permits the stone to pass into the lumen causing acute intestinal obstruction. c. Squamous metaplasia of the surface epithelium due to chronic irritation. d. Malignant change. 2- Cystic duct obstruction causes: a- Empyema. b- Mucocele. 3- Common bile duct obstruction causes: a- Obstructive jaundice b- Cholangitis. c- Biliary cirrhosis. 4- Obstruction of ampulla of Vater causes acute hemorrhagic pancreatitis. 5- Biliary colic radiating to the right shoulder.

TUMORS OF THE GALL BALDDER

A-BENIGN TUMORS: a. Adenoma b. Papilloma d. Angioma d. Fibroma B-MALIGNANT TUMORS : a. Carcinoma (adenocarcinoma & squamous cell carcinoma ) b. Sarcoma c.Lymphoma d. Carcinoid tumor. c. Lipoma e. Leiomyoma

CARCINOMA OF THE GALL BLADDER Incidence: It is more common in females than males (4:1) at the age of sixty Etiology:
Chronic cholecystitis and gall stones are predisposing factors for malignant change

Pathology:
Gross picture: The tumor usually develops in the fundus and appears as:Polypoidal growth, or - Diffuse infiltrative mass Microscopic picture: a. Adenocarcinoma (most common) with different grades of differentiation b. Squamous cell carcinoma

Spread: 1. 2. 3. 4.

Direct spread to the liver Lymphatic spread: to cystic and periportal lymph nodes Blood spread: to the lungs Transcelomic implantation on omentum and peritoneum

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DISEASES OF THE EXOCRINE PANCREAS

PANCREATITIS:
TYPES: 1-Acute interstitial pancreatitis:
- The mild form is characterized by interstitial edema and inflammation

2-Acute necrotizing pancreatitis:

- Severe form characterized by necrosis of pancreatic parenchyma.

3-Acute hemorrhagic pancreatitis:

-The severest form characterized by hemorrhage in pancreatic parenchyma.

ACUTE HEMORRHAGIC PANCREATITIS Definition:

Acute inflammation of the pancreas caused by destructive action of pancreatic enzymes

Predisposing factors:
1-Gall stones 2-Acoholism 3-Shock 4-Trauma to pancreas 5-Infections: e.g mumps

Pathogenesis: The pancreas secretes pro-enzymes (inactive) enzymes (e.g proteases,

elastases and phospholipases) which require activation by trypsin enzyme in the duodenum. Amylase and lipase are secreted in active forms. The activated enzymes cause lipolysis and damage of elastic fibers of blood vessels leading to hemorrhage. The activated enzymes also convert pre-kallikerin to kallikerin that activate kinin and clotting systems leading to local inflammation and thrombosis.

The activation process occurs by:1-Obstruction of pancreatic flow : Causes of obstruction include: o Obstruction of ampulla of Vater by gall stone
o Spasm of sphincter of Oddi. o Pancreatic calculi. Mechanism of activation: o Impaction of stone causes bile reflux mixing of bile with pancreatic secretion leads to activation of pro-enzymes. o Obstruction leads to increased intra- ductal pressure rupture of fine ducts and release of pancreatic enzymes. 2-Reflux of duodenal juice: Into the pancreas results in activation of pro-enzymes. 3-Acinar cell injury by viruses, trauma and ischemia with subsequent release of enzymes

Pathological features:
1-Pancreas: a- Swollen, edematous and firm in early stages b- Necrosis of parenchyma and blood vessels leading to hemorrhage and the color becomes black and soft consistency 2-Omentum and mesentery: 131

Diseases of the Liver, Gall Bladder and Exocrine Pancreas

Pancreatic lipase splits fat into glycerol and fatty acids. Glycerol is absorbed and fatty acids combine with calcium to form calcium soap which appears as chalky white patches on the surface of omentum and mesentery. 3-Peritoneum: Show hemorrhagic exudate . 4-Pancreatic enzymes: Serum lipase and amylase are increased

Clinical manifestations:
1-Severe epigastric pain 2-Nausea, vomiting and fever 3- Shock

Complications:
1-Chronicity: recurrent mild attacks leading to chronic pancreatitis 2-Bacterial infection of necrotic tissues leading to localized or diffuse peritonitis 3-Pseudocysts in lesser sac 4-Diabetes mellitus in severe form 5-Shock 6-Usually fatal condition

CHRONIC PANCREATITIS Definition: It is a disease characterized by repeated mild attacks of acute pancreatitis and
replacement of pancreatic parenchyma by fibrous tissue .

Etiology:
1-Chronic alcoholism 2-Repeated acute pancreatitis 3-Biliary tract disease 4-Protein deficient malnutrition.

Morphology:
Pancreas is small, firm and nodular. Cut section: coarse bands of fibrous tissue, sometimes pancreatic calculi in ducts and cysts.

Effects:
1- Diabetes mellitus 3- Pseudocyts 2- Malabsorption and steatorrhea (bulky fatty stool). 4- Obstructive jaundice

CARCINOMA OF EXOCRINE PANCREAS

Etiology:
1- Peak age between 60-80 years 2- Heavy smoking and alcoholism. 3- High fat diets.

Distribution:
60% in head, 15-20% in body , 5% in tail and 20% diffuse involvement .

Gross picture:
a- Small ill- defined hard nodular growth b- Large with extensive invasion and metastasis

Microscopic picture: 1. Adenocarcinoma: Well defined mucus or non- mucus secreting adenocarcinoma
arising from the pancreatic duct epithelium(90%) and surrounded by extensive fibrosis. 2. Adenosquamous carcinoma 3. Anaplastic carcinoma

Biological behavior:
1-Spread: a. Direct spread : i- Carcinoma of head region infiltrate duodenum and common bile duct . 132

Diseases of the Liver, Gall Bladder and Exocrine Pancreas

ii- Carcinoma of body and tail regions infiltrate diaphragm ,left kidney ,adrenal and spleen. b. Lymphatic spread :To regional lymph nodes c. Blood spread : to liver and lungs d. Transcoelomic: to peritoneum. 2-Obstructive jaundice: in case of cancer head. 3-Venous thrombosis: due to release of tissue thromboplastin from necrotic tissue. 4-Ascites: due to portal vein thrombosis and peritoneal implants.

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