GIT Pathology-2

Hepato-Pancreato-Biliary
diseases
Dr. Wael Maher MD; PhD Dr. Dalia Magdi MD; PhD
A.Professor of pathology A.Professor of pathology
SRU, FOMSCU, KU SRU, ASU
Liver
 Liver

Alcoholic Liver Chronic Liver

General features
Normal Disease failure
of liver injury
 Blood flow from portal to CV through SINUSOIDS
• Fenestrated sinusoidal endothelium
• Rest on loose connective tissue (space of Disse’)

the hepatic sinusoids

Bile flow from central hepatocytes to Portal

 Assessment of general Functions of Liver

=SGOT
=SGPT

Hepatocytes synthesize:
fibrinogen, prothrombin, factor V, VII, IX, X, XI, XII,
protein C and S, antithrombin

Sinusoidal endothelial cells synthesize:

Factor VIII and von Willebrand factor.

PT…Ext.Pathway…(7,10,5,2,1)…tissue factor
PTT..Int.Pathway (12,11,9,8,10,5,2,1).
 Liver

Alcoholic Liver Chronic Liver

General features
Normal Disease failure
of liver injury
 General Features of Liver Disease
➢ Hepatocyte apoptosis (caspase cascades):
• Shrinkage, nuclear condensation, fragmentation (nuclear and cellular) into acidophilic apoptotic bodies.
➢ Ballooning degeneration
• Swelling of hepatocytes with pale cytoplasm. Leads to cell lysis and replacement by inflammatory cells

➢ NECROSIS
• Focal (Spotty) necrosis: Scattered hepatocytes, usually apoptosis
• Centri-lobular (Peri-venular) necrosis: Necrotic hepatocytes around central vein.
• Piecemeal necrosis: Hepatocytes at limiting plate (replacement with inflammatory cells or fibrosis)
• Bridging necrosis: Necrotic zone link structures (central veins to portal tracts or bridge adjacent portal tracts )
• Confluent necrosis: Widespread parenchymal loss (zonal loss of hepatocytes).
• Submassive necrosis: Prominent necrosis involving entire lobules in most of liver; associated with hepatic failure
• Massive necrosis: All hepatocytes in biopsy
➢ Interface hepatitis: Inflammatory cells spell from inflamed portal tracts into periportal parenchyma
➢ Steatosis: Accumulation of fat (clear vacuoles). Micro and Macro vesicular
➢ Mallory-Denk bodies:
• Alcoholic hepatitis. Clumped eosinophilic material in ballooned hepatocytes.
• Tangles of intermediate filaments such as keratins 8 and 18 + other proteins (ubiquitin)

➢ Regeneration
➢ Fibrosis (Scar Formation)
➢ Cirrhosis
lobular hepatitis
Bile ductules

Ballooning degeneration

Apoptotic hepatocytes (“acidophil

bodies) (Arrow)

Focus of mononuclear infiltration surrounding

hepatocyte (double arrows).
Bridging necrosis

Centrilobular necrosis
 Steatosis

Microvesicular

Macrovesicular
Interface hepatitis
 General Features of Liver Disease
• Regeneration
• Replacement of lost hepatocytes by mitotic replication of adjacent hepatocytes + activation of the intrahepatic stem
cell niche (canal of Hering)
• Fibrosis (Scar Formation)
• Hepatic stellate cell (Ito cell). In its quiescent form, it is a lipid (vitamin A) storing cell.
• When activated (chronic inflammation, toxins,..etc.), they are converted into fibrogenic myofibroblasts.

• If injury persists, scar deposition (collagen and fibronectin) begins, often in the space of Disse.
• Subendothelial fibrosis…disappearance of endothelial fenestration” capillarization of the sinusoids”…More
necrosis and disturbed cell function.
• Zones of parenchymal loss transform into dense fibrous septa.
• Fibrous septa encircle surviving, regenerating hepatocytes….Cirrhosis.
• Fibrosis of Space of Disse’
• Capillarization of the sinusoids
• Separation of perisinusoidal hepatocyte islands from sinusoidal blood flow by
collagenous septa.
• Formation of intra hepatic shunts (due to angiogenesis and loss of
parenchymal cells)…shunting of blood from terminal portal veins and arteries
to central veins…intrahepatic portal hypertension and compromised liver
synthetic function.
 General Features of Liver Disease
• Cirrhosis:
• Diffuse transformation of the whole liver into regenerative nodules surrounded by fibrous bands and variable degrees of
vascular shunting (often portosystemic).
• Pathogenesis:
• Death of liver cells with loss of architecture.
• Fibrosis: Activation of hepatic stellate cells…transformed into Fibrogenic myofibroblasts.
• Regenerating nodules: Surviving hepatocytes regenerate and proliferate to form regenerating nodules
• Vascular reorganization: Parenchymal damage and fibrosis disrupt the vascular architecture of the liver .
• Clinical Features
• Initial phase: =“compensated” cirrhosis, the patient may be asymptomatic.
• Later phase: =“decompensated” cirrhosis, presents with complications of portal hypertension, Liver dysfunction.
• Consequences (DHHHC)
• Decrease in the synthesis and excretion functions of the liver.
• ---coagulation factors, --- serum albumin
• CARCINOMA.
• Hepato-renal syndrome, Hepatopulmonary syndrome
• Portal Hypertension.
• >5 mm Hg. But when >10 mm clinically significant portal and oesophageal varices.
• Can occur in ACUTE liver failure, but more widespread in CHRONIC liver failure.
• Pathogenesis
• Contraction of myo-fibroblasts and vascular SMCs…# blood flow
• Scarring and the formation of nodules…# blood flow
• Anastomosis between the arterial and portal system in the fibrous septa:
• Imposing high a. P on the portal system.
• Increase in portal venous blood flow:
• Due to Splanchnic a. VD by released mediators: NO, prostacyclin, TNF.
• Increased a. blood flow leads to increased v. flow into the portal system.
 General Features of Liver Disease
• Consequences of Portal HTN : (APPCE)
• Ascites: “TRANSUDATE”
• #albumin, salt &H2O retention (due to 2ndry hyperaldost.+ +++ADH + +++Est.), Splanchnic VD & hyperdynamic circulation (--a.BP,--
RBF,++RAS).
• Portosystemic venous shunts
• Dilation of collateral vessels and development of systemic-portal bypasses
• Main sites are:
• Esophagogastric junction….gastroesophageal varices…Hematemsis
• Veins around and within the rectum: It results in rectal varices (manifest as hemorrhoids).
• Retroperitoneum: Collaterals in retroperitoneum communicate between the ovarian and iliac veins.
• Umbilicus: Produce prominent dilated subcutaneous veins extending from the umbilicus
toward the rib margins (caput medusae).
• Porto-pulmonary HTN
• Congestive splenomegaly
• --- in the numbers of platelets and WBCs… Hge and +++ infection.
• Hepatic Encephalopathy
• Neurocognitive abnormalities in patients with liver disease or portosystemic shunting
• Pathogenesis
• Normal: N2 compounds (e.g. NH3) produced by gut bacteria…to liver via portal circulation…metabolized by urea cycle… Urea in urine
• In patients with liver failure or portosystemic shunts:
• Ammonia bypasses the liver, accumulates in the systemic circulation; crosses the BBB, absorbed into astrocytes, metabolized to glutamine
• Glutamine +++ OP within the astrocyte + mitochondrial dysfunction
• Ppt.Factors: +++ingestion of proteins, Constipation, GIT bleeding “varices”, Aspiration of ascites, Hypokalemia, Infection, Trauma and surgery
 “mercaptans”

• Spider angioma

• Bleeding
• DIC
 General Features of Liver Disease
• Morphology of Cirrhosis
• Gross
• Size: First ++++, then -----.
• Irregular surface. Firm
• Depending on the size of the nodules, there are three macroscopic types:
• Micronodular form (nodules < 3 mm)
• Macronodular cirrhosis (nodules > 3 mm)
• Mixed cirrhosis consists of nodules of different sizes.
• Microscopically
• Regenerating nodules of hepatocytes
• Fibrosis between these nodules.
• Variable degrees of vascular shunting
 Liver

General features of Alcoholic Chronic

Normal liver injury Hepatitis Liver Disease Liver failure
 Hepatitis
• Definition:
• Inflammation of liver resulting in liver injury.
• Acute Hepatitis.
• Active hepatocellular damage and necrosis. Lobular (zone 3), less than 6 m. duration
• Clinically: Significant elevation (at least 2x upper normal reference range) of serum ALT or AST
in a patient with no previous history of liver disease
• Chronic hepatitis
• Liver disease with persistent necro-inflammatory activity lasting longer than 6 m duration.
• Portal tract. Progressive fibrosis that ultimately leads to cirrhosis
• Most common cause: Viral hepatitis
• Pathogenesis
• Immunological response and accompanying inflammation (e.g. in HCV)
• Persistent inflammatory response leads to liver cell necrosis and subsequently to liver fibrosis
• Risk of liver cirrhosis is greater in HCV infections (20%) than in HBV infections.
 Hepatitis
• Microscopically
• Both acute and chronic hepatitis evoke a lympho-plasmacytic (mononuclear) infiltrate.
• Acute hepatitis:
• Ballooning degeneration. Spotty necrosis. Apoptotic bodies
• Predominantly parenchymal (lobular) inflammation; sinusoidal, zone 3 with mononuclear cell infiltrate
• Chronic hepatitis:
• Portal inflammation. Interface hepatitis. Portal fibrosis
• Parenchymal inflammation and necrosis
• Fibrosis / cirrhosis
 Hepatitis Hepatitis A and E: Only AcutE hepatitis
Hepatitis B: Blood, Birthing, “Bonking”
Hepatitis C: Chronic hepatitis
• Acute Hepatitis (Viral), Chronic hepatitis (Viral) Hepatitis D: Defective virus
Hepatitis E: Endemic in Equatorial

Zoonotic disease with animal reservoirs:

monkeys, cats, pigs, and dogs

High mortality rate among pregnant women

Clinico-pathologic Syndromes of Viral Hepatitis

1- Acute Asymptomatic Infection With Recovery
2- Acute Symptomatic Infection With Recovery
3- Fulminant Hepatic Failure
4- Carrier stage
5- Coinfection of HIV and hepatitis viruses (HCV, HBV)
HAV
• IgM anti-HBc antibody is replaced by IgG anti-HBc.
• As in the case of anti-HAV, there is no direct assay for IgG anti-HBc; its presence is inferred from decline of IgM anti-
HBc in the face of rising total anti-HBc.

• Persistence of HBeAg = progression to chronic hepatitis.

• Anti-HBe abs = acute infection has peaked and on the wane
• Anti-HBs may persist for life…protection...Vaccine.
• Internalization depends on clathrin-mediated endocytosis.
• Acidification of the endosome induces HCV glycoprotein membrane
fusion.
• NS5A= protein essential for assembly of HCV into mature virions
??????
 Liver

General features of liver Alcoholic

Normal injury Hepatitis Liver Disease
 Alcoholic Liver disease
• Excessive alcohol (ethanol) consumption is the leading cause of liver disease in most Western countries.
• Forms of alcoholic liver injury:
• Hepatocellular steatosis or fatty change
• Alcoholic (or steato-) hepatitis
• Steatofibrosis
• Cirrhosis: For some unknown reason, cirrhosis develops in a small fraction of chronic alcoholics (10-15%).

• Changes begin in acinus zone 3 “Centri-lobular” and extend outward toward the portal tracts.
• Hepatic Steatosis (Fatty Liver).
• Lipid droplets in hepatocytes. Reversible if stopping alcohol.
• Alcoholic (Steato-) Hepatitis.
1. Hepatocyte swelling (Ballooning and steatosis) and necrosis.
2. Mallory-Denk bodies, Giant mitochondria
3. Neutrophilic reaction (around degenerating hepatocytes, with Mallory bodies)
• Alcoholic steatofibrosis
• Fibrosis begins around central veins...then space of Disse…then spreading outward,
encircling individual or small clusters of hepatocytes in chicken wire fence pattern.
• Then to portal tracts……central-portal fibrous septa.
• Early stages of scarring can regress with cessation of alcohol use
• Cirrhosis
• When alcohol use continues without interruption over the long term,
• Classic micronodular or Laennec cirrhosis
• Irreversible.
Giant mitochondria
 Alcohol MEOS
• Alcohol abuse is a more widespread hazardous drug.
• After consumption, alcohol is absorbed unaltered in the stomach and small bowel
• Distributes to all of the tissues and body fluids in direct proportion to blood level.
• Less than 10% is excreted unchanged in the urine, sweat, and BREATH. (Breath test)
• Metabolism in Liver:
• ADH, ALDH use NAD+ as a cofactor, producing reduced NADH in both steps
• Alcohol consumption led to consumption of NAD+…+++ NADH…+++ Acetaldehyde and Acetate
• +++NADH lead to # TCA in mitochondria and β-oxidation of FAs…---ATP and FAs oxid.
• +++ Acetate leads to FAs and cholesterol biosynthesis.
• In high conc., ehanol is metabolized by MEOS system
• Because it uses oxygen, this pathway generates free radicals that damage tissues.
• Because it consumes NADPH, the antioxidant glutathione (GSH) cannot be regenerated
• Cytochrome P-450 enzymes induction leads to +++ alcohol catabolism in the ER and +++ conversion
of drugs (e.g., acetaminophen) to toxic metabolites
• When alcohol is present in the blood at high concentrations, it competes with CYP2E1 substrates and may
delay the catabolism of other drugs, thereby potentiating their effects.
• In addition:
• Release of bacterial endotoxin from the gut into the portal circulation
• +++ inflammatory responses in the liver, due to the activation of NF-κB, and release of TNF,
IL-6, and TGF-α.
• Acetaldehyde forms chemical adducts with cellular proteins in hepatocytes and form
neoantigens….initiate immune response…. cell injury
 Liver

General features of liver Alcoholic

Normal injury Hepatitis Liver Disease
 Liver

General features of liver Alcoholic

Normal injury Hepatitis Liver Disease
Gall bladder
 Gall bladder

Cholelithiasis
Normal Jaundice (Gallstones)
 Normal Gall bladder
• As much as 1 L of bile is secreted by the liver per day.
• Between meals, bile is stored in the gallbladder, where it is concentrated.
 Gall bladder

Cholelithiasis
Normal Jaundice (Gallstones)
 Bilirubin Metabolism Jaundice

Cholestasis
Excess in plasma can’t be
excreted in urine.

Conjugated bilirubin:
-Water-soluble, nontoxic.
-Excess in plasma can be
excreted in urine.

Execrated into bile through MRP2 transporter

 Jaundice
Hemolytic Obstructive Heaptocellular
Prehepatic Post hepatic Hepatic
Retention Regurgitation Retention regurgitation
Causes RBCs hemolysis Obstruction of bile ducts: Liver cell damage
Intra and extra hepatic
Blood Haembilirubin Cholebilirubin (Direct) Haem and cholebilirubin
Indirect Bile salts Bile salts
Urine +++ Urobilinogen Cholebilirubin Cholebilirubin
Normal color Bile salts Bile salts
DARK DARK
Stool +++ Stercobilin ---Stercobilin ---Stercobilin
DARK PALE PALE
Staetorrhea Staetorrhea
Liver function tests Normal +++Alkaline IMPAIRED
phosphatase and
cholesterol
Neonatal Jaundice (= physiologic jaundice of the newborn)
• Because the hepatic machinery for conjugating and excreting bilirubin does not fully mature until about 2 weeks of age….transient and mild
unconjugated hyperbilirubinemia.
• May be exacerbated by breastfeeding, due to the presence of bilirubin-deconjugating enzymes in breast milk..
 Jaundice
• Causes of hereditary Jaundice
• Disturbed bilirubin metabolism
• Disorder affecting conjugation of bile acids…+++ Unconjugated
G • Gilbert's syndrome “AD”
U • Mutation in the UGT1A1 gene.----Activity UGT.
C • Crigler-Najjar syndrome “AR”
• Mutation in the UGT1A1 gene. Absence or decreased UGT.
• Disorder affecting the secretion of bile acids …+++ Conjugated
• Dubin–Johnson syndrome “AR”
• Rare. Mutation in the canalicular MRP2.
• Defect in the ability of hepatocytes to secrete conjugated
bilirubin into the bile.
• Black pigmentation in liver: Melanin-like pigmented
granules within the enlarged lysosomes present in the
cytoplasm of hepatocyte.

UGT= Bilirubin uridine diphosphate glucuronosyltransferase enzyme

MRP2= multiple drug-resistance protein 2
 Gall bladder

Cholelithiasis
Normal Jaundice (Gallstones)
 Gall stones
• Types:
• Cholesterol stones (> 50% of crystalline cholesterol monohydrate)
• Pigment stones (insoluble Ca salts of unconjugated bilirubin + inorganic Ca salts)

• Risk factors
• Age and sex: Middle to older age. Females.
• Environmental factors. (EO)
• Estrogen exposure (oral contraceptive use and during pregnancy)
• +++ hepatic cholesterol uptake and synthesis ……. +++ biliary secretion of cholesterol.
• In the last trimester of pregnancy: GB empties more slowly and causes stasis and increases the precipitation of cholesterol crystals.
• Obesity and rapid weight loss (+++ biliary cholesterol secretion)
• Acquired disorders: Any disorder causing Gallbladder stasis…promote cholesterol & pigment stones.
• Drugs: (Cholesterol stone)
• Clofibrate (lower blood cholesterol) results in excessive secretion of cholesterol in the bile.
• Hereditary factors.
• A positive family history increases the risk
• Inborn errors of metabolism e.g. impaired bile salt synthesis and secretion
 Gall stones
• Pathogenesis of Cholesterol Stones.
• Detergents: Bile salts (water soluble…bile acids + glycine or taurine), water-insoluble lecithins. Four conditions to form cholesterol
gallstones:
1- Super-saturation of bile with cholesterol: Due to: ++ biliary cholesterol secretion or -- bile salts
2- Hypomotility of the gallbladder. promote the aggregation of cholesterol crystals.
3- Accelerated nucleation and crystallization
• Pro-nucleating factors: Mucin, non-mucin glycoproteins and biliary Ca are important pronucleating factors.
• Hypersecretion of mucus: Mucus traps the nucleated crystals and favors their aggregation into stones.
• Ca salts: Ca carbonate, ca bilirubinate and ca phosphate in bile serve as a nidus for cholesterol crystallization.
4- Growth to stone-sized aggregates.

• Pathogenesis of Pigment Stones.

• Disorders +++ unconjugated bilirubin in bile…precipitate as Ca bilirubinate around a nidus of mucinous glycoproteins
• Chronic hemolytic anemias…BLACK stone
• Stasis+ Infection of the biliary tract (E.coli, A, liver fluke C. sinensis)…BROWN stone
• Dead bacteria and parasites may act as nuclei and accelerate ppt
• Stasis favors the bacterial infection as well as accumulation of mucus.
 Gall stones
Types and Morphology
Cholesterol stones Pigment gallstones
• In GB and bile ducts
• ONLY in GB
• Types.
• Types • Black
• Pure (100% cholest.): • Sterile bile
• Yellow, round to ovoid. • Oxidized Ca salts of unconjugated bilirubin+ little
• Finely granular, hard surface, Ca carbonate, phosphate + few cholesterol
• Cut section: Radiating crystalline palisade. • > 1.5 cm in diameter, MULTIPLE, and friable.
• Radiolucent. • Spiculated.
• Radiopaque (calcium salts)
• Mixed (50% cholest.)
• Brown stones
• Ca carbonate, phosphates, and bilirubin
• Infected bile.
• Gray-white to black • Similar compounds as Black stone, BUT more
• Cut section: Lamellated. cholesterol and Ca salts of palmitate and stearate.
• Multiple with faceted surfaces. • Soft and greasy
• Radiopaque • Radiolucent (calcium soaps)
 Gall stones
Complications
• Migration…Pain.
• Inflammation
• GB: Cholecystitis, Empyema, perforation, fistulas
• BD: Cholangitis.
• Malignancy (gallbladder carcinoma)
• Obstructive cholestasis and pancreatitis.
• Small stones are more dangerous.
• Large stones may erode directly into an adjacent loop of small bowel, generating intestinal
obstruction (“gallstone ileus” or Bouveret syndrome).
 Chronic Cholecystitis
• Repeated bouts of acute cholecystitis.
• Gallstones are usually present (90%):
• Chronic bile supersaturation with cholesterol
• Initiation of inflammation + GB dysmotility.
• E. coli and enterococci can be cultured from the bile.

• Morphology
• Gross: Contracted (from fibrosis), normal in size, or enlarged (from obstruction).
• Microscopic: Lymphocytic infiltrate with mucosal outpouchings (Rokitansky-Aschoff sinuses).
Marked subepithelial and subserosal fibrosis.
Mural dystrophic calcification (porcelain gallbladder) (+++++risk of malignancy)

• Complications
• Bacterial superinfection with cholangitis or sepsis.
• Gallbladder perforation…local abscess formation. Gallbladder rupture….diffuse peritonitis.
• Biliary enteric (cholecystenteric) fistula.
• Porcelain gallbladder has increased risk of cancer.
 Pancreas

Acute Cholelithiasis
Normal (Gallstones)
pancreatitis
Normal Pancreas
Mechanisms protect the pancreas from self-digestion
by its secreted enzymes:
• Most enzymes are synthesized as inactive proenzymes
(zymogens), which are packaged within secretory granules.
• Most proenzymes are activated by trypsin, which itself is
activated by duodenal enteropeptidase (enterokinase) in the small
bowel; thus, intrapancreatic activation of proenzymes is
normally minimal.
• Acinar and ductal cells secrete trypsin inhibitors, including
serine protease inhibitor Kazal type l (SPINK1), which further
limit intrapancreatic trypsin activity.
 Pancreas

Acute
Normal
pancreatitis
 Pancreatitis
• Definition
• Auto-digestion of the pancreas by its own enzymes, due to failure of protective
mechanisms

• Two types:
• Acute and Chronic pancreatitis.
Acute Pancreatitis