Hoorcollege Lever

78
Liver/LAMI lever: Topografie en functie echter bovenbuik zeer groot en belangrijk orgaan galsynthese en -secretie excretie van bilirubine eiwitsynthese • albumine • stollingsfactoren gluconeogenese deaminatie van aminozuren detoxificatiefunctie (alcohol, …) opslag triglyceriden, glycogeen, vitamines

description

Hoorcollege over de lever

Transcript of Hoorcollege Lever

Page 1: Hoorcollege Lever

Liver/LAMI

De lever: Topografie en functie

•rechter bovenbuik

• zeer groot en belangrijk orgaan

• galsynthese en -secretie

• excretie van bilirubine

• eiwitsynthese

• albumine

• stollingsfactoren

• gluconeogenese

• deaminatie van aminozuren

• detoxificatiefunctie (alcohol, …)

• opslag triglyceriden, glycogeen, vitamines

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LeverDe leverfuncties:

~ complexe interacties tussen:

- vasculatuur- a. hepatica propria- v. portae hepatis- sinusoïden- centrale venen

- hepatocyten

- galdraineersystemen- galcanaliculi- intrahepatische galductuli

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Het leverkapsel (van Glisson)

Kapsel van ongeordend dens bindweefsel.

Omgeeft de hele lever, behalve ter hoogte van de hilus, waar het als een bindweefselschede rond de vaten en de galwegen de lever binnendringt.

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Lever: de levervasculatuur

Afferent- Arteria hepatica propria: zuurstofrijk bloed, uit de aorta (via truncus coeliacus)

- Vena portae hepatis: zuurstofarm bloeduit tractus digestivus en de milt

Efferent- Centrale vene → hepatische vene → v. cava inferior

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From NetterCiba collection III/3

De lever

? ?

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Terminale tak van de arteria hepatica

Terminale tak van de vena portae

Sinusoïden

Terminale hepatische venule (centrale vene van de lobule)

De lever: de levervasculatuur

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LIVER

Bile

Hepatic artery

Portal vein

GITHepatic veins

Liver is the blood-processing glandular intermediary between you and your GIT that determines blood quality in two ways METABOLIC by Hepatocytes PROTECTIVE by Kupffer cells (Ms)

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HEPATIC PARENCHYMA working tissue

Plate of hepatocytes

SINUSOID

Plate of hepatocytes

Endothelial cells

SpaceSINUSOID

Kupffer cellblood

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CV

CV

CV

PT

PT

PT

PT

PTPT PT PT

PT

PTPT PT

portale tractus (PT); centrale vene (CV)

Lever: hepatocyt-heterogeniteit

(Klassiek) Lobulusconceptversus

Acinusconceptversus

Portaal lobulusconcept

CV

CV

CV

PT

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LIVER: low-power section

BD PV HA

Portal triad

Central vein

Sublobular vein at the edge of lobule Lobule

CV

Capsule

Hepatic parenchyma

Portal triad lies in CT comprising a Portal area

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BLOOD & BILE FLOWS IN THE LIVER

PORTAL VEIN HEPATIC DUCT

Hepatic artery

CENTRAL VEIN

SUBLOBULAR VEIN INFERIOR VENA CAVA

Centrifugal flow of bile within plates of hepatocytes in canaliculi

Bile ductule

Portal venule

Hepatic arteriole

Centripetal blood flow in sinusoids

65

4

3

2

1

7

HEPATIC VEIN

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Microscopic anatomy of the liver. The portal tract carries branches of the portal vein, hepatic artery, and bile duct system. The portal vein gives rise to branching septal veins, which penetrate the hepatocellular parenchyma at regular intervals. Blood from the septal veins enters directly into the parenchymal sinusoids between hepatocytes. The hepatic artery gives off capillaries that supply the bile duct system; these capillaries usually dump into the portal vein but may deposit blood directly into sinusoids. Arterioles also occasionally convey blood directly to the sinusoids. The bile duct system gives off bile ductules, which traverse the mesenchyme of the portal tract to penetrate the parenchyma; at that point, they become hemicircular, abutting hepatocytes (not shown) to form the canals of Hering. Bile traveling through the bile canalicular system between hepatocytes enters into the biliary tree through these canals of Hering. Blood from the portal vein and hepatic artery travels through the sinusoids of the parenchyma toward the terminal hepatic vein, leaving the liver by this route. On the basis of blood flow, three zones can be defined, zone 1 being the closest to the blood supply and zone 3 being the farthest. Pathologists refer to the regions of the parenchyma as "periportal, midzonal, and centrilobular," the last term owing to the historical concept that the terminal hepatic vein was at the center of a "lobule."

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CELL TYPES & ARRANGEMENT OF LIVER

Microvilli

Hepatocytes in plates

Bile canaliculus SPACE OF DISSE

Fenestrated Endothelial cells

SINUSOID Kupffer cell

STELLATE CELL

HEPATOCYTE ENDOTHELIAL CELL KUPFFER CELL STELLATE CELL

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CELL TYPES & ARRANGEMENT OF LIVER

Microvilli

Hepatocytes in plates

Tight junctionsBile canaliculus SPACE OF DISSE

Fenestrated Endothelial cells

SINUSOID Kupffer cell

Reticular fiber

STELLATE CELL

Hepatocytes work on plasma, not blood cells, and need time to act. The space of Disse & the fenestrations provide a backwater for the microvillated hepatocytes to work

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LM

• gepolariseerde veelvlakkige metabool actieve cellen:

• sinusoïdaal oppervlak

• intercellulair oppervlak

• canaliculair oppervlak

• grote, ronde, centrale celkern (vaak binucleair)

• vaak polyploïd

• heterochromatine-rijk

• duidelijke nucleolus

• bleek (glycogeen) en granulair eosinofiel (mitochondriën) cytoplasma

Lever: de hepatocyten

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EM

• groot en actief perinucleair Golgi-apparaat

• rijk aan RER, GER en vesikels

• veel vrije ribosomen, glycogeen, en lysosomen

• talrijke mitochondriën

• vetdruppels

Lever: de hepatocyten

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Lever: de hepatocyt

Drie belangrijke oppervlakken:

Hepatocyt - galcanaliculus

Hepatocyt - bloedvat

Hepatocyt - hepatocyt

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Sinusoïdaal oppervlak

70% v/h totale hepatocytenoppervlak

uitwisseling van stoffen tussen de sinusoïden en de hepatocyten

EM

• onregelmatige korte microvilli

•‘coated pits’ (endocytose)

• perisinusoïdale ruimte van Disse

• tussen het sinusoïdale oppervlak v/d hepatocyt & endotheelcel in de wand v/d sinus

• collageneuze reticulinenetwerk

Lever: de hepatocyt

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Sinusoïdaal oppervlak

EM

• onregelmatige korte microvilli (pijlpunten)

•‘coated pits’ (endocytose)

• perisinusoïdale ruimte van Disse (groene pijl)

• tussen het sinusoïdale oppervlak v/d hepatocyt (H) & endotheelcel in de wand v/d sinus (S)

• collageneus reticulinenetwerk

• fenestraties v/h capillair (gebogen pijlen)

Lever: de hepatocyt

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15% v/h totale hepatocytenoppervlak

via dit oppervlak komt de gal uit de hepatocyt in de canaliculi terecht

EM: galcanaliculus

• buisje, gevormd door ondiepe groeven op het oppervlak van aangrenzende hepatocyten

• sluitlijsten

• het lumen is gevuld met onregelmatige microvilli

• celmembraan rijk aan alkalische fosfatase en adenosinetrifosfaat

• pericanaliculaire actinefilamenten (hepatocyt)

Lever: de hepatocyt

Canaliculair oppervlak

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Pitt cells

– Rare cells– Natural killer cells– Function:

• Important barrier in tumor defense

• Role in clearance of hepatotropic viruses ?

• Role in tissue rejection after liver transplantation ?

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Hepatic stellate cells (ITO)

Function:

• Vitamin A storage• Fibrogenesis– Resting state: production of collagen III, IV – Activated cell:

– collagen I, III, IV, VI, fibronectin– Production of cytokins e.g. EGF– Regulation of blood flow in sinusoids

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Kupffer cells

Described by Kupffer in 1876

– ± 2 % of the non-parenchymal cells

– Zone 1 > zone 3

– Origin ? Circulating monocytes

– Function: Phagocytic activity• Bactericidal capacity

• Clearing of viruses

• Clearing of endotoxins

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Sinusoidal endothelial cells

– Flat epithelium

– Fenestrae

– Filtration function

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Kupffer cell deals with gut endotoxins & other bad stuff

CELL TYPES & ARRANGEMENT OF LIVER

Microvilli

Tight junctions Bile canaliculus

Hepatocytes in plates

SPACE OF DISSE has ECM materials, but no distinct basal lamina

Fenestrated Endothelial cells

SINUSOID

Reticular fiber STELLATE CELL

makes collagen fibrils & ECM materials

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HEPATOCYTE

GOLGI

Lysosome

GER

Golgi complex

Microvilli

Tight junction

Bile canaliculus

Mitochondrion

Smooth ER

Glycogen

PEROXISOME

Space of Disse

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SOME HEPATOCYTE FUNCTIONS*

GOLGI

Lysosome

GER

Golgi complex

Microvilli

Tight junction

Bile canaliculus

Mitochondrion

Smooth ER

Glycogen

PEROXISOME

Space of Disse

GLYGOGEN SYNTHESIS

LIPID UPTAKE & METABOLISM

DETOXIFICATIONS by p450s, e.g., of phenobarbitol, ethanol

BILE-ACID UPTAKE & TRANSPORT (pumps & transporters)

PROTEIN SYNTHESES e.g., of albumin, complement, fibrinogen, etc

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ZONES IN LIVER PARENCHYMA I

Portal vein branch

Central vein

}

Peri-portal zone

}

Peri-venous/ peri-central zone

Lobule

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ZONES IN LIVER PARENCHYMA II Alternative terms

Portal vein branch

Central vein

}

Peri-portal zone ZONE 1

}

Centrilobular/ peri-central zone ZONE 3

Lobule

ZONE 2}

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Liver: Function

• Exocrine gland– The provision of bile acids and alkaline fluid for the

digestion and absorption of fats and for the neutralisation of gastric acid in the intestine

– The degradation and conjugation of waste products of metabolism of metabolism

– The detoxification of poisonous substances– The excretion of waste metabolites and detoxified

substances in bile substances in bile

• Endocrine gland

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Bile

• 250 – 600 ml/day • Stored in the gallbladder ( 50 ml)• Derived fromThe hepatocytes• – 75 % of the bile volume • – Mix of inorganic and organic substances, e.g.

lipids, bile acids, lecithin and cholesterol• Contains

• albumin • IgA mucosal immunity• bile pigments, namely bilirubin• toxic metabolites

The duct cells

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Bile

• The duct cells– 25 % of the bile volume– Watery, alkaline fluid, rich in bicarbonate– To provide the appropriate pH for the

process of micelle formation– Neutralises the stomach acid of the

intestinal chyme

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Bile acids

• Consist of• Primary : cholic acid, chenodeoxycholic acid• Secundary: deoxycholic acid, lithocholic acid

• Derivatives of cholesterol• Essential for the formation of micelles in

bile, which functions as a transport mechanisme for cholesterol

• Essential for the effective digestion and absorption of dietary fats

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Bilirubin

Conjugated (± 99 %) (glucuronic acid,glucuronosyl transferase)

Bilirubin monoglucuronides (20 %)Bilirubin diglucuronides (80 %)Water-soluble Excretion into bile

Unconjugated (± 1 %)HydrophobicRemains in circulation

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Function

• Metabolic functions– Carbohydrate metabolism– Fat metabolism– Protein metabolism– Storage of vitamins– Storage of iron– Blood coagulation– Immunity– Excretion of drugs, hormones, …

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Carbohydrate metabolism

- Important role in the homeostasis of glucose- Absorptive phase:

• Glycogenesis:- Storage of glycogen through glycogen synthesis:

glucose to glycogen- Perivenular hepatocytes (zone 3)

• Glycolysis:– Glucose to Pyruvate – Perivenular hepatocytes (zone 3)

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Carbohydrate metabolism

• Metabolism of fructose and galactose• Postabsorptive phase:

– Gluconeogenesis:- Aminoacids or glycerol of triglycerides to glucose - Periportal hepatocytes (Zone 1)

– Glycogenolysis:• glycogeen to glucose• Periportal hepatocytes (Zone 1)

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Fatty acid metabolism

• Continuous cycling of fatty acids between liver and adipose tissue – Absorptive phase:

– Synthesis of fatty acids

– Synthesis of lipoproteins

– Perivenular hepatocytes (zone 3)

– Postabsorptive phase: –Degradation of fatty acids through β-oxidation

–Ketogenesis

–Periportal hepatocytes (zone 1)

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Synthesis of proteins

• Albumin: • Major blood protein, responsable for the maintenance of

the osmotic pressure• Transports fatty acids, steroid hormones, fat-soluble

soluble vitamins and drugs, Ca vitamins and drugs, Ca2+ , lipophylic substances

• Liver synthesizes and exports up to 12 g/day

– Acute phase proteins e.g. cerulosplasmin, α1- antitrypsin, antitrypsin, α2-macroglobulins

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Liver protein function

Arginase

• Only situated in hepatocytes

• Detoxification of ammonia

• Ureagenesis occurs in periportal hepatocytes

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Other metabolic functions

– Storage of vitaminsPredominantly vitamin A, but also large quantities of vitamin D and vitamin B12 D

– Blood coagulationSynthesis of products, involved in blood coagulation such as fibrinogen, prothrombin, vitamin K

– Storage of ironSynthesis of transferrin, which functions as a transport protein for iron protein for ironSynthesis of apoferritin, which is capable of binding of iron, as a result of which it transforms into ferritin

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Other metabolic functions

– Role in hormone metabolism– Clearance of peptide hormones such as

insulin,growth hormone, glucagon … – Metabolisation of steroid-hormones to a more

water soluble and less biologically active form, which is excreted either through the bile or the urine

– Excretion of Ca2+through bile

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Enzymatic detoxification mechanisms

Liver plays an important role in drug metabolism or biotransformation

Phase 1: – Oxidation or reduction of parent component :increased polarity

or increased polarity or water solubility – May produce toxic intermediates– Cytochrome p -450 system :Perivenular hepatocytes (zone 3)Phase 2:– Conjugation with glucuronic acid through

glucuronyltransferases :Perivenular hepatocytes (zone 3) – Conjugation with sulphate through sulfotransferases :

Periportal hepatocytes (zone 1)– May produce less toxic intermediates– Increases further the water solubility : increases excretion

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Liver Conclusions

1. largest abdominal organ

2. lobulus -- acinus

3. Involved in several metabolic processes

4. metabolisation of drugs: Cave hepatotoxicity

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De galblaas: topografie en functie

• eivormig hol orgaan aan de onderzijde v/d lever

• musculaire wand

• opslag en concentratie van verdunde, waterige gal uit de lever, via de ductus hepaticus communis

• de gal belandt uiteindelijk in het duodenum

• via de ductus cysticus en de ductus choledochus

• via de ampulla hepatopancreatica (Ampul van Vater) (samen met de ductus pancreaticus)

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Scanning beelden van de mucosale plooien in de galblaas (links). Rechts: detail SEM beeld van het luminale oppervlak van het galblaas epitheel. Het apicaal oppervlak v/d epitheelcellen is bedekt met microvilli (Bloom & Fawcett; a textbook of Histology; 1975).

De galblaas

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Eénlagig hoog-cilindrisch epitheel zonder slijmbekercellen

LM

• basale nuclei

• borstelzoom

EM

• talrijke korte microvilli

• verstrengelde laterale wanden

• sluitlijsten

De galblaas

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Lamina propria

• losmazig bindweefsel

• plooien of plicae

• tubulo-alveolaire muceuze klieren thv galblaashals

• bloedvaten

• krypten van Aschoff-Rokitansky thv fundusgebied

De galblaas

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GALL BLADDER

Highly folded & outpouching T MUCOSA with regular simple columnar epithelium

Thin T MUSCULARIS

T SEROSA except where gallbladder attaches to liver

& no Goblet cells

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Muscularis externa

• glad spierweefsel

• onreglmatig

• vnl schuine vezels

• er is geen muscularis mucosae!

• de spierlaag v/d galblaas is homoloog met muscularis externa v/h darmkanaal

• goed ontwikkelde laag perimusculair dicht bindweefsel

De galblaas

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Adventitia (serosa)

Dicht bindweefsel

- Bovenzijde van de galblaas- Continu met het leverkapsel (van Glisson)

Peritoneaal mesotheel

- Naar de buikholte gerichte zijde van de galblaas

De galblaas

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• In-situ photograph of the chest and abdominal contents

• Liver is the largest parenchymal organ, lying just below the diaphragm.

• The right lobe (at the left in the photograph) is larger than the left lobe.

• The falciform ligament is the rough dividing line between the two lobes.

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External surface of a normal liver. The color is brown and the surface is smooth. A normal liver is about 1200 to 1600 grams.

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The cut surface of a normal liver has a brown color. Note the portal vein carrying blood to the liver, which branches at center left, with accompanying hepatic artery and bile ducts. At the lower right is a branch of hepatic vein draining blood from the liver to the inferior vena cava.

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Liver is divided histologically into lobules. The center of the lobule is the central vein. At the periphery of the lobule are portal triads. Functionally, the liver can be divided into three zones, based upon oxygen supply. Zone 1 encircles the portal tracts where the oxygenated blood from hepatic arteries enters. Zone 3 is located around central veins, where oxygenation is poor. Zone 2 is located in between.

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Hepatic fatty change. The lipid accumulates in the hepatocytes as vacuoles. These vacuoles have a clear appearance with H&E staining. The most common cause of fatty change in developed nations is alcoholism. In developing nations, kwashiorkor in children is another cause. Diabetes mellitus, obesity, and severe gastrointestinal

malabsorption are additional causes.

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• Ongoing liver damage with liver cell necrosis followed by fibrosis and hepatocyte regeneration results in cirrhosis. This produces a nodular, firm liver. The nodules seen here are larger than 3 mm and, hence, this is an example of "macronodular" cirrhosis.

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• Here is another example of macronodular cirrhosis. Viral hepatitis (B or C) is the most common cause for macronodular cirrhosis. Wilson's disease and alpha-1-antitrypsin deficiency also can produce a macronodular cirrhosis.

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Micronodular cirrhosis. The regenerative nodules are quite small, averaging less than 3 mm in size. The most common cause for this is chronic alcoholism. The process of cirrhosis develops over many years.

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Massive necrosis. A, Cut section of liver. The liver is small (700 gm), bile-stained, and soft. The capsule is wrinkled. B, Microscopic section. Portal tracts and terminal hepatic veins are closer together than normal, owing to necrosis and collapse of the intervening parenchyma. The rudimentary ductal structures are the result of early ductular regeneration. An infiltrate of mononuclear inflammatory cells is present.

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Mallory's hyaline is seen here, but there are also neutrophils, necrosis of hepatocytes, collagen deposition, and fatty change. These findings are typical for acute alcoholic hepatitis. Such inflammation can occur in a person with a history of alcoholism who goes on a drinking "binge" and consumes large quantities of alcohol over a short time.

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A much more serious problem produced by portal hypertension results when submucosal veins in the esophagus become dilated. These are known as esophageal varices. Varices are seen here in the lower esophagus as linear blue dilated veins. There is hemorrhage around one of them. Such varices are easily eroded, leading to massive gastrointestinal hemorrhage.

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• One of the most common findings with portal hypertension is splenomegaly, as seen here. The spleen is enlarged from the normal 300 grams or less to between 500 and 1000 gm. Another finding here is the irregular pale tan plaques of collagen over the purple capsule known as "sugar icing" or "hyaline perisplenitis" which follows the splenomegaly and/or multiple episodes of peritonitis that are a common accompaniment to cirrhosis of the liver.

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Cirrhosis resulting from chronic viral hepatitis. Note the broad scar and coarse nodular surface.

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Chronic viral hepatitis due to hepatitis C virus, showing portal tract expansion with inflammatory cells and fibrous tissue and interface hepatitis with spillover of inflammation into the adjacent parenchyma. A lymphoid aggregate is present.

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Acute viral hepatitis showing disruption of lobular architecture, inflammatory cells in the sinusoids, and hepatocellular apoptosis

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Diagrammatic representations of the morphologic features of acute and chronic hepatitis. Bridging necrosis (and fibrosis) is shown only for chronic hepatitis; bridging necrosis may also occur in acute hepatitis (not shown).

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Schematic of the potential outcomes of hepatitis B infection in adults, with their approximate frequencies in the United States.

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Sequence of serologic markers in acute hepatitis A viral hepatitis.

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Illustration of the morphologic features of cholestasis (right) and comparison with normal liver (left). In the parenchyma (upper panel), cholestatic hepatocytes (1) are enlarged with dilated canalicular spaces (2). Apoptotic cells (3) may be seen, and Kupffer cells (4) frequently contain regurgitated bile pigments. In the portal tracts of obstructed liver (lower panel), there is also bile ductular proliferation (5), edema, bile pigment retention (6), and eventually neutrophilic inflammation (not shown). Surrounding hepatocytes (7) are swollen and undergoing degeneration.

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Dubin-Johnson syndrome, showing abundant pigment inclusions in otherwise normal hepatocytes (H&E).

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Bilirubin metabolism and elimination. 1, Normal bilirubin production from heme (0.2 to 0.3 gm/day) is derived primarily from the breakdown of senescent circulating erythrocytes, with a minor contribution from degradation of tissue heme-containing proteins. 2, Extrahepatic bilirubin is bound to serum albumin and delivered to the liver. 3, Hepatocellular uptake and (4) glucuronidation in the endoplasmic reticulum generate bilirubin monoglucuronides and diglucuronides, which are water soluble and readily excreted into bile. 5, Gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. The urobilinogens and the residue of intact pigments are excreted in the feces, with some reabsorption and excretion into urine.

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•The major clinical consequences of portal hypertension in the setting of cirrhosis, shown for the male.

•In women, oligomenorrhea, amenorrhea, and sterility are frequent, owing to hypogonadism.

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Schematic of stellate cell activation and liver fibrosis in comparison to the normal liver. Kupffer cell activation leads to secretion of multiple cytokines; cytokines also may be released by endothelial cells, hepatocytes, and inflammatory cells entering the liver (not shown). These cytokines "activate" stellate cells, whereby they loose their lipid droplets (which are present in the quiescent state) and acquire a myofibroblastic state. Stellate cell proliferation is stimulated in particular by platelet-derived growth factor (PDGF); tumor necrosis factor (TNF) is a potent stimulant of the change to a myofibroblastic phenotype. Contraction of the activated stellate cells is stimulated by endothelin-1 (ET-1). Deposition of extracellular matrix (fibrogenesis) is stimulated especially by transforming growth factor α; (TGF-α). Chemotaxis of activated stellate cells to areas of injury, such as where hepatocytes have undergone apoptosis, is promoted by PDGF and monocyte chemotactic protein-1 (MCP-1). Kupffer cells also are a major source of TNF released into the system circulation.

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Photomicrograph of liver (trichrome stain). Note the blood-filled sinusoids and cords of hepatocytes; the delicate network of reticulin fibers in the subendothelial space of Disse stains light blue.