Hoorcollege Lever
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Transcript of Hoorcollege Lever
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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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Liver/LAMI
LeverDe leverfuncties:
~ complexe interacties tussen:
- vasculatuur- a. hepatica propria- v. portae hepatis- sinusoïden- centrale venen
- hepatocyten
- galdraineersystemen- galcanaliculi- intrahepatische galductuli
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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
From NetterCiba collection III/3
De lever
? ?
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Liver/LAMI
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/LAMI
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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Liver/LAMI
HEPATIC PARENCHYMA working tissue
Plate of hepatocytes
SINUSOID
Plate of hepatocytes
Endothelial cells
SpaceSINUSOID
Kupffer cellblood
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Liver/LAMI
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/LAMI
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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Liver/LAMI
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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Liver/LAMI
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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
Lever: de hepatocyt
Drie belangrijke oppervlakken:
Hepatocyt - galcanaliculus
Hepatocyt - bloedvat
Hepatocyt - hepatocyt
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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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Liver/LAMI
Sinusoidal endothelial cells
– Flat epithelium
– Fenestrae
– Filtration function
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Liver/LAMI
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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Liver/LAMI
HEPATOCYTE
GOLGI
Lysosome
GER
Golgi complex
Microvilli
Tight junction
Bile canaliculus
Mitochondrion
Smooth ER
Glycogen
PEROXISOME
Space of Disse
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Liver/LAMI
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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Liver/LAMI
ZONES IN LIVER PARENCHYMA I
Portal vein branch
Central vein
}
Peri-portal zone
}
Peri-venous/ peri-central zone
Lobule
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Liver/LAMI
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/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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/LAMI
Liver protein function
Arginase
• Only situated in hepatocytes
• Detoxification of ammonia
• Ureagenesis occurs in periportal hepatocytes
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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
Eénlagig hoog-cilindrisch epitheel zonder slijmbekercellen
LM
• basale nuclei
• borstelzoom
EM
• talrijke korte microvilli
• verstrengelde laterale wanden
• sluitlijsten
De galblaas
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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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Liver/LAMI
• 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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Liver/LAMI
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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Liver/LAMI
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/LAMI
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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Liver/LAMI
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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Liver/LAMI
• 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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Liver/LAMI
• 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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
• 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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Liver/LAMI
Cirrhosis resulting from chronic viral hepatitis. Note the broad scar and coarse nodular surface.
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Liver/LAMI
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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Liver/LAMI
Acute viral hepatitis showing disruption of lobular architecture, inflammatory cells in the sinusoids, and hepatocellular apoptosis
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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
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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Liver/LAMI
Dubin-Johnson syndrome, showing abundant pigment inclusions in otherwise normal hepatocytes (H&E).
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Liver/LAMI
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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Liver/LAMI
•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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Liver/LAMI
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.