Morphologic patterns of hepatic injury and cirrhosis (1)
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If we see brown color (CK7) (bile), it’s canalicular cholestasis (çünkü normalde bile gözükmüyor)
Limiting membrane (interface) → stem cell’lerin olduğu yer, rejenerasyon için önemli
Balooning → steatosis; feathery degeneration → bile
Hydropic change → acute reversible change as a response to non-lethal injuries, swelling of the cytoplasm
Extreme form of hydropic change called as baloon degeneration, it’s considered as a form of apoptosis
The histomorphological appearance of ballooning degeneration is used in criteria of steatohepatitis
microvesicular steatosis → Multiple tiny droplets that do not displace the nucleus
o causes ALF without necrosis
o Acute fatty liver of pregnancy, Reye syndrome, valproic acid toxicity
macrovesicular steatosis → A single large droplet that displaces the nucleus
o The livers of obese or diabetic individuals, hepatitis C viral infection
In Alcoholic liver disease, both macro and microvesicular steatosis
Councilman body (acidophil bodies) → toxic/immun mechanisms -> cytoplasmic shrinkage, cell
membrane blebbing, chromatin condensation (pyknosis), nuclear fragmentation (karyorrhexis) and
cellular fragmentation into small membrane-bound‘apoptotic bodies’.
Ischemic injury, drug, toxic agent induced injury → centrilobular necrosis (zone 3)
Eclampsi → periportal necrosis (zone 1)
Necrosis of entire lobules submassive necrosis; Necrosis of most of the liver massive necrosis
Most severe form of bridging necrosis → portal-to-central
interface hepatitis / piecemeal necrosis → At the limiting membrane between the portal tract-adjacent
hepatic parenchma inflammation and necrosis
T lymphocytes in both acute and chronic hepatitis.
Cirrhosis → fibrosis and normal hexagonal architecture is replaced by nodules
In acute and chronic injury, stellate cells (lipid storing, vit A storing cells) activated and converted into
highly fibrogenic myofibroblasts
o Kupffer cells and lymphocytes release cytokines and chemokines
o Disruption of ECM, Directs toxins stimulate stellate cells and scar deposition begins
o Activated stellar cells → PDGF (prolif), TNF (prolif), endothelin-1 (contraction), TGF-Beta (fibrogenesis)
Yukardakiler fibrosis nasıl oluyor, fibrosis → Irreversible, the vascular architecture of the liver is disrupted
Regression → matrix metalloprotienases produced by hepatocytes
Liver functions (2)
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Liver accounts for 20-30% of the total oxygen consumption
Detoxification: (1) Xenobiotics (2) Steroids (3) Thyroid Hormone (4) Endogenous metabolites
In the liver, glucose is derived from: Cori cycle (from lactate), Alanine cycle (from alanine)
Formation of vitamin A from carotins, Depo of cyanocobalamine and folic acid
Phosphorilation of vitamins B, formation of coenzyme forms
1. Well-fed (= absorptive state), 2. Starvation (= postresorptive state)
The main site of amino acid degradation is the liver (significant quantities of ammonia are released)
NH3 is released from glutamate by oxidative deamination (catalyzed by glutamate dehydrogenase
Aspartate (Asp), the second amino group donor in the urea cycle, also arises from glutamate (catalyzed by
aspartate transaminase)
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The amino group of alanine is transferred to 2-oxoglutarate by alanine transaminase
Urea can cross membranes by diffusion (small, uncharged molecule)
o its nitrogen atoms are derived from ammonia and aspartate, and the carbonyl carbon From hydrogen
carbonate
Bilirubin (degraded product of hemoglobin) is transported in the blood bound to albumin. The liver takes
up bilirubin and conjugates it with glucuronic acid
Conjugated bilirubin is excreted via the bile ducts into the gut, it is converted to urobilinogen (most of it is
oxidized to urobilin in the colon and excreted)
Hyperbilirubinemia:
o Pre-hepatic: excessive formation of bilirubin by increased degradation of erythrocytes
o Hepatic: insufficient processing of bilirubin as a result of liver defects
o Post-hepatic: by impaired excretion of gall
Unconjugated bilirubin can cross the blood-brain barrier, leading to brain damage
Urine urobilinogen: insufficient function of the liver
Urine bilirubin: when plasma direct bilirubin is elevated (obstructive and hepatocellular icterus)
Detoxification mechanism (3)
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Phase 1 (hydroxylation) → catalyzed by monooxygenases / cytochrome P450s
Cytochrome P450s are generally located in the smooth endoplasmic reticulum of cells and are particularly
enriched in the liver
Mitochondrial Cytochrome P450s also exist and are involved in the hydroxylation of steroids
The liver uses this same system in bile acid (cholic acid, chenodeoxycholic acid)
synthesis and the hydroxylation of cholecalciferol to 25-hydroxycholecalciferol (Vitamin D3)
The kidney uses it to hydroxylate vitamin D3 to its biologically active 1,25-dihydroxylated form.
Monooxygenases (cytochrome P450) incorporate one atom from molecular oxygen into a substrate
creating a hydroxyl group, with the other atom being reduced to the water
In Cytochrome P450 Monooxygenase System, NADPH provides the reducing equivalents
The new hydroxyl group serves as a site for conjugation with a polar compound, such as glucuronic acid
Phase II reactions: Glucuronidation, Sulfation, Conjugation with glutathione, Acetylation, Methylation
Glucuronidation → UDP-glucuronic acid is the glucuronyl donor, the reactions are catalyzed by
glucuronosyltransferases
Sulfation → The sulfate donor in sulfation reactions is adenosine 3-phosphate-5-phosphosulfate (PAPS)
Conjugation with glutathione → A number of potentially toxic electrophilic xenobiotics (such as certain
carcinogens) are conjugated to the nucleophilic GSH
The enzymes catalyzing these reactions are called glutathione S-transferases and are present in high
amounts in liver cytosol
o Glutathione genetik info olmadan kendiliğinden sentezlenebilir
Portal hypertension and clinical presentation of liver cirrhosis (4)
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A(ascites)B(bleeding[esophageal varices])C(caput medusae)D(diminished liver function)E(enlarged spleen)
Normal portal pressure is 5 to 10 mm Hg and exceeds inferior vena caval pressure by 4 to 5 mm Hg (portal
venous gradient).
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• Normal portal sinusoid pressure is 3-4
mmHg
• In cirrhosis, the hepatic sinusoid is less leaky
• Vasoconstrictors: ET1, RAAS, vasopressin
• Vasodilators: NO, TNF, ET3, VIP, CGRP, ANF,
glucagon, substance P, PGs, encephalin
• Portal HT olunca intrahepatic NO azalıyor
(vasoconstriction), splanchninc NO artıyor
(vasodilation). Bunlar sonucunda portal HT daha
da kötüleşiyor.
Inflammation contributes to portal hypertension via TNF (splanchnic vasodil.-hyperdynamic circulation).
SIBO: Small Intestinal Bacterial Overgrowth → contributes to portal ht
• Cardinal signs of ph: splenomegaly, collateral
vessels, ascites
• Coronary vein and short gastric veins →
esophageal varices
• IMA → hemorrhoids
• Umbilical vein → caput medusae
• Retroperitoneal collaterals → bare areas of liver
• Hepatorenal syndrome → renal vasoconstriction da
olunca bu oluyor
• Clinically significant portal hypertension is defined
as an increase in HVPG to >10 mmHg (normalde 5-7)
Pathology of metabolic liver diseases (19)
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Hemochromatosis → Adult form caused by mutations of HFE
o Symptoms become evident after age 40
o Liver, skin, pancreas, heart, joints → pigmentation and fibrosis
o Increased HCC risk
o Phlebotomy to reduce iron overload
o Primary → Fe deposition first in perivenular cells in primary, first in Kupffer cells in secondary
o No inflammation
o Biochemical determination of hepatic tissue iron concentration is the standard for quantitating
hepatic iron content
o Testes may be small and atrophic
Secondary hemochromatosis → transfusion, iron injection, thallasemia, chronic HBV HCV
Wilson → Liver, brain, kidneys, cornea, heart, pancreas, and joints
o Excess unbound Cu causes hemolysis
o Morphology: Acute hepatitis, chronic hepatitis, cirrhosis, massive liver necrosis, Vacuolated
hepatocellular nuclei, Mallory bodies (((NOT SPECIFIC)))
o Basal ganglia atrophy
o Copper → Rodanine stain; Copper-associated protein → orcein, victoria blue
o Cu also accumulates in chronic obstructive cholestasis so histology not useful, dry weight useful
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o Molecular +, K-F rings +, Ceruloplasmin < 20 mg/dL, neurologic manifestations, Liver bx > 75 μg/gm dry
wt.
NASH → may progress to cryptogenic cirrhosis
NASH → If mitochondrial function cannot adapt to the increased FFA flux and respiratory oxidation
collapses, lipid-derived toxic metabolites activate inflammatory pathways and hepatocyte lipotoxicity
leading to endoplasmic reticulum stress and the unfolded protein response also participate in the
pathogenesis of NASH.
TNF-α and Low serum levels of adiponectin are correlated with NASH.
NASH → Hepatocyte balooning, lobular inflammation, Steatosis, perivenular and perisinusoidal fibrosis,
mallory bodies
Liver biopsy is the most reliable diagnostic tool for NASH
Serum Ferritin elevation indicates liver fibrosis not iron overload
Hyperuricemia is associated with cirrhosis related deaths or hospitalizations
Acute viral hepatitis (20)
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Serum aminotransferases> 500 U/L and often 1000 U/L
ALT characteristically higher than AST
Elevation of aminotransferase levels begins in the prodromal phase
PT(>3 seconds above the control value or INR>1.7) should raise concern and prompt close monitoring
USG → For exclusion of biliary tract disease if suspected
HAV → fecal-oral route (eg, shellfish, strawberries, onions) or water; inc time 2-6 weeks; no chronic;
caution for travellers -endemics in developing countrieso Centri lobular cholestasis may be severe in adults. (adults more symptomatic than children)
o Vacciantion for chronic hepatitis patients (especially HCV)
HBV present in 50% of HCC patients, most of them also have cirrhosis. (final stage of HBV is cirrhosis)
cccDNA for replication of HepB.
IgM anti-HBc is the sole marker of HBV infection during the window period (no HBsAg or anti-HBs)
HBV may be transmitted through percutaneous routes and close person-to-person contact
HCV RNA for confirmation of chronic inf.
Acute hepatitis C is asymptomatic in most people, incub period 8 weeks
Antiviral treatment for acute HepC
Patients with both HBV and HDV infection tend to have low-level HBV replication and low-level or
undetectable HBV DNA
HEV → through the fecal-oral route (fecally contaminated water drinking), no person-to-person
ALP elevations in patients with cholestatic features, more often in hepatitis E than in the other viral
hepatitis
IgM anti-HEV is undetectable after a few months, and IgG anti-HEV does not persist much beyond 1 year.
Hereditary and metabolic diseases of the liver in the adult (21)
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Wilson → males chronic and neuropsychiatric, females acute and hepatic; ATP7B mut.
o AR, problem is defective cerruloplasmin not low cerruloplasmin
o CNS, kidney, cornea, steatosis in liver, spongy degen of cortex
o Liver disease in young, neuropsychiatric in elderly
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o Liver: steatosis -> chronic hepatits -> compensated cirrhosis ---- ALF olabilir
o Biriken Cu dolayısıyla liver necrosis var → thrombocytopenia, coagulopathy, elevated LFT
o Coagulopathy and encephalopathy olursa → ALF denir
o Basal ganglialar etkilenir → Parkinsonism
o Sunflower cataracts and KF rings specific for Wilson
o Fatal if untreated
Hereditary hemochromatosis → AR, erkeklerde daha çok (mensturation), becomes apparent after 40 yrs
o Organ damage due to ROS
o Pituitary and gonadal involvement → testicular atrophy can be seen (hypogonadism)
o Classical triad: cirrhosis, DM, skin pigmentation
o Hepatomegaly >%95 ; cirrhosis de olabilir (HCC’ye de dikkat o yüzden)
o DM %65, insulin resistance %100
o Pseudogout → calcium phosphate accumulation
o Transferrin saturation > 45%
o En iyi treatment phlebotomy
o Deferoxamine demiri çökeltmek için kullanılabilir.
Gallstone disease (22)
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Black pigment stones → hemolysis, cirrhosis; brown pigment stones → parasites or bacteria
Gallbladder hypomotility, hepatic cholesterol hypersecretion, genetic factors
Estrogen increases gallstone formation by enhancing hepatic synthesis and secretion of cholesterol.
o Paritesi yüksek kadınlarda daha sık görülür bu yüzden.
Prolonged fasting increases gallstone risk.
Nucleation var pathogenesiste.
Hypercholesterolemia: obesity, diabetes, pregnancy → cholesterol stones
Hyeprbilirubinemia: scleral icterus, hemolytic anemia → bilirubin stones
Biliary pain → patient restless and moves about seeking position of relief, visceral pain (poorly localized)
o Almost never assoc. with fever, lab results normal, elective laparoscopic cholecystectomy
o Prophylactic cholecystectomy should also be offered to patients with increased risk for gallbladder
cancer, such as patients with large stones (≥3 cm in diameter) or a “porcelain” gallbladder
Acute cholecytitis → edema, transmural inflammation, ischemia, thickening
o Patient lies motionless because minor movement (even breathing) causes pain, nausea common.
o Murphy’s sign
o Inflammation markers high, bilirubin markers generally normal
o Necrosis and perforation olabilir; laparoscopic cholecystectomy
Choledocholithiasis → pain and elevated cholestatic enzymes; spasm; ALP, GGT, TB, CB; MRI; Rad Endo US
o If bacteria proliferate, life-threatening cholangitis may result
o Endoscopic retrograde cholangiopancreatography (ERCP) to remove the stone
The presence of jaundice or abnormal liver biochemical test (ALP, GGT) results strongly points to the bile
duct rather than the gallbladder as the source of the pain.
Cholangitis → most serious and lethal complication of gallstones, may cause sepsis, intrahepatic abscess
o Charcot's triad → RUQ pain, jaundice, fever
o Reynolds' pentad → Charcot’s + Altered mental status and hypotension
Hepatomegaly in childhood (23)
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The presence of a palpable liver does not always indicate hepatomegaly.
Accumulation of fluid or air in the thorax (eg, pneumothorax) also may displace the liver inferiorly.
Children who have orthopedic abnormalities such as narrow chest walls or pectus excavatum can
erroneously appear to have hepatomegaly.
HMG five mechanisms → inflammation, inappropriate stroage, infiltration (primary or metastatic tumors),
vascular congestion (CHF, Budd-Chiari Syndrome..), biliary obstruction
A history of hyperbilirubinemia after 2 weeks of age requires rapid assessment of the underlying disorder
to rule out extrahepatic biliary atresia.
A family history of early infant death or hepatic, neurodegenerative, or psychiatric disease suggests a
metabolic etiology.
Prenatal history of Rh or ABO incompatibility suggests isoimmunization and hemolysis as the cause of
hepatomegaly.
History of prolonged hyperbilirubinemia in infancy may point to CF or alpha-1-antitrypsin deficiency.
Acholic stool usually suggests obstruction of the biliary tract, but it also can be seen in severe
hepatocellular injury.
Acute onset of hepatomegaly associated with hyperbilirubinemia in an older child raises the suspicion of
infection with hepatitis A.
Auscultation over the liver may detect bruits or increased flow to the liver
Signs of chronic liver disease, such as spider angiomas, xanthomas, and palmar erythema, are more
common among adults.
If the patient has a distinctive breath or urine odor, consider organic acidemias.
Failure to thrive and hepatomegaly in infancy result from a metabolic disease
hepatic dysfunction (conjugated/direct bilirubin) and hemolytic disease or congenital disorders of bilirubin
metabolism (unconjugated/indirect bilirubin).
Ultrasonography with Doppler flow imaging of hepatic vessels usually is the most helpful initial study.
Computed tomography (CT) or magnetic resonance imaging (MRI) may be superior to ultrasonography in
detecting small focal lesions, such as tumors, cysts, or abscesses.
Radionuclide scanning is most helpful in the young infant to distinguish biliary atresia from neonatal
hepatitis.
o In biliary atresia, hepatic uptake of the radionuclide is normal, but excretion into the intestine is
absent.
o In neonatal hepatitis, uptake by the diseased liver parenchyma is impaired, but there is excretion into
the intestines.
Intraoperative cholangiography is the method of choice in neonates for ruling out atresia.
Percutaneous liver biopsy can be performed in infants as young as1 week of age.
Viral hepatitis in childhood (24)
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HAV → inc period 15-40 days, often asymptomatic, ALF possible, clinical improvement with the onset of
jaundice, vaccine, Fecal-oral (foodborne or waterborne)
HBV → Vertical, parenteral, sexual, perinatal; inc period 50-180 days;
o Perinatal HBV acquisition is usually asymptomatic; however, if mother is HBeAg positive at birth, ~6 of
infants will develop acute liver failure by 2—3 months of age
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o Co-morbidities → Gianotti-Crosti syndrome, polyarteritis nodosa, glomerulonephritis
o HBV Ig to infants born to HBsAg positive mothers
HCV → Vertical, parenteral, or sexual; inc period 30-150 days;
o Perinatal transmission rates are ~5%, and increase to 15%—20% if the mother is coinfected with HIV
o Comorbidities → glomerulonephritis, cryoglobulinemia, autoimmune hepatitis, Sjorgren's syndrome
o HCV RNA testing in the first 2 months of life is problematic: false-positives and false-negatives
HDV → Vertical, parenteral, or sexual
HEV → Fecal-oral (foodborne, waterborne), no vaccine, no carrier state nor chronic infection
Infantile cholestasis (25)
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Conjugated hyperbilirubinemia is never physiologic or normal. (normalde <20% of total bilirubin)
Biliary atresia, A1AT def, Alagille syndrome, CF, galactosemia, tyrosinemia type 1, progressive familial
intrahepatic cholestasis
Sweat chloride test for CF
GGT high in BA, ALGS, PFIC, BASD (Bile Asid Synthesis Defect)
Abdominal pain in childhood (26)
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The most common non-surgical condition is gastroenteritis, while the most common surgical condition is
appendicitis.
Red flags → severe or inceasing abd pain, blood in stool, abdominal distension, bilious (green) or bloodstained vomit, palpable abd mass, child unresponsive or excessively drowsy, child non-mobile and change
in gait pattern due to pain
Important non-abdominal causes of abdominal pain → Diabetic ketoacidosis, headache (migraine),
Henoch Schonlein purpura, pneumonia, sepsis, toxin exposure or OD
Health promotion & primary prevention-Nutrition, lifestyle and GI dis (27)
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Rectal bleeding urgent referral.
Dietary factors account for at least 30 percent of all cancers.
Vegetarians are about 40 percent less likely to develop cancer compared to meat eaters.
Grilling or broiling meat over a direct flame -> Polycyclic aromatic hydrocarbons (PAHs) -> cancers
Polycyclic aromatic hydrocarbons (PAHs) may play a role in the development of stomach cancer in
humans.
Meat consumption may play a significant role in kidney and pancreatic cancer risk.
Alcohol → relationship for liver, breast, and colorectal cancer
A diet rich in dairy products during childhood is associated with a greater risk of colorectal cancer in
adulthood.
Smoking for 35 years was associated with higher colon cancer rates. Another study examined the type of
tumors present in colon cancer patients and found that those who smoked were more likely to have
microsatellite instability tumors (MSI), which contain unstable DNA.
High-fiber diet reduces GIT diseases.
Carotenoids reduce cancer.
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Vitamin C, found in citrus fruits and many vegetables, may lower risks for cancers of the esophagus and
stomach.
Pathology of Intrahepatic Biliary Tract Disease (28)
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PBC → autoimmune, chronic, progressive, cholestatic; middle aged women
o Nonsuppurative inflammatory granulomatous destruction of medium-sized intrahepatic bile ducts
▪ Portal inflammation, portal fibrosis, cirrhosis, liver failure
o antimitochondrial Ab
o Precirrhotic stage → Interlobular bile ducts are infiltrated by lymphocytes and may show noncaseating
granulomatous inflammation (noncaseating çünkü lymphocytes)
▪ Bu da ductopenia’ya yol açar
o Different degrees of severity in different portions of the liver
o Cirrhotic stage → Obstruction to intrahepatic bile flow leads to progressive secondary hepatic damage
▪ Ductular prolif (e ducta hasar var), inflammation, necrosis (cirrhotic dedik zaten) of periportal
hepatic parenchyma, cholestasis, mallory bodies, Cu dep, fibrosis-cirrhosis
Secondary biliary cirrhosis → Prolonged obstruction of the extrahepatic bile ducts
o stone, stricture, tumor, head of pancreas tumor; In children biliary atresia, choledochal cyst, cystic
fibrosis (CF gallstone ve obstruction’a sebep olabilir)
Primary sclerosing cholangitis → hardening due to fibrosis, inflammation, segmental obliteration of intra
and extrahepatic bile ducts (obliterative cholangitis)
o Radiology: stenosis-secondary dilatations (rastgele biyopsi alınca inflammation olan bir small ducta
denk gelmek zor olduğundan radiology faydalı)
o Assoc with IBD, increased cholangiocarcinoma risk
o Lymphocytic inflam., progressing atrophy of bile duct epithelium, fibrosing cholangitis -> obliteration
of the lumen, concentric periductal fibrosis “Onion-skin fibrosis”, between areas of stricture and
dilatation (boncuk boncuk görünüm)
Lack of remodeling results in the persistence of periportal epithelial sleeves or "ductal plate
malformation" (DPM).
o Autosomal recessive polycystic kidney disease
o Caroli disease: DPM of the larger IHBDs
o Von Meyenburg complexes: DPM of smaller interlobular ducts (liver cysts in autosomal dominant
polycystic kidney disease)
▪ embrionic bile duct remnant, bile duct hamartomas
Congenital hepatic fibrosis → bands of collagenous tissue (no inflamm.), forming septae
o Enlarged liver, yani cirrhosis değil (cirrhosis’de liver küçülüyodu çünkü)
Alagille syndrome → Paucity (kıtlık) of intrahepatic bile ducts, liver structure normal
Pathology of hepatic nodules and tumors (29)
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Cavernous hemangioma → most common benign liver tumvascular channels in a bed of fibrous tissue
Nodular hyperplasia → FNH and NRH, seen in non-cirrhotic liver
o FNH → young-middle aged women, secondary to arterial anomaly
▪ Central stellate scar; not capsulated; central scar shows fibromuscular hyperplasia
▪ Nodularity like cirrhosis (unutma bunlar non-cirrhoticlerde gözüküyo), normal hepatocytes
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Septae (hypoperfused yerler septa, hyperperfused yerler hyperplastic oluyor) show foci of
lymphoid infiltrates
o NRH → spherical nodules in the entire liver due to thrombosis in small portal veins or obstruction
▪ Lead to development portal hypertension (damar tıkanık çünkü)
▪ Fibrosis yok, sirozdan farkı bu
▪ No fibroinflamatory septa (FNH)
▪ Perinodular congestion → plump hepatocytes are surrounded by rims of atrophic hepatocytes
Borderline (dysplastic) nodule → small cell dysplasia, intralobar artery (çünkü neoplasia, angiogenesis var)
o No portal area, difference from macroregenerative nodules
Large cell dysplasia → malignancy potential
Hepatocellular adenoma → Lobular due to hemorrhage (çünkü demand>supply) and necrosis
o No portal tract or bile duct (ANGIOGENESIS VAR, ÇÜNKÜ NEOPLASIA)
▪ Instead prominent solitary arteriel vessels and draining veins are distributed through the tumor
o Abundant glycogen, steatosis is common
Hepatocellular carcinoma → yellow-green nodules (bile), PV IVC RH -> lung metastasis
o Elevated serum alpha fetoprotein levels, Hep Par (+)
o HBV, HCV, alcoholic cirrhosis, primary hemochromatosis, aflatoxins, A1AT def., hereditary tyrosinemia,
NASH, glycogen storage disease
o Trabecular, acinar, solid pattern
Fibrolamellar carcinoma → HCC variant, do not have underlying chronic liver diseases (no cirrhosis)
o Central scar, fibrous septa, nodule is green due to bile (difference from FNH [orda açık renkti])
o Lamellae of dense collagen bundles (stained with trichrom), Polygonal cells
Cholangiocarcinoma → PSC, Caroli dis, HCV, Thorotrast; perihilar, distal, intrahepatic
o All risk factors for CCA cause chronic inflammation and cirrhosis
o Extrahepatic CCA → Firm, gray nodules within bile duct wall, Mucin +/-, Squamous features +/▪ Markedly desmoplasia, no bile within tumor cells
o Intrahepatic CCA → occur in non-cirrhotic liver and may create treelike tumorous mass
Thorotrast related angiosarcoma → Granular extracellular pigment (thorotrasttan ötürü)
Epitheloid hemangioendothelioma → Multiple grey-yellow hard nodule
Infectious Enterocolitis (30)
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Cholera → non-invasive, toxin leads to massive diarrhea
Campylobacter enterocolitis (C. jejuni most common) → traveller’s diarrhea (yani food poisoning)
o Dysentery assoc with invasion, enteric fever
o acute self-limited colitis: campylobacter, salmonella, shigella
▪ Neutrophilic infiltration, cryptitis, crypt abscesses
▪ Crypt architecture preserved (chronic rahatsızlıklarda crypt architecture zarar görüyor)
Shigellosis → dysentery, M cells
o mucosa is hemorrhagic and ulcerated, and pseudomembranes may be present
o Aphthous-appearing ulcers may occur
Salmonella → typhoid fever (S. typhi) and non-typhoid salmonella (S. enteritidis)
o Typhoid fever → Gallbladder colonization with S. typhi or S. paratyphi may be associated with
gallstones and the chronic carrier state.
▪ Oval ulcers on Peyer’s patches in ileum, typhoid nodules on the liver
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Yersinia → Peyer's patch shows hyperplasia, granulomas can be seen
o The mucosa may become hemorrhagic, and aphthous-like erosions and ulcers may develop
Enterotoxigenic E. Coli → Produce heat-labile toxin (LT) and heat-stable toxin (ST), traveller’s diarrhea
Enterohemorrhagic E. Coli → Shiga-like toxins, dysentery, antibiotics are not recommended (kötüleştirir)
Enteroinvasive E. Coli → no toxins, invasive
Enteroaggregative E. Coli → Attach to enterocytes via adherence fimbriae and are aided by dispersin
Pseudomembranous colitis → often triggered by antibiotic therapy colonization by Clostridium difficile
o mucopurulent exudate that forms an eruption reminiscent of a volcano – pseudomembranes
Whipple disease → organism-laden macrophages cause lymphatic obstruction -> malabsorptive diarrhea
o distended, foamy macrophages (tbc’de de görülüyor ama orda AF +) periodic acid-schiff (PAS) positive,
AF negative
Ascaris lumbricoides → eosinophil-rich inflammatory reaction, hepatic abscess or Ascaris pneumonitis
Entamoeba histolytica → Amebic Dysentery, flask-shaped ulcer, amebiasis (cecum and ascending colon)
o Amebic liver abscesses (metastazdan ayırt etmek lazım)
Giardia lamblia → characteristic pear shape, no invasion
Malabsorption syndromes, vascular disorders and diverticular disease (31)
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A hallmark of malabsorption is steatorrhea (çünkü yağı ememedim)
Intestinal graft-versus-host disease is an important cause of malabsorption and diarrhea
Most common ones: pancreatic insufficiency, Celiac disease, and Crohn disease
CF → defect in intestinal chloride ion secretion (due to absence of CFTR) -> defective luminal hydration ->
intestinal obstruction or pancreatic intraductal concretions -> exocrine pancreatic insufficiency
o The malabsorbtion associated with cystic fibrosis is the result of pancreatic insufficiency
o The result is failure of the intraluminal phase of nutrient absorption
Celiac → Biopsy specimens from the second portion of the duodenum or proximal jejunum are generally
diagnostic; hyperplastic crypts, atrophic villi, intraepithelial lymphocytosis (CD8+)
o The incidence of lymphocytic gastritis and lymphocytic colitis is also increased.
o Most common celiac-assoc cancer: Enteropathy-associated T- cell lymphoma, Small intestinal
adenocarcinoma also more frequent
Abetalipoproteinemia → AR, inability to secrete lipoproteins into the vessels -> TGs accumuluate within
the epithelial cells -> lipid vacuolization of small intestinal epithelium cells
Ischemic bowel disease → mucosal (mucosa, mm), mural (m,mm,sm), transmural (m,mm,sm,mp,serosa)
o Hypoxic injury and reperfusion injury (en büyük hasar burda çünkü O2 yeniden gelince ROS coşuyor)
o The lesions are most often segmental and patchy, the mucosa is hemorrhagic and may be ulcerated,
bowel wall is also thickened by edema
o Substantial portions of the bowel are generally involved in transmural infarction due to acute arterial
obstruction. The demarcation between normal and ischemic bowel is sharply defined.
o Coagulative necrosis var ve perforation görülebilir. Serositis olabilir.
o atrophy or sloughing of surface epithelium, fibrous scarring of the lamina propria
Sigmoid Diverticular Disease → psueodo-diverticular outpouchings, elevated intraluminal pressure
important in the pathogenesis
o The causes include; low fiber diets, colonic spasm, and the unique anatomy of the colon.
o flask-like outpouchings alongside the taeniae coli
o Diverticulae are most common in the sigmoid colon
o most often, totally absent muscularis propria
Pathology of circulatory disorders of liver (32)
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Budd-Chiari syndrome – large vessels; Venoocclusive disease – sinusoidal obstruction syndrome
Budd-Chiari syndrome → major thrombosis of veins; liver’da BP arttı: hepatomegaly, ascites, pain
o Swollen, red-purple liver with a tense capsule
o Severe centrilobular congestion → necrosis; daha yavaş olursa → fibrosis
Venoocclusive disease → nontrombotic; toxic-physical injury (generall after bone tx)
o Obliteration of hepatic vein radicles, subendotelial swelling and reticulated collagen in hepatic vein
o Acute: centrilobular congestion, hepatocellular necrosis, hemosiderin-laden macrophages
o Chronic: perivenular fibrosis, venule obliteration, congestion mild
Obstruction of small intrahepatic branch → focal infarct
Main hepatic artery occlusion does not always produce ischemic necrosis (dual blood supply)
PH -> esophageal varices and ascites → ectatic vein recanalization + splenomegaly → Banti syndrome
Acute thrombosis of PV does not cause ischemic infarction but instead results in a sharply demarcated
area of red-blue discoloration → infarct of Zahn
o No necrosis, atrophy of hepatocytes (az kan), dilatation of sinusoids (tıkanıklık var mecbur)
Idiopathic PV hypertension → portal vein flow impaired by progressive portal vein sclerosis, no cirrhosis
Peliosis hepatis → sinusoids of liver proliferate and dilate, engorgement of capillary beds, cystic bloodfilled cavities within liver
Acute RHF → centrilobular congestion (same as outflow obstruction) – centrilobular hepatocyte atrophy
Acute LHF → hepatic hypoperfusion and hypoxia - centrilobular necrosis (ischemic necrosis)
chronic passive congestion (cardiac cirrhosis) → right-sided cardiac decompensation
o Centrilobular fibrosis → reverse lobulation,
o central congestion and fibrosis, pale periportal areas → nutmeg liver
o Zon 3- severe presinusoidal collagen deposition
Pathology of drug and toxin induced liver diseases (33)
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Intrinsic → predictable, dose-related, acute, by drug, usually necrosis, fulminant, e.g. acetaminophen
Idiosyncratic → unpredictable, not dose-related, drug allergy, inflammation, weeks-months after,
hypersensitivity, e.g. INH, ketoconazole
DILI is the most common cause of cholestatic hepatitis.
Centrizonal (zone 3) necrosis is characteristic of acetaminophen and halothane.
Isolated necrosis affecting zones 1 and 2 is rare.
Atorvastatin-induced acute hepatitis → Mixed parenchymal inflammation is present, consisting of
lymphocytes, plasmahistiocytic cells, and neutrophils. There is no bile duct damage or fibrosis
The histological features can be indistinguishable from other causes of acute hepatitis
bile duct injury, prominent eosinophilic (alerji) infiltrate, granulomas, sharply defined perivenular
necrosis, or cholestasis out of proportion to hepatocellular injury
microvesicular steatosis → aspirin, tetracycline, VPA
Necrosis with marked inflammatory activity → idiosyncratic adverse drug reactions
Necrosis with little or no inflammation → acetaminophen, cocaine
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Acetaminophen toxicity → Marked hepatocellular necrosis is present in a zonal, centrilobular pattern,
while the inflammatory infiltrate is minimal, some steatosis
Granuloma → assoc with granulomas in other tissues; Allopurinol, Phenytoin, Isoniazid, Quinine, Penicillin
o Fibrin-ring granulomas → Fat vacuole surrounded by a ring of fibrin deposition and epithelioid cells.
Budd-Chiari syndrome (thrombotic) → oral contraceptive
Sinusoidal dilatation → oral contraceptive
Peliosis hepatis → androgenic anabolic steroids, thorotrast
Venoocclusive disease (sinusoidal obstruction syndrome) → azatiopirin, Ectatic
Alcoholic liver disease → hyperbilirubinemia, elevated alkaline phosphatase, neutrophilic leukocytosis
o Mallory bodies → Bile duct cytokeratin and other proteins, characteristic but not specific
Alcoholic and nonalcoholic liver diseases (34)
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The liver can oxidize (change) only about 15 gr of alcohol an hour
Oxidative metabolism (when you drink normal) → acetate
Microsomal enzyme oxidation system (when you drink a lot) → acetaldehyde açığa çıkıyor, toxic
threshhold between AFLD and NAFLD → 20 gram/day for women (140/week), 30 grams/day for men
(210/week)
Risk factors → females, smokers, high fat diet, obesity
10 year or longer consumption of ~80g of alcohol a day results in cirrhosis
No signs and symptoms; Fatigue, weakness, RUQ pain
Acute alcoholic hepatitis → fever (<38.5C), hepatomegaly, jaundice, ascites; Maddrey score
o Coagulopathy,jaundice and/or encephalopathy are poor prognostic indicators
o Corticosteroids, anti-TNF (pentoxifylline)
Fatty Liver (Steatosis) → reversible if stopped drinking
NAFLD fatty liver → macrovesicular steatosis with nucleus positioning at cell periphery
NASH → Mallory bodies, ballooning degeneration, lobular neutrophil inflammation, perisinusoidal fibrosis
Double Hit Hypothesis in NAFLD
NAFLD → Most patients (77%) are asymptomatic; FIB-4 and NAFLD fibrosis score
Reference intervals and interpretation of laboratory tests (35)
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For satisfactory reference intervals we have to obtain data from at least 120 reference individuals.
We do not need to confirm that the reference individuals are healthy
Reference intervals are calculated from the data of 95% of the reference individuals
o The data of upper and lower of 2.5% of population are excluded
For serial results to be significantly different, the difference between two results must be greater than the
combined variation of analytical and within-subject/person variation
o This value is known as critical difference or reference change value
Delta check is accepted as the difference between two serial results
o If Delta check < RCV the difference is not significant
Tumors of the liver (36)
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Hepatic hemangiomas are the most common benign mesenchymal hepatic tumors.
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o US yeterli, biopsy not necessary
Benign’lar kadınlarda malignant’lar erkeklerde daha sık görülür.
FNH → Usually asymptomatic, excellent prognosis
Hepatic adenoma → abd pain (52%) localized to the epigastrium or right upper quadrant
o Percutaneous liver biopsy or fine-needle aspiration are usually not indicated (because adenomas have
a tendency to bleed following biopsy)
o Hepatic adenomas have the potential for malignant transformation.
NRH → micronodular, benign, not assoc w cirrhosis, assoc with lymphoproliferative disorders
o Portal hypertension, radyolojide siroz gibi gözükebilir (bi sürü nodule) ama fibrosis yok
Once cirrhosis is present, up to 20% of patients will develop HCC over 10 years.
o The most important risk factor for HCC is cirrhosis.
o HCV HBV. HBV’liler siroz olmadan HCC olabilir, HCV’liler önce siroz olur
o Severe pruritus, jaundice, splenomegaly, variceal bleeding
o Ascites, asterixis (PH bulguları hep)
o fever of unknown origin (her daim önemli bu)
o AFP higher than 400 ng/mL
o Generally Chemotherapy and Radiation therapy have not had much of a role in the treatment of HCC.
Fibrolamellar HCC → This tumor generally occurs in younger patients without a history of cirrhosis.
o The tumor is well demarcated and encapsulated and may have a central fibrotic area. (central scar)
o FHCC does not produce AFP, but is associated with elevated neurotensin levels.
Choalngiocarcinoma → risk factor PSC, surgical resection best option
Drugs used in inflammatory bowel disease + pancreatic disease (37)
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Current therapy for IBD seeks to dampen the generalized inflammatory response.
Patients with mild disease may be treated with 5-aminosalicylates (with ulcerative colitis or Crohn’s
colitis), topical corticosteroids (ulcerative colitis), antibiotics (Crohn’s colitis or Crohn’s perianal disease),
or budesonide (Crohn’s ileitis).
Patients with moderate disease or patients who fail initial therapy for mild disease may be treated with
oral corticosteroids to promote disease remission; immunomodulators (azathioprine, mercaptopurine,
methotrexate) to promote or maintain disease remission; or anti-TNF antibodies.
Patients with moderate disease who fail other therapies or patients with severe disease may require
intravenous corticosteroids, anti-TNF antibodies, or surgery. Natalizumab is reserved for patients with
severe Crohn’s disease who have failed immunomodulators and TNF antagonists. Cyclosporine is used
primarily for patients with severe ulcerative colitis who have failed a course of intravenous
corticosteroids.
Mesalamine → Used in combination with glucocorticoids for severe ulcerative colitis
o jejunum is primary site of absorption
o Can be delivered as a suppository for rectal disease
o Mesalamine compounds → pentase, asacol, lialda, anema and suppositories
o Sulfapyridine is absorbed from the colon. Sulfapyridine undergoes hepatic metabolism (including
acetylation) (sistemik toxic etkileri oluyor) followed by renal excretion. By contrast, after azoreductase
breakdown of balsalazide, over 70% of the carrier peptide is recovered intact in the feces and only a
small amount of systemic absorption occurs
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o 5-ASA inhibits the activity of nuclear factor-κB (NF-κB)
o Hypersensitivity to sulfapyridine (or, rarely, 5-ASA) can result in fever, exfoliative dermatitis,
pancreatitis, pneumonitis, hemolytic anemia, pericarditis, or hepatitis.
o Sulfasalazine impairs folate absorption and processing -> folate supplements recommended
o other aminosalicylate formulations are well tolerated
o olsalazine may stimulate a secretory diarrhea
Prednisone and prednisolone are the most commonly used oral glucocorticoids.
Hydrocortisone enemas, budesonide (rapid first-pass metabolism)
Steroids not useful for maintaining disease remission.
After absorption, azathioprine is rapidly converted by a nonenzymatic process to 6-Mercaptopurine
o The bioavailability: azathioprine (80%) > 6-MP (50%) (BUNLAR IMMUNOSUPPRESIVE)
o Azathioprine and 6-MP have a serum half-life of less than 2 hours; however, the active 6-thioguanine
nucleotides are concentrated in cells resulting in a prolonged half-life of days.
o The prolonged kinetics of 6-thioguanine nucleotide results in a median delay of 17 weeks before onset
of therapeutic benefit from oral azathioprine or 6-MP is observed in patients with IBD.
o Among patients who depend on long-term glucocorticoid therapy to control active disease, purine
analogs allow dose reduction or elimination of steroids in the majority.
o Catabolism of 6-MP by TPMT is low in 11% and absent in 0.3% of the population à increased risk of
bone marrow depression. (TMPT olmayınca 6-thioguanine birikiyor, half-life’ı çok uzun)
o Increased risk of lymphoma, nonmelanoma skin cancers
o Allopurinol inhibits XO metabolism → + 6-TG (contraindicated) -> severe leukopenia
METHOTREXATE → inhibits dihydrofolate reductase, interfere with IL-1
o Crohn’da kullanılıyo UC’de kullanılmıyo
o used to induce and maintain remission in patients with Crohn’s disease
o may also stimulate increased release of adenosine
o bone marrow depression (folate az, DNA sentezi azaldı), Folate supplementation reduces the risk
Cyclosporin → inhibitor of calcineurin and a potent immunomodulator, çok adverse effect
Anti-TNFs → Infliximab, adalimumab, and golimumab are antibodies of the IgG1 subclass.
o Certolizumab is a recombinant antibody that contains an Fab fragment that is conjugated to
polyethyleneglycol (PEG) but lacks an Fc portion.
o chronic treatment of patients with moderate to severe Crohn’s disease who have had an inadequate
response to conventional therapies.
o Infection due to suppression of the Th1, Reactivation of latent tuberculosis
Anti-integrins → effective against to moderate to severe Crohn’s disease.
o Integrins are a family of adhesion molecules on the surface of leukocytes.
o Natalizumab and vedolizumab: monoclonal antibodies directed against integrins subunit
o Natalizumab may cause reactivation of a human polyomavirus (JC virus) in CNS → lead develop
progressive multifocal leukoencephalopathy
Tofacitinib (JAK inhibitor) → used to treat moderate-to-severe ulcerative colitis in patients who fail to
respond to biological therapies.
Antiemetics (38)
SLAYT
Drugs affecting secretory and motor functions of GI system (39)
SLAYT
Drugs for constipation and diarrhea (40)
SLAYT