Liver

General Pathology (MHS) The Liver  Sometime in December 

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Normal Liver Located in the RUQ of the abdomen

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Wt 1500g (2.5% of TBW)

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In surgery, divided into 8 lobes – caudate lobe (1 st lobe), the remaining (2nd to 8th lobe); designated on the basis of blood supply

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Apoptotic cell death (when ( when there is continuous –shrun –shrunke ken, n, pyknot pyknotic ic and intens intensely ely injury) eosinophilic cells obtaining fragmented nuclei

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Lytic cell death (outcome of balooning degeneration) Centrilobular – drug and toxic reactions

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Midzonal - rare

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Periportal – eclampsia

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Focal Focal// spotty spotty – scatte scattered red cells cells withi within n hepati hepatic c lobules Bridging necrosis - contigous

C. INFL INFLAM AMMA MATI TION ON Hepati Hepatitis tis – injury injury to the liver liver associ associate ated d with with influx of acute and chronic inflammatory cells Viral hepatitis quiescent quiescent lymphocyte lymphocyte may collect collect into the o portal tracts Spil Spilll over over the peri peripo port rtal al pare parenc nchy hyma ma as o activated lymphocytes •

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Histologically, are composed of hexagonal lobules o In the center: terminal hepatic vein In the the peri periph phery ery:: hepa hepati tic c trac tractt (por (porta tall vein vein,, o hepatic artery & bile duct) o Hepatic plates with thin layer of endothelial cells Stella Stellate te cells cells which which are are precur precursor sors s of fibrou fibrous s o tissue which proliferates in cirrhosis

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D. RE REGE GENE NERA RATI TION ON Regenerat Regeneration ion occurs in all but most fulminant fulminant hepatic disease Hepatocyte proliferation is marked by: Mitoses o  Thickening of the hepatocyte cords o Diso Disorrgani ganiz zati ation of the the par parench enchym yma al o architecture •

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E. FIBROSIS Fibrous tissue – for formed in response to inflammation or direct toxic insult Points to generally irreversible hepatic damage •

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Patterns of Hepatic Injury A. DEGENERATION AND INTRACELLULAR ACCUMULATION •

Swelli Swelling ng (rever (reversib sible) le),, balloo balloonin ning g (clumpi clumping ng o organelles) degeneration

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Feathery degeneration (in cholestasis) cholestasis)

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Steatosis (there is displacement of nucleus) fatt fatty y

Micr Microv oves esic icul ular ar -

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pregnancy Macrovesicular Macrovesicular – diabetic/ obese px Both – alcoholic fatty liver

live liverr

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B. NECROS NECROSIS IS AND AND APOP APOPTOS TOSIS IS Ischemic coagulative necrosis- poorly stained & mummified, lysed nuclei •

MR*, Mel, Eisa (kami ba trans n2?)

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acut acute e

Hepatic Failure

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End point 80-90 % of hepatic functional capacity is eroded o 70-95 % mortality o Morphologic alterations that causes hepatic failure Massive hepatic necrosis o o Chronic liver disease – most common route Hepatic dysfunction without overt necrosis o Clinical features  Jaundice o Hypoalbuminemia o Hyperammonemia o Fetor hepaticus o o Portosystemic shunting o

Hyperestrogenemia

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General Pathology – Diseases of the Liver by  MHS   MHS  •

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Life threatening o Susceptible to multiple organ failure Coagulopathy o Impaired synthesis of CF II, VII, IX, X Mass Massiv ive e GI blee bleedi ding ng e.g. gastroes gastroesopha ophageal geal 

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varices  Further metabolic load on the liver Hepatic encephalopathy o

Subtle behavioral changes to confusion

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àcoma Neurologic signs  

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stupor

Rigidity Hyperreflexia

 Asterixis Increase ammonia levels

Hepatorenal syndrome Functional abn o   

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Na retention Impaired water excretion Decrease renal perfusion and GFR Drop in urine output assoc with rising BUN and creatinine

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Cirrhosis Among top 10 causes of death

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Characteristics

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Bridging fibrous septae

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Parenchymal Parenchymal nodules formed by septae

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Disruption of the architecture

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Pathogenesis Collagen Types I & III are normally in o Portal tract, central vein, space of Disse  Type I & III collagen à deposited in lobules 

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Clinical features o May be clinically silent Anorexia o Weight loss o o

New vascular channels

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Deposition of collagen in Space of Disse (loss of  hepatic plates and endothelial cells) Loss Loss of fenestrati fenestrations ons in sinusoidal sinusoidal endothelial endothelial cells No exchange of solutes between hepatocytes & plasma Impaired secretion of proteins

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Vitamin A fat storing cells (normally)located (normally) located in

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space of Disse Activ ctivat ated ed in

cirr cirrho hosi sis s

(sti (stimu mula lated ted

into into

myofibroblasts)  Robust mitotic activity Shift from resting lipocyte to myofibroblast  phenotype Increase capacity for synthesis of   extracellular matrix

Mecha echani nis sm of cir cirrhoti hotic c deaths Progressive Progressive liver failure o o

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Perisinusoidal Perisinusoidal stellate cells o Source of fibrosis

Weakness Osteoporosis Frank debilitation

Complications related to portal hypertension Development of   hepatocellular carcinoma

Portal Hypertension Increase resistance to blood flow Pre-h Pre-hepa epatic tic,, post post hepatic hepatic,, intrahepatic In cirrhosis •

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General Pathology – Diseases of the Liver by  MHS   MHS  o

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Inc Inc resi resist stanc ance e to port portal al flow flow at the the leve levell of  sinusoids Compression of terminal hepatic vein Expansile nodules

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Clinical Consequences o o

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Ascites – at least 500 ml Intestinal fluid leakage, renal retention of Na & H20 Portosystemic venous shunts - bypass Rectum, cardioesophagea geal jxn (65%) 5%), retroperitoneum Falciform ligament (periumbilical collaterals) Congestive splenomegaly – 1,000g Hepatic encephalopathy

 Jaundice & Cholestasis Bili Biliru rubi binn- end end prod produc uctt of  heme degradation UGT1A1 – a product of UGT 1 gene located on chromosome 2q37 Causes of Jaundice Predominantly  o Unconjugated  Hyperbilirubinemia Excess Excess produc productio tion n  of bilirubin  Hemolytic anemias Resorpti Resorption on of blood  from internal hemorrhage Ineffective  erythropoiesis synd syndro rome mes s (e.g (e.g., ., perniciou pernicious s anemia, anemia, thalassemia) Reduc educe ed hepa epatic tic  uptake Drug Drug inte interfe rfere renc nce e  with membrane carrier systems Some cases of Gilbert syndrome  Impaired bilirubin conjugation  Physiologic jaundice of the newborn (decreased UGT1A1 activity, decreased excretion) excretion) Breast milk jaundice (β-glucuronidases in milk)

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Deficiency of canalicular membrane transporters Dubin-Johnson syndrome, Rotor syndrome)Impaired bile flow

Alcoholic Liver Disease Forms Hepatic steatosis o Alcoholic hepatitis o Hepatocyte swelling & necrosis Mallory bodies  Neutrophilic reaction  Fibrosis  Alcoholic cirrhosis 

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Pathogenesis

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Metabolic Liver Diseases A. Non-alcoho Non-alcoholic lic fatty fatty liver liver disea disease se & steat steatosis osis Stro Strong ng asso assoc c with ith obes obesit ity, y, dysl dyslip ipid idem emia ia,, hyperinsulinemia and insulin resistance Small Small and large large vesicl vesicles es of fat acumulate acumulate in hepatocytes Also an intermediate form of renal damage •

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B. Hemo Hemochr chrom omat atos osis is Excessive accumulation of body iron • •

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Genetic Genetic deficiency deficiency of UGT1A1 UGT1A1 activity activity (Crigler (Crigler-Najjar syndrome types I and II)Gilbert syndrome (mixed etiologies)Diffuse hepatocellular disease (e.g., viral or drug- induced hepatitis, cirrhosis) Predominantly Conjugated Hyperbilirubinemia

Cirrhosis Cirrhosis may occur, occur, presumabl presumably y the result of  years of subclinical pregression

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 Total body iron 2-6 g normally, 0.5 g is stored in the liver May exceed 50 g, 1/3 accumulate in the liver Fully developed cases exhibit Micronodular cirrhosis o Diabetes mellitus (75-80 % of cases) o Skin pigmentation (75-80 % of cases) o Hemochromatosis Hemochromatosis gene – 6p21.3 HFE gene regulates intestinal absorption of  o dietary iron Excessive iron Lipid Lipid perox peroxida idatio tion n via iron iron cataly catalyzed zed free free o radical reactions Stimulation of collagen formation o

General Pathology – Diseases of the Liver by  MHS   MHS  o

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Interaction Interaction of reactive reactive oxygen species and

iron iron itse itself lfwi with th DNA DNA à lethal lethal injury injury predisposition to hepatocellular carcinoma Morphology Hereditary hemochromatosis hemochromatosis o

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Deposition of hemosiderin  Cirrhosis Pancreatic fibrosis  Liver

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Golden Golden yellow yellow hemosideri hemosiderin n granules granules in the cytoplasm in periportal hepatocytes Stain blue with Prussian blue  Progressive Progressive involvement of the lobule  Direct hepatotoxin  Hereditary hemochromatosis o

Often in males, evident before 40

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Hepatomegaly

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Abdominal pain Skin pigmentation Derranged glucose homeostasis Cardiac dysfunction

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Accumulation of toxic levels of copper in many tissues and organs (liver, brain & eye) Cerulloplasmino o o

Copper +α2 globulin (ER) 90-95 % of plasma copper Desialylated, endocytosed by liver, excreted in the bile

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Gene  ATP7B, chromosome 13 – encodes 7.5 kB transcript transcript for transmembran transmembrane e copper transport ATPase 1:200 – frequency of mutated alleles

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Defe Defect ctiv ive e

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bili biliar ary y

excr excret etio ion n

lead leads s

Autosomal recessive disorder Most commonly diagnosed genetic liver disease in children α1 antitrypsin: o

Inhi Inhibi biti tion on

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cathe atheps psin in G, and and prot protei eina nase se 3 (fro from neutrophils) Small Small 384 amino amino acid plasma glycoprot glycoprotein ein synthesized by hepatocytes Gene at chromosome 14

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C. Wils Wilson on dise diseas ase e Autosomal recessive •

Diagnosis o Decrease serum ceruloplasmin Increase hepatic copper o Increase urinary excretion of copper o

D. α1 antitrypsin deficiency

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 Treatment o Penicillamine

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coppe copperr

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prot protea ease se,,

part part.. ..

elas elasta tase se,,

Pulmonary emphysema & liver disease Morphology Round to oval cytoplasmic inclusions o o Strongly PAS positive and diastase resistant Neonatal hepatitis, fibrosis, cirrhosis o Clinical features Neonatal hepatitis o May remain silent until cirrhosis occurs later o in life  10-20 % of newborns  Treatment liver transplantation

E. Neon Neonat atal al cho chole lest stas asis is 1 in 2500 live birth • •

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accumu accumulat lation ion in the liver liver à reactive reactive oxygen oxygen species à toxic liver injury Liver Changes Fatty Fatty change with vacuolated nuclei o Acute hepatitis like o o Chronic hepatitis Massive liver necrosis o Brain changes Basal Basal gangli ganglia, a, paticu paticular larly ly the putame putamen n is o affected Eye lesion Kayser Fleischer rings – deposits of copper in o Decemet’s membranes in the cornea Clinical features o Onset is variable, rare before 6 years old Acute or chronic liver disease o Neuropsychiatric manifestation o

of

Major conditions: o Biliary atresia Neonatal hepatitis o Morphologic features Lobular disarray o o

o o o o

Giant Giant cell cell transf transform ormati ation on of hepato hepatocyt cytes es (unique feature) Hepatocellular and canalicular cholestasis Mononuclear infiltration of portal areas Reactive changes in Kupffer cells Extramedullary hematopoiesis

Hepatic Disease Assoc with Pregnancy A. Pree Preecl clam amps psia ia 7-10 % of pregnancies •

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Maternal Maternal HPN, proteinuri proteinuria, a, peripheral peripheral edema, edema, coagulati coagulation on abnormali abnormalities, ties, varying varying degrees degrees of  DIC Eclampsia –if with convulsions and hyperreflexia HELLP HELLP syndro syndrome me – hemoly hemolysis sis,, elevat elevated ed liver liver enzymes, low platelets

General Pathology – Diseases of the Liver by  MHS   MHS  •

Morphology o Normal in size, firm, pale Ischemic infarction can be seen o Fibrin deposits in sinusoid o Hemorrhage in space of Disse o o

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Hepatic hematoma

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rupture

 Treatment o  Termination of pregnancy

B. Acute Acute Fatt Fatty y Liver Liver of Pregna Pregnancy ncy Spectr Spectrum um from from modest modest to subcli subclinic nical al hepati hepatic c dysfunction to hepatic failure, coma & death 20-40 % coexistent preeclampsia

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B. Angi Angios osar arco coma ma  Tumor of adults •

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Associated with vinyl chloride exposure, arsenic or thorotrast Poor prognosis

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Vascularized tissue

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C. Hepato Hepatocel cellul lular ar carcin carcinoma oma Malignant tumor of  •

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Diagnosis: Biopsy – microvesicular steatosis o Depe Depend nds s on high high leve evel of sus suspic picion & o confirmation by special stains oil red-O

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Liver Nodules A. Focal Nodula Nodular r Hyperp Hyperplas lasia ia Sponteneous mass lesion

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Lighter than surrounding liver

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Well demarcated demarcated but poorly encapsulated

B. Focal Nodula Nodular r Hyperp Hyperplas lasia ia Sponteneous mass lesion • •

Lighter than surrounding liver

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Well demarcated demarcated but poorly encapsulated

Benign Neoplasm A. Caver Caverno nous us heman hemangi giom oma a underneath capsule

85 % of cases of HCC occur in countries with high rates of chronic hepatitis B virus infection Cirrhosis is present in 85-90 % of patients Etiologic associations: Viral infection o Chronic alcoholism o Food contaminants (aflatoxin) o Morphology  o Pale tan to yellow liver with nodules Factors implicating HBV & HCV in HCC Repeated cycles of cell death an d o regeneration Hepa Hepato tocy cyte te dysp dyspla lasi sia a resu result lt from from poin pointt o mutation in selected cellular genes o Damage DNA repair mechanism Geno Genomi mic c inst instab abil ilit ity y is more more like likely ly in the the o presence of integrated HBV DNA, (giving rise deletions, translocations, and duplications). o X-protein, that is a transcriptional activator of many genes and is present in most tumors with integrated HBV DNA.

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benign benign tumor tumor of blood blood vessel vessels, s, compo composed sed of  tortuous vessels complication: hemorrhages

B. Live Liver r cel celll aden adenom oma a •

young women in oral contraceptives

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Morphology: o

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Pale, yellow tan, and frequently bile stained nodules Well demarcated Sheets and cords of cells resembling normal hepatocytes

Malignant Tumors A. Hepa Hepato tobl blas asto toma ma  Arise from embryonic cells of the liver  • •

Most common liver cell tumor of young children

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Fatal within few years if not resected

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Morphology o Epithelial type Mixed epithelial and mesenchymal type o

D. Chol Cholan angi gioc ocar arci cino noma ma Cells are similar to biliary tract epithelium • • •

Malignancy of the biliary tree Risk factors: Exposure to thorotrast o Primary sclerosing cholangitis o

General Pathology – Diseases of the Liver by  MHS   MHS  o

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Congen Congenita itall fibro fibropol polycy ycysti stic c diseas disease e of the biliary system Opisthorchis sinensis – in the orient

E. Meta Metast stat atic ic Tumor umors s Breast CA • •

Lung CA

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Colon CA

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Leukemia Leukemia and lymphomas

Quiz 1 – 3 Patterns of Hepatic Injury 4 Cells that are the cause of fibrosis – stellate cells 5 Excess iron – hemochromatosis 6 Accumulation of Cu – Wilson Dse 7 Benign tumor in women on OCPs – liver cell adenoma 8 – 9 S/Sx of portal hypertension – ascites, portocaval shunts etc

Madami pa ata kaming utang na trans… Paunti unti na lang akong mag uupl uuploa oad. d.  Thanks for for the understanding Haay, sarap magbakasyon (pag may life ka other than acads!) :-p

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