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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Apoptotic cell death (when there is continuous injury) –shrunken, pyknotic and intensely eosinophilic cells obtaining fragmented nuclei

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Lytic cell death (outcome of balooning degeneration) Centrilobular – drug and toxic reactions Midzonal - rare Periportal – eclampsia Focal/ spotty – scattered cells within hepatic lobules Bridging necrosis - contigous

Wt 1500g (2.5% of TBW) In surgery, divided into 8 lobes – caudate lobe (1st lobe), the remaining (2nd to 8th lobe); designated on the basis of blood supply

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Histologically, are composed of hexagonal lobules o In the center: terminal hepatic vein o In the periphery: hepatic tract (portal vein, hepatic artery & bile duct) o Hepatic plates with thin layer of endothelial cells o Stellate cells which are precursors of fibrous tissue which proliferates in cirrhosis

C. INFLAMMATION • Hepatitis – injury to the liver associated with influx of acute and chronic inflammatory cells • Viral hepatitis o quiescent lymphocyte may collect into the portal tracts o Spill over the periportal parenchyma as activated lymphocytes D. REGENERATION • Regeneration occurs in all but most fulminant hepatic disease • Hepatocyte proliferation is marked by: o Mitoses o Thickening of the hepatocyte cords o Disorganization of the parenchymal architecture E. FIBROSIS • Fibrous tissue – formed in response to inflammation or direct toxic insult • Points to generally irreversible hepatic damage

Patterns of Hepatic Injury A. DEGENERATION AND INTRACELLULAR ACCUMULATION

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Swelling (reversible), ballooning (clumping o organelles) degeneration

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Feathery degeneration (in cholestasis)

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Steatosis (there is displacement of nucleus)

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Microvesicular - acute fatty liver of pregnancy Macrovesicular – diabetic/ obese px Both – alcoholic fatty liver

B. NECROSIS AND APOPTOSIS • Ischemic coagulative necrosis- poorly stained & mummified, lysed nuclei

MR*, Mel, Eisa

(kami ba trans n2?)

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

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General Pathology – Diseases of the Liver by MHS •

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Life threatening o Susceptible to multiple organ failure o Coagulopathy  Impaired synthesis of CF II, VII, IX, X Massive GI bleeding e.g. gastroesophageal varices  Further metabolic load on the liver Hepatic encephalopathy

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Subtle behavioral changes to confusion à stupor

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àcoma Neurologic signs  

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Rigidity Hyperreflexia

 Asterixis o Increase ammonia levels Hepatorenal syndrome o Functional abn   

Na retention Impaired water excretion Decrease renal perfusion and GFR

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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 Bridging fibrous septae Parenchymal nodules formed by septae o Disruption of the architecture Pathogenesis o Collagen Types I & III are normally in o

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 Portal tract, central vein, space of Disse Type I & III collagen à deposited in lobules o New vascular channels o Deposition of collagen in Space of Disse (loss of hepatic plates and endothelial cells) o Loss of fenestrations in sinusoidal endothelial cells o No exchange of solutes between hepatocytes & plasma o Impaired secretion of proteins Perisinusoidal stellate cells o Source of fibrosis o Vitamin A fat storing cells (normally)located in space of Disse o Activated in cirrhosis (stimulated into myofibroblasts)  Robust mitotic activity  Shift from resting lipocyte to myofibroblast phenotype  Increase capacity for synthesis of extracellular matrix

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Clinical features o May be clinically silent o Anorexia o Weight loss o Weakness o Osteoporosis o Frank debilitation • Mechanism of cirrhotic deaths o Progressive liver failure o Complications related to portal hypertension o Development of hepatocellular carcinoma Portal Hypertension • Increase resistance to blood flow • Pre-hepatic, post hepatic, intrahepatic • In cirrhosis

General Pathology – Diseases of the Liver by MHS Inc resistance to portal flow at the level of sinusoids o Compression of terminal hepatic vein o Expansile nodules Clinical Consequences o Ascites – at least 500 ml o Intestinal fluid leakage, renal retention of Na & H20 o Portosystemic venous shunts - bypass o Rectum, cardioesophageal jxn (65%), retroperitoneum o Falciform ligament (periumbilical collaterals) o Congestive splenomegaly – 1,000g o Hepatic encephalopathy

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Jaundice & Cholestasis • Bilirubin- end product of heme degradation • UGT1A1 – a product of UGT 1 gene located on chromosome 2q37 • Causes of Jaundice o Predominantly Unconjugated Hyperbilirubinemia  Excess production of bilirubin  Hemolytic anemias  Resorption of blood from internal hemorrhage  Ineffective erythropoiesis syndromes (e.g., pernicious anemia, thalassemia)  Reduced hepatic uptake  Drug interference with membrane carrier systems  Some cases of Gilbert syndrome  Impaired bilirubin conjugation Physiologic jaundice of the newborn (decreased UGT1A1 activity, decreased excretion) Breast milk jaundice (β-glucuronidases in milk)

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

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

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

Metabolic Liver Diseases A. Non-alcoholic fatty liver disease & steatosis • Strong assoc with obesity, dyslipidemia, hyperinsulinemia and insulin resistance • Small and large vesicles of fat acumulate in hepatocytes • Also an intermediate form of renal damage • Cirrhosis may occur, presumably the result of years of subclinical pregression B. Hemochromatosis • Excessive accumulation of body iron • 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 o Micronodular cirrhosis o Diabetes mellitus (75-80 % of cases) o Skin pigmentation (75-80 % of cases) • Hemochromatosis gene – 6p21.3 o HFE gene regulates intestinal absorption of dietary iron • Excessive iron o Lipid peroxidation via iron catalyzed free radical reactions o Stimulation of collagen formation

General Pathology – Diseases of the Liver by MHS

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Interaction of reactive oxygen species and

iron itselfwith DNA à lethal injury à predisposition to hepatocellular carcinoma Morphology o Hereditary hemochromatosis

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 Deposition of hemosiderin  Cirrhosis  Pancreatic fibrosis Liver

Golden yellow hemosiderin granules in the cytoplasm in periportal hepatocytes  Stain blue with Prussian blue  Progressive involvement of the lobule  Direct hepatotoxin Hereditary hemochromatosis o Often in males, evident before 40

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Hepatomegaly Abdominal pain Skin pigmentation Derranged glucose homeostasis Cardiac dysfunction

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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 for transmembrane copper transport ATPase 1:200 – frequency of mutated alleles

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Defective

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biliary

excretion

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Autosomal recessive disorder Most commonly diagnosed genetic liver disease in children

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α1 antitrypsin:

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C. Wilson disease • Autosomal recessive • Accumulation of toxic levels of copper in many tissues and organs (liver, brain & eye) • Cerulloplasmin-

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

D. α1 antitrypsin deficiency

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copper

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

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Inhibition of protease, part.. elastase, cathepsin G, and proteinase 3 (from neutrophils) o Small 384 amino acid plasma glycoprotein synthesized by hepatocytes o Gene at chromosome 14 Pulmonary emphysema & liver disease Morphology o Round to oval cytoplasmic inclusions o Strongly PAS positive and diastase resistant o Neonatal hepatitis, fibrosis, cirrhosis Clinical features o Neonatal hepatitis o May remain silent until cirrhosis occurs later in life  10-20 % of newborns Treatment liver transplantation

E. Neonatal cholestasis • 1 in 2500 live birth • Major conditions: o Biliary atresia o Neonatal hepatitis • Morphologic features o Lobular disarray o Giant cell transformation of hepatocytes (unique feature) o Hepatocellular and canalicular cholestasis o Mononuclear infiltration of portal areas o Reactive changes in Kupffer cells o Extramedullary hematopoiesis Hepatic Disease Assoc with Pregnancy A. Preeclampsia • 7-10 % of pregnancies

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Maternal HPN, proteinuria, peripheral edema, coagulation abnormalities, varying degrees of DIC Eclampsia –if with convulsions and hyperreflexia HELLP syndrome – hemolysis, elevated liver enzymes, low platelets

General Pathology – Diseases of the Liver by MHS •

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

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Hepatic hematoma à rupture

Treatment o Termination of pregnancy

B. Acute Fatty Liver of Pregnancy • Spectrum from modest to subclinical hepatic dysfunction to hepatic failure, coma & death • 20-40 % coexistent preeclampsia • Diagnosis: o Biopsy – microvesicular steatosis o Depends on high level of suspicion & confirmation by special stains oil red-O Liver Nodules A. Focal Nodular Hyperplasia • Sponteneous mass lesion • Lighter than surrounding liver • Well demarcated but poorly encapsulated B. Focal Nodular Hyperplasia • Sponteneous mass lesion • Lighter than surrounding liver • Well demarcated but poorly encapsulated Benign Neoplasm A. Cavernous hemangioma • underneath capsule • benign tumor of blood vessels, composed of tortuous vessels • complication: hemorrhages

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B. Angiosarcoma • Tumor of adults • Associated with vinyl chloride exposure, arsenic or thorotrast • Poor prognosis • Vascularized tissue C. Hepatocellular carcinoma • Malignant tumor of • 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: o Viral infection o Chronic alcoholism o Food contaminants (aflatoxin) • Morphology o Pale tan to yellow liver with nodules • Factors implicating HBV & HCV in HCC o Repeated cycles of cell death and regeneration o Hepatocyte dysplasia result from point mutation in selected cellular genes o Damage DNA repair mechanism o Genomic instability is more likely in the 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.

B. Liver cell adenoma

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young women in oral contraceptives

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

Malignant Tumors A. Hepatoblastoma • Arise from embryonic cells of the liver • Most common liver cell tumor of young children • Fatal within few years if not resected • Morphology o Epithelial type o Mixed epithelial and mesenchymal type

D. Cholangiocarcinoma • Cells are similar to biliary tract epithelium • Malignancy of the biliary tree • Risk factors: o Exposure to thorotrast o Primary sclerosing cholangitis

General Pathology – Diseases of the Liver by MHS o o

Congenital fibropolycystic disease of the biliary system Opisthorchis sinensis – in the orient

E. Metastatic Tumors • Breast CA • Lung CA • Colon CA • 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 uupload.  Thanks for the understanding Haay, sarap magbakasyon (pag may life ka other than acads!) :-p

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