Liver

LIVER DR. MAGKASI LIVER  1,400 – 1,600 gms  2.5% of body weight  Dual blood supply o Portal vein: 60% - 70% o Hepatic artery: 30% - 40% General Features of Hepatic Disease  Vulnerable to metabolic, toxic, microbial, circulatory, and neoplastic insults  Dominant primary diseases o Viral hepatitis, alcoholic liver disease, NAFLD o Hepatic damage maybe secondary o Enormous functional reserve o Insidious process o May heal without clinical detection Patterns of Hepatic Injury 1. Degeneration and intracellular accumulation 2. Necrosis and apoptosis 3. Inflammation 4. Regeneration 5. Fibrosis Degeneration and Intracellular Accumulation Degeneration  Ballooning degeneration – toxic or immune  Feathery degeneration – cholestatic injury Accumulation  Iron and copper  Triglyceride droplets – steatosis o Microvesicular – AFLP, valproic acid toxicity, Reye Syndrome o Macrovesicular – obese, diabetic Necrosis and Apoptosis  Coagulation necrosis  Lytic necrosis  Apoptosis  Zonal distribution o Centrilobular, midzonal and periportal Inflammation  Acute or chronic inflammatory cells  Necrosis incites inflammatory reactions  Inflammation may precede necrosis granulomatous inflammation Regeneration  Marked by mitosis, thickening of hepatocytes cords & some disorganization of the parenchymal structures  Canal of Hering-bile ductile unit serves as reserve compartment for restitution, ductular reaction  Even with submassive or massive necrosis, as long as connective tissue framework in intact, perfect restitution Fibrosis  Response to inflammation or direct toxic insult  Irreversible

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Affects patterns of blood flow and perfusion of hepatocytes Cirrhosis

Hepatic Failure  Most severe clinical consequence of liver disease  May be due to sudden, massive liver destruction (fulminant hepatic failure)  Or due to insidious destruction of hepatocytes or by repetitive waves of parenchymal damage  80-90% functional capacity destroyed  Liver transplantation only hope  80% mortality Chronic liver disease  Most common route to hepatic failure  Endpoint of relentless chronic hepatitis leading to cirrhosis Hepatic dysfunction without overt necrosis  Hepatocytes are viable but unable to perform functions  Tetracycline toxicity, acute fatty liver pregnancy Hepatic Failure: Clinical Features  Jaundice  Hypoalbuminemia  Hyperammononemia  Fetor hepaticus  Impaired estrogen metabolism (palmar erythema, spider angiomas, male hypogonadism and gynecomastia)  Coagulopathy  Encephalopathy  Hepatorenal syndrome o Drop in urine output o Rising BUN, creatinine o Poor prognosis  Hepatopulmonary syndrome o Chronic liver disease o Hypoxemia o Intrapulmonary vascular dilations (IVPD) Cirrhosis: Characteristics  Bridging fibrous septae  Parenchymal nodules  Disruption of liver architecture Features to be understood:  Parenchymal and subsequent fibrosis are diffuse  Nodularity is part of diagnosis, resulting from repeated cycles of regeneration and scarring  Vascular architecture reorganized forming bypass channels  Fibrosis is a key feature of progressive liver damage – slow regression with cessation of injury; reversal is rare Pathogenesis  Death of hepatocytes  ECM deposition  Vascular reorganization

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Deposition of type I and II collagen is space of Disse Activation of stellate cells and Kupffer cells

Clinical Features  40% is asymptomatic  Nonspecific clinical manifestations  Incipient or overt hepatic failure  Hepatopulmonary syndrome  Death from: o Progressive liver failure o Complication of portal hypertension o Hepatocellular carcinoma Portal Hypertension  Increased resistance to portal blood flow o Caused by contraction of vascular smooth muscle cells and myofibroblasts and disruption of blood flow, by scarring and formation of parenchymal nodules  Increase in portal venous blood flow resulting from a hyperdynamic circulation o Caused by arterial vasodilation, primarily in splanchninc circulation Consequences: 1. Ascites  Detectable when at least 500ml  Generally serous Pathogenesis  Sinusoidal hypertension  Percolation of hepatic lymph into the peritoneal cavity  Splanchnic vasodilation and hyperdynamic circulation 2. Splenomegaly  1000 gms wt  Induce hypersplenism with thrombocytopenia and pancytopenia 3. Jaundice and Cholestasis  Causes of Jaundice: o Bilirubin overproduction o Hepatitis Common Virus Hepatitis A (HAV) name Common Disease “Infectious” Name Virus Picornavirus naked capsid RNA

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o Obstruction to the flow of bile Function of Hepatic Bile: o Emulsification of dietary fat o Elimination of bilirubin, excess cholesterol, xenobiotics and other waste products

Jaundice  Occurs when equilibrium between bilirubin production and clearance is distributed by 1. Excessibe extrahepatic production of bilirubin 2. Reduced hepatocyte uptake 3. Impaired conjugation 4. Decreased hepatocellular excretion 5. Impaired bile flow Cholestasis  Etiology: impaired bile formation and blood flow  Accumulation of bile in hepatic parenchyma  Morphology  Caused by: o Intrahepatic or extrahepatic obstruction of bile channels o Defects in hepatocyte bile secretion  Treatment: o Extrahepatic biliary obstruction – surgery o Intrahepatic cholestasis – medical/transplant  Elevated ALP and GGT Infectious Disorders  Viral – foremost hepatic infection  Military tuberculosis  Malaria  Staphylococcal bacteremia  Salmonellosis  Candida  Amebiasis Viral Hepatitis  Infectious Mononucleosis (EBV)  CMV in newborn or immunosuppressed  Yellow fever virus

Hepatitis B (HBV)

Hepatitis C (HCV)

Hepatitis D (HDV)

Hepatitis E (HEV)

“Serum”

“Post-transfusion” or “non-A, non-B” Flavivirus enveloped RNA

“Delta”

“enteric” Calcivirus naked capsid RNA

Acute Hepatitis

Parenternal, Sexual Occasionally severe

Parenternal, sexual Usually subclinical

No

Yes

Yes (high)

Defective enveloped circular RNA Parenternal, sexual Co-infection with HBV occasionally – superinfection with HepB Yes

Acute hepatitis

-Acute Hepa -Chronic Hepa -Cirrhosis -Hepato-cellular carcinoma (HCC)

-Acute Hepa -Chronic Hepa -Cirrhosis -HCC

-Acute Hepa -Chronic Hepa -Cirrhosis -HCC

Transmission

Fecal-oral

Severity

Mild

Chronicity or carrier state Clinical disease

Hepadnavirus enveloped DNA

Fecal-oral Normal patients: mild, pregnant patients: severe No

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Laboratory diagnosis

Symptoms and anti-HAV IgM

Prevention

Vaccine, hygiene

Symptoms and serum levels of HBsAg, HBeAg, and anti-Hbc IgM Vaccine

HBV Infection 4-26 weeks incubation HBV can produce: 1. Acute hepatitis with recovery and clearance of virus 2. Non-progressive chronic hepatitis 3. Progressive chronic disease ending in cirrhosis 4. Fulminant hepatitis with massive liver necrosis 5. Asymptomatic carrier state Natural course of disease: 1. HBsAg- appears before onset of symptoms; declines in 6 months 2. Anti-HBs do not rise until acute is over; may persist for life 3. IgM anti-HBc become detectable in serum before onset of symptoms HEPATITIS C VIRUS  Major cause of liver disease worldwide  Most common chronic blood borne infection  Progression to chronic disease occurs in majority of infected individuals  20-30% develops to cirrhosis  Persistent infection and chronic hepatitis are hallmarks of infection  A clinical feature that is quite characteristics of chronic HCV infection is episodic elevation of serum aminotransferases, with intervening normal or near normal periods  Fulminant hepatic failure rarely occurs HEPATITIS D VIRUS  Dependent for its cycle on HBV  Acute coinfeciton  Superinfection (30-50) days later  Helper independent latent infection in liver transplant setting  Detectable in blood and liver just before and in early days of acute asymptomatic disease  IgM and anti-HDV is the most reliable indicator of recent HDV exposure  Vaccination for HBV can also prevent HDV infection Clinicopathologic Syndromes of Viral Hepatitis 1. Acute asymptomatic infection with recovery: serologic evidence only 2. Acute symptomatic infection with recovery  Incubation period  Symptomatic preicteric phase  Symptomatic icteric phase  Convalescence 1. Chronic Hepatitis  Continuing hepatic disease for more than 6 months 2. The carrier state  An individual who harbors and can transmit an organism, but has no manifestations of symptoms

Symptoms and anti-HCV ELISA

Anti-HCV ELISA

Hygiene Bacterial, Parasitic, and Helminthic Infections  Bacterial etiology o S. aureus, S. typhi, & T. pallidum o Bacterial gut flora in ascending cholangitis  Parasitic and helminthic o Malaria, schitosomiasis, strongyloidiasis, cryptosporidiosis,, leishmaniasis, echinococcosis, liver flukes  Liver abscess o Amebic, pyogenic Liver Abscess  Solitary or multiple; echinococcal or amebic  Spread thru portal vein arterial supply direct extension penetrating trauma ascending infection  Rx: surgical drainage; antibiotics  MR: 30-90%;80% surgery with early dx Autoimmune Hepatitis  A chronic and progressive hepatitis of unknown etiology  Salient features o Female predominance (78%) o Absences of viral serologic markers o Elevated serum IgG & gamma-globulin levels o High serum titers of autoantibodies  Types I and II, based on the patterns of circulating antibodies  Type I – associated with HLA DR-3 o ANA, SMA, AAA, anti-SLA/LP antibodies  Type II o ALKM-1, ACL-1  Lymphocyte and plasma cell infiltrates are prominent  May progress to cirrhosis without clinical diagnosis  Untreated, 40% die within 6 months, cirrhosis in at least 40% of survivors  Responsive to immunosuppressive therapy  Liver transplantation for patients with severe disease Drug and Toxin-induced Disease  Injury may result from: o Direct toxicity to hepatocytes of biliary epithelial cells o Conversion of xenobiotic to active toxin, or o Immune mechanisms  Maybe predictable (INTRINSIC) or unpredictable (IDIOSYNCRATIC)  Predictable drug reactions:  Acetaminophen- leading cause of drug-induced acute liver failure  Amanita phalloides toxin, CCl4, alcohol  Isoniazid, Nonsteroidal analgesics, antiseizure medications – prescription drugs with idiosyncratic reactions  Reye syndrome

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Potentially fatal mitochondrial dysfunction of liver, brain; exceedingly rare; microvesicular steatosis Exposure to toxin or therapeutic agent should always be a differential dx in liver disease

Alcoholic Liver Disease  Excessive comsumption of alcohols is the most leading cause of liver disease in most Western countries  Forms of alcoholic liver disease o Hepatic steatosis o Alcoholic hepatitis o Cirrhosis  Pathogenesis: o Up to 80gms, mild, reversible hepatic change o 80gms or more, significant risk of severe hepatic injury o 160gms or more daily for 10 to 20 yrs, consistently severe injury o Only 10-15% of alcoholics develop cirrhosis  Factors for development and severity of alcoholic liver disease o Gender o Ethnic differences o Genetic factos o Co-morbid conditions: HCV and HBV  Detrimal effects of alcohol & its byproducts on hepatocellular functions: o Excess NADH + H+ promotes lipid synthesis o Impaired assembly & secretion of lipoproteins o Increased peripheral fat catabolism  Alcohol can become sources of calories in diet, displacing other nutrients and leading to malnutrition and vitamin deficiency  Alcohol causes relased of bacterial endotoxin in gut inducing inflammatory responses in the liver  Acetaldehyde – induces lipid peroxidation disrupts cytoskeletal and membrane function Clinical Features:  Hepatic steatosis: hepatomegaly with mild increase in billirubin and & ALF  Alcoholic hepatitis: acute following a bout of heavy drinking; minimal Sx or fulminant hepatic failure; nonspecific Sx; 10-20% risk of death  Alcoholic cirrhosis – portal HPN

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Most common cause of cryptogenic cirrhosis 10-30% eventually develop cirrhosis Morphology: steatosis, steatohepatitis and cirrhosis

Hemochromatosis  Excessive accumulation of body iron especially in parenchymal organs, e.g. liver and pancreas  Result from genetic defect causing excessive absorption (hemochromatosis) or parenteral administration of iron, (hemosiderosis) e.g., transfusion.  Total iron > 50 gm (NV=2-6 gm)  Adult form of hemochromatosis is almost always caused by mutations of HFE  Characteristic features 1. Micronodular cirrhosis in all patients 2. Diabetes mellitus in 75- 80% of patients 3. Skin pigmentation 75- 80% of patients  Iron accumulation is lifelong manifest 5th or 6th decades  Male prominence (5 to 7:1)  Mechanisms of direct tissue toxicity of excessive iron: 1. Lipid peroxidation via iron-catalyzed free rad 2. Stimulate collagen formation 3. Reactive O2 & iron interacting with DNA causing lethal injury or predisposition to HCC  Hepcidin- main regulator of iron absorption encoded by HAMP gene  Transcription of hepcidin is increased by inflammatory cytokines and iron and decreased by iron deficiency, hypoxia and ineffective erythropoiesis  Hepcidin lowers plasma iron levels; a deficiency in hepcidin causes iron overload. Hemochromatosis: Diagnosis and treatment  Very high serum iron and ferritin, exclude secondary causes, liver biopsy  Screening of family members  Diagnosed in the subclinical, precirrhotic stage  Regular phlebotomy with normal life expectancy  Autosomal recessive, mutation of ATP7B gene  Impaired excretion of copper into bile and failure to incorporate copper into ceruloplasmin  Marked by accumulation of toxic levels of copper in many tissues or organs, principally liver, brain and eye.

Treatment: Alcohol withdrawal and proper nutrition Cause of death: 1. Hepatic coma 2. Massive GIT hemorrhage 3. Intercurrent infection 4. Hepatorenal syndrome 5. Hepatocellular carcinoma (1-6%)

Wilson disease: clinical features  Extremely variable at age onset  Most common presentation: acute or chronic liver disease  Neuropsychiatric Sx, e.g., behavioral changes to frank psychosis, Parkinson dse-like  Dx: decreased serum ceruloplasmin, increased in hepatic Cu content, and increase in urinary excretion of Cu; demo of Kayser-Fleischer rings

Nonalcoholic Fatty Liver Disease  In common with individuals who do not consume alcohol or in those with very small quantities  Men & women equally affected  Strong association with obesity, dyslipidemia, hyperinsulinemia & insulin resistance, and type 2 diabetes  Increased AST and ALT  Most common cause of chronic liver disease in US

Alpha-1-AT Deficiency  Autosomal recessive  Marked by abnormally low serum levels or A1AT protease inhibitor (PI)  Inhibits proteases, elastase, cathepsin G, and proteinase 3  Gene located in chromosome 14  PIMM, 90% genotype, normal A1AT

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Pi-null, no detectable serum A1AT, rare PiZZ, 10% normal A1AT -> clinical disease

A1AT deficiency: pathogenesis  Mutant polypeptide (A1AT-Z) is abnormally folded and polymerizes -> retention in the ER of Hepatocytes  A1AT not hepatotoxic  10% PiZZ develop clinical disease due to log in ER protein degradation pathway->intense autophagocytic response-> autophagocytosis of mitochondria A1AT deficiency: clinical features  Remain silent until cirrhosis appears in middle to later life; pulmonary emphysema  HCC in 2-3% of PiZZ  Rx; orthotopic liver transplant; avoidance of cigarette smoking Neonatal Cholestasis  Prolonged conjugated hyperbilirubinemia in the neonates  Jaundice, dark urine, light or achcolic stools, hepatomegaly, hypoprothrombinemia  Dx; liver biopsy Neonatal Cholestasis: morphology  Lobular disarray w/ focal necrosis;  Panlobular giant cell transformation with rosette formation;  Cholestasis  Mild portal mononuclear infiltrates;  Reactive kupffer cells;  Extramedullary hematopoiesis Intrahepatic Billary Tract Disease 1. Secondary Billary cirrhosis 2. Primary Billary cirrhosis 3. Primary sclerosing cholangitis 4. Anomalies of the Biliary tree Nodules and Tumors Nodular hyperplasias  Focal nodular hyperplasia  Nodular regenerative hyperplasia Benign neoplasms  Cavernous hemangioma  Liver cell adenoma Malignant tumors  Hemangioblastoma  Hepatic cellular CA  Angiosarcoma  Cholangiosarcoma Benign neoplasms  Cavernous hemangioma- most common benign tumor; discrete red-blue, soft nodules, 90% associated with cholelithiasis  Morphology: mononuclear cells, fibrosis, prominent RA sinus, porcelain gallbladder  Xanthogranulomatous cholecystitis, hydrops of gallbladder  Complications: bacterial superinfection, perforation & abscess, rupture, fistula, aggravation of pre-existing medical problems ***...eto un diniscuss na slides ni doc.  ==============================================

Pigment Stones  Demography: Asian > Western, rural > urban  Chronic hemolytic syndromes  Biliary infection  GIT disorders: ileal disease (e.g. Crohn disease), ileal resection or bypass, cystic fibrosis with pancreatic insufficiency Cholelithiasis: Clinical Features  80% are “silent”  90% - cholesterol stones: the rest are pigment stones composed of bilirubin calcium salts  Sx: excruciating colicky or constant biliary pain  Complications: empyema, perforation, fistula, cholangitis, and obstructive cholestasis or pancreatitis, intestinal obstruction, risk for cholangiocarcinoma Cholecystitis  Acute, chronic or acute superimposed on chronic  Almost always in association with gallstones  Most common indications for abdominal surgery  Acute calculous cholecystitis: 90% precipitated by obst’n of the ncek or cystic duct  Acute acalculous cholecystitis: severely ill patients without gallstones o Postoperative state after major nonbiliary surgery o Severe trauma/burns, MOF, prolonged IV hyperalimentation, postpartum state

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