Liver Flashcards
Jaundice, cholestasis
Hypoalbuminemia
Hypoglycemia
Hyperammonia (defective urea cycle function)
Palmar erythema (local vasodilation)
Spider angioma (central pulsating dilation of arteriole with small vessel radiation)
Hypogonadism (hyperestrogenemia) and gynecomastia
Gynecomastia
Weight loss
Muscle wasting
Severe Hepatic Dysfunction
Ascites with peritonitis Splenomegaly Esophageal varices Hemorrhoids Caput medusae
Portal hypertension associated with Cirrhosis
Coagulopathy Hepatic encepalopathy Hepatorenal syndrome Portopulmonary hypertension Hepatopulmonary syndrome
Complications of Hepatic failure
Hepatocyte integrity (Elevation: Liver disease)
AST
ALT
LDH
Biliary excretory function
Serum bilirubin (Total, Direct, Delta:linked to albumin)
Urine bilirubin
Serum bile acid
Plasma membrane (damage to bile canaliculi)
Serum alkaline phosphatase
Serum gamma glutamyl transpeptidase
Serum 5’ nucleotidase
Hepatocyte function
Serum albumin Prothrombin time (V,VII,X,PT,fibrinogen) Hepatocyte metabolism: Serum ammonia Aminopyrine breath test (heptic demethylation) Galactose elimination (IV injection)
Most severe consequence of liver disease, end point of progressive damage
Loss of 80-90% hepatic function
Insidious piecemeal destruction, repetitive waves of parenchymal damage or sudden, massive destruction
Hepatic failure
Drugs or viral hepatitis
Clinical hepatic insuff to hepatic enceph within 2-3 weeks
MASSIVE HEPATIC NECROSIS
Liver transplant
Acute Liver Failure with Massive Hepatic Necrosis
Most common route to hepatic failure, endpoint of chronic liver damage
Parenchymal, biliary or vascular in origin
Ends in cirrhosis
Chronic liver disease
Acute liver failure extending more than 3 months
subacute
Viable hepatocyte but unable to perform metabolic function
Mitochondrial injury in Reye syndrome
Acute Fatty Liver of pregnancy
Toxin mediated injury
Hepatic dysfunction without overt necrosis
Bile two major functions
1 primary pathway for elimination of bilirubin, chole and xenobiotics
2 emulsification of fat in gut by bile salt and phospholipid
Yellow discoloration of skin and sclerae icterus occurs when system retention of bilirubin exceeds
2 mg/dl jaundice
Systemic retention of bilirubin + BILE SALTS AND CHOLESTEROL
Cholestasis
Oxidize heme to biliverdin
Biliverdin is reduced to bilirubin by
Heme oxygenase
Biliverdin reductase
Bilirubin hepatocyte uptake
Carrier mediated uptake at sinusoidal membrane
Cystosolic protein bindingn and delivery to ER
Conjugation with one or two molecules of glucoronic acid by bilirubin UDP GT uridine diphosphate glucuronosyl transferase
Excretion of water soluble nontoxic bilirubin glucuronides into bile (conjugated)
Conjugated bilirubin is deconjugated by gut bacterial B glucuronidase and degraded to
colorless urobilinogen
Physiologic jaundice or neonatal jaundice happens bec hepatic machinery for bilirubin conjugation and excretion only matures at around
2 weeks
Common 7% benign heterogenous inherited mild fluctuating unconjugated hyperbilirubinemia
Dec hepatic levels of glucorosyltransferase from mutation in encoding gene
No morbidity
Gilbert Syndrome
Autosomal recessive defect in transport protein for hepatocellular excretion of bilirubin glucuronides across canalicular membrane
Exhibit hyperbilirubinemia
Darkly pigmented liver from polymerized epinephrine metabolites
Hepatomegaly without functional problem
Dubin-Johnson Syndrome
Enzyme in bile duct and canaliculi of hepatocyte
Elevated in cholestasis
ALP
Hemolytic anemia
Resorption of blood from intestinal hemorrhage
Ineffective EPO syndrome (pernicious, thalassemia)
excess bilirubin production
predominantly unconjugated hyperbilirubinemia
drug interference with membrane carrier system
diffuse hepatocellular disease (viral, drug induced)
reduced hepatic uptake
predominantly unconjugated hyperbilirubinemia
physiologic jaundice of newborn
Impaired bilirubin conjugation
Predominantly unconjugated hyperbilirubinemia
Def of canalicular membrane transporter
Drug induced canalicular membrane dysfunction (ocp cyclosporine)
Hepatocellular damage/toxicity
Dec hepatocellular excretion
Predominantly conjugated hyperbilirubinemia
Inflammatory destruction of intrahepatic bile duct (primary sclerosing, graft-vs-host, liver transplant) gallstone, ca of pancreas
Impaired intra or extra-hepatic bile flow
Predominantly conjugated hyperbilirubinemia
Most common cause of jaundice involving accumulation of unconjugated bilirubin
Hemolytic anemia
Most common cause of jaundice involving accumulation of conjugated bilirubin
Hepatitis intra or extrahepatic obstruction
Rigidity Hyperreflexia Nonspecific EEG Seizure ASTERIXIS (flapping tremor) nonrhythmic rapid ext and flex movement of head and extremities esp when arms are held in extension with dorsiflexed wrist
Hepatic
Encephalopathy
Factors contributing to hepatic enceph
severe loss of hepatocellular function
shunting of blood from portal to systemic circulation around chronically diseased liver
Key pathogenesis in hepatic enceph
Elevation in blood ammonia
Impairing neuronal function and promoting generalized brain edema in acute
Deranged neurotrasmitter production monoaminergic, opiodergic, y-aminobutyric acid and endocannabanoid system in chronic
Diffuse process characterized by fibrosis and conversion of normal liver architecture to structurally abnormal nodule
Cirrhosis
Cirrhosis main characteristics
1 fibrous septa - delicate bands or broad scars around lobules
Long standing fibrosis is irreversible as long as vascular shunts are present, regression if cause reversed
2 parenchymal nodule - small to large, encircled by fibrous bands
Preexistent hepatocyte displaying replecative senescence at time of fibrosis
Newly formed hepatocyte capable of replication gives rise to ductular reactions at periphery of nodules
3 involvement of most of liver
3 processes central to pathogenesis of cirrhosis
Death of hepatocyte
Extracellular matrix deposition
Vascular reorganization
In cirrhosis this type of collagen is deposited in space of Disse instead of type IV
Type I & III
Major source of excess collagen in cirrhosis normally functioning as storage of Vitamin A
Activate and transform to myofibroblast during fibrosis due to ROS, TNF, IL1 and lymphotoxin
Stellate cells of perisinusoid
Ito cells in space of Disse
stellate cells produce that initiate fibrosis formation
TGF B
Even in late stage disease this may happen significant restoration or remodelling due to dynamic process of ECM synthesis, deposition and resorption by metalloproteases
cirrhotic regression
Vascular lesions that contribute to liver function defect
Loss of sinusoidal endothelial fenestration and inc basement membrane formation -> thin walled sinusoid becoming fast flowing vascular channel -> impaired protein movement
Portal vein-hepatic vein shunt
Hepatic artery-portal vein shunt
Dominant intrahepatic cause of portal hypertension
cirrhosis
Inc resistance to portal flow and compression of central vein by perivenular fibrosis and parenchymal nodule
Inc blood flow to portal vein from vasodilation of splanchnic circulation (hyperdynamic circulation) from inc NO from bacterial DNA
Imposed arterial pressure on normally low pressure portal veins
Portal hypertension
Collection of excess fluid in peritoneal cavity at least 500 ml to be clinically detectable
Serous, 3g/dL of albumin
Serum ascites:albumin gradient >/= 1.1 g/dL
scant mesothelial cell and mono
Ascites
Neutrophilic -infection
RBC -cancer
Hydrothorax on right from peritoneal fluid seepage through diaphragm lymphatics
Ascites pathogenesis
Inc movement of intravascular fluid into spase of Disse by sinusoidal HTN and hypoalbuminemia
Leakage of fluid from hepatic interstitium to peritoneum. Hepatic lymph flow >20l (normal 800-1000ml) which is rich in proteins and low in TAG
Renal retention of Na and water 2 to hyperaldosteronism despite total body sodium mass more than normal
Principal sites of portosystemic shunt
Rectal veins
CEJ veins
Retroperitoneum and falciform ligament of liver (periumbilical and abdominal)
Renal failure without primary abnormality of kidney in severe liver failure bec splanchnic vasodilation and systemic vasoconstriction leading to dec renal blood flow of cortex
Dec UO and inc BUN, Crea
Hyperosmolar urine devoid of protein and abn sediment (low in sodium) vs RTN
Tx: transplant, HD
Hepatorenal syndrome
Exclude circulatory collapse
Pulmonary arterial HTN assoc with liver disease or portal HTN
Excessive pulmo vasocon and vaso remodelling leading to R HF
Most common clinical manifestation are
Portopulmonary HTN
Hepatopulmonary HTN
Dyspnea with severe arterial hypoxemia and cyanosis
Pathognomonic of hepatopulmonary HTN
Platypnea (easier breathing while lying down vs sitting and standing)
Orthodeoxia (fall of arterial blood oxygen with upright posture)
Most common cause of drug induced acute liver failure
Acetaminophen
Agent that causes cholestasis in those who metabolize it slowly
chlorpromazine
Fatal immune-mediates hepatitis in persons exposed to this anesthetic
Halothane
Bland hepatocellular cholestasis without inflamm
OCP, anabolic steroid, ERT use
Cholestatic injury
Cholestasis with lobular inflamm and necrosis bile duct destruction
Antibiotics
Phenothiazine
Cholestatic hepatitis
Spotty hepatocyte necrosis (methyldopa, phenytoin) Submassive necrosis of zone 3 (acetaminophen, halothane) Massive necrosis (isoniazid, phenytoin)
Hepatocellular necrosis
Macrovesicular
Ethanol, methotrexate, corticosteroids, TPN
Steatosis
Microvesicular
Mallory body
Amiodarone
Ethanol
Steatohepatitis
Periportal
Pericellular fibrosis
Methotrexate, isoniazid, enalapril
Fibrosis
Cirrhosis
Noncaseating epitheloid granuloma
Sulfonamide
Granulomas
Sinusoidal obstruction
Obliteration of central vein (high dose chemo, bush tea)
Budd-Chiari (OCP)
Sinusoidal dilation (OCP, others)
Peliosis hepatis: blood filled cavities not lined by epithelial cell (Anabolic steroids, tamoxifen)
Vascular lesion
Hepatic adenoma (OCP, anabolic) Hepatocellular CA (Thorotrast) Cholangiocarcinoma (Thorotrast) Angiosarcoma (Thorotrast, vinyl chloride)
Neoplasm
Nodular masses of liver separated by granulation tissue and scar
Nodularity and scarring entire or patchy involvement
Mononuclear infiltrates predominate all phases bec of T cell immunity
Ballooning degeneration, empty cell with pale cytoplasm rupturing and undergoing necrosis cytolysis (dropped out appearance) and apoptosis eosinophilic shrunk hepatocyte
If awat from portal tract and in parenchyma (lobar hepatitis)
Central-portal bridging necrosis followed by parenchymal collapse
Hepatitis
Minimal or absent portal inflamm
Acute hepatitis
Dense MONONUCLEAR portal infiltrate of variable prominence
Interface hepatitis
Scarring
Fibrous septa -> cirrhosis
Dx
Chronic hepatitis
Liver biopsy
Distinction between acute and chronic hep is based on
Pattern of cell injury
Severity of inflammation
Acute hep- less inflammation and more hepatocyte death than chronic
Hexagon centered on a central vein with portal tract at three of its apices
Regions: periportal, midzonal, centrilobular
Hepatic lobule
Blood supply as reference with portal vessels at their base
on the basis of distance from blood supply, 3 zones
1 closest to blood source
2 and 3 farther
Hepatic acinus
Appears before onset of symptom
Peaks in overt disease
Declines undetectable at 3-6 m
HBsAg
Does not rise until acute disease is over and not detectable for few weeks to months after disappearance of
HBsAg
May persist for life conferring immunity
Basis for vaccination
Anti-HBs
Appear in serum soon after HBsAg
Signify active viral replication
Persistence indicates continued viral replication infectivity and progression to chronic hepatitis
HBeAg
HBV-DNA
DNA polymerase
Implies that acute infection has peaked and on the wane
anti-Hbe
Detectable in serum shortly before the onset of symptoms, concurrent elevation of serum AST ALT
Replaced by IgG
IgM Anti-HBc
Accumulation of HBsAg in cytoplasm
Large pale finely granular pink cytoplasm inclusions on ER
Ground glass hepatocyte in chronic hep B
Fatty change from altered lipid metab
Lymphoid infiltrates in portal tract with fully formed lymphoid follicle
Bile duct injury by direct infection of cholangiocyte
Hepatitis C
Pathognomonic of yellow fever
Apoptosis of hepatocyte, eosinophilic
Councilman bodies
Only causes acute hepatitis
Hepa A
Hepa E
Cause chronic hepatitis
Hepa B, C, D
Inflammatory cells in both acute and chronic Hep
Difference in pattern of injury
T cell
Most important for grading and staging of disease used to decide whether px will undergo antiviral tx
Liver biopsy in chronic hep
sSRNA Hepatovirus, Picornavirus Fecal oral Incubation: 2-6 w Freq of chronic liver disease: Never Lab dx: Detection of serum IgM
Hepatitis A
Partially dsDNA Hepadnavirus Parenteral, sexual contact, perinatal Incubation: 4-26w Freq of chronic liver: 10% Dx: Detection of HBsAg or HBcAg ab
Hepatitis B
ssRNA
Flaviridae
Parenteral, intranasal cocaine use is risk factor
Incubation: 2-26w
Freq of chronic liver disease: 80%
Dx: PCR assay for HCV RNA, 3rd gen ELISA for ab detection
Hepatitis C
Circular defective ssRNA
Subviral particle in Deltaviridae
Parenteral
Incubation: 4-26w
Freq of chronic liver: 5% coinfec, = 70% for superinfection
Dx: Detection of IgM and IgG ab, HDV RNA serum, HDAg liver
Hepatitis D
ssRNA Hepevirus Fecal-oral Incubation: 2-8 weeks Freq of chronic liver: Never Laboratory diagnosis: PCR assay for HEV RNA, detection of IgM and IgG
Hepatitis E
Female, absent viral serology, inc IgG, high autoantibody, autoimmune disease (RA, Sjogren’s)
Early phase of severe cell injury and inflamm followed by rapid scarring (early wave of hepatocyte damage and necrosis)
Very severe hepatocyte injury with confluent necrosis
Marked inflammation with advanced scarring
Burned out cirrhosis with Little ongoing cell injury or inflamm
Mononuclear infiltrate with abundant PLASMA CELL
Responds to immunosuppresive therapy
Autoimmune hepatitis
Drugs that induce autoimmune hepatitis
Minocycline
Nitrofurantoin
Fatty liver disease (3)
Steatosis
Hepatitis
Fibrosis
Fat accumulation begins in centrilobular area
Small to large dropleta filling and expanding cell displacing the nucleus (central vein -> hepatocyte)
Hepatocellular steatosis
More pronounced with alcohol use than NAFLD
Steatohepatitis with ballooning, Mallory-Denk, neutrophil infiltration
Single or scattered foci of cells undergoing swelling and necrosis
Most prominent in centrilobular region
Hepatocyte ballooning
Tangled skeins of intermediate filament (ubiquinated keratin of 8 and 18)
Visible eosinophilic cytoplasmic inclusion in hepatocyte
Mallory-Denk body
Neutrophilic infiltration permeating the lobule and accumulating degenerating hepatocyte
Lymph and mac un portal tract
Neiutrophil infiltration
Fatty liver disease on histology may appear
Fibrosis on perisinusoids
chicken wire fence pattern
Fibrosis(central vein sclerosis) then Space of disse outwards becoming chicken wire fence creating central-portal fibrous septa
Liver becomes nodular, cirrhotic
Micronodular cirrhosis
Cryptogenic cirrhosis - burned out NASH
Fatty liver disease
Laennec cirrhosis
Hepatic steatosis
Alcoholic hepatits
Fibrosis and cirrhosis
Alcoholic fatty liver disease
Ingestion of this amount of ethanol produce mild hepatic change (fatty liver)
Chronic intake of this amount is norderline risk factor for severe
80g
40-80g/day
Metabolite of ethanol that induces lipid peroxidation and acetal-dehyde protein adduct for maturation disrupting cytoskeleton and membrane function
Acetaldehyde
Generated during oxidation of ethanol by microsomal ethanol oxidizing system reacting with damage membranes and protein
ROS
Major feature of alcoholic hepatitis and liver disease
TNF is main effector of injury
IL1, 6 and 8
Cytokine mediated inflammation
Most susceptibe region to toxic injury
Centrilobular
Major accelerator of liver disease in alcoholic
Concurrent Hepa C
In patients with metabolic syndrome, the best predictor of severe fibrosis and disease progression in NAFLD are
Type 2 DM
Obesity
Others: HTN, Dyslipidemia
