Download path 835 to 843 [9-2

path 835 to 843 General Features of Hepatic Disease
 Hepatic failure – may be sudden and massive (fulminant hepatic failure) or more often represents end stage of
progressive chronic damage to liver
o End-stage liver disease can occur by insidious destruction of hepatocytes or repetitive discrete waves of
parenchymal damage
o 80-90% of hepatic functional capacity must be lost before hepatic failure occurs
o Causes of liver failure
 Acute liver failure – associated w/encephalopathy w/in 6 mo after initial diagnosis; caused by
massive hepatic necrosis (most often drugs or toxins; acetaminophen most common); can be
caused by hepatitis A or B; caused by combo of toxicity and immune-mediated hepatocytes
destruction
 Fulminant liver failure – encephalopathy develops w/in 2 weeks of onset of jaundice
 Subfulminant liver failure – encephalopathy develops w/in 3 mo of onset of jaundice
 Chronic liver disease – most common route to hepatic failure; end point of chronic hepatitis
ending in cirrhosis
 Hepatic dysfunction w/o overt necrosis – hepatocytes may be viable but unable to perform
normal metabolic function (tetracycline toxicity and acute fatty liver of pregnancy)
o Clinical features – jaundice, hypoalbuminemia (predisposes to peripheral edema), and
hyperammonemia (causes cerebral dysfunction)
 Fetor hepaticus – chartacteristic body odor described as “musty” or “sweet and sour”; related to
formation of mercaptans by GI bacteria on sulfur-containing methionine and shunting of
splanchnic blood from portal into systemic circulation (portosystemic shunting)
 Palmar erythema – local vasodilation caused by impaired estrogen metabolism and
hyperestrogenemia
 Spider angiomas – caused by excess estrogen; each angiomas central, pulsating, dilated arteriole
from which small vessels radiate
 High estrogen leads to hypogonadism and gynecomastia in men
o Patients susceptible to encephalopathy, respiratory failure w/pneumonia, and sepsis w/renal failure;
coagulopathy can develop (impaired synthesis of clotting factors)
 Intestinal absorption of blood places further metabolic load on liver, which worsens failure
o Hepatic encephalopathy – manifested by disturbances in consciousness (abnormal behavior, confusion,
stupor; neurologic signs include rigidity, hyper-reflexia, and asterixis (nonrhythmic rapid extensionflexion movements of head and extremities best seen when arms held in extension w/dorsiflexed wrists
 Associated w/elevated ammonia levels in blood and CNS, which impairs neuronal function and
promotes generalized brain edema
 Only minor morphologic changes in brain (astrocyte swelling)
 Reversible if underlying hepatic condition corrected
o Hepatorenal syndrome – renal failure in pt w/severe chronic liver disease; no intrinsic morphologic or
functional causes for renal failure
 Sodium retention, impaired free-water excretion, and decreased renal perfusion and GFR
 Caused by decreased renal perfusion pressure due to systemic vasodilation, activation of renal
SNS w/vasoconstriction of afferent renal arterioles, and increased synthesis of renal vasoactive
mediators (further decrease glomerular filtration)
 Heralded by drop in urine output, rising BUN and creatinine
 Rapid development of renal failure associated w/precipitating stress factor (infection, GI
hemorrhage, or major surgical procedure)
 Treatment of choice is liver transplant; patients survive 2 weeks-6 months w/o one
o Hepatopulmonary syndrome (HPS) – chronic liver disease, hypoxemia, and intrapulmonary vascular
dilations (IVPD)
 Hypoxemia caused by ventilation perfusion mismatch (predominant cause; lack of uniform
blood flow in presence of stable alveolar ventilation), limitation of oxygen diffusion (diffusionperfusion defect; inadequate time for oxygen exchange in capillaries due to rapid flow of blood
in dilated vessels), or shunting of blood from pulmonary arteries to pulmonary veins
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Enhanced production of NO is key mediator in development of HPS
Pt’s have decreased arterial O2 saturation (orthodeoxia) and increased dyspnea (platypnea) on
moving from supine to upright
 Can have cutaneous spider nevi in pt’s w/IVPD
 Most respond to oxygen therapy; liver transplant is only curative treatment
Cirrhosis – caused mainly by alcohol abuse, viral hepatitis, and non-alcoholic steatohepatitis (NASH); can also be
caused by biliary disease and iron overload
o Defined by 3 morphologic characteristics
 Bridging fibrous septa linking portal tracts w/one another and portal tracts w/terminal hepatic
veins; fibrosis is key feature to progressive damage to liver (collagen deposition and remodeling)
 Parenchymal nodules containing hepatocytes encircled by fibrosis; nodularity results from cycles
of hepatocyte regeneration and scarring
 Disruption of architecture of entire liver; parenchymal injury and fibrosis are diffuse; focal injury
w/scarring doesn’t constitute cirrhosis (nor does diffuse nodular transformation w/o fibrosis)
o Central pathologic processes – death of hepatocytes, ECM deposition, vascular reorganization
 In normal liver, interstitial collagen (types I and III) concentrated in portal tracts and around
central veins; thin strands of type IV collagen in space of Disse
 In cirrhosis, types I and III collagen deposited in space of Disse (fibrotic septal tracts)
 Formation of new vascular channels in fibrotic septa that connect vessels in portal region to
terminal hepatic veins, shunting blood from parenchyma
 Deposition of collagen in space of Disse accompanied by loss of fenestrations of sinusoidal
endothelial cells (capillarization of sinusoids), impairing function of sinusoids as channels that
permit exchange of solutes between hepatocytes and plasma
 Predominant mechanism of fibrosis – proliferation of hepatic stellate cells and activation into
highly fibrotic cells
 Portal fibroblasts, fibrocytes, and cells derived from epithelium-mesenchymal
transitions may produce collagen
 Hepatic stellate proliferation and activation into myofibroblasts initiated by increase in
expression of PDGFR-β
 Kupffer cells and lymphocytes release cytokines and chemokines that modulate
expression of genes in stellate cells involved in fibrogenesis (TGF-β, MMP-2, TIMP-1,
TIMP-2)
 As stellate cells converted into myofibroblasts, they release chemotactic and vasoactive
factors, cytokines, and growth factors
 Contraction of cells stimulated by ET-1
 Stimuli for stellate cell activation may originate from
o Chronic inflammation (production of inflammatory cytokines TNF, lymphotoxin,
IL-1β, and lipid peroxidation products
o Cytokine and chemokine productin of Kupffer cells, endothelial cells,
hepatocytes, and bile duct epithelial cells
o In response to destruction of ECM
o Direct stimulation of stellate cells by toxins
o Surviving hepatocytes stimulated to regenerate and proliferate as spherical nodules w/in confines of
fibrous septa; outcome is fibrotic nodular liver where delivery of blood to hepatocytes severely
compromised as well as ability of hepatocytes to secrete substances into plasma
 Disruption of interface between parenchyma and portal tracts may obliterate biliary channels,
leading to jaundice
o Present w/anorexia, weight loss, weakness, and potentially signs and symptoms of hepatic failure;
usually precipitated by superimposed metabolic load on liver (systemic infection or GI hemorrhage)
o Ultimate mechanism of death by cirrhosis is progressive liver failure, complication related to portal
hypertension, or development of hepatocellular carcinoma
o Cessation of liver injury may give time for resorption of fibrous tissue and reversal of cirrhosis, but portal
hypertension and risk of hepatocellular carcinoma remain
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Portal hypertension – can be prehepatic (obstructive thrombosis, narrowing of portal vein before it ramifies in
liver, or massive splenomegaly w/increased splenic vein blood flow), intrahepatic (cirrhosis, schistosomiasis,
massive fatty change, diffuse fibrosing granulomatous disease (sarcoidosis), diseases affecting portal
microcirculation (nodular regenerative hyperplasia)), or posthepatic (right-sided heart failure, constrictive
pericarditis, hepatic vein outflow obstruction)
o Increased resistance to portal flow at level of sinusoids caused by contraction of smooth muscle cells
and myofibroblasts and disruption of blood flow by scarring and formation of parenchymal nodules
o Sinusoidal endothelial cells have decrease in NO production and release of ET-1, angiotensinogen, and
eicosanoids (vasoconstriction in liver)
o Sinusoidal remodeling and anastomosis between arterial and portal system in fibrous septa contribute
to portal hypertension by imposing arterial pressures on low pressure portal venous system
o Sinusoidal remodeling and intrahepatic shunts interfere w/metabolic exchange between sinusoidal
blood and hepatocytes
o Portal hypertension can be caused by increase in portal venous blood flow resulting from hyperdynamic
circulation (caused by arterial vasodilation, primarily in splanchnic circulation)
 Increased splanchnic arterial blood flow leads to increased venous efflux into portal venous
system; NO is most significant cause of splanchnic arterial vasodilation
 NO production stimulated by reduced clearance of bacterial DNA absorbed from gut due
to decreased function of mononuclear phagocyte system and shunting of blood from
portal to systemic circulation, bypassing pool of Kupffer cells in liver
o 4 major clinical consequences of portal hypertension: ascites, formation of portosystemic venous
shunts, congestive splenomegaly, and hepatic encephalopathy
 Ascites usually caused by cirrhosis; fluid generally serous (low protein); concentration of solutes
such as glucose, Na, and K similar to blood; fluid may have few mesothelial cells or mononuclear
leukocytes (influx of neutrophils suggests secondary infection); presence of blood cells points to
disseminated intra-abdominal cancer
 Seepage of peritoneal fluid through transdiaphragmatic lymphatics may produce
hydrothorax, more often on right side
 Sinusoidal hypertension alters Starling’s forces and drives fluid into space of Disse,
which is then removed by hepatic lymphatics; movement of fluid promoted by
hypoalbuminemia
 Percolation of hepatic lymph into peritoneal cavity – excess hepatic lymphatic flow
exceeds thoracic duct capacity; hepatic lymph rich in proteins and low in triglycerides,
so protein in ascitic fluid
 Splanchnic vasodilation and hyperdynamic circulation – arterial vasodilation in
splanchnic circulation reduces arterial BP; w/worsening of vasodilation, heart rate and
cardiac output unable to maintain BP, triggering vasoconstrictors (renin-angiotensin
system) and increases ADH; portal hypertension, vasodilation, and Na and water
retention increases perfusion pressure of interstitial capillaries, causing extravasation of
fluid into abdominal cavity
 Portosystemic shunts – w/rise in portal system pressure, flow reversed from portal to systemic
circulation by dilation of collateral vessels and development of new vessels
 Venous bypasses develop wherever systemic and portal circulation share capillary beds
o Rectum (hemorrhoids), esophagogastric junction (esophageal varices),
retroperitoneum, and falciform ligament of liver (periumbilical and abdominal
wall collaterals)
 Each episode of esophageal variceal bleeding has 30% mortality
 Splenomegaly – massive splenomegaly may secondarily induce hematologic abnormalities such
as thrombocytopenia or pancytopenia
Jaundice and Cholestasis
 Hepatic bile also eliminates bilirubin, excess cholesterol, xenobiotics, and other waste products not watersoluble enough to excrete in urine
o Jaundice – yellowing of skin; icterus – yellowing of sclera
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Cholestasis – where bile can’t flow from liver to duodenum; causes systemic retention of bilirubin and
other solutes eliminated in bile
Majority of bilirubin derived from breakdown of senescent RBCs by mononuclear phagocytic system, especially
in spleen, liver, and bone marrow; most of rest derived from turnover of hepatic heme or hemoproteins (P450
cytochromes) and premature destruction of RBC precursors in bone marrow
o Intracellular heme oxygenase oxidizes heme to biliverdin, which is immediately reduced to bilirubin by
biliverdin reductase
o Bilirubin formed outside liver released and bound to serum albumin
o Hepatic processing of bilirubin involves carrier-mediated uptake at sinusoidal membrane, conjugation
w/1-2 molecules of glucuronic acid by bilirubin UDP-glucuronyl transferase (UGT1A1) in ER and
excretion of water-soluble, nontoxic bilirubin glucoronides into bile
o Most bilirubin glucuronides deconjugated in gut lumen by bacterial β-glucuronidases and degraded to
colorless urobilinogens
 Urobilinogens and residue of intact pigment largely excreted in feces
 20% of urobilinogens reabsorbed in ileum and colon, returned to liver, and re-excreted into bile
 Small amount of reabsorbed urobilinogen excreted in urine
o UGT1A1 catalyzes glucuronidation of steroid hormones, carcinogens, and drugs; mutations cause
hereditary unconjugated hyperbilirubinemias (Crigler-Najjar syndrome types I & II and Gilbert syndrome)
o Bile salts – conjugation of bile acids w/taurine or glycine
 Bile acids are major catabolic products of cholesterol; water-soluble sterols
 Primary bile acids are cholic acid and chenodeoxycholic acid
 Bile acids in bile salts act as highly effective detergents; primary physiologic role is solubilize
lipids secreted by hepatocytes into bile and dietary lipids in gut lumen
 95% of secreted bile acids reabsorbed from gut lumen and recirculate to liver (enterohepatic
circulation)
Unconjugated bilirubin virtually insoluble in water and exists in tight complexes w/serum albumin; this form
can’t be excreted in urine even when blood levels high
o Very small amount of unconjugated bilirubin exists as albumin-free anion in plasma; may diffuse into
tissues, particularly brains in infants, and produce toxic injury; may increase in severe hemolytic disease
or when protein-binding drugs displace bilirubin from albumin
o Kernicterus – severe neurologic brain damage caused by hemolytic disease (i.e., erythroblastosis fetalis)
Conjugated bilirubin nontoxic and only loosely bound to albumin; excess conjugated bilirubin in plasma can be
excreted in urine
o Prolonged conjugated hyperbilirubinemia causes portion of circulating pigment to become covalently
bound to albumin (bilirubin delta fraction)
Jaundice occurs when equilibrium between bilirubin production and clearance disturbed by one or more factors:
o Excessive extrahepatic production of bilirubin (unconjugated)
o Reduced hepatocyte uptake (unconjugated)
o Impaired conjugation (unconjugated)
o Decreased hepatocellular excretion (conjugated)
o Impaired bile flow (conjugated)
Neonatal jaundice – hepatic machinery for conjugating and excreting bilirubin doesn’t fully mature until 2 weeks
of age, so many newborns develop transient mild unconjugated hyperbilirubinemia (physiologic jaundice of
newborn); may be exacerbated by breastfeeding (bilirubin-deconjugating enzymes in breast milk)
Crigler-Najjar syndrome type I – hepatic UGT1A1 completely absent; colorless bile contains trace amounts of
unconjugated bilirubin
o Liver morphologically normal
o Serum unconjugated bilirubin reaches very high levels, producing severe jaundice and icterus
o W/o liver transplant, fatal w/in 18 months of birth
Crigler-Najjar syndrome type II – UGT1A1 enzyme activity greatly reduced, capable of forming only
monoglucuronidated bilirubin
o Have very yellow skin
o Phenobarbital Tx can improve bilirubin glucuronidation by inducing hypertrophy of hepatocellular ER
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Gilbert syndrome – benign inherited condition presenting w/mild, fluctuating hyperbilirubinemia in absence of
hemolysis or liver disease
o Hepatic bilirubin-glucuronidating activity 30% of normal
o Caused by homozygous insertion of 2 extra bases in UGT1 gene, leading to reduced transcription
o No functional derangements
o Typically most noticeable under stress (intercurrent illness, strenuous exercise, or fasting)
o May be more susceptible to adverse effects of drugs metabolized by UGT1A1
Dubin-Johnson syndrome – autosomal recessive disorder characterized by chronic conjugated
hyperbilirubinemia; caused by defect in hepatocellular excretion of bilirubin glucuronides across canalicular
membrane (absence of protein multidrug resistance protein 2, responsible for transport of glucuronides and
related organic anions into bile)
o Liver darkly pigmented because of pigmented granules in cytoplasm of hepatocytes (pigment in
lysosomes and is composed of polymers of epinephrine metabolites)
o Chronic or recurrent jaundice of fluctuating intensity, but otherwise fine and normal life expectancy
Rotor syndrome – asymptomatic conjugated hyperbilirubinemia associated w/multiple defects in hepatocellular
uptake and excretion of bilirubin pigments; liver morphologically normal; jaundice but no other problems
Cholestasis – patients may have jaundice, pruritis, skin xanthomas (accumulation of cholesterol), or symptoms
related to intestinal malabsorption (lack of fat-soluble vitamins A, D, and K)
o Characteristic finding is elevated serum alkaline phosphatase and GGT (enzymes present on apical
membranes of hepatocytes and bile duct epithelial cells)
o Accumulation of bile pigment w/in hepatic parenchyma
 Elongated green-brown plugs of bile visible in dilated bile canaliculi; rupture leads to
extravasation of bile, which is quickly phagocytosed by Kupffer cells
 Bile pigment accumulation in hepatocytes, which take on fine foamy appearance (feathery
degeneration)
o Distention of upstream bile ducts and ductules by bile; bile stasis and back-pressure induce proliferation
of duct epithelial cells and looping and reduplication of ducts and ductules in portal tracts
 Labyrinthine ductules reabsorb secreted bile salts, protecting downstream obstructed bile ducts
from toxic detergent action of bile salts
o Portal tract edema and periductular infiltrates of neutrophils
o Leads to focal dissolution of hepatocytes by detergents, giving rise to bile lakes filled w/cellular debris
and pigment
o Unrelieved obstruction leads to portal tract fibrosis and ultimately cirrhosis
o Intrahepatic cholestasis – due to intrahepatic biliary tree disease or hepatocellular secretory failure;
don’t operate on this patient because it won’t help and could potentially harm
o DIFFERENTIATE BETWEEN INTRAHEPATIC AND EXTRAHEPATIC CHOLESTASIS BEFORE OPERATING!!
Progressive Familial Intrahepatic Cholestasis (PFIC) – autosomal recessive intrahepatic cholestatic conditions
o PFIC-1 (Byler disease) – normal GGT activity, lack of bile ductular proliferation in portal tracts;
characterized by cholestasis beginning in infancy; severe pruritus due to high serum bile acid levels;
progresses to liver failure before adulthood
 Mutation in ATP8B1 gene that causes impaired bile secretion
 Benign recurrent intrahepatic cholestasis – mild form of PFIC-1 w/intermittent attacks of
cholestasis over life w/o progression to chronic liver disease
o PFIC-2 – normal GGT activity, lack of bile ductular proliferation in portal tracts; caused by mutations in
hepatocyte canalicular bile salt export pump (BSEP) encoded by ABCB11 gene; BSEP is member of ABC
family of transporters; mutations cause severely impaired bile salt secretion into bile
 Extreme pruritus, growth failure, and progression to cirrhosis in first decade
 Higher risk for cholangiocarcinoma
o PFIC-3 – mutations in ABCB4 gene (encodes MDR3 protein, which is liver-specific canalicular transport
protein); characterized by high serum GGT; absence of secreted phosphatidylcholine in bile, which
leaves apical surfaces of biliary tree epithelia subject to full detergent action of secreted bile salts,
resulting in toxic destruction of epithelia and release of GGT into circulation