Chapter 18 Flashcards
What are the serum measurements for hepatocyte integrity
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Lactate dehydrogenase (LdH0
What are the tests that look for biliary excretory function
Serum bilirubin
Ruin bilirubin
Serum bile acids
What are the tests that look for damage to the bile canaliculus
Serum alkaline phosphatase
Serum gamma-glutamic transpeptidase (GGT)
What are the tests that look for hepatocyte synthetic function
Serum albumin
Coagulation factors, PT, PTT, fibrinogen, prothrombin, factors V, VII, IX, and X
Hepatocyte metabolism: serum ammonia aminopyrine breath test (hepatic demethylation
Reversible changes in hepatocytes
Steatosis
Cholestasis
What is steatosis
Accumulation of bilirubin in the liver
Cholestasis
Accumulation of bilirubin in the liver
How does hepatocyte necrosis occur
Fluid flows into the cell, the cell swells, and ruptures (lysis) when osmotic regulation is interrupted
Bless also form to carry off intracellular stuff to the extracellular
Macrophages cluster at these sites of injury
Predominate mode of death in ischemic/hypoxic injury
Significant part of the response to oxidative stress
Hepatocyte apoptosis
Hepatocyte shrinkage, nuclear chromatin condensation(pkynosis), fragmentation (karyorrhexis) and cellular fragmentation into acidophilus apoptotic bodies
AKA
Acidophil bodies: apoptotic hepatocytes so named due to their deeply eosinophilic stain
-COUNCILMAN BODIES: YELLOW FEVER(SAME THIN, HISTORICAL TERM)
CONFLUENT NECROSIS INT HE LIVER
WIDESPREAD PARENCHYMAL LOSS; SEVERE, ZONAL LOSS OF HEPATOCYTES
MAY BEGIN AS A ZONE OF HEPATOCYTE DROPOUT AROUND THE CENTRAL VEIN
PRODUCE A SPACE FILLED WITH CELLULAR DEBRIS, MACROPHAGES, AND REMNANTS OF THE RETICULAR MESHWORK
SEEN IN ACUTE TOXIC INJURY, ISCHEMIC INJURIES OR VIRAL/AUTOIMMUNE HEPATITIS
Bridging necrosis in the liver
This zone links central veins to portal tracts or bridges portal tracts
Vascular insult leads to parenchymal extinction due to large areas of contiguous hepatocyte death
Collapse of supporting framework can occur
Cirrhosis may result
Regeneration in the liver
Mitosis replication adjacent to those that have died, even when there is significant confluent necrosis
Stem cell like: hepatocytes an replicate even in the setting of chronic injury
-stem cell replenishment is not a significant part of parenchymal repair
Severe forms of acute liver failure activates the primary intrahepatic stem cell niche (canal of hearing)
-contribution unclear
Ductal reactions : when hepatocytes in patients with chronic disease reach replication senescence and clear evidence of stem cell activation appears
Scar deposition in the liver
Principle cell type involved in scar deposition is the fat containing, myofibroblastic hepatic stellate cell
Quiescent form:stores lipid and vitamin A (fat soluble)
Injury: activated and converted to highly fibronectin myofibroblasts
- cytokines released by Kupfer cells and lymphocytes: TGFB, MMP-2 (metaloproteinase-2), and TIMP-1 and 2 (tissue inhibitors of metalloproteinases 1 and 2).
- contraction stimulated by endothelin1
Is scar deposition in liver reversible
If the injurious agent is eliminated
Fibrous septa development in the liver
Collapse of reticular where large swaths of hepatocytes have disappeared and stellate cells are activated
Regenerating hepatocytes become surrounded in late chronic disease leads to diffuse scarring (cirrhosis
Hepatic failure
Hepatic failure ensures when 80-90% of the functional capacity of the liver is lost
80% mortality without transplant
May be due to acute injury, chronic progressive injury, or acute on chronic injury
What is acute hepatic failure
Occurs within 26 weeks (6 months) of initial injury
Absence of preexisting liver disease
Associated with encephalopathy and coagulopathy
Causes of acute hepatic failure
-massive hepatic necrosis, a result of drugs/toxins
Acetaminophen (50% onset within one week) hepatitis A, autoimmune hepatitis
Hepatitis B
Hepatitis C, cryptogenic
Drugs/toxins, hepatitis D
Hepatitis E, esoteric causes (wilson disease, buds-chiaroscuro)
Fatty change of the microvesicular type (fatty liver of pregnancy, valproate, tetracycline, Reye’s syndrome)
Morphology acute hepatic failure
-massive hepatic necrosis leads to broad regions of parenchymal loss surrounding areas of regenerating hepatocytes
Small shrunken liver
Early scarring may occur in weeks-moths
Diffuse microvesicular steatosis: diffuse poisoning of liver cells without obvious cell death and parenchymal collapse; related to fatty liver of pregnancy or idiosyncratic reactions to toxins
What does a patient initially present with with acute hepatic failure
Nausea, vomiting, and jaundice which progresses to a life threatening encephalopathy and coagulation defects
Patients with acute hepatic failure and liver transaminases
Moderate increase
Why do people with acute hepatic failure gethepatomegalt
Hepatocyte swelling, infiltrates and edema initially
Eventually there is a shrunken liver as the parenchyma is destroyed
Decline in serum transaminases is an indication of fewer viable hepatocytes ,not recovery
Prognosis acute hepatic failure
Poor prognosis
Decrease in liver enzymes, indicating few remaining hepatocytes, confirmed with worsening jaundice, coagulopathy and encephalopathy
Sequelae acute hepatic failure
Jaundice and icterus: yellowing of skin , sclera and mucus membranes
Cholestasis: systemic retention of not only bilirubin but also other solutes eliminated in bile which increases the risk of life threatening bacterial infection
Hepatic encephalopathy: due to increased serum ammonia that ranges from subtle behavioral abnormalities to marked confusion and stupor to deep coma and death
- rigidity and hyperreflexia
- asterixix is a characteristic sign
Coagulopathy: impaired clotting due to lack of production of vitamin K dependent (II, VII, IX, and X) and independent clotting factors
- easy bruising-early sign
- can lead to intracranial bleeding->herniation->death
Disseminated intravascular coagulation-liver is responsible for removing activated coagulationfrom the circulation
Portal hypertension:intrahepatic obstruction most likely; leads to ascites and hepatic encephalopathy
Hepatorenal syndrome: form of renal failure in individuals with liver failure in whom their kidneys are morphologically and functionally normal
- na retention , impaired free water excretion, decreased renal perfusion, and decreased glomerular infiltration rate
- decreased renal perfusion pressure due to systemic vasodilation, activation of renal sympathectomy nervous system (afferent arteriole vasoconstriction), increased RAAS activation->decrease GFR
- onset-hypo-nutria, elevated BUN creatinine
Asterixis
Characteristic sign of acute hepatic failure
Nonrhythmic, rapid extension flexion of the head and extremities
Seen with arms in extension and dorsiflexied wrists
Chronic liver failure
Associated with cirrhosis though not mutually exclusive
Chronic hepatitis B and C, non alcoholic fatty liver disease, alcoholic fatty liver disease
The ultimate cause of death in chronic liver failure is the same as in __ ___ ___
Acute liver failure
Ultimate cause of death from acute and chronic liver failure
Hepatic encephalopathy
Bleeding from esophageal varices
Bacterial infections
Cirrhosis
Diffuse transformation of the entire liver into regenerative parenchymal nodules surrounded by fibrous bands and variable degrees of vascular (portosystemic) shunting
No single cirrhosis, but rather multiple variable cirrhosis
Cirrhosis is no longer considered end stage liver disease because the fibrosis is potentially reversible with increasing numbers of effective treatments for cirrhosis causing conditions
Child Pugh classification of cirrhoissi
Helps monitor the decline of the patients ont he path to chronic liver failure
Class A (child Pugh)
Well compensated
Class B (child Pugh)
Partially compensated
Class C (child Pugh
Decompensated
What does stem cell activation in liver cirrhosis cause
Ductular reactions which increase with advancing stage of disease and are usually most prominent in cirrhoisis
Portal HTN cirrhosis decreased incidence morphology
Biopsy specimens with narrow, densely compacted fibrous septa separated by areas of intact hepatic parenchyma
Portal HTN increased incidence with liver cirrhosis
Broad bands of dense scar with dilated lymphatic space, less parenchyma; more likely to progress and lead to end stage disease
Clinical signs of cirrhosis before it becomes end stage
Only seen in 40% of patients
Jaundice+pruritis
Hypoalbuminemia->systemic edema
Hyperammonemia
Factor hepaticus:mercaptan formation
Males hyper-estrogenemia due to impaired metabolism can lead to palmar erythema, spider angiopathy, hypogonadism, and gynecomastia
Increased risk of developing hepatocellular carcinoma
Prehepatic causes of portal HTN
Obstructive thrombosis
Narrowing of the portal vein before entering the liver
Massive splenomegaly with increased splenic blood flow
Posthepatic causes of portal HTN
Severe right heart failure
Constrictive pericarditis
Hepatic vein outflow obstruction
Intrahepatic causes portal HTN
Usually due to cirrhosis
Schistomiasis
Massive fatty change
Diffuse fibrosis granulomatous disease such as sarcoidosis
Diseases effecting the portal microcirculation such as nodular regenerative hyperplasia
Increased resistance to portal flow
Increased portal venous flow due to hyper dynamic circulation
What is the most common cause of portal HTN
Cirrhosis
What causes increased resistance to portal flow
Contraction of vascular smooth muscle and myofibroblasts
Decreased NO production
Increased endothelin1, angiotensinogen, eicosanoids production
Disruption of blood flow by scarring and formation and parenchymal nodules
Remodeling and anastomoses impose arterial pressure on a normally low pressure system
Interferes with metabolic exchange of sinusoidal blood and hepatocytes
What causes increased portal venous flow due to hyper dynamic circulation
Splanchnic arterial vasodilation-increased efflux into the portal venous system
Due to NO, prostacyclin and TNF
Clinical portal HTN
Ascites
Portosystemic shunt formation
Congestive splenomegaly
Hepatic encephalopathy
Ascites
Excessive fluid in the peritoneal cavity
Detectable with accumulation of 500 ml
85% of ascites is due to __ __
Cirrhosis
85% of ascites is due to__
Cirrhosis
What happens with long standing ascites
Seepage of peritoneal fluid through trans-diaphragmatic lymphatic channels—>hydro-thorax, espicially onthe RIGHT
Composition of ascites
Fluid is serous, <3mg/dl of protein (albumin)
Neutrophils: suggests infection
Blood:suggests disseminated intraabdominal cancer
What leads to ascites
Sinusoidal HTN
Precolation of hepatic lymph in peritoneal cavity
Splanchnic vasodilation
Mechanism of sinusoidal ascites
Hepatic sinusoidal HTN drives fluid into the space of disse which is drained by lymphatics
Promoted by hypoalbuminemia->peripheral edema
What is the space of disse
Beneath the endothelial cells
What is found in the space of disse
Fat containing myofibroblastic hepatic stellate cells are found in the space of disse
Mechanism of ascites: percolation of hepatic lymph in peritoneal cavity
Normal flow is 800-1000ml; increased to 20L
The thoracic duct isn’t ably to keep up and fluid leaks out->peripheral interstitial edema
Mechanism of ascites: splanchnic vasodilation
Causes systemic hypotension which leads to vasoconstriction
RAAS activation leads to Na retention (and H2O follows)
Increased perfusion pressure of the interstitial capillaries
-transudation(protein poor) into the abdominal cavity
Portosystemic shunts
Flow is reversed from the portal into the systemic circulation where there are shared capillary bed
Esophageal varices: 40% of patients with advanced cirrhosis; rupture can cause massive hematemesis with 30% mortality
Falciform ligament and caput Medusa: dilated subcutaneous veins extend from umbilicus to rib margins
Rectum: hemorrhoids
Splenomegaly
Due to long standing congestion
Can cause thrombocytopenia(or pancytopenia
Due to long standing congestion
Can cause thrombocytopenia (or pancytopenia due to hypersplenism)
Hepatopulmonary syndrome
Hypoxia+dyspnea due to Ventillation/perfusion (V/Q) mismatch from rapid blood through dilated vessels with decreased time for diffusion
What exacerbates hepatopulmonary syndrome
Upright position due to gravity
What improves hepatopulmonary syndrome
Recumbent position
PortopulmonaryHTN
Dyspnea on excretion and clubbing
Pulmonary arterial HTN in liver disease and portal HTN
Excessive pulmonary vasoconstriction and vascular remodeling with concomitant portal hypertension
Acute on chronic liver failure
Individuals with stable, well-compensated chronic liver disease develop sudden signs of acute liver failure
Commonly have established cirrhosis and extensive vascular shunting
Significant amounts of parenchyma have borderline vascular supply and are vulnerable to superimposed insult
Short term mortality of acute on liver failure
50%
Hepatic A virus
Benign, self limited disease
Does not cause chronic hepatitis or a carrier state
Rarely lethal
Transmission hepatitis A
Fecal oral via contaminated water
Raw or steamed shellfish that get it from human sewage contaminated seawater
Donated blood atrisk for HAV
No rare
What kind of virus is HAV
Single stranded + RNA
Anti-HAV immunoglobulin Ig_ are seen in the serum with onset of HAV—implies acute infection
M
In HAV infection as Ig_ declines, Ig_ appears implying memory
M G
After HAV infection Ig_ persistence for years conferring long term immunity
G
Clinical HAV
Mild or asymptomatic and rare after childhood
Hepatitis B
Infection that has a predilection for the liver and can cause a wide spectrum of disease manifestations , with most of the cases leading to asymptomatic chronic disease or clearance
5 different forms of HBV induced illness
Acute hepatitis with recovery and clearance of virus
Non-progressive chronic hepatitis
Progressive chronic disease ending in cirrhosis
Acute hepatic failure with massive liver necrosis
Asymptomatic, ‘healthy’ carrier state
Chronically is an important precursor for hepatocelullar carcinoma
Transmission hepatitis b
High prevalence ares (AFrica, Asia): childbirth
Intermediate prevalence: horizontal (breaks in skin/mucus membranes in children with close body contact)
Low prevalence: unprotected sex, IV drug use
HBV viral characteristics
Partially dsDNA virus
Mature virus=spherical double layered “Dane particle” with outer surfac protein+lipid envelope around an electron dense slightly hexagonal core
Serum markers for HBV
HBsAg
Anti-HBs
HBeAg, HBV-DNA and DNA polymerase
Anti-HBc
HBsAg
Appears before the symptoms, peaks during the overt disease, and lasts for about 12 weeks
*donated blood is screened for HBsAg
Anti-HBs Ab
Doesn’t rise until the disease is over, about the same time that the HBaAg goes away. The IgG form is what provides the immunity
Anti-HBs may persist for _, conferring protection-basis for current vaccination strategies using non infectious HBsAg
Life
HBeEg, HBV-DNA and DNA polymerase
All appear after HBsAg and indicate there is active viral replication
___ espicially can be used to track the disease and antibodies to it indicate the disease is about to wane
HBeAg
Persistent HBeAg
Indicator of continued viral replication, infectivity, and probably progression to chronic hepatitis
Anti-HBe antibodies
Acute infection has peaked and is on the wave
Anti-HBc Ab
Appears just before the onset of symptoms and shows up with increased aminotransferase levels (liver damage)
What is the best predictor of HBV chronicicity
Age at the time of infection
Younger age-increased probability of chonicity
What is the main determinant of the outcome of HBV
Host immune response to the virus is the main determinant of the outcome of the infection
Strong response by virus specific CD4 and CD8 interferon (IFN-y)-producing cells is associated with the resolution of acute infection
HBV does not cause direct hepatocyte injury-what causes injury
CD8 cytotoxic T cells attack infected hepatocytes
Complete cure of HBV
Difficult due to viral insertion into host DNA
Limits the development of an effective immune response
Virus persists in the face of rugs that impair its replication
Goal of treatment in chronic HBV
Slow progression of disease, reduce liver damage and prevent cirrhosis and cancer
How do we prevent spread of HBV
Vaccination and screening of blood donations prevents it
Treat HBV
Most cases are self limited and resolve without treatment
What percent of HBV patients Barbour chronic disease
5-10%
Is fulminant hepatitis common
No rare
Morphology HBV*
In chronic HBV, liver biopsy shows finely granular ground glass hepatocytes packed with HBsAg
-cells with endoplasmic reticulum swollen by HBsAg-diagnostic hallmark
What is the diagnostic hallmark of HBV
Liver biopsy shows finely granular ground glass hepatocytes packed with HBsAg
-cells with endoplasmic reticulum swollen by HBsAg
Hepatitis C virus characteristics
SsRNA virus
Genomic instability+antigenic variability=no vaccine
Anti-HCV igG antibodies do not confer effective immunity and re infection is possible
Infection and clearance HCV
More mild than HBV with most acute cases being asymptomatic, but 80-90% of patients develop chronic infection and 20% get cirrhosis
Exists as closely related genetic variants inside infected patients
Clinical HCV
Characteristic repeated bouts of hepatic damage
Persistent infection and chronic hepatitis=hallmarks of HCV infection
Acute illness is generally asymptomatic chronic HCV infection==persistent elevations in serum aminotransferases
-wax and wane, but never normal
Cryoglobulinemia is found in 35% of individuals with chronic hepatitis C infection
Diagnose HCV
HCV RNA is detected in blood for 13 weeks during active infection with concurrent increase in aminotransferase levels (will see the increase in ALT/AST chronically)
What is HCV associated with
Metabolic syndrome (genotype3) Can give rise toinsulin resistance and non alcoholic fatty liver disease
Treatment HCV
Genotype 2 and 3 have best response to treatment, espicially in patients with IL-28B gene (encodes IFN-y involved in resistance to HCV) polymorphisms
-better response to IFN-a and ribavirin
Newer regimens may improve prognosis
Morphology HCV
Leads to portal lymphoid follicle, bile duct reactive changes and lobular regions of microvesicular steatosis
Bile duct injury is possible that can histologically mimic primary biliary cirrhosis (easily distinguished clinically)
Chronic HCV shows lymphoid aggregates or fully formed lymphoid follicles; fatty change of scattered hepatocytes
Hepatitis D is dependent for its life cycle on _
HBV
How is HDV dependent on HBV
External coat antigen surrounds an internal “delta antigen” the only protein produced by the virus
A vaccine for HBV also prevents __
HDV
What are the setting of HDV
Co-infection
Superinfection
How get confection HDV
HBV must become established first to provide the HBsAg necessary for development of complete HDV virions, resulting in acute hepatitis indistinguishable from acute hepatitis of HBV-only etiology
Prognosis HDV confection
Self limited
Followed by clearance of both viruses
When is there a higher rate of acute hepatitis failure with HDV coingection
In IV drug users
How detect coinfection with HDV
Best indicated by detection of IgM against both HDAg and HBcAg
Superinfection HDV
When a chronic carrier of HBV is exposed to a new inoculum of HDV get superinfection 30-50 days later
Severe acute hepatitis in a previously unrecognized HBV carrier, or exacerbation of pre existing chronic hepatitis B infection
Acute phase superinfection HDV
Active HDV replication and suppression of HBV with high transaminase levels
Chronic phase superinfection HDV
HDV replication decreases , HBV replication increases, transferase levels fluctuate, and disease progresses to cirrhosis and sometimes hepatocellular carcinoma
Lab values superinfection HDV
HBsAg present in serum, anti HDV persist for months or longer
Who gets HDV
Western countries: largely restricted to IV drug users and those who have had multiple blood transfusions
Clinical HDV
HDV RNA is detectable in the blood and liver just before and in the early days of acute symptomatic disease
Ig_ anti-HDV is the msot reliable indicator of a recent HDV exposure
M
How get HEV
Enterically transmitter, water borne infection
Zoonotic=animal resivoirs(increased risk with exposure to monkeys, cats, pigs, and dogs)
Who gets HEV
Occurs primarily in young to middle aged adults
HEV causes 30-60% of sporadic acute hepatis in ___(more than HAV)
India
Characteristic feature HEV
Higher mortality rate among pregnant women-almost 20%
Treat HEV
Self limiting
What is HEV not associated with
Chronic liver disease or persistent fire is in immunocompentent patients
In HEV virions are shed in __ during the acute illness
Stool
What type of virus i HAV
SsRNA
What type of virus is HBV
Partially dsDBA
What kind of virus is HCV
SsRNA
What type of virus in HDV
Circular defective SsRNA
What type of virus is HEV
SsRNA
What family is HAV in
Hepatovirus (picornavirus)
What family is HBV in
HepaDNAvirus
What family is HCV
Flaviviridae
What family is HDV
Subviral particle in deltavirdae family
What family is HEV
Hepevirus
Transmission HAV
Fecal-oral (contaminated H2O)
Transmission HBV
Parenteral, sexual contact, perinatal
What family is HCV
Parenteral, intranasal cocaine
Family HDV
Parenteral
Family HEV
Fecal oral
Incubation HAV
2-6 weeks
HBV incubation
2-26 weeks (avg 8)
HCV incubation
4-26 weeks (avg9)
HDV incubation
2-26 weeks (avg 8)
HEV incubation
4-5 weeks
HAV progression to chronic
Never
HBV progression to chronic
5-10%
HCV progression to chronic
> 80%
HDV progression to chronic
10% coinfection
90-100% superinfection
HEV progression to chronic
Never
Diagnosis HAV
IgM antibodies
HBV diagnosis
HBsAg, antiHBcAg; PCR for DNA
HCV diagnosis
PCR for DNA, Elisa for Ab
HDV diagnosis
IgM and IgG antibodies; HDV RNA serum; HDAg in liver
Diagnosis HEV
Serum IgM and IgG; PCR for HEV RNA
Which hepatitis show fulminant
A, B, D
Which hepatitis fulminant in pregnant women
HEV
Clinicopathological syndromes of hepatitis
Acute asymptomatic infection with recovery (serologic evidence only)
Acute symptomatic hepatitis with recovery (anicteric or interic)
Chronic hepatitis
Acute liver failure
Carrier state
Acute asymptomatic infection with recovery (serologic evidence only)
Worldwide, HAV, and HBV infections are frequently subclinical events in childhood verified only in adulthood by the resented of anti-HAV or anti HBV antibodies
Acute symptomatic hepatitis with recovery (anicteric or icteris) four phases
Incubation(peak infectivity during last asymptomatic days of incubation period and early days of acute symptoms)
Symptomatic pre-icteric phase
Symptomatic interic phase
Convalescence
Chronic hepatitis
With progression to cirrhosis
Without progression to cirrhosis
Acute liver failure
With massive hepatic necrosis
With submissive hepatic necrosis
Carrier state hepatitis
“Healthy carrier’: individual with HBsAg, no HBeAg, andi HBeAg, normal aminotransferases low or undetectable serum HBV DNA, and liver biopsy showing a lack of significant infalmmation and necrosis
Inactive carrier
Not recognized in the United States
Acute hepatitis morphology
Lymphoplasmactyic (mononuclear) infiltrate
Spotty necrosis or lobular hepatitis scattered throughout a lobule
Necrosis empty cytoplasm , cell membrane ruptures leads to hepatocyte dropout
Collapsed sinusoidal collagen reticulin framework
Apoptosis; hepatocytes shrink, become eosinophilic, pyknotic, fragmented
Lack of portal inflammation
Severe acute hepatitis morphology
CONFLUENT NECROSIS of hepatocytes around central veins
Cellular debris, collapsed reticulin fibers, congestion +/- hemorrhage
Variable inflammation
Central portal BRIDGING NECROSIS leads to parenchymal collapse
Can lead to massive hepatic necrosis/acute failure
Can develop post hepatitis. Cirrhosis with abundant scarring
Chronic hepatitis morphology
Mononuclear portal infiltration
Mild: inflammatory infiltrates are limited to portal tracts
Progressive dise: extension of chronic inflammation from portal tracts with interface hepatitis
Linking of orca and portal central regions=bridging necrosis
Continued loss of hepatocytes=fibrous septum formation
Associated hepatocyte regeneration=cirrhosis
What causes toxic shock syndrome
Staphylococcus aureus
What causes typhoid fever
Salmonella typhi
What causes secondary or tertiary syphilis
Treponema pallidum
Ascending cholangitis
Acute infalammation response within the intrahepatic biliary tree due to intrabiliary bacterial microflora during a partial or complete obstruction
What is autoimmune hepatitis
Chronic, progressive hepatitis
Presence of autoantibodies
Therapeutic response to immunosuppression
What triggers autoimmune hepatitis
Viral infection, drug/toxin exposure
Patients at risk for autoimmune hepatitis
Caucasion: DRB1* alleles (HLA association)—genetic predisposition
Most frequent in white Northern Europeans
Females predominance
What are the two types of autoimmune hepatitis
2 types based on circulating antibodies
Type 1 autoimmune hepatitis
Middle aged older people
ANA (anti-nuclear), ASMA (anti-smooth msucle), ANTI-SLA/LP (anti-soluble liver antigen/liver-pancreas antigen), AMA (anti-mitochondrial) antibodies
Type 2 autoimmune hepatitis
Children and teenagers
Anti-LKM1 (anti-liver kidney microsome-1) antibodies against CYP2D6
ACL1 (anti-liver cytosolic) antibodies
Early phase of severe parenchymal destruction followed rapidly by scarring
-fibrosis take years to develop in chronic viral hepatitis, does not develop in acute hepatitis
Severe necroinfalmmatory activity indicated by interface hepatitis or parenchymal collapse
Mononuclear infiltrate: plasma cells
Hepatocyte ROSETTES in areas of activity
Early phase autoimmune hepatitis
Severe parenchymal destruction followed rapidly by scarring
Fibrosis takes years to develop in chronic viral hepatitis, does not develop in acutehepatitis
Severe necroinflammatory activity indicated by interface hepatitis or parenchymal collapse
Mononuclear infiltrate: plasma cells
Hepatocyte ROSETTES in areas of activity
Progressive or indolent automimmune hepatitis that lead to liver failure initial and chronic siding
Initial: severe hepatocyte injury with necrosis but little scarring
Chronic: burned out cirrhosis with little necroinflammatory activity; likely due to years of subclinical disease
With autoimmune hepatitis, acute onset with fulminant disease in _ weeks
8
Autoimmune hepatitis hepatic encephalopathy
Yup
What happens if autoimmune hepatitis is untreated
40% mortality in 6 months
Both type 1 and type 2 are likely to lead to liver failure
What percent of autoimmune hepatitis survivors have cirrhosisi
40%
Characteristic autoimmune hepatitis
Plasma cells are prominent and characteristic component of the inflammatory infiltrate in biopsy specimens showing autoimmune hepatitis
Prognosis autoimmune hepatitis
Between in adults than in children (delay in diagnosis in pediatric population)
Treat autoimmune hepatitis
80% of patients respond to immunosuppression for long term survival
End stage autoimmune hepatitis
Liver transplant with 75% survival at 10 years, recurrent ein 20% of patients
Drug or toxin liver damage
May be immediate or delayed
Mild to severe
Predictable (intrinsic, dose dependent) or unpredictable (idiosyncratic, multi-factorial)
Due to direct toxicity, conversion of a xenobiotic to a toxin or from immune mediated toxicity
Recovery usually occurs with removal of the offending agent
What is the most common cause of acute liver failure necessitating liver transplant in the USA
Acetaminophen
Why does acetaminophen cause liver failure
Due to toxic metabolite produced from the CYP450 breakdown in acinus zone 3 hepatocytes
What is zone 3
Closest to the terminal hepatic vein (central vein) and furthest from the portal vein
Central vein turns into the hepatic vein
Zone 2
Tries to compensate and become injured
Severe acetaminophen overdose
The zone of injury extends into zone 1 (periportal hepatocytes) and this is when you start getting acute hepatic failure
Why can alcohol or codeine make acetaminophen
Upregulate CYP450 and make things worse
Chlorpromazine and liver
Cholestasis in patients who are slow to metabolize it to an innocuous byproduct
Halothane and liver
Fatal immune mediated hepatitis in some patents exposed on multiple occasions
What are the types of liver disease caused by alcohol
Hepatocellular steatosis or fatty change
Alcoholic hepatitis
Streatofibrosis up to and including cirrhosis (only in a small fraction)
- patterns of scarring typical for all fatty liver diseases including alcohol
- cirrhosis develops in only a small fraction of chronic alcoholics
Hepatic steatosis (fatty liver)
Microvesicular lipid droplets within hepatocytes
With chronic use accumulates in microvesicular droplets which displace the nucleus
Large, soft, greasy, yellow liver
No fibrosis
Completely reversible if patients abstains from alcohol
Alcoholic (steato-) hepatitis
Hepatocyte swelling (fat, H2O, proteins)+necrosis
Mallory-denk bodies
Neutrophilic reaction to degenerating hepatocytes, espicially those with Mallory dunk bodies
Mallory desk bodies
Intracellular eosinophilic aggregates of intermediate filaments (keratin 8 and 18, ubiquitin) in ballooning hepatocytes
-hepatocytes are epithelial cells
Mallory desk bodies==damaged intermediate filaments(in hepatocytes, cytokeratin)
What are Mallory denk bodies seen in
Alcoholic hepatitis, non alcoholic fatty liver disease, wilson disease, and chronic biliary tract disease
Mallory denk bodies mean alcoholic hepatitis
Characteristic finding in alcoholic hepatitis but not specific
Alcoholic steatofibrosis
Activation of sinusoidal stellate cells+portal fibroblasts=fibrosis (fibrosis begins with sclerosis of central veins (zone3)
Scarring in a chicken wire fence pattern
Laennec cirrhosis with continuous use due to developing modularity and progressive inter webbing of the scare
Liver is large, brown, shrunken and non fatty
Closer to cirrhosis =less likely to regress
Alcoholic steatlfibrosis scarring in chicken wore fence pattern
Fibrosis spreads outward and encircles individual or small clusters of hepatocytes
Acloholic steatofibrosis laennec cirrhosis with continuous use due to developing modularity and progressive inter-webbing of the scares
Classic micro nodular cirrhosis first described for end stage alcoholic liver disease
Cirrhosis==chronic liver disease; laennec (aka micro nodular)==chicken-wire==alcoholic steatofibrosis
Large bands of fibrous tissue surrounding nodules
Risk factors for developing alcoholic cirrhosis
10-115% of alcoholics develop cirrhosis
Females are more susceptible
African American>caucasion
Iron overload, HBV, HCV=increased severity of liver disease
Mutation for alcohol intolerance
Homozygous ALDH*2 (asians) has alcohol intolerance
Flushing, nausea, lethargy
Hepatocellular steatosis pathogenesis
Impaired lipoprotein assembly and secretion
Increased peripheral catabolism of fat-> release of free fatty acids into the circulation
Shunting of substrates away from catabolism and towards lipid biosynthesis (due to increased NADH production by enzymes of metabolism)
-alcohol dehydrogenase and acetaldehyde dehydrogenase-> increased NADH production
Alcoholic hepatitis pathogenesis
Acetylaldehyde induced lipid peroxidation and protein adduct formation (carcinogen)
Induced CYP450-increases conversion of other agents to form potentially toxic metabolites
Impaired methionine metabolism
Release of bacterial endotoxin (LPS)
Release of endothelin1
Decreased perfusion of hepatic sinusoids
Effect of impaired methionine metabolism
Decreases glutathione levels that are normally protective of ROS
What happens when alcohol causes the release of bacterial endotoxin (LPS)
Pro inflammatory
Estrogen increases gut permeability to endotoxin (LPS)->increased expression of the LPS receptor (CD14, TLR4) in kupffer cells==women are more sensitized to pro inflammatory effects
Alcoholic liver disease pathogenesis
Chronic disorder of steatosis, hepatitis, progressive fibrosis and deranged perfusion
Due to an agent that was initially only marginally harmful
Clinic hepatic steatosis
Hepatomegaly
Mild increase of serum bilirubin and alkaline phosphatase levels
Severe dysfunction Is rare
Alcoholic liver disease clinical
AST:ALT>2:1
90% 5 year survival with abstinence in patients free of jaundice, ascites, or hematemesis
50-60% 5 year survival in patients that do not discontinue use
Alcoholic hepatitis clinical
Increased bilirubin, alkaline phosphatase and aserum aminotransferase
Neutrophilic leukocytosis
Nonspecific symptoms: malaise, anorexia, weight loss, abdominal discomfort
Follows a bout of heavy drinking
Treatment alcoholic hepatitis
Cessation of alcohol+adequate nutrition may slowly clear disease
Each bout of alcoholic hepatitis has a _% risk of death
10-20
If a patient with alcoholic hepatitis refrains from alcohol can they still progress to cirrhosis
Yup
_% of people with alcoholic hepatitis progress to cirrhosis without treatment
1/3
Clinical alcoholic cirrhosis
Hepatic dysfunction: increased aminotransferase, bilirubin, alkaline phosphatase, hyperproteinemia (globulins, albumin, clotting factors)
Anemia
May be clinically silent
Generally irreversible
End stage alcoholic hepatitis
Hepatic coma
Massive GI hemorrhage
Intercurrent infection(predisposed to infection)
Hepatorenal syndrome after bout with hepatitis
Hepatocellular carcinoma
What is the most common cause of chronic liver disease in the USA
Non alcoholic fatty liver disease
Non alcoholic fatty liver disease
Spectrum of disorders with hepatic steatosis
Patients consume<20g alcohol/week
80gm/day of alcohol is considered the threshold for the development of alcoholic liver disease
Risk factors for non alcoholic fatty liver disease
Increased incidence due to increased obesity and the association with metabolic syndrome
Contributes to progression of other liver disease (HBV, HCV)
Increased risk of hepatocellular carcinoma
Hispanic>african American>caucasion
Two hit model of non alcoholic fatty liver disease
Insulin resistance leads to hepatic steatosis
Hepatocellular oxidative injury leads to liver cell necrosis and inflammatory reactions
What factors can lead to hepatic steatosis, obesity, and insulin resistance
Increased high calorie food intake, high fructose corn syrup, decreased exercise, genetic predisposition
How does metabolic syndrome lead to nonalcoholic fatty liver disease
Dysfunctional adipose tissue (endocrine organ), decreased production of adiponectin, increased TNFa, IL6=hepatocyte apopotosis
Why get apoptosis with non alcoholic fatty liver disease
Oxidative damage to mitochondria and plasma membranes
Mitochondria and non alcoholic fatty liver disease
Oxidative damage
Further damaged by decreased autophagy and formation of mallory denk bodies
Scar tissue non alcoholic fatty liver disease
Scar tissue deposition due to kupffer cells, TNF-a, TGF-b which activates stellate cells (which are also activated through the hedgehog signalling pathway
Level of __ __ activity correlated with the stage of fibrosis in non alcoholic fatty liver disease
Hedgehog pathway
Morphology non alcoholic liver disease
Pathological steatosis=involvement of >5% of hepatocytes
Overlaps with histology of alcoholic hepatitis, but
- mononuclear cells more prominent
- portal fibrosis more prominent
- mallory denk less common
90% of cryptogenic cirrhosis is not considered “burned out” non alcoholic fatty liver disease
Morphology children non alcoholic fatty liver disease
Diffuse steatosis and portal fibrosis
Portal+parenchymal infiltrate parenchymal neutrophils
Clinical non alcoholic fatty liver disease
Usually asymptomatic or have nonspecific symptoms with RUQ pain
Increase AST, ALT—liver dysfunction
D
Diagnosis non alcoholic fatty liver disease
Liver biopsy
Most common cause of death with non alcoholic fatty liver disease
Cardiovascular death
What is non alcoholic fatty liver disease associated with
Obesity and diabetes
What will liver biopsy show non alcoholic fatty liver disease
Pattern will be microvesicular steatosis, with large lipid vacuoles filling hepatocytes
Treat non alcoholic fatty liver disease
Correct obesity, hyperlipidemia, insulin resistance
-address the underlying metabolic syndrome
WHO criteria for diagnosis of the metabolic syndrome
One of: diabetes mellitus, impaired glucose tolerance, impaired fasting glucose, or insulin resistance
Two of: BP>140/90
TG>1.695 and HDL.9 (male) >.85 (female) or BMI>30
Microalbuminuria: urinary albumin excretion>20 or albumin: Cr>30
Hemochromatosis
Excessive iron absorption deposited in parenchymal organs such as the liver and pancreas followed by heart, joints, and endocrine organs
How get hemochromatosis
Hereditary or due to excessive intake (secondary)
Hereditary hemochromatosis
Slow progression with symptoms appearing in 4th-5th decades for males, later (if ever) for females due to menstruation until menopause
- iron accumulation is lifelong
- injury caused be excess iron is slow and progressive
Secondary (acquired) hemochromatosis
Most common cause is associated with ineffective erythropoiesis (severe thalassemia and myelodysplastic syndrome)-excessive iron from transfusion+increased absorption
Transfusions, when given repeatedly over a period of years (ie. patients with chronic hemolytic anemia)->systemic hemosiderosis and parenchymal organ injury
Chronic liver disease->loss of hepatocyte mass->impaired hepcdin production_>increased iron uptake from the gut->iron overload
Fully developed , severe hemochromatosis
Micronodular cirrhsosis in all patients
Diabetes mellitus in 75-80%
Abnormal skin pigmentation in 75-80%
Hereditary hemochromatosis cause
Mutation in the HFE gene, whose product is involved in intestinal iron uptake by its effects on hepcidin levels
What do we se with hereditary hemochromatosis
Intestinal absorption of dietary iron is abnormal
Net accumulation of .5-1g/yearmanifests with accumulation 20g
One of the msot comon genetic disorders in humans
Iron toxicity hemochromatosis
Lipid peroxidation cia iron-catalyze ROS
Stimulation of collagen formation by activation of hepatic stellate cells
Interaction of ROS and Fe itself with DNA leads to lethal cell injury and predisposition to hepatocellular carcinoma
Is iron toxicity in hemochromatosis reversible
If cells not fatally injured
How treat iron toxicity hematochromatosis
Removal of excess iron promotes recovery of function
Hepcidin
Main regulator of iron absorption
Action of hepcidin
Lowers plasma iron levels
Hepcidin binds __ and internalized the transport channel, preventing iron from leaving intestinal cells and macrophages
Ferroportin
Transcription of hepcidin is increased by:
Inflammatory cytokines and iron
Transcription of hepcidin is deacreased by :
Iron defiency, hypoxia, and ineffective erythropoiesis
Deficient hepcidin
Iron overload
Mutations in hepcidin
Hemochromatosis
What is the most common cause of adult hemochromatosis
HFE mutation(C282Y>H63D)
Chromosome 6, near an HLA locus
What does HFE mutation of hepcidin cause
Adult form of hemochromatosis
What does HFE mutation C282Y cause
Inactivation of HEF->inactivation/defiency of hepcidin->hemochromatosis
Who gets C282Y
White population
Penetrance C282Y
Low penetrance
H63D hepcidinmutation(less common than C282Y) who gets it
Worldwide distribution
TFR@ hepcidin mutation
Less common
Hepcidin mutation HJV or HAMP
Juvenile hemochromatosis
-more severe form of the disease than the adult variety
Hemochromatosis liver
Deposition of hemosiderin in liver, seen with Prussian blue stain
Golden yellow hemosiderin granules initially form, and fibrous septa slowly develop
Leads to small, shrunken liver micronodular cirrhosis
Iron is directly hepatotoxic and there is no inflammation
Late stages the liver is dark brown black due to iron accumulation
Hemochromatosis pancreas
Deposition of hemosiderin, seen with Prussian blue stain
Intensely pigmented
Diffuse interstitial fibrosis
Parenchymal atrophy
Hemosiderin in islet and acinar cells
Hemochromatosis heart
Enlarger with hemosiderin granules in myocardial fibers-> striking brown coloration
Delicate interstitial fibrosis
Hemochromatosis skin
Pigmentation due to increased melanin production causing a gray slate color
Some due to hemosiderin deposition in dermal macrophages and fibroblasts
Mechanism is unknown
Hemochromatosis acute synovitis
Leads to pseudo gout from calcium pyrophosphate deposition
Hemochromatosis testes
Small, atrophic testes due to hypothalamic pituitary axis disruption and decreased hormone production
Clinical tetras hemochromatosis
Hepatomegaly, abnormal skin pigmentation (espicially in sub exposed areas), deranged glucose homeostasis or DM due to destruction of pancreatic islet cells and cardiac dysfunction (arrhythmia, cardiomyopathy)
Atypical arthritis
Hypogonadism
Who gets hemochromatosis
Males over 40
What do people with hemochromatosis have high risk for
200x increased risk of hepatocellular carcinoma
Does treatment of iron overload in hemochromatosis remove risk of cancer
Not fully bc DNA alterations that occur prior to time of diagnosis and initiation fo treatment
Diagnose hematochormis
Diagnosible long before irreversible tissue damage occurs
Look for iron in the tissues with Prussian blue
-Prussian blue stains hepatocellular iron blue
Screen for high levels of serum iron and ferritin
Screen family members
Screening hematochromatosis
Diagnosis can be made before irrreversible tissue damage occurs
Screen for very high levels of serum iron and ferritin, exclusion of secondary causes or iron overload and liver biopsy if still in doubt
Heterozygous hematochromatosis
Still accumulate excess iron, but not to a level that causes significant tissue damage
Treat hematochromatosis
Regulat phlebotomy (blood letting) depletes tissue stores or iron=normal life expectancy
Neonatal (congenital) hemochromatosis
Severe liver disease and extrahepatic hemosiderin deposition of unknown origin
Is neonatal hemochromatosis inherited
No
Why get neonatal hemochromatosis
Liver injury occurs in utero; may be due to materanla alloimmune injury to fetal liver
Extrahepatic hemosiderin deposition (buccal) has to be documented for proper diagnosis
Treat for neonatal hemochromatosis
No treatment, supportive care and possible liver transplant
Wilson disease mutation
AR disorder via ATP7B
Wilson disease problem
Impaired shopper excretion into bile and failure to incorporate copper into ceruloplasmin which leads to toxic levels of copper in the liver, kidney and eye (also kidney, bones, joints)
Pathogenesis wilson
Copper absorption and delivery to the liver is normal but excretion into bile is reduced, it is not incorporated into ceruloplasmin and ceruloplasmin secretion into the blood is inhibited
Copper accumulated in the liver cause injury via ROS
Non ceruloplasmin bound copper spills into circulation leads to hemolysis and pathology elsewhere
Why does copper cause toxic liver damage
Promotes formation of free radicals by the Fenton reaction
Binds to sulfhydral groups of cellular proteins
Displaces other metals from hepatic metalloenzymes
Morphology Wilson’s disease
Fatty change
Acute and chronic hepatitis with Mallory denk bodies
Eventually leads to cirrhosis
+/- necrosis
CNS toxicity: basal ganglia atrophy and cavitation
Kayser-fleischer rings:green brown copper deposits in descent membrane
Can use rhodamine or orcein stains to look for the copper
In Wilson’s there is __ urinary excretion of copper and _ plasma ceruloplasmin
Elevated
Low
How does wilson present
Acute or chronic liver disase that presents between 6-40 years
Neurological involvement: movement disorders or rigid dystonia (may be confused with parkinsonism)
Copper toxicity(wilson) primarily impacts the __ __, espicially the ___
Basal ganglia
Putamen
Huntington signs
Poor coordination, chorea, or choreathetosis
Parkinson sign
Spastic dystonia, mask life fancies, rigidity, and gait disturbances
Psychotic symptoms wilson
Land these patients in mental institutions
Why do people with wilsons get hemolytic anemia
Copper toxicity to RBC membranes-elevated direct bilirubin
Diagnosis wilson
Decreased serum ceruloplasmin
Increased hepatic copper content (most sensitive and accurate)
- demonstration of hepatic copper content in excess 250 microgram/gram is most helpful
- increased urinary copper excretion (most specific screening test)
Treatment wilson
Long term chelation therapy or zinc based therapy
Liver transplant if unmanageable cirrhosis develops;this is curative
A1 antitrypsin defiency (a1AT defiency)
AR disorder of protein folding
PiMM a1AT
Wild type 90% of people
PiZz a1AT
Most common clinically relevant genotype
PiZz homos
10% of the normal circulating a1-antitrypsin level
How does PiZz present
Very early with liver disease-a1 antitrypsin defiency is the most commonly diagnosed inherited hepatic disorder in infants and children
A1AT have _ serum a1-antitrypsin
Low
What does a1-antitrypsin do
Inhibit proteases (neutrophil elastase, cathepsin G, and proteinase 3)
What does a1AT defiency lead to
Pulmonary emphysema because activity of destructive proteases is not inhibited
Hepatic disease(cholestasis or cirrhosis) because of hepatocellular accumulation of the misfolded protein->ER stress->ER stress (misfolded protein) response->apoptosis
A1AT defiency is the most commonly diagnosed inherited hepatic disorder of _ and _
Infants and children
Pathogenesis a1AT defiency
Mutation prevents migration of the protein from the ER to the golgi, leading to accumulation of the protein in the liver
All patients with PiZz genotype accumulate protein but only10-25% develop liver disease
Morphology a1AT defiency
Characterized by presence of round to oval cytoplasmic globular inclusions in periportal hepatocytes (*****acidophilic, PAS(+) following diastase digestion of the liver
Number of globules does not represent severity of disease
Ranges from cholestasis to hepatitis to cirrhosis
Clinical a1AT defiency
Neonatal hepatitis+cholestasis jaundice in 10-20% of affected newborns
Adolescence:present with hepatitis , cirrhosis or pulmonary disease (may regres and recur)
May be silent until later in life
Hepatocellular carcinoma in 2-3% of PiZz adults
Treat a1AT defiency
Orthotopic liver transplant (cure)
In patients with pulmonary disease, the single most preventative measure is avoidance of cigarette smoking
Function of bile
Emulsification of dietary fat in the lumen of the gut through the detergent action of bile salts
The elimination of bilirubin, excess cholesterol, xenobiotics, and other waste products that are insufficiently water soluble to be excreted into urine
Most of the bilirubin in the serum is what
Complexed onto albumin-unconjugated
Is there any bilirubin free in the plasma
Super small amount
Can album -bilirubin be excreted in urine
No, no matter how high the serum concentration
A little bit os serum bilirubin-albumin is able to diffuse into tissues, espicially in what
Into premature infants brain(erythroblastosis fetalis leading to kernicterus)
Normal bilirubin levels
.3-1.2 mg/dL
Jaundice levels of bilirubin
> 2.5 mg/dL
Neonatal jaundice
The ability to conjugate and excrete bilirubin doesn’t occur until about 2 weeks of age
It is normal and expected for newborns to go through transient phases of jaundice in the beginning of life
Can be exacerbated by breastfeeding due to bilirubin-deconjugate enxymes present in milk
Crigler najjar syndrome 1
AR complete enzyme defiency
No UGT1A1 activity
Unconjugated hyperbilirubinemia
Prognosis crigler najjar 1
Fatal in neonatal period
More severe than II
ARcrigler najjar II
AD, variable penetrance
Decreased UGT1A1 activity
Unconjugated hyperbilirubinemia
Prognosis criglerr najjar II
Mild clinical course with only occasional kernicterus
Gilbert syndrome
AR decreased UGT1A1 activity
Innocuous
Unconjugated hyperbilirubinemia
Dubin johnson
AR
Mutated MRP2
Conjugated hyperbilirubinemia
Innocuous
Impaired excretion of bilirubin glucuronides
Signs of dubin johnson
Black liver
Mutated canalicular MDR protein 2
Pigmented cytoplasmic globules
Innocuous
Rotor syndrome
AR
Conjugated hyperbilirubinemia
Cholestasis
Impaired bile formation and flow->accumulation of bile pigment within the hepatic parenchyma
Signs of cholestasis
Jaundice, pruritus, skin xanthomas, malabsorption, vitamin ADEK deficiencies
Labs cholestasis
Characteristic elevated serum y-glutamyl transpeptidase (GGT) and alkaline phosphatase
ALT and AST are normal as they indicate there has been loss of hepatocytes integrity
In cholestasis there is accumulation of bile pigment in the __ __ and longated green-brown plugs of bile are found in dilated bile canaliculi
Hepatic parenchyma
What are feathery degeneration of periportal hepatocyte (zone 1) incholestasis
Droplets of bile pigment that can be found in hepatocytes with a fine, foamy appearance
In in cholestasis there are __ ammlry denk bodies
Periportal
What are some common causes of large bile duct obstruction in adults
Extrahepatic cholelithiasis, malignancies of the biliary tree or head of the pancreas, strictures resulting from previous surgical procedures
Large bile duct obstruction commmon causes in kids
Biliary atresia, cystic fibrosis,choledochal cysts, and syndromes in which there are insufficient intrahepatic bile ducts
Treat cholestasis
Extrahepatic bile obstruction is treatment with surgery
Common causes of large bile duct obstruction in kids
Biliary atresia, cystic fibrosis, choledochal cysts, and syndromes in which there are insufficient intrahepatic bile ducts
Ascending cholangitis
A secondary bacterial infection of the biliary tree that aggravates the inflammatory injury
What causes ascending cholangitis
Subtotal or intermittent obstruction
What causes ascending cholangitis
Enteric bugs like coliforms and enterococci
Charcot triad of ascending cholangitis
Fever, RUQ pain, jaundice
Also get chills
Histology ascending cholangitis
Influx of periductular neutrophils directly into the bile duct epithelial and lumen
Ascending cholangitis may be superimposed on the chronic process so that there is acute-on-chronic __ __
Liver failure
What can ascending cholangitis lead to
Suppurative cholangitis (most severe; risk of sepsis)
Suppurative cholangitis
Purple NT bile fills and distended bile ducts
Frequently complicated by sepsis (instead of cholestasis)—sepsis is life threatening
How can intrahepatic bacterial infection directly cause cholestasis of sepsis
Abscess formation, bacterial cholangitis
How can liver cirrhosis cause cholestasis of sepsis
Ischemia related to hypotension caused by sepsis, espicially when liver is cirrhosis
How can circulating microbial products cause cholestasis of sepsis
Most likely to lead to the cholestasis of sepsis
Most commmon form of this==canalicular cholestasis
- bile plugs within predominantly ventriloquial canaliculi
- associated with activation of kupffer cells and mild portal inflammation
- hepatocyte necrosis is scant or absent
Ductular cholestasis
Dilated canals of hearing and bile duct ulcers at the interface of portal tracts and parenchyma become dilated and contain obvious bile plugs
Biliary cirrhosis
Due to chronic biliary obstruction and ductular reactions that lead to periportal fibrosis and eventually hepatic scarring and nodule formation
There may also be bile infarcts from the detergent effects of the extravasated bile
Primary heptolithiasis
Disease of intrahepatic gallstone formation that leads to repeated bouts of ascending cholangitis, progressive inflammatory destruction of hepatic parenchyma, and predisposes to biliary neoplasia
Where is primary hepatocyte I asis common
East Asia
Morphology primary hepatolithiasis
Pigmented Ca bilirubinate stones in distended intrahepatic bile ducts
Ducts show chronic inflammation, mural fibrosis, and peribiliary gland hyperplasia
Biliary dysplasia may also be seen—>may evolve to invasive cholangiocarcinoma
What do people with primary hepatolithiasis have an increased risk of getting
Cholangiocarcinoma by unknown mechanism
Neonatal hepatitis
Liver injury/inflammation in the neonate
Leads to jaundice, dark urine, light or acholic stools, hepatomegaly
There may be varying levels of impaired hepatic synthetic function
Neonatal cholestasis
Prolonged conjugated hyperbilirubinemia in the neonate after 2 weeks (not physiological jaundice of the newborn)
Morphology neonatal hepatitis
- panlobular giant-cell transformation of hepatocytes
- lobular disarray with local liver cell apopotosis and necrosis
- hepatocellular and canalicular cholestasis
- mild mononuclear infiltration of the portal areas with reactive changes in kupffer cells
- extramedullary hematopoiesis
Biliary atresia
Complete or partial obstruction of the lumen of the extrahepatic biliary tree within the first three months of life
What is the most common cause of neonatal cholestasis and death from liver disease in early childhood
Biliary atresia
Pathogenesis of fetal biliary atresia
Associated with other anomalies resulting from ineffective establishment of laterality of thoracic and abdominal organs during development
Due to aberrant intrauterine development of the extrahepatic biliary tree
Pathogenesis of perinatal biliary atresia
Most common 80%
Destruction of the normal biliary tree shortly after birth
Rotavirus, CMV, reovirus, autoimmune are all implicated
Genetic basis
Morphology biliary atresia
Inflammatory and fibrosis stricture of the hepatic or common bile ducts
Progressive destruction of the intrahepatic biliary tree
Clinical presentation biliary atresia
Neonatal cholestasis, but normal weight gain
Normal stools change into acholic stools
Jaundice lasts longer than 2 weeks
Serum bilirubin in biliary atresia
6-12 mg/dL
What happens if biliary atresia is left untreated
Leads to cirrhosis in 3-6 months after birth, death by 2
Treatment biliary atresia
If limited to common duct(typeI) or left/right hepatic ducts(typeII):Kauai procedure
Obstruction above the porta hepatitis(typeIII): not correctable (90%) and needs liver transplant
-no patent bile ducts amendable to surgical anastomsis
Primary biliary cirrhosis
Non-suppurative, inflammatory destruction of small/medium-sized intrahepatic bile ducts
-not the large or extrahepatic ducts
Does primary biliary cirrhosis progress to cirrhosis
Not really
Primary cirrhosis shows __ __ lesions
Florid duct
Who gets primary biliary cirrhosis
Disease of middle aged women :40-50 year old femmes that live in Northern European countries (England Scotland) or northern US(Minnesota)
North south gradient
Family member with primary biliary cirrhosis
Morphology primary biliary cirrhosis
Anti-mitochondrial antibodies )anti-PDC-E2)
Florid duct lesion: interlobular ducts are actively destroyed by lymphoplasmacytic inflammation with or without granulomas
Patchy loss of the ducts
Feathery degeneration and ballooned, bile stained hepatocytes with mallory denk bodies
Hepatocyte loss, regenerative hyperplasia, hepatomegaly
Widespread duct loss that leads to cirrhosis and periportal/periseptal cholestasis->end stage
Widespread modularity without the surrounding scar tissu seen in cirrhosis (nodular regenerative hyperplasia)->portal HTN
How diagnose primary biliary cirrhosis
Biopsy (look for florid duct lesion)
Primary biliary cirrhosis causes increased serum what in the asymptomatic individual
Alkaline phosphatase and GGT
Clinical presentation primary biliary cirrhosis
Patients may have progressive fatigue and pruritis
Secondary symptoms may appear: hyperpigmentatoin, xanthelasmas, steatorrhea, vitamin D malabsorption_>osteomalacia/osteoporosis
Associated systemic findings of primary biliary cirrhosis
Other autoimmune disorders; shorten syndrome (xerostomia, xeropthalmia), sclerosis, thyroiditis, rheumatoid arthritis, raynaud phenomenon, and celiac disease
Treat primary biliary cirrhosis
Early stage-ursodeoxycholic acid to slow progression
Late stage-liver transplant (ursodeoxycholic acid is ineffective)
Primary sclerosing cholangitis
Inflammation and fibrosis of intrahepatic and extrahepatic bile ducts with dilation of preserved segments
-see beading on radiographs
What do you see on radiographs with primary sclerosing cholangitis
Beading seen on radiographs
Who gets primary sclerosing cholangitis
More likely to affect males 20-40 yo
If first degree relative has primary sclerosing cholangitis
Associated conditions of primary sclerosing cholangitis
IBD(ulcerative colitis) coexists win about 70% of patients with PSC
May lead to biliary intraepithelial neoplasia and cholangiocarcinoma with fatal utcomes
__ are found in 65% of patients with primary sclerosing cholangitis
PANCAs
Atypical perinuclear antineutrophillic cytoplasmic antibodies
Morphology large duct in primary sclerosing cholangitis
Neutrophilic infiltration of the epithelium on a chronic inflammatory backgrounf
The inflammation and edema lead to obstruction and scarring that narrow the lumens
Smaller ducts morphology primary sclerosing cholangitis
Little inflammation with onion skin fibrosis around an atrophic duct lumen that leads to obliteration by a tombstone scar
What happens to the liver as primary sclerosing cholangitis progresses
The liver becomes cholestasis that can lead to primary biliary cirrhosis
Clinical primary sclerosing cholangitis
Persistent elevation of serum alkaline phosphatase
There may be progressive fatigue pruritis and jaundice
Acute bouts of ascending cholangitis
Typically progresses over 5-17 years leading to cholestasis
Diagnosis primary sclerosing cholangitis
Radiology of the larger ducts will show strictures and beading with pruning of the smaller ducts
Diagnosis is made by radiologic imaging of the biliary tree
Treat primary sclerosing cholangitis
No real treatment
Transplant at end stage
Choledochal cysts
Congenital dilation of the common bile duct
Who gets choledochal cysts
Present most often in kids before 10 years old as jaundice or recurring abdominal pain (symptoms of typical biliary colic)
3-4x more likely in females
Fibropolycystic disease
Group of different lesions int he liver due to congenital malformations of the biliary tree (ductal plate malformation)
Presentation fibropolycystic disease
Most are incidental findings, but can also present as hepatosplenomegaly or portal HTN without hepatic dysfunction in late childhood or adolescence
What is fibropolycystic disease associated with
Commonly happens in association with autosomal recessive polycystic renal disease
Patients have an increased risk of cholangiocarcinoma
What are the 3 sets of pathological findings of fibropolycystic disease
Von meyenburg complexes
Caroli disease
Congenital hepatic fibrosis
Von meyenburg complexes
Small bile duct hamartomas that are normal if limited, but indicative of FPD if they are diffuse
Caroli disease
Biliary cysts in isolation that lead to clinical symptoms
Carli syndrome: biliary cysts that occur with congenital hepatic fibrosis
Congenital hepatic fibrosis
Portal tracts are enlarged by irregular broad bands of collagenous tissue that form septa to divide the liver into irregular islands
- abnormally shaped bile ducts embedded in the fibrous tissue still connected to the biliary tree
- may have portal HTN as a result
Circulatorydisorders
Clinically significant liver function abnormalities do not always develop
Hepatic morphology may be strikingly affected
What can compromise the hepatic artery
Liver infarcts are rare due to dual blood supply to the liver
Loss of blood supply intrahepatic can lead to localized infarct that is pale or hemorrhagic
Transplanted livers are more likely to become infarcted as they only have blood supple from the arterial system
What does hepatic artery compromise result in
Impaired blood flow to the liver
__ __ obstruction/thrombosis also impairs blood flow to the liver
Portal vein
Most common cause of impaired blood flow THROUGH the liver
Cirrhosis
What besides cirrhosis causes impaired blood flow through the liver
Physical sinusoidal occlusion
What causes physical sinusoidal occlusion
Sickle cell disease
Disseminated intravascular coagulation
Eclampsia
Diffuse intrasinusoidal metastatic tumor
What may portal vein occlusions cause
Esophageal varices
What is the most common cause of intrahepatic blood flow obstruction
Cirrhosis
What is the most common cause of small portal vein branch obstruction
Schistosomiasis
What causes obliterating portal venopathy
HIV
Peliosis hepatis
Sinusoidal dilation that occurs in any condition in which efflux of hepatic blood is impeded
Blood lakes (due to sex hormones, infection)
Right sided heart failure or terminal event
Passive congestion
Left sided heart failure
Hepatic hypoperfusion and hypoxia->ischemic coagulative necrosis of hepatocytes in the central region of the lobule (centrilobular fibrosis)
Chronic CHF
Cardiac sclerosis with centrilobular fibrosis
Nutmeg liver:hypoperfusion and retrograde congestion
Budd chiari syndrome
Obstruction of two or more major hepatic veins that leads to hepatomegaly, pain and ascites
Prognosis budd chiari
High mortality
Morphology budd chiari
Liveris swollen red purple, and has a tense capsule
There are different areas of preserved or regenerating parenchyma alternating with hemorrhagic collapse
Severe centrilobular congestion and necrosis, or fibrosis if slowly developing
Affected veins may contain thrombi
Treatment budd chiari
Surgery to create a portosystemic venous shunt permits reverse flow throug the portal vein and improves the prognosis (5 year survival>67%)
Sinusoidal obstruction syndrome
Obliteration of the terminal hepatic venues by subendothelial swelling and collagen deposition
Causes of sinusoidal obstruction syndrome
Jamaican bush tea drinkers
3 weeks after stem cell transplant
Cancer patients receiving chemotherapy
Toxic injury to the sinusoidal endothelium
Morphology sinusoidal obstruction syndrome
Centrilobular congestion, hepatocellular necrosis, and accumulation of hemosiderin macrophages
Obliteration of the lumen of the venue is identified with special stains for connective tissue
Clinical sinusoidal obstruction syndrome
Histology=gold standard of diagnosis
Clinical diagnosis=tender hepatomegaly, ascites, weight gain, jaundice
Passive congestion and centrilobular necrosis and liver
Hepatic manifestations of systemic circulatory compromise
Liver and bone marrow transplant
Graft vs host
Attack the liver
Liver transplant and liver
Host vs graft
Attacks the liver
Acute GVHD time
10-50 days
GVHD chronic days
100+ days
Acute GVDH
Donor lymphocytes attach the epithelial cells of the liver
Hepatitis with necrosis or hepatocytes and bile duct epithelial cells
Inflammation of the portal tracts and parenchyma
Chronic GVHD
Portal tract inflammation, selective bile duct destruction, and eventual fibrosis
Acute transplant rejection is ___ and chronic transplant rejection is ____
Cellular
Vascular
Acute(cellular) transplant rejection
Characterized by infiltration of a mixed portal inflammatory infiltrate
Associated with bile duct injury and endothelitis
Chronic (vascular) transplant rejection
Obliteration arteriopathy of small and large arteries leads to ischemic changes int he liver parenchyma
Vanishing bile duct syndrome*
What are some hepatic diseasesassociated with pregnancy given that 3-5% of pregnant patients have abnormal liver function tests
Viral hepatitis (most common cause of pregnant jaundice)
Hepatic complications that are directly attributable to pregnancy in .1%
Preeclampsia and eclampsia
Viral hepatitis and pregnancy
HAV, HBV, HCV, or HBV+HBD
HEV infectionruns a more severe course in pregnancy and has a mortality rate of 20%
Preeclampsia
Maternal HTN, proteinuria, peripheral edema, and coagulation problems
When does preeclampsia become eclampsia
When hyperreflexia and convulsions
HELLP syndrome:subclinical manifestation of preeclampsia
Hemolysis
Elevated liver enzymes
Low platelets (thrombocytopenia)
Liver in preeclampsia and eclampsia
Periportal sinusoids contain fibrin deposits associated with hemorrhage into the space of disse with associated hemorrhagic necrosis
Blood presssure can lead to hematoma and may rupture
Clinic preeclampsia and eclampsia
Modest to severe elevation of serum aminotransferases and mild elevation of serum bilirubin
When does acute fatty liver of pregnancy occue
Latter half of pregnancy, often int he third trimester
Prognosis acute fatty liver of pregnancy
Hepatic dysfunction that can lead to hepatic failure, coma, and death in severe cases
In acute fatty liver of pregnancy there is elevated __
Serum aminotransferase levels
What are symptoms from incipient hepatic failure in acute fatty liver of pregnancy
Bleeding, nausea, vomiting, jaundice, and coma
Diagnosis of acute fatty liver of pregnancy
Characteristic diffuse microvesicular steatosis of hepatocytes on biopsy
May be lobular disarray with hepatocyte dropout, reticulin collapse, and portal tract inflammation (looks like viral hepatitis)
Prognosis acute fatty liver of pregnancy
Can progress very quickly to hepatic failure and death in a few days
How do u treat acute fatty liver of pregnancy
Termination of pregnancy
Intrahepatic cholestasis of pregnancy presentation
Onset of pruritus, followed by darkening of urine and occasionally light (acholic) stools and jaundice in the 3rd trimester
Labs intrahepatic cholestasis of pregnancy
Serum bilirubin and alkaline phosphatase may be slightly elevated
Bile salt levels are greatly increased
Prognosis intrahepatic cholestasis of pregnancy
Generally a benign condition to mother
Incidence of fetal distress, stillbirth, and prematurity is moderately increased
Nodule hyperplasia of the liver (not a true neoplasm)
Single or multiple nodules may develop n a non cirrhosis liver either from focal nodular hyperplasia or nodular regenerative hyperplasia
What causes nodular hyperplasia of the liver
Due to focal or diffuse alterations in hepatic blood obliteration of portal vein radicle and compensatory flow of arterial blood supply
What is focal nodular hyperplasia
Benign;well demarcated but poorly encapsulated
Spontaneous mass lesion that appears in a normal liver
Who gets focal nodular hyperplasia
Young to middle aged adults
Morphology focal nodular hyperplasia
Tighter than the surrounding liver and is sometimes yellow from steatosis
Central grey-white depressed stellate scar (containing vessels with fibromuscular hyperplasia) that fibrous septa radiate outward from
Nodular regenerative hyperplasia
Entire liver is transformed into nodules, looks similar to focal nodular hyperplasia, but there is no fibrosis
Wha can nodular regenerative hyperplasia lead to
Portal HTN
What is nodular regenerative hyperplasia associated with
Conditions that affect intrahepatic blood flow like HIV or autoimmune
Symptoms nodular regenerative hyperplasia
Usually asymptomatic, only found at autopsy
Morphology nodular regenerative hyperplasia
Plump hepatocytes are surrounded by rims of atrophic hepatocytes
What is the most common benign liver tumor
Cavernous hemangiomas
Cavernous hemangiomas are tumors of the ___ ___
Blood vessels
Morphology cavernous hemangiomas
Red blue nodules located directly under the capsule
Vascular channels in a bed of fibrous CT
Are cavernous hemangiomas more common in males or females
Females
How find cavernous hemangiomas
Found incidentally or after hemorrhage
-might be mistaken radiographically or intraoperatively for metastatic tumors
What are hepatocellular adenomas
Benign neoplasm developing from hepatocytes
Rupture of hepatocellular adenoma
Intrabdominal bleeding that is a surgical emergency
What are hepatocellular adenomas associated with
Oral contraceptive therapy and anabolic steroids (so sex hormones)
-HEPATOCELLUAR ADENOMAS WERE UNKNOWN BEFORE THE ADVENT OF ORAL CONTRACEPTIVES
What are the three types of hepatocellular adenomas
HNF1-a inactivated adenomas
B-catenin activated adenomas
Inflammatory adenomas
HNf1-a inactivated adenomas are associated with what
MODY-3
Risk of malignant transformation with HNF-1-a inactivated adenomas
No risk of malignant transformation
Describe HFN1-a inactivated adenomas
Fatty with no atypia
Look for NO staining with liver fatty acid binding protein (LFABP)
b catenin activated adenomas associated with what
Use of oral contraceptives and anabolic steroids (so sex hormones)
B catenin activated adenomas risk of malignant transformation
Very high
Describe b catenin activated adenomas
High degree of dysplasia
Look for glutamine synthetase diffusely and b catenin in the nucleus
Inflammatory adenomas associated with what
NAFLD
Mutations in gp130 (IL6, JAK-STAT pathway)
Inflammatory adenomas risk of malignant transformation
Small, but definite risk of malignant transformation
Describe inflammatory adenomas
Characteristically have in addition areas of fibrotic stroma, mononuclear inflammation, ductular reactions, dilated sinusoids, and telangiectatic vessels
Over express CRP and serum amyloid A
What is the most common liver tumor of early childhood
Hepatoblastoma
What are the types of hepatoblastoma
Epithelial
Mixed epithelial and mesenchymal type
Epithelial type of hepatoblastoma
Small polygonal fetal cell or smaller embryonal cells forming acini, tubules, or papillary structures vaguely looking like liver development
Mixed epithelial and mesenchymal type of hepatoblastoma
Foci of mesenchymal differentiation with osteoporosis, cartilage, or striated muscle
Hepatoblastoma frequently activates ___ pathway
WNT pathway (APC mutation) *patients with familial adenomatous polyposis frequently develop hepatoblastoma
What are hepatoblastoma associated with
Familial adenomatous polyposis and beckwith-wiedemann syndromes
What is the most common primary malignancy of hepatocytes
Hepatocellular carcinoma
Risk factors for hepatocellular carcinoma
HBV in Asian countries, HCV in USA (both turn chronic)
Alcohol, AFLATOXIN, a1AT, hemochromatosis, NAFLD, wilson disease, adenomas
Genetic factors for hepatocellular carcinoma
B catenin activation and p53 inactivation (aflatoxin) are the two most common mutational events
May be associated with Il-6/HNF4-a
Hepatocellular carcinoma low grade dysplastic nodules: precursor lesion
No atypia, have a higher risk of becoming high grade nodules
Shown to be colonial and are probably neoplastic
Hepatocellular carcinoma high grade dysplastic nodules:precursor lesions
Signs of atypia, have a great risk of becoming HCC and HCC foci are often found already in nodules
What is the most important pathway for emergence of HCC in viral hepatitis and alcoholic liver disease**
High grade dysplastic nodules
Hepatocellular carcinoma morphology large cell change
Scattered hepatocytes near portal tracts or septa that are larger than normal hepatocytes with large multiple pleomorphic nuclei
Nuclear cytoplasmic ratio is normal
Large cell change is a marker of increased risk of hepatocellular carcinoma-considered directly pre malignant in hepatitis B
Hepatocellular carcinoma small cell change morphology
High nuclear cytoplasmic ration and mild nuclear hyperchromasia/pleomorphism
Hepatocytes will commonly form tiny nodules within a single parenchymal lobule
Directly premalignant
Hepatocellular carcinoma may appear as what morphologically
Large univocal mass
Multifocal, widely distributed nodules
Diffusely infiltration cancer
Hepatocellular carcinoma intrahepatic metastases
By either vascular invasion or direct extension, become more likely once tumors reach 3 cm in size
Hepatocellular carcinoma small, satellite tumor nodules are around what
The larger, primary masss
Hepatocellular carcinoma vascular metastasis
The most likely route for extrahepatic metastasis, espicially by the venous system
Hepatocellular carcinoma hematogenous metastases
Espicially to the lung, tend to occur late in the disease
Presentation of hepatocellular carcinoma
Common liver dysfunction symptoms and hepatomegaly
_% of patients with advanced hepatocellular carcinoma have elevated a-fetoprotein. What does this mean
50
Insensitive as a screening test for pre malignant or early lesions
Diagnosis hepatocellular carcinoma
Imaging
What causes death hepatocellular carcinoma
Cachexia, GI or varices bleeding, liver failure, or rarely from tumor rupture and hemorrhage
Prognosis hepatocellular carcinoma
Die in 2 years
Fibrolamellar carcinoma
Rare variant of hepatocellular carcinoma
Who gets fibrolamellar carcinoma
<35
Presentation fibrolamellar carcinoma
Single large hard scirrhous tumor with fibrous bands coursing through it
What is a fibrolamellar carcinoma composed of
Well differentiated cells rich in mitochondria growing in nests or cords separated by parallel lamellae of dense collagen bundles
Cholangiocarcinoma
Second most common primary malignant tumor after HCC
Cancer of the biliary tree coming from bile ducts within and outside the liver
Adenocarcinoma
Risk factor for cholangiocarcinoma
Liver flukes (opisthorchis, clonorchis)
Chronic inflammation of the large bile ducts
HBV, HCV, NAFLD (same as HCC)
Extrahepatic cholangiocarcinoma
Perihilar tumors (klaskin tumors) located at the junction of the hepatic ducts (most common)
Common bile duct, posterior to the duodenum
Intrahepatic cholangiocarcinoma
Only 10% of tumors
Premalignant lesion of cholangiocarcinoma
Biliary intraepithelial neoplasia (low to high grade: Bi1IN-1,2,3)
3 is the highest grade and has the highest risk of malignant transformation
Morphology extrahepatic cholangiocarcinoma
Form grey nodules in the bile duct wall that can be diffuse to papillary
Generally small lesions at the time of diagnosis
Intrahepatic morphology cholangiocarcinoma
Track along the intrahepatic portal tract system that creates a branching tumor within a portion of the liver
Cholangiocarcinomas are __ differentiated with __/__ structures lined by __ epithelial cells
Moderately well
Glandular/tubular
Epithelial
Prognosis cholangiocarcinoma
Median time to death is 6 months for intrahepatic, but overall for any location is 14% 2 year survival
Clinical presentation intrahepatic cholangiocarcinoma
Present as obstruction to bile flow or symptomatic liver mass
Clinical presentation of extrahepatic cholangiocarcinoma
Biliary obstruction , cholangitis, and RUQ pain
Combined hepatocelular and cholangiocarcinoma
Suggest an origin from a multipotent stem cell
Mutinous cystic neoplasms and intraductal papillary biliary neoplasia
May occur as in situation lesion or as invasive cholangiocarcinoma
Angiosarcoma
Has historic association with vinyl chloride, arsenic, or thorotrast
Hepatic lymphomas. Who gets is
Middle aged men
What are hepatic lymphomas associated with
HBV, HCV, HIV< PBC
Describe hepatic lymphoma
Most are diffuse large B cell lymphomas, then MALTomas
Hepatosplanic delta-gamma T cell lymphoma, who get is
Young adult males
Hepatosplenic delta-gamma T cell lymphoma is a predilection for
Hepatic and splenic sinusoids as well as the marrow
Is metastases or primary liver cancer more common
Metastases
Most common places that metastases to the liver
Colon, breast, lung, pancreas
How does metastases to the liver present
Appear as multiple nodular metastases that replace most of the parenchyma and lead to hepatomegaly, but can also appear as just a single nodule
Usually clinically silent until late stage
What is the most common congenital gallbladder anomaly
A fundus that is folded inwards, creating a phrygian cap
More than 95% of biliary tract disease is attributable to ___
Cholelithiasis
Cholelithiasis
Stones of either cholesterol or pigment (bilirubin) that collect in the gallbladder
Why are cholesterol stones more common in developed countries and pigment stones more common in developing countries: cholelithiasis
Diet
Infections
Risk factors for cholelithiasis
Middle to older age female
Obesity, metabolic syndrome
Estrogen exposure (OC, pregnancy)
Native Americans
Gallbladder stasis
ABCG8 variant (ABC transport)
Pathogenesis for cholesterol cholelithiasis
Collect when their concentration increases above the capacity of the bile-precipitate out of bile
Can happen when there is too much cholesterol, crystal nucleation, mucus secretion, or hypomotility
Cholesterol stones are more common in the US and western countries-probably do to diet
Pathogenesis of pigment stones
Stones of unconjugated bilirubin and inorganic calcium salts
Can happen when there are elevated levels of unconjugated bilirubin in the bile
- chronic hemolytic anemia
- severe ideal dysfunction or bypass
- bacterial contamination of the biliary tract leading to release of beta-glucuronidases(e coli, ascaris, lumbricoides, liver fluke c sinensis)
Arise primarily in te setting of bacterial infections of the biliary tree and parasitic infestations
Cholesterol stones morphology
In gallbladder
Pure cholesterol stones look pale yellow, finely granular, hard, crystalline palisade
- stones composed largely of cholesterol are radiolucent
- sufficient calcium carbonate renders 10-20% of them radiopaque
- BECOME MORE BLACK and are more lamellated when they are mixed with other substances
Pigment stones morphology
Black stones are found in sterile bile ducts and are made up mostly of bilirubin, salts, and mucin. Appear friable with speculated and molded contours
50-70% of black stones are radioopaque due to calcium salts
Brown stones are found in infected large bile ducts ; composition is the same, but also have some cholesterol mixed in and are found in ducts with infections. Soap like, greasy, soft, laminated
-radiolucent because they contain calcium soaps
Clinical presentation gall stones
Usually asymptomatic
Biliary colic=excruciating constant pain
Pain in RUQ that radiates to the right upper shoulder or the back, which is worse after a fatty meal***
With cholesthiasis , large stones are less likely to enter the cystic or common ducts and produce obstruction
Small stones (gravel) are more dangerous
Gallstones ileus/bouveret syndrome: when a large stone erodes directly into an adjacent loop of small bowel and generates intestinal obstruction
Primary complication of gallstones
Acute cholecystitis
Acute calculous cholecystitis
From chemical irritation and inflammation from a stone
- absence of bacterial infection (though one may develop later in the course)
- 90% of the time caused by obstruction of the neck or cystic duck by a stone
- most common reason for an emergency cholecystectomy
Acute acalcuous cholecystitis
May occur in severely ill patients
- accounts for the other 10%
- frequently develops in diabetic patients who have symptomatic gallstones
- though to result from ischemia (cystic artery=end artery)
- primary bacterial infection 9salmonella typhi and staphylococci)
- incidence of gangrene and perforation is much higher in acalculous that’s in calculous
Risk for acute cholecystitits
Sepsis with hypotension and multisystem organ failure, inspired, major trauma and burns, diabetes, infections
Morphology acute cholecystitis
Gallbladder is enlarged and tense, may be green-black, bright red, or blotchy
Serosa covering is typically covered in a fibrous exudate
In calculous cholecystitis, the stone is blocking the exit and causes the lumen to fill with cloudy or turbid material that may contain fibrin
Gallbladder empyema
When the exudate is virtually pure pus
Mild gallbladder empyema
Wall is thickened, edematous, and hyperemic
Severe gallbladder empyema
Wall is green-black and necrotic (gangrenous cholecystitis)
Acute emphysematous cholecystitis
When the gallbladder is invaded by gas forming organisms (clostridium and coliforms)
Acute emphysematous cholecystitis
When the gallbladder is invaded by gas forming organisms
Clinical acute cholecystisis
Most patients have experienced pain before the acute attack
The acute attack: progressice pain in the RUQ or epigastric that lasts longer than 6 hours
Mild fever, anorexia, tachycardia, sweating, nausea, and vomiting
Acute cholecystitis bilirubin and alkaline phosphatase
Slightly elevated
What does hyperbilirubinemia in acute cholecystisis cause
Obstruction of the common bile duct
Treat acute cholecystisis
25% will need surgery, other patients will recover in 10 days
There is a greater risk of __ and __ in patients that have acalculous cholecystitis
Gangrene
Perforation
Chronic cholecystisi
Chronic inflammation of the gallbladder that is due to stones in 90% of the time
Can be due to repeated acute attacks, but many times is not
At risk population is the same as that for cholelithiasis
Morphology chronic cholecystitis
Serosa may be dulled to subserosal/subepithelial fibrosis
Wall is variably thickened, has a grey white appearance
Reactive proliferative may lead to fusion of the mucosal folds and give rise to buried crypts of epithelial in the gallbladder
Rokitansky-aschoff sinus cholecystisis
Outpouching of the mucosal epithelium through the wall
-diverticulum of the gallbladder
Porcelain gallbladder chronic cholecystitis
Rare calcification of the wall that increases the risk of developing cholangiocarcinoma
Xanthogranulomatous cholecystisis chronic cholecystisis
Very thick wall and the gallbladder is shrunken, nodular with foci of necrosis and hemorrhage that was triggered by rupture of R-A sinuses. Leads to foam (xanthoastrocytoma) cells
Hydrops of the gallbladder chronic cholecystitis
Atrophic, chronically obstructed, often dilated gallbladder that may contain only clear secretions
Clinical chronic cholecystitis
Recurring acute symptoms with intolerance for fatty foods
Beware of bacterial secondary infections, perforation, fistula, and obstruction
What is the most common malignancy of the extrahepatic biliary tract
Adenocarcinoma of the gallbladder
Who is at risk for carcinoma of the gallbladder
Women
Chile, Bolivia, northern India, south western ethnic US population
HAVING GALLSTONES
Pathogenesis gallbladder carcinoma
Biggest risk factor is having gallstones, 1-2% of stone patients get cancer
95% of gallbladder cancers arise in the setting of gallstones
Though that chronic inflammation is reason cancer comes
Morphology carcinoma of the gallbladder infiltrating
Poorly defined area of mural thickening and induration
More common
Morphology carcinoma of gallbladder exophytic
Grows intot he lumen (and invades the underlying wall)
Is exophytic or infiltrating carcinoma of gallbladder associated wth better prognosis
Exophytic
Is infiltrating or exophytic more common carcinoma of gallbladder
Infiltrating
In gallbladder carcinoma, deep ulceration can lead to what
Fistula penetration into other viscera
In carcinoma of gallbladder, what does it commonly seed
Cystic duct, adjacent bile ducts, portal hepatic lymph nodes, peritoneum, GI tract and lungs
When is most gallbladder carcinoma found
At surgery when he gallbladder is though to have stones
What are presenting symptoms of gallbladder carcinoma
Same as those for cholelithiasis: abdominal pain, jaundice, anorexia, nausea, vomiting
When galll bladder carcinoma is found, what is the prognosis, most of which is already advanced
5 years survival is <10%
____ oncoprotein is overexpressed in 33-67% of cases of gallbladder carcinoma
ERBB2 (Her-2/neu)
