Chapter 18-Liver Flashcards
What is the main blood supply for the liver
The portal vein provides 60-70% of blood flow
What are the three components of the portal triad
- Portal veins
- Hepatic arteries
- Bile ducts
Ischemic and hypoxic events are most likely to affect which zone of the hepatic lobule
Zone 1
Drugs and toxins in the liver are most likely to damage which lobular zone
3
What are the main primary diseases of the liver
- Viral hepatitis
- NAFLD
- Alcoholic liver disease
- hepatocellular carcinoma
What are the cytosolic serum measurements that can be ordered to investigate the integrity of the liver
AST
ALT
Lactate dehydrogenase (LDH)
What is the serum measurement that can be take for testing the biliary excretory function
- Serum bilirubin
- Urine bilirubin
- Serum bile acids
What is direct serum bilirubin looking at
The amount of conjugated bilirubin
Which tests can be ordered to evaluate the love of damage to the bile canaliculus
Serum alkaline phosphatase
Serum gamma-glutamic transpeptidase (GGT)
Which serum level can be used to test for the amount of hepatic demethylation
Aminopyrine breath test
What are the two major hepatic changes that are reversible
Steatosis and cholestasis
What is the process and condition if there are councilman bodies or acidophil bodies present
Hepatic apoptosis
What is confluent necrosis and where does it normally begin
Widespread necrosis where there is zonal loss due to toxic or ischemic events, usually starting around a central vein
What is a bridging necrosis event
Zone of necrosis that links central veins to portal tracts or bridges them
IN the regeneration of the liver, which cytokines are present in the priming phase
TNF and IL6
IN the regeneration of the liver, which cytokines are present in the growth phase
HGF and TGF-alpha
What is the principal cell involved in the hepatic scar deposition
Hepatic stellate cell
What is the function of the stellate cell in a quiescent form
Lipid Vitamin A storage
What does the stellate cell become in the phase of hepatic repair
Highly fibrotic myofibroblasts
What is the process that initiates the stellate cells to become myofibroblasts
- Increased production of platelet derived growth factor Beta receptor (PDGFR-Beta) in the stellate cells
- Increased production of TGF-Beta and receptors
- increased metalloproteinase 2 (MMP2)
- Increased tissue inhibators of metalloproteinase 1 and 2 inhibators (TIMP2)
Once stellate cells become myofibroblasts, what is their function
Are contractile cells and are activated by endothelin-1 (ET-1)
What percentage of the liver functional capacity must be affected to cause hepatic failure
80 to 90%
What defines a case of acute hepatic liver failure
Acute liver illness with encephalopathy and coagulation that occurs 26 weeks after an initial liver injury, and must in the absence of pre-existing liver disease
What is the most common cause of acute liver failure
Massive hepatic necrosis, most often induced by drugs or toxins
Ingestion of which toxic is the most common cause of acute liver toxicity
50% occur due to ingestion (accidental or purposefully) of acetaminophen
IN Asia, what is the most common cause of acute liver toxicity
Hepatitis B and E
What is the time frame that acetaminophen causes liver toxicity
Within a week
IN the case of direct liver toxicity like with acetaminophen, what is the size and characteristic of the liver
Small and shrunken, without signs of scarring or regeneration due to the quick nature of the toxicity and failure.
What are the feature of the liver when damage is caused by viral infection
Failure is due to weeks or months of injury, so while the attack is acute, it will still show signs of regeneration and scarring
What are the conditions that can cause poisoning of the liver cells without any evidence of cell death and parenchymal collapse
Diffuse microvascular steatosis related to fatty liver of pregnancy and reactions to toxins
Which toxins can cause diffuse microvascular steatosis
Valproate and tetracycline
What is the general clinical presentation of acute liver failure
- Nausea, vomiting, and jaundice
- Followed by encephalopathy and coagulation defects
Cholestasis increases the risk of which condition
Life threatening bacterial infections
Hepatic encephalopathy is characterized by what presentations
- Confusion, stupor, coma or death
- Rigidity and hyperreflexia
- asterixis (rapid extension/flexion of the head and extremities)
How will Asterixis present and is characteristic of which condition
Rapid flexion/extension of the head and extremities, best seen with arms are in extension and wrists are dorsiflexed.
-Indicative of hepatic encephalopathy
The encephalopathies seen in hepatic failure are due to abnormal levels of what in the serum
Ammonia leading to neural dysfunction
What is the relation between hepatic failure and coagulation issues
Liver produces vitamin K dependent and independent clotting factors, so impaired hepatic function decreases, there is a decrease in the ability to clot, along with the development of DIC
What is hepatorenal syndrome defined as
Renal failure that is occurring in patients with hepatic failure, with no appearance or reason for kidney failure
What is the result of hepatorenal function on the serum concentrations
Decreased GFR and renal perfusion pressure due to:
- Systemic vasodilation
- activation of SNS
- Increased renin/angiotensin axis
- Increased renal vasoconstriction
What is chronic liver failure most associated with and what is the morphology of the result
Liver cirrhosis, characterized by regenerative parenchymal nodules surrounded by fibrous bands and vascularization
How do cirrohosis livers appearances during a biopsy tend to not develop portal hypertension
-narrow, dense, and compacted septa which are separated by large islands of intact parenchyma
How do cirrohosis livers appearances during a biopsy tend develop portal hypertension
-Broad bands of dense scarring, with dilated lymphatic spaces, with less intervening healthy parenchyma
How will patients with cirrhosis present in the clinic
Anorexia, weight loss, weakness
What are the normal causes of fatality in those patients with cirrhosis
- Hepatic encephalopathy
- Bleeding of esophageal varicose veins
- Bacterial infections
During chronic liver injury, even if the cause is removed, which risks factors still remain
- Portal hypertension due to formation of irreversible shunts
- Hepatocellular carcinoma
What are common effects seen in chronic liver failure with regards to hormones and their result
Impaired estrogen metabolism, leading to hyperestrogenemia:
- palmar erythema (local vasodilation)
- spider angiomas
- hypogonadism and gynocomastia
What are the common causes of prehepatic conditions leading to portal hypertension
Obstructive thrombosis
Narrowing of the portal vein
Increased splenic venous blood flow
What are the common causes of posthepatic conditions that lead to portal hypertension
Right sided heart failure
Constructive pericarditis
Hepatic vein outflow obstruction
What is the main cause of intrahepatic conditions leading to portal hypertension
Cirrhosis
What is the leading cause of hepatic hypertension
Cirrhosis
Alteration in sinusoidal endothelial cells contribute to intrahepatic vasoconstriction and Portal Hypertension through which chemicals
- Decrease in NO
- Increased endothelin-1 (ET-1)
- Angiotensinogen
- Eicosanoid
What is the correlation between splanchnic circulation changes and portal hypertension
- Increased portal venous blood flow from hyperdynamic circulation caused by vasodilation in the Splanchnic circulation
- Overall leads to increased venous efflux
What is the most common cause of ascites
Cirrhosis
In the case of patients with ascites, what does the presence of neutrophils in the fluid mean
Infection
In the case of patients with ascites, what does the presence of blood in the fluid point to
Disseminated intra-abdominal cancer
With long standing ascities, what is the process of hydrothroax and which side is it more common on
-Seepage of peritoneal fluid through trans-diaphragmatic lymphatics, usually on the right side
What are the three mechanism that can lead to ascites pathogenesis
1-sinusiodal hypertension
2-percolation of hepatic lymph into the peritoneal cavity
3-Splanchnic vasodilation and hyperdynamic circulation
What is happening in the sinusoidal hypertension as a result of ascities pathogensis
Alterations in Starling’s forces, which drive fluid into space of Disse (also promoted by hypoalbumininemia), where it is removed by hepatic lymphatics
What is the happening in the percolation of hepatic lymph into the peritoneal cavity as a result of portal hypertension and formation of ascites
With cirrhosis, normal lymph flow is far exceeding what is normally does, so there is more than the thoracic duct can handle. As a result, protein rich and triglyceride poor fluid accumulates as part of the ascites fluid
In the case of patients with ascites, what does the presence of splanchnic vasodilation and hyper-dynamic circulation as a result of portal hypertension that results in ascites
Arterial vasodilation in the splanchnic circulation and reduces that arterial blood pressure. The CO is unable to compensate and as a result vasoconstrictors are activated,leading to excess fluid leaving into the abdominal cavity
What is the result on the spleen as a result of liver congestion
Splenomegaly, leading to hypersplenism, such as thrombocytopenia and pancytopenia
What is hepatopulmonary syndrome and what is a common cause
Seen in 30% of patients with cirrhosis and portal hypertension:
-When the intrapulmonary vasculature dilates, including capillaries, resulting in hypoxia
What is mechanism of hepatopulmonary syndrome
-Intrapulmomsry vasculature, including capillaries, dilate. This results in ventilation/perfusion mismatch and hypoxia, creates and right to left shunt
What position that exacerbates hepatopulmonary syndrome
Dyspnea in the upright position
What are the clinical findings of portopulmonary hypertension and what is the common cause
Caused by liver disease and portal hypertension, leading to vasoconstriction and vascular remodeling of the pulmonary arteries
-dyspnea upon exertion and clubbing of the fingers
What is a cause of acute on chronic liver failure with regards to hepatitis origin
-Chronic Hepatitis B infection in a patients who become infected with hepatitis D
What is the cause of acute on chronic liver failure with regards to ascending cholagitis
Ascending cholagitis in a patients with primary sclerosing cholagitis is fibropolycystic liver disease
Overall, what is the very general mechanism of acute on chronic liver disease
-A well compensated chronic liver disease undergoes distress when an acute and new toxin/event causes changes that the remaining parenchyma can not handle
What is the usually clinical course and outcome of Hepatitis A infection
Usually benign, self limited disease with 2-6 weeks of incubation period
What are the common locations that Hepatitis A infections are occuring
Places with poor hygiene and sanitation with a fecal oral transmission
Which marker is a reliable indication for an acute hepatitis A infection
Anti HAV IgM titer, as a rise in this also indicates lack of fecal shedding
What are the five potential outcomes from a hepatitis B infection
1-Acute hepatitis with recovery and clearance
2-nonprogressive chronic hepatitis
3-progressive chronic disease with cirrhosis
4-acute hepatic failure with massive liver necrosis
5-asympatmatic healthy carrier
Which cancer is hepatitis B an important precursor for
Hepatocellular carcinoma (even in the absence of cirrhosis)
The carrier rate for hepatitis B is largely determined by which factor
The age of infection, as infection in children leads to a higher carrier rate
What is the main transmission route for hepatitis B
90% is due to transmission during childbirth
In areas of low levels of Hepatitis B prevalence, what is the most common route of transmission
Sexual contact or drug use
How are most hepatitis B infections prevented
Use of the vaccine as it is 95% successful
What is the location of hepatitis B during active and chronic infections
In the Blood
What percentage of patients with chronic hepatitis due to hepatitis B recover
1-2% of the patients spontaneously clear the infection
What is the result of most patients with an acute or subclinical disease
Recovery
What is the result of the majority of patients who develop chronic hepatitis
Cirrhosis
What is the function of the hepatitis B preform region
Directs the secretion of the core region aka HBeAg
What is the activity of the Pol portion of hepatitis B
A polymerase that is a DNA polymerase and reverse transcriptase
What portion of the hepatitis B virus has been indicated in cancer and which cancer is it
HBx (activates transcription) in hepatocellular carcinoma
What are the levels of HBsAg over the course of a hepatitis B infection
HBsAg:
- Appears before onset of symptoms
- Peaks during disease
- Undetectable by week 12
What are the levels of anti-HBs antibody over the course of a hepatitis B infection
Anti-HB antibodies:
- Rises after acute distress
- Usually after the disappearance of HBsAg
What are the levels of HBeAg, HBV-DNA, and DNA polymerase over the course of a hepatitis B infection
Appear in serum after HBsAg, and present during viral replication
What marker is the HBeAg used to monitor
Continues viral replication, infectivity, and progression to chronic hepatitis
What does the presence of anti-HBe antibodies imply
Acute infection has peaked and is winding down
What is the main determinant of the result of a hepatitis B viral infection
Host immune response
During the hepatitis B infection, what is causing the destruction to the liver
CD8 T cells
What is the best predictor of chronicity of hepatitis B infection
Age (the younger at onset, more likely to develop)
What are the common risk factors for hepatitis C
- IV drug users (54%)
- Sexual partners (36%)
- Surgury in last 6 months (16%)
- Needle stick (10%)
- Contact with infected with HCV (10%)
What is the target of the hepatitis C antibodies and what is the characteristic of that target
-E2 protein is the target, but serves to be the most variable portion of the virus
Why is there no vaccine to hepatitis C
-Genomic instability and antigenic variability as even the presence of IgG does not incur lifelong immunity
What is a typical feature of the clinical infection course of disease for hepatitis C
-Repeated bouts of hepatic damange due to the reactivation of preexisting infection or the emergence of an endogenous, new strain
Which condition is very commonly associated with hepatitis C infected patients
Chronic disease in (80-90%), resulting in cirrhosis in 20% of them
In those patients with chronic hepatitis, which test should be run for diagnosis and what is it evaluating
Hepatitis C RNA testing for assessment of viral replication and conformation of diagnosis
In patients with chronic hepatitis C viral infection, what is a characteristic serum finding
Persistent elevations in serum aminotransferases
Which syndrome is highly associated with hepatitis C infection
Metabolic syndrome, as it can cause insulin resistance and NAFLD, particularly with genotype 3
Treatment of hepatitis C infection with what can possibly provide a cure
Pegylated IFN
Ribavirin
Patients with which hepatitis C genotype are generally likely to have a better response to treatment
2 or 3
Which polymorphism can result in better responses to hepatitis C treatment
Polymorphism in the IL28B gene
What is the general clinical outcome in a patient who is infected with a co-infection of the Hepatitis B and D
Usually self limiting and there is clearance of both viruses in healthy non-IV drug users
Which population is at a higher risk of acute hepatic failure when co-infected with hepatitis B and D
IV drug users
What is the result in patients who are infected with chronic hepatitis B and are inoculated with hepatitis D
Superinfection, resulting in chronic hepatitis D in almost all patients
What is the most reliable indicator of hepatitis D viral infection
IgM anti-HDV antibodies
What is the route of infection of hepatitis E and what is the common patient population affected
Zoonotic disease (pigs) that is a water Bourne infection primarily occurring in young to middle aged adults
Which patients are at an increased risk of poor prognosis as a result of infection with hepatitis E
Pregnant women as mortality is 20%
What is the relationship between hepatitis E and immunocompetent patients with regards to chronic conditions
Does not cause chronic liver disease or persistence of viremia
What are the clinical features of hepatitis infections with acute asymptomatic infection with recovery
- Subclinical and only found accidental
- Minimally elevated serum transaminases
What are the clinical features of hepatitis infections with scute symptomatic infection with recovery
1) Incubation period
2) symptomatic preicteric phase
3) symptomatic icteric phase
4) Convalescence
What are the clinical features of hepatitis infections with acute liver failure
Hepatitis A and E are most common causes
-activation of stem cells from canal of Hering, no other real symptoms/treatments other than supportive
What are the clinical features of hepatitis infections with chronic hepatitis
All Changes continuing or relapsing diseases for longer than 6 months:
- Elevations in transaminases
- prolonged prothrombin time
- fatigue
- hepatomegaly, hepatic tenderness and mild splenomegaly
Which condition is commonly found to have cyroglobulemia
Chronic hepatitis C infection (in 35% of patients)
What percentage of patients with an acute hepatitis C viral infection with progress to a chronic hepatitis
80%
The presence of spotty necrosis or lobular hepatitis are indicative of which kind of injury
Acute viral hepatitis
In severe acute hepatitis, where is the damage seen and what are the common histological findings
Occurs around the central veins and accompanying severity are central-portal bridging necrosis, along with even worse parenchymal collapse
What is the characteristic histological feature of chronic viral hepatitis
Mononuclear portal infiltration
What condition is found to have interface between the hepatocellular parenchyma and portal tract stroma, along with scarring
Progressive chronic hepatitis
What is the histological progression of chronic hepatitis infection histologically
- Only the portal ducts exhibit fibrosis at first
- Over time, there is increasing ductular reaction, which reflects the stem cell action
Which condition is characterized by histological feature of ground glass hepatocytes
Hepatitis B, caused by ER swelling by HBsAg
Which condition shows lymphoid aggregates or fully formed lymphoid follicles, commonly with fatty changes
Hepatitis C
Which parasite is the common cause of cholangiocarcinoma in Southeast Asia
Liver flukes
What are hydatid cysts caused by and what is usually used to confirm the diagnosis
Caused by echinococcal infections and are confirmed by their calcification in the cyst walls
Autoimmune hepatitis is commonly associated with which HLA
DRB1 alleles
What are the common patient populations seen to have autoimmune hepatitis
White females
Which autoimmune hepatitis is known to affect middle aged to older individuals
Type 1
Which autoimmune hepatitis is known to affect individuals in their teens and children
Type 2
Type 2 autoimmune hepatitis are known have antibodies against which antigens
- antinuclear (ANA)
- antismooth muscle actin (SMA)
- anti-soluble liver antigen/liver-pancreas (SLA/LP)
- anti-mitochondrial (AMA)
Type 1 autoimmune hepatitis are known have antibodies against which antigens
- Anti-liver Kidney microsomes 1(LKM-1)
- Anti-CYP2D6
- Anti-liver cytosol-1 (ACL-1)
How is autoimmune hepatitis distinguished from viral hepatitis
The time frame, as viral hepatitis is a slower longer period of destruction and subsequent scarring. Autoimmune hepatitis is rapid damage, followed by rapid scarring
Which condition is characterized histologically by plasma cell predominance in inflammatory infiltrates and “rosettes” in ares of activity
Autoimmune hepatitis
How would acute hepatic damage be differentiated as the origin from drug toxicity or autoimmune hepatitis
Both will have little/no scarring:
Autoimmune hepatitis- Confluent necrosis
Drug toxicity- Lobule necrosis
Which patient population tends to have a better prognosis with regards to autoimmune hepatitis
Adults over children
What is the result of liver transplantation in patients with autoimmune hepatitis
-High 10 year survival, but there is a 20% chance of recurrence
What conditions are autoimmune gastritis associated with
Autoimmune conditions, particularly primary biliary cirrhosis (more common) or primary sclerosing cholangitis
What is the most common agent the produces toxic liver injury
Alcohol
What is the manner in which predictable reactions affect all people
Dose dependent manner
What is the most common toxins causing acute hepatic failure and the need for a liver transplant
Acetaminophen
What aspect of acetaminophen is toxic and where is it formed
CYP450 in the liver creates a toxic byproduct
What are two examples of idiosyncratic reactions that cause liver damage
- chlorpromazine
- halothane
What is the leading cause of liver disease in most western countries
Excessive alcohol consumption
What are the three distinctive forms of alcoholic liver injury
1-Hepatocellular steatosis or fatty change
2-Alcoholic hepatitis
3-Steatofibrosis
What are the morphological findings in hepatic steatosis (fatty liver)
-Lipid begins as small droplets that coalesce into large droplets which distend the hepatocytes and push the nucleus aside, but is completely reversible
What does the presence of hepatocytes swelling and necrosis, Mallory Denk bodies, and Neutrophilic reactions signify
Alcoholic (steato-) hepatitis
What is the histological findings of the hepatocytes swelling and necrosis that is seen in alcoholic hepatitis
Ballooning of cells and necrosis due to the accumulation of fat and water
What is the histological findings of Mallory-Denk bodies
Clumped, amorphous, eosinophilia material in ballooned hepatocytes, leaving almost an “empty” cytoplasm
-characteristic of alcoholic liver disease
What are the contents of the Mallory Denk bodies made of
Keratins 8 and 18 in complex with proteins such as ubiquitin
What are the morphological characteristics of the neutrophil reaction seen in alcoholic hepatitis
Neutrophils penetrate the lobule and accumulate around the Mallory Denk bodies
What are the histological findings of alcoholic steatofibrosis
- Fibrosis of the central vein and space of Disse, resulting in a chicken wire pattern
- Continues use results in perisinusoidal scarring leading to mucronodular or Leanne’s cirrhosis
- Can have the loss of hepatocytes and fatty accumulation
Which gender is more likely to develop hepatic injury and what is the cause
Women, because the estrogen dependent response to LPS in the liver
Which nationalities are more likely to develop cirrhosis
African Americans
Polymorphisms in which genes can cause the increased risk for hepatic injury
ALDH2
What is the response on cells during exposure to alcohol
-Steatosis, mitochondrial and cellular membrane dysfunction, hypoxia, and oxidative stress
What is the reasoning behind alcohol causing steatosis
Shunting of substrates from catabolism toward lipid biosynthesis due to increased NADH
What are the biochemical results of alcohol ingestion
- Increased NADH
- Decreased assembly and secretion of lipoproteins
- Increased free fatty acids
What are the methods in which alcohol can cause cellular dysfunction
- Acetaldehyde causes lipid peroxidation and skeletal membrane dysfunction
- CYP450 metabolism causes production of ROS
- impaired methionine production and decreased glutathione
Alcoholic hepatitis can usually arise following which event
Heavy bout of drinking
What are the common serum finding of alcoholic liver disease that can differentiate it from other chronic liver diseases
-AST elevated 2:1 over ALT
What are the common causes of death in end stage alcoholics
- Hepatic coma
- massive GI bleed
- Intercurrent infection
- Hepatorenal syndrome
- Hepatocellular carcinoma
What is the most common cause of chronic liver disease in the US
NAFLD
What condition does NAFLD increase the risk for and how is it different from the other forms that cause it
Increased risk for hepatocellular carcinoma, but does so without the presence of scarring like the other causes
What about the cells in NAFLD place it at a higher risk for dysfunction
- Increased production of proinflammatory cytokines
- Increased risk for lipid peroxidation generated by oxidative stress
Which pathway correlates with the amount/stage of fibrosis in NAFLD
Shh
What are the 4 conditions that at least one must be present to be considered for metabolic syndrome
- DM
- Impaired glucose tolerance
- Impaired fasting glucose
- insulin resistance
What are the conditions that 2 must be present to be considered for metabolic syndrome
- BP >140/90
- waist/hip > .9
- BMI >30
- dyslipidermia (TG > 1.965, HDL 20 microgram/min)
pathological steatosis is defined as having what
More than 5% of hepatocytes
In NASH, how is it differentiated from NAFLD
Mononuclear cells are more prominent, Mallory-Denk bodies are less prominent
Previous cryptogenic cirrhosis cases are now being thought to represent which condition
Burned out NAFLD
How does pediatric NAFLD different from adult cases
- More diffuse steatosis
- Portal rather than central fibrosis
- Portal and parenchymal mononuclear inlitration rather than neutrophils
What is the most reliable diagnosis for NAFLD and NASH
Liver biopsy
What serum levels are elevated in 90% of patients with NASH
ALT and AST
What is the frequent cause of death in patients with NASH
Cardiovascular disease
What is the name of the stain that is used to show the chicken wire pattern in steatosis
Masson trichromatic stain
What is the general mechanism of hemochromatosis
Excessive iron absorption that gets deposited in the parenchymal organs such as liver pancreas, as well as heart, joints and endocrine organs
What occurrence leads to secondary hemochromatosis
Excess blood transfusions or other parenteral administration of iron
Which three findings are exhibited in fully developed cases of hemochromatosis
- Micronodular cirrhosis in all patients
- DM in 75 % of patients
- Abnormal skin pigment in 75% of patients
What is the common age that hemochromatosis will emerge in men, and what about women
40s and 50s for men
Later for women due to menstration
What are the mechanism that excessive iron in hemochromatosis causes damage
- Lipid peroxidation bur iron catalyzed free radicals
- Stimulation of collagen formation by the activation of stellate cells
- Integration of reactive oxygen species with DNA, leading to injury and HCC
What is the main regulator of iron absorption and the gene responsible for it
Hepcidin, which is coded by HAMP game
What are the conditions that will increase the coding of hepcidin
Inflammatory cytokines and iron
What are the conditions that will decrease the amount of coding for hepcidin
- Iron deficiency
- Hypoxia
- ineffective erythropoiesis
What is the mechanism of action for hepcidin
Binds to the efflux channel ferroportin, which causes the internalization and proteolysis and the inhibition of release from intestinal cells and macrophages. Overall, this results in the lower plasma levels of iron
What are the proteins that regulate the level of hepcidin
- HJV
- TFR2
- HFE
Most adult forms of hemochromatosis are caused by which mutation and what is the function of that protein
HFE, which codes and HLA class 1 like molecule that controls intestinal absorption of dietary iron by regulating the levels of hepcidin synthesis.
What is the mutation in the HFE gene that causes hemochromatosis
Cytosine to tyrosine at 282 (aka C282Y)
Which hemochromatosis most common mutation gene is most common in which patient group
HFE mutation most common in white patients
Which mutations causing hemochromatosis is more likely to cause severe juvenile hemochromatosis
HAMP and HJV
Which condition is characterized by the following conditions:
- Deposition of hemosiderin in liver, pancreas, myocardium etc
- Cirrhosis
- pancreatic fibrosis
Hemochromatosis
What is the stain used to identify hemochromatosis and what is being identified
-Prussian blue stain looking for hepatocellular iron
What are secondary conditions seen with hemochromatosis
- Pseudogout
- Testes are small and atropic
What are the clinical manifestations of hemochromatosis
- Hepatomegaly
- abdominal pain
- abnormal skin color
- DM due to pancreatic damage
What are the two causes of death usually in patients with hemochromatosis
HCC and cardiac disease
Which condition does hemochromatosis predispose patients for
200x more likely to develop HCC
What is the effect of fixing the iron overloading in hemochromatosis
Risks still remain for the HCC because of the DNA damage already being done
What is the presenting features of neonatal hemochromatosis and what is the cause
Cause is not hereditary, but normally damage to the liver in utero
- Severe liver disease
- Extrahepatic hemosiderin Deposition
How is neonatal hemochromatosis detected
Buccal biopsy for extra hepatic deposition
What are the most common causes of secondary hemochromatosis
Ineffective erythropoiesis:
- thalassemia
- myelodyspastic syndromes
Wilson’s disease is caused by a mutation in which gene
ATP7B
What is the heritability of Wilson’s disease
Autosomal recessive
In Wilson disease, what is being deposited and in what common locations
-Copper, normally in the eye, brain, liver
What is the mechanism of disease in Wilson disease
ATP7B gene loss results in the decreased expression of copper transporters that eliminate excess copper
What are the three mechanisms that excess copper causes toxicity
1-Formation of free radicals by the Fenton reaction
2-Binding to sulfhydryl groups of proteins
3-Displacing other metals in hepatic metalloenzymes
Which stains are used for the identification of copper in Wilson disease
Rhodamine stain (copper) Orcein stain (copper assoacited proteins)
Wilson’s disease primarily affects which portion of the brain
Basal ganglia, mainly the putamen
Which conditions may be confused with Wilson disease
Parkinson
What are the diagnostic features of Wilson disease
- Decreased serum ceruloplasm
- Increased hepatic copper content (most sensitive/accurate)
- increased urinary excretion of copper (most specific)
What is the heritability of alpha-1 antitrypsin deficiency
Autosomal recessive
What the organs affected in alpha-1 antitripsin deficiency
Liver (over accumulation of misfolded proteins)
Lungs (lack of Alpha1AT to inhibit elastase)
What is the most common clinically significant mutations
PiZ coding for the PIZZ protein
What is the most commonly diagnosed inherited hepatic disorder in infants and children
Alpha1- Antitrypsin deficiency
Where in the liver does the misfolded PIZZ protein accumulate
ER of the hepatocytes
What is the stain used for identifying alpha-1 antitrypsin deficiency
PAS stain with diastase
Which histological feature is characterized in alpha 1 antitrypsin
Cytoplasmic globular inclusions in the hepatocytes, which will stain magenta
In patients with alpha1 AT deficiency, which activity should be avoided at all costs
Smoking, as it will increase the rate of emphysema
What are the properties of unconjugated bilirubin properties with the solubility, toxicity, and ability to be excreted
Insoluble in water, so is tightly bound to albumin
No not be excreted in urine
Toxic
What are the properties of conjugated bilirubin with regards to solubility, toxicity, and ability to be excreted in urine
- Water soluble, and loosely bound to albumin
- Non-toxic
- Can be excreted via urine (when levels are high)
What is the function of the protein UGT1A1
Hepatic conjugating enzyme
What are the heritability of the diseases that results in excess conjugated bilirubin
Autosomal recessive
What are the only conditions that result in predominantly conjugated hyperbilirubinemia, and was is the result
Usually innocuous
- Dubin Johnson syndome
- Rotor Syndrome
What is cholestasis
Impaired bile formation and bile flow that gives rise to accumulation of bile pigment in the hepatic parenchyma
What are the clinical presentations of a patient with cholestatis
- Jaundice
- Pruritus
- Skin xanthomas
- intestinal malabsorption of vitamins A,D,K,E
What are the clinical lab findings that would indicate cholestasis
Elevated alkaline phosphate
Elevated glutamyl transpeptidase (GGT)
Which conditions may histologically have fine foamy appearance, looking like “feathery degeneration” as a result of bile pigmentation accumulation
Cholestasis
What is the most common cause of bile duct obstruction in adults
-Extrahepatic cholelithiasis
What are the three main causes of bile duct obstruction
- Extrahepatic cholelithiasis
- Malignancies of biliary tree/head of pancreas
- strictures from procedures
What is ascending cholangitis
Secondary bacterial infection of the biliary tree
What is the clinical presentation of cholangitis
Fever, chills, abdominal pain, and jaundice
What is the most severe form of cholangitis
Suppurative, where the purulent bile fills and distends the bile ducts
What is the histological hallmark of ascending cholangitis
Influx of peridcutal neutrophils directly into the bile duct epithelium and lumen
What are the histological findings seen in acute biliary obstruction
- neutrophil influx into the bile duct epithelium
- feathery degeneration (from cholestasis)
- Mallory-Denk bodies
- formation of bile infarcts
Which condition is most likely to cause cholestasis of sepsis
-Response to circulating microbial products, especially those in gram neg bacteria
What is the most common form of cholestasis
Canalicular cholestasis (around the centrilobular canaliculi)
What is the prognosis of ductular cholestasis
Poor, especially if there are bile plugs present, causing the dilation of tracts, often accompanying or proceding septic shock
What is hepatolithiasis
Disorder of intrahepatic gallstones that leads to repeated cases of ascending cholangitis, leading to progressive inflammatory destruction of hepatic parenchyma
Which condition is more likely to develop during hepatolithiasis
Cholangiocarcinoma
What is the only common location for hepatolithiasis
Asia, aka oriental cholangitis
What is the morphology for hepatolithiasis
Pigmented calcium bilirubinate stones in a distended intrahepatic bile duct
Which condition produces histological findings that look like irregular shapes, similar to jigsaw puzzle shapes
Biliary cirrhosis
What are the major causes of prolonged conjugated hyperbilirubinemia in neonates
- biliary atresia
- neonatal Hepatitis
Why is it crucial to differentiate between biliary atresia and neonatal hepatitis
Because the treatments are different:
- Biliary atresia (Kasai procedure to fix)
- Neonatial hepatitis (procedures may cause complications)
What are the clinical presentations of neonatal hepatitis
- Jaundice
- Dark urine
- acholic stools
- hepatomegaly
What are the histological findings of neonatal hepatitis
- Giant cell transformation of hepatocytes
- hepatocellular and canalicular cholestasis
- mononuclear infiltrates of portal areas
- reactive changes in Kupffer cells
- extramedullary hepatopoiesis
What is biliary atresia
Complete or partial obstruction of the lumen of the Extrahepatic biliary tree within the first 3 months of life
What is the number one cause of death from liver disease in early childhood and accounts for 50% of children referred for liver transplants
Biliary atresia
What are the common conditions seen in association with the fetal form of biliary atresia
Abnormal development of organs:
- lack of laterality of Thoracic duct
- inversus malrotation of abdominal viscera
- interrupted IVC
- polyspenia
- Congentical eart disease
What is the overall cause of fetal form of biliary atresia
Aberrant intrauterine development of the extrahepatic biliary tree
What is the most common cause of biliary atresia
Perinatal form
What is the pathogensis of the perinatal form of biliary atresia
Normal development of the biliary tree, but is destroyed following birth.
Which conditions of biliary atresia are correctable
- Limited to the common duct (Type 1)
- Limited to the right and left hepatic bile ducts (Type 2)
Which condition of biliary atresia is not correctable
Type 3, obstruction of the ducts at or above the porta hepatic
What are the clinical presentations of biliary atresia
- Normal north weight and postnatal weight
- Normal stools will begin to change to acholic stool
- Death within 2 years without transplant
What is the primary biliary cirrhosis characterized by
No suppurative, inflammatory destruction of small and medium sized hepatic bile ducts. Large ducts are not involved
Where is primary biliary cirrhosis most prevalent geographically
Northern European and Minnesota
How related is primary biliary cirrhosis in families
Increased risk
What is the most characteristic laboratory finding in primary biliary cirrhosis
Antimitochondrial antibodies
What are the target of the most commonly seen antibodies in primary biliary cirrhosis
E2 of the pyruvate dehydrogenase complex
What is the histological finding in the condition of primary biliary cirrhosis
- Florid duct lesions, where the interlobular bile ducts are actively being destroyed by lymphocytes
- Periportal/periseptal cholestasis
What is a distinguished organ size characteristic of primary biliary cirrhosis
Hepatomegaly
What is a treatment for primary biliary cirrhosis that slows down the progression of the disease
Ursodeoxychilic acid
What are the symptoms seen as primary biliary cirrhosis progresses
- Skin hyper pigmentation
- xanthelasmas
- steatorrhea
- Vitamin D osteomalacia
What is primary sclerosing cholangitis characterized by
Inflammation and obliterative fibrosis of the intrahepatic and extrahepatic bile ducts
Which conditions are commonly associated with primary sclerosing cholangitis
IBD, and UC
Which HLA is associated with primary sclerosing cholangitis
HLA-B8
Which conditions is commonly seen when there are degenerating bile ducts entrapped in an “onion skin” scar
primary sclerosing cholangitis
Aka a tombstone scar
What is the laboratory finding that may accidentally find primary sclerosing cholangitis
Elevated levels of alkaline phosphate
What are choledochal cysts
Congenital dilations of the common bile duct
Which patient group is commonly seen to have choledochal cysts
Female Children before age of 10
The development of Choleductal cysts increase the risk of which condition in older patients
Bile duct carcinoma
What are the common conditions seen with fibropolycystic disease
1-Von meyeberg complexes (bile duct hamartomas)
2- Small biliary cysts (Caroli disease)
3- Congentical hepatic fibrosis
What are the conditions assoacited with fibropolycystic disease caused by
Ductal plate malformations
Fibropolycystic liver disease commonly occurs with which condition
Autosomal recessive polycystic renal Disease
Which gene is involved in polycystic kidney disease as well as fibrocystic liver disease
Polycystin
Patients with fibrocystic liver disease are at a higher risk for which condition
-Cholangiocarcinoma
When will a hepatic artery thrombosis cause infarction
In transplanted patients because there is only arterial supply to the biliary ducts
In those patients with extrahepatic portal vein obstruction, which condition is assoacited 25% of the time, and which underlying condition is commonly present
Cirrhosis is present in 25% of cases, with an underlying thrombophlebitis genotype
What can the intrahepatic portal vein radicle be abstracted by
Acute thrombosis
What is the result of intrahepatic portal vein radicles being blocked by an acute thrombosis
- Does not cause an ischemic infarction
- Causes a sharply demarcated area of red/blue discoloration called the infarct of Zahn
- Results in severe hepatocellular atrophy and stasis around the sinusoids
WHich condition is going to result in the infart of Zahn
Acute Thrombotic event in the intrahepatic portal vein radicles
What are the results of a small portal vein branch disease
Noncirrhotic portal hypertension with portal fibrosis and obliteration of the small portal vein branches
What is the most common small portal vein branch obstruction
Schistosomiasis, where the eggs lodge and obstruct
Small portal vein branch disease seen in East Asia is commonly in which patient group and with which associated condition
Female, Japanese, and rheumatologist diseases
Which treatments or conditions increase the risk of small portal vein branch disease
- Untreated HIV
- anti-retroviral treatment
What is the most common intrahepatic cause of blood flow obstruction
Cirrhosis
Which conditions can cause sinusoidal occlusion through the liver
- Sickle cell
- DIC
- Eclampsia
- metastatic cancer
What is the condition of peliosis hepatis
Sinusoidal dilation that causes the efflux of hepatic blood to be impeded
What are some causes of peliosis hepatis
- Bartonella
- Sex hormone administration
What are fetal outcomes of peliosis hepatis if the underlying cause is not treated
-Intraabdominal hemorrhage or hepatic failure
Which condition is defined as obstruction of two or more major hepatic veins producing liver enlargement, pain, and ascites
Budd Chiari syndrome
During Budd-chiari Syndrome, what is the actual mechanism causing damage
Increased intrahepatic blood pressure
Which conditions are hepatic vein thrombosis associated with
myeloproliferative disorders:
- polycythemia Vera
- coagulation disorders
- antiphospholipid antibody syndrome
- paroxysmal nocturnal hemoglobinuria
- HCC
What is the morphology seen during budd-Chiari syndrome
Liver is swollen with a red-purple, tense capsule
-Alternating pattern of hemorrhagic places with those that are regenerating
What is the mortality rate in untreated acute hepatic vein thrombosis
High
What are the primary settings that sinusoidal obstructive syndrome develops
- Following allogenic hematopoietic stem cell transplantation within the first 3 weeks
- cancer patients receiving chemotherapy
What is the pathogenesis of sinusoidal obstructive syndrome
Toxic injury to the sinusoidal endothelium, which obstructs the blood flow
What is the histological characteristic of sinusoidal obstruction syndrome
Obliteration of the terminal hepatic venules by subendothelial swelling and collagen deposition
What is the cause of passive congestion of the liver
Right sided heart failure
What is the morphology of the liver following right sided heart failure
Congestion of the centrilobular sinusoids
What is the cause of the appearance of the nutmeg liver
Right sided heart failure provides the passive congestion (red portion) while the left sided heart failure results in hypoxia (orange color)
How many days after transplantation does graft versus host disease occur with liver transplantation
10 to 50 days following
What are the morphological changes seen in graft versus hosts disease in the liver
Hepatitis with necrosis of hepatocytes and bile duct epithelial cell, inflammatory cells in the bile duct epithelium
What is the final pathogenesis of chronic rejection of a liver
Obliterative arteriopathy of the small and large arteries, which lead to the ischemic changes in the liver parenchyma, ultimately resulting in vanishing bile duct syndrome
What is the most common cause of jaundice in pregnancy
Viral hepatitis
How does pregnancy change the course of a viral hepatitis infection, and what is the exception
Does not change the course of the viral hepatitis infection, except for HEV, which causes more severe of a cause in pregnant women, leading to 20% fatality
What are the presentations of preeclampsia
- Maternal hypertension
- Proteinuria
- Peripheral edema
- Coagulataive abnormalities
What are the clinical presentations of eclampsia
Hyperreflexia and convulsions
What are the histological findings of preeclampsia
Periportal sinusoids containing fibrin deposits associated with hemorrhage into the space of Disse, which leads to Periportal coagulative necrosis
When do pregnant women usually present with acute fatty liver of pregnancy
latter half, usually the third trimester
What histological and morphological finding can occur and usually resulting in fatality
Subscapular hematoma under the Glisson capsule, which can rupture
What is the proposed cause of acute fatty liver of pregnancy
Mother lacks long chain 3-hydroxyacyl CoA dehydrogenase, so when it is produced by the fetus, it causes damage to the mother
What is the onset of intrahepatic cholestatis of pregnancy
Third trimester
What are the clinical presentations of intrahepatic cholestasis of pregnancy
Darkening of the urine
Occasional light stools
Jaundice
Large increase in the level of bile salts
What is focal nodal hyperplasia and it’s characteristic
- Well demarcated, but poorly encapsulated nodule
- In young to middle age adults
- Central stellate scaring
Nodular regenerative hyperplasia is most commonly associated with which conditions
HIV infected people
Rheumatic diseases such as SLE
What is the most common type of benign liver tumors
Cavernous hemangioma
What are the types of benign liver neoplasm
- Cavernous hemangiomas
- Hepatocellular adenomas
What is the medical emergency associated with hepatocellular adenomas
Intraabdominal bleeding
What would place a patient at a higher risk for hepatocellular adenomas
Oral contraceptives
Anabolic steroids
What is the increased risk factor of the oral contraceptives for hepatocellular adenoma
30-40x
The majority of hepatocellular adenomas have a mutation of what
Inactivating somatic mutation of HNF1-alpha
How many mutations are required for the patients with hepatocellular adenoma tumors with the MODY3
A second somatic mutation
Which form of the hepatocellular adenomas are at the highest risk of becoming malignant
Beta-catenin activated hepatocellular adenomas
Which condition are inflammatory hepatocellular adenomas associated with
NAFLD
What is the only hepatocellular adenoma that does not have a risk of becoming malignant
HNF1 alpha
The inflammatory hepatocellular adenoma is associated with which factors
Gp130, IL6
Via JAKSTAT signaling
Which tumor is present if there is complete absence of Liver Fatty acid binding protein (LFABP)
HNF1-alpha hepatocellular adenoma, and immunostaining for it is diagnostic
Which tumor is present if with immunostaining, there is a high presence of glutamine synthetase
Beta catenin hepatocellular adenoma (targets downstream GLU synthetase)
Which factors are overexpressed in the inflammatory hepatocellular adenomas
-CRP and serum amyloid A
What is the most common tumor of early childhood
Hepatoblastoma
What are the cell types present in the epithelial type of hepatoblastoma
-small polygonal fetal cells that form acini, tubules
What are the cells included in the mixed epithelial and mesenchymal type of hepatoblastoma
-osteosarcoma, cartilage, or striated muscle
What is the characteristic pathway activated in hepatoblastoma
WNT
Which genes are commmonly mutated in hepatoblastoma
- APC
- Beta catenin
- FOXG1
Which familial conditions normally can develop hepatocellular adenomas
- Familial adenomastous polyposis
- Beckwith-Wildemann syndrome
Most hepatocellular carcinomas are associated with areas with this endemic infection
HBV
In cases with patients who have HCV, what comes before the malignancy HCC
Cirrhosis
What gender is more likely to develop hepatocellular carcinoma
Male
What are the most common setting for the emergence of HCC
Chronic liver diseases
In Asian and African countries, what can HBV synergize with to increase the risk of HCC
Aflatoxin
Which metabolic diseases increase the risk of hepatocellular carcinoma
- Metabolic syndrome, with the obesity, DM, NAFLD
- Hemochromatosis
- alpha1-AT
What are the two most common early mutations in the development of hepatocellular carcinoma
P53 and Beta catenin
Which mutation in HCC are more likely to be associated with non HBV and more genetic instability
Beta catenin
What mutation in HCC is strongly assocaited with aflatoxin
P53
What cell size change is directly a premalignant sign
Small cell change
What cell size change associated with hepatitis B is a premalignant
Large cell size change
What are the histological findings of large cell changes
Normal nuclear to cytoplasmic ratio but scattered normal hepatocytes with larger than normal nuclei
What are the histological changes seen in small cell changes
High nuclear to cytoplasmic ratio and the cells are separated by a thickened plates
In high grade dysplasia can nodules, what is the characteristic of the blood supply and how does this compare to the low grade
High grade- arteries dominate
Low grade- arteries and veins
What is the most likely route of extrahepatic masses to spread
Arterial supply
Where do primary liver tumors preferentially spread
Lungs, usually very late in the course
What are the clinical presentation of hepatocellular carcinomas
Fatigue, weight loss, hepatomegaly, abdominal pain in the URQ
Elevations of which serum component is elevated in advanced hepatocellular carcinomas
Serum alpha-fetoprotein
What are the histological findings of fibrolamellar carcinoma
Large, hard “scirrhous” tumor with fibrous bands
-Cords and nests of oncocytic hepatocytes separated by dense bundles of collagen
What are the 4 causes of death in those patients with hepatocellular carcinoma
1-cachexia
2-GI or esophageal varices bleeding
3-liver failure and coma
4-rupture of the tumor
What is the cholangiocarcinoma
Primary malignant tumor of the biliary tree/ducts
What areas and which parasite are associated with higher levels of cholagiocarcinoma
in the southeast Asian countries where the liver flukes are endemic
Which conditions have an increased risk of developing cholangiocarcinoma
- NAFLD
- HBV and HCV
- liver flukes (opisthorchis and Clonorchis)
- Chronic inflammation ofthe bile ducts
The majority of choleangiocarcinomas are what type and in which location
50 to 60% are Klatskin tumors, which are at the junction of the right and left hepatic ducts (aka perihilar)
What is the prognosis of choleangiocarcinomas
very very bad
What is the most common premalignant lesion for cholangiocarcinoma
Biliary intraepithelial neoplasia 3 (BilIN-3)
What type of tumor is choleangiocarcinomas and which product is secreted
Adenomas, which secrete mucin
What are the typical histological findings of a choleangiocarcinoma
- Desmoplasia
- lymphovascular and perineural invasion
Which liver malignancy will form a wreath like patter around a central trapped nerve
Perineural
What are the causes of a liver angiosarcoma forming
- Vinyl chloride
- Arsenic
- Thorotrast
What are hepatic lymphomas associated with and which form do most take
- HCV, HBV, HIV, PBC
- Diffuse B cell lymphomas
What are the common locations that metastasizing to the liver is common
-Colon, Breast, lung, pancreas
