What are the three ways cholesterol leaves the liver?
VLDL Secretion
Bile Salt Synthesis & Secretion
Free Cholesterol Secreted in Body
What are the two ways to get cholesterol out of the body?
Conversion to bile acids/salts
Fecal secretion
What is cholesterol synthesized from?
Acetyl CoA
What is the first step of cholesterol synthesis, and where does it take place?
Synthesis of 3-hydroxy-3-methylglutaryl (HMG) CoA from Acetyl CoA
Takes place in the cytoplasm of the liver cell
What is the second step of cholesterol synthesis? What enzyme catalyzes this reaction, and what is the reducing agent?
Reduction of HMG-CoA to Mevalonate
Catalyzed by HMG-CoA Reductase
Reducing Agent: NADPH
What is the rate-limiting step of cholesterol synthesis?
Reduction of HMG-CoA to Mevalonate
The synthesis of cholesterol from mevalonate is carried out by a complex series of steps. This pathway requires a lot of what two molecules? What does this mean for the body?
ATP & Acetyl CoA
You cannot make this compound if the body is starving
Why is it so difficult for the body to rid itself of cholesterol?
Because the molecule is so hydrophobic
HMG-CoA reductase is subject to many kinds of metabolic control. What role does SREBP-2 play?
The precursor of SREBP-2 (SREBP-SCAP) is retained in the ER when cholesterol levels are high. If cholesterol levels are lowered, however, then the SREBP-2 precursor is trafficked to the Golgi where proteases cleave the precursor. This releases soluble SREBP-2 so that it can move to the nucleus and promote transcription of the HMG-CoA reductase gene, which promotes production of cholesterol.
Regulation of HGM-CoA reductase is subject to many kinds of metabolic control. What role do sterols play?
Degradation of HMG-CoA reductase is accelerated when sterol levels are high. This serves to eliminate excess CoA to reduce cholesterol levels in the body.
Regulation of HGM-CoA reductase is subject to many kinds of metabolic control. What role does phosphorylation by the AMP kinase play?
HMG-CoA is inactive when it is phosphorylated. AMP kinase serves to phosphorylate HMG-CoA. This phosphorylation is activated with there are low levels of ATP in the cell.
Bile acids are synthesized from free cholesterol in the liver. How is this done?
Bile acids are conjugated to molecules of glycine or taurine by an amide linkage to form bile salts.
Conversion of bile acids to bile salts increases the _______ nature of the compounds, making bile salts much better "detergents" for digesting lipids.
Amphipathic
What type of circulation results in a 95% reabsorption of bile salts that are secreted into the intestine during digestion?
Enterohepatic Circulation (between the intestine and the liver)
What is the total loss of bile salts from the intestine per day?
~ 0.5g/day
A deficiency of bile salts in the liver can cause the formation of ______ which develop when the ratio of cholesterol to bile salts is high and cholesterol precipitates out of suspension in the gallbladder.
Gallstones
What are two ways in which bile salt deficiency occurs?
When there is a disruption of enterohepatic circulation and the bile salts are not reabsorbed
There is liver disease that is preventing new synthesis of bile acids in the liver
Membrane phospholipids are specialized lipids in which a polar, ionic compound is attached by a phosphodiester bridge to _____ or _____?
Diacylglycerol
Sphingosine
What are the most abundant phospholipids?
Glycerolphospholipids
Sphingomyelin is a complex membrane phospholipid based on a _______?
Ceramide
How do Glycosphingolipids differ from Sphingomyelin?
They are also derived from a ceramide, but they do not contain a phospate group
The plasma membrane is at a steady state balanced between exocytosis of secretory vesicles and endocytosis of plasma membrane proteins. Some membrane lipids are recycled and reused, whereas others are targeted to the lysosome for degradation. Accumulation of lipid from inadequate degradation is called ______, and causes what?
Lipidoses
Lysosomal Storage Diseases
Sphingomyelin degradation requires which lysosomal enzyme to cleave the phosphoryl choline?
Sphingomyelinase
Neimann-Pick disease is caused by a deficiency in what? What does it lead to?
Deficiency of Sphingomyelinase
Leads to lipidoses in liver, spleen, and CNS (in type A)
This is a deficiency in the degradation of Beta-glucosidase, an ezyme that breaks down glucocerebroside; this causes the accumulation of
glucocerebroside in cells.
Gaucher Disease
What are the main two types of liver function tests, and what is each for?
AST/ALT: Hepatocellular
ALK Phos: Cholestatic
What are located in hepatocytes and released after hepatocellular injury? What are the two forms?
Transaminases
AST & ALT
What is mild transaminitis with predominant AST indicative of (3)?
Hepatic: Alcohol, Steatosis, Cirrhosis
What is non-hepatic mild Transaminitis indicative of (4)?
Hemolysis
Myopathy
Thyroid Disease
Strenuous Exercise
The AST:ALT ratio is elevated 2:1 in what disease?
Alcohol Disease
What disease is characterized by these symptoms?
Associated Conditions: Obesity, Diabetes, Hyperlipidemia
Diagnosis: AST/ALT < 1, exclude other causes, U/S, liver bx
What is the diagnosis?
This disease has widely variable clinical presentations: asymptomatic LFT abnormality; severe hepatitis with jaundice; cirrhosis and complications of portal HTN
It is often associated with other autoimmune dz
Diagnostic Labs:
compatible clinical presentation
ANA or ASMA with titer 1:80 or greater
IgG > 1.5 upper limits normal
liver bx - portal lymphocytes + plasma cells
Autoimmune Hepatitis
What is the diagnosis?
Characteristics:
AR -- Copper Metabolism
Chronic hepatitis or fulminant hepatitis
What is the diagnosis related to these symptoms?
Clinical Features:
Lung Disease: inadequate protease inhibitor activity
Liver Disease: accumulation of variant A1AT in hepatocytes
Alkaline Phosphatase is produced by biliary epithelial cells. What pathologies are indicated by an elevation in APT (6)?
Biliary Duct Obstruction
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
Infiltrative Liver Disease
Hepatitis/Cirrhosis
Medications
What is the diagnosis?
Cholestatic Liver Disease (ALP)
Most common symptoms:
Pruritis, fatigue; many pts asx, and dx by abnormal LFT
Female:Male ratio 9:1
Diagnosis:
Compatible clinical presentation
AMA titer 1:80 or greater
Liver bx -- bile duct obstruction
Treatment: Ursodeoxycholic acid 15 mg/kg
Primary Biliary Cirrhosis
What is the diagnosis?
Cholestatic Liver Disease (ALP)
Inflammation of large bile ducts
90% associated with IBD
Diagnosis:
ERCP
No autoantibodies, no elevated globulins
Biopsy -- concentric fibrosis around bile ducts
Cholangiocarcinoma: 10-15% lifetime risk
Treatment: liver transplantation
Primary Sclerosing Cholangitis
What kind of history if associated with abnormal LFTs?
Pain
Edema, increased abdominal girth, confusion, GI bleeding
PMH: DM, hyperlipidemia, autoimmune
Medications
Alcohol
Sex, drugs, blood transfusion pre-1990
Family history of liver disease
What can be seen in the Physical Exam in the evaluation of abnormal LFTs?
Skin: spider angiomata, gynecomastia
Liver size, splenomegaly
Clubbing, palmer erythema, D-contracture
Ascites
Edema
Mental status, asterixis
Obesity
Hyperpigmentation, Kayser-Fleischer Rings
Bilirubin is a product of hemoglobin breakdown. What are its two forms?
Unconjugated (indirect): insoluble; increase in hemolysis; Gilbert Syndrome, meds
Conjugated (direct): soluble; increase in obstruction, cholestasis, cirrhosis, hepatitis, primary biliary cirrhosis, etc; no elevation until loss of > 50% capacity
What are the three classifications of Maternal Liver Disease?
Intrahepatic Cholestasis of Pregnancy (ICP)
Acute Fatty Liver of Pregnancy (AFLP)
HELLP
What is the diagnosis?
Pregnant Patient
Symptoms:
Intense pruritis, variable LFT, intact liver function
Treatment: UDCA Cholestyramine, Hydroxyzine
Intrahepatic Cholestasis of Pregnancy (ICP)
What is the diagnosis?
Pregnant Patient
Presents in 3rd trimester with HA, N/V, abd pain
Often associated with pre-eclampsia/eclampsia
Labs:
Increased ALT
Increased bilirubin
Increased PT
Treatment: glucose, correct PT, delivery
Acute Fatty Liver of Pregnancy (AFLP)
What is the diagnosis?
Symptoms:
Hemolysis, increased LFTs, decreased platelets
Labs:
Schistocytes
plt <100
LDH >600
AST > 70
HELLP
What is the most common cause of drug-induced liver disease?
Acetaminophen
What does albumin reveal about liver disease?
Poor marker of liver function
Decreased by trauma, inflammatory conditions, malnutrition
What does Prothrombin Time (PT) reveal about liver disease?
Insensitive: no change until liver loses 80% capacity
What does Ammonia reveal about liver disease?
No correlation between brain and serum values
Only one contribution to encephalopathy
A diverse group of metabolic disorders from enzyme deficiencies in heme synthesis
Porphyrias
Where does synthesis of porphyrias occur?
Liver and Bone Marrow
What is the rate limiting step in hepatic synthesis?
ALA synthase
What is the predominant site of synthesis in 5/7 of the porphyrias?
Liver
What disease or class of diseases is associated with these symptoms?
Abdominal Pain
Tachycardia
Dark Urine
Neuropsych Features: hysteria, depression, psychosis, confusion, hallucinations, seizures, and comas
Periphery Sensory Deficits
Weakness leading to ascending paralysis or quadriplegia
Overproduction of ALA and PGB (neurotoxic)
Acute Porphyrias
Are acute porphyrias more common in males or females?
5x F > M
What is the diagnosis?
Most common acute porphyria
Primarily manifests as derangement in ANS or psychiatric disorder
Partial deficiency of PBG deaminase
AD with variable expression
Acute Intermittent Porphyria (AIP)
What is the most common ACUTE porphyria?
Acute Intermittent Porphyria (AIP)
What are the treatment options for Acute Porphyrias?
IVFs and glucose administration
IV hematin
Avoidance of precipitants
Women triggered by menses improved with OCPs
HCC screening/surveillance
Special sunscreen
What is the diagnosis?
Deficient activity of uroporphyrinogen decarboxylase (UROD)
Most common human porphyria
Presents mid to late life
Porphyria Cutanea Tarda
What is the most common Porphyria?
Porphyria Cutanea Tarda
What porphyria is often co-morbid with these disorders?
Factors/Diseases contributing to iron accumulation or oxidative stress in hepatocytes
Excessive Alcohol Consumption
Estrogen Use
Chronic HCV
Hepatic Siderosis
HIV
Smoking
End Stage Renal Disease
Porphyria Cutanea Tarda
These dermatologic findings are common in what porphyria?
Blisters
Bullae
Increased Fragility
Scarring
Pigment Changes
Hirsuitism (cheeks, forearms)
Pseudoscleroderma
Porphyria Cutanea Tarda (PCT)
What are the treatments for Porphyria Cutanea Tarda (PCT)?
Phlebotomy (preferred)
Low Dose Hydroxychloroquine or Chloroquine
Avoid Offending Agents
What is the diagnosis/porphyria type?
UROD Deficiency
AR form of familiar PCT
Rare
More severe
Presents in childhood (<2yrs)
Features resemble congenital erythropoietic porphyria (CEP)
Hepatoerythropoietic Porphyria (HEP)
What is the diagnosis/porphyria type?
AR
First yr of life
Blisters/Disfiguring lesions in exposed areas
Erythrodontia
Brownish discoloration of teeth
Coombs neg. hemolytic anemia
Splenomegaly
Congential Erythropoietic Porphyria (CEP)
What is the treatment of Congential Erythropoietic Porphyria (CEP)?
Splenectomy
Transfusion/Hematin Infusions
BMT curative in severly affected patients
What is the second most common type of Porphyria?
Erythropoietic Protoporphyria (EPP)
What is the diagnosis/porphyria type?
Partial deficiency of FECH
Final step in heme synthesis
AD with variable penetrance
Extreme Photosensitivity -- scars and lichenification
Mild hypochromic
Microcytic anemia
5-10% develop liver disease
Erythropoietic Protoporphyria (EPP)
What is the treatment of Erythropoietic Protophorphyria (EPP)?
IV hematin
Charcoal
Cholestyramine
BMT
What are the histological changes to the liver from Acute Porphyria (4)?
Elevated transaminases
Bile acid levels
Liver Biopsy shows steatosis and iron deposition
Increased HCC risk
What are the histological changes to the liver due to PCT/HEP (6)?
Liver enlargement
Fatty infiltration
Inflammation
Granulomatous changes
Siderosis and Fibrosis may lead to Cirrhosis
Only slight increased HCC risk
These are the largest lipoprotein particle. They package fat that is consumed in the diet and absorbed through the intestine. Their primary function is to deliver dietary lipid to adipose tissue and the liver.
Chylomicrons
These particles are synthesized in the liver to secrete lipids that are either recycled through the liver or newly synthesized by the liver. In the blood plasma, they distribute their triacylglycerol content to peripheral tissues. These are classified as bad cholesterol.
VLDL/LDL
These particles are responsible for reverse cholesterol transport. They are synthesized in the intestine and liver, and are small empty particles that pick up lipid in the peripheral circulation, and return it to the liver. These particles return cholesterol from the periphery to the liver to be excreted as bile. These are classified as good cholesterol.
HDL
What is the signature apoplipoprotein for the chylomicron?
Apo B-48
What is the signature apolipoprotein of VLDL/LDL?
Apo B-100
These particles consist of a hydrophilic phospholipid coat and a hydrophobic core (the lipid cargo). The apoproteins are associated with the phospholipid monolayer.
Lipoprotein Particles
This apolipoprotein family are important structural molecules that regulate the synthesis of the specific particle.
Apolipoprotein B
This apolipoprotein type is found on HDL particles and is a cofactor for the Lecithin cholesterol acyl transferase (LCAT) that converts plasma cholesterol to cholesteryl ester in that particle
Apo A-I
This apolipoprotein type plays an important role in activating lipoprotein lipase (LPL) enzymes that are linked to the endothelial cell walls of capillaries. These LPL proteins cleave the triacylglycerol content of the lipoprotein particles so that the fatty acids can be taken up by nearby tissues.
Apo C-II
This apolipoprotein type plays a role in clearance of the lipoprotein particles from the blood plasma. It serves as a ligand that binds a cell surface receptor. The ligand/receptor complex is internalized by the cell, engulfing the lipoprotein particle
Apo E
How is the identification of lipoprotein particles in the blood done?
Electrophoretic Mobility
What blood lipid would be elevated in an individual with an LPL deficiency?
Triacylglycerol
Identify the Helminth:
Symptoms:
Fluid filled cysts found mostly in the liver and lungs
Can be asymptomatic for several years
Cysts can lead to blood sputum and cause neurologic or hepatic disorders
Hepatic cysts may cause abdominal pain and biliary duct obstruction
Cyst rupture can cause fever, eosinophilia, and anaphylaxis
How is this transmitted, diagnosed, treated, and prevented?
Echinococcus Granulosis
Transmission: Ingesting eggs from soil, water, or dog fur
Diagnosis: Imaging and serology (parasites in aspirates from cysts)
Treatment: Surgical removal of cysts followed by albendazole
Prevention: Prevent dogs from eating sheep entrails
Identify the Helminth: Symptoms:
Abdominal Pain
Biliary Obstruction
Multiloculated Cysts in Liver
Can gradually invade neighboring tissues
How is this transmitted, treated, diagnosed, and prevented?
Echinococcus Multilocularis
Transmission: Digestion of eggs in feces
Diagnosis: Imaging and Serology (parasites in aspirates from cysts)
Treatment: Albendazole is drug of choice; Surgery to remove cysts
Which Schistosome spp. is found in Africa/Latin America?
Mansoni
Which Schistosome spp. is found in Africa/Middle East?
Haematobium
Which Schistosome spp. is found in Asia?
Japonicum
What dictates the epidemiology for Schistosome spp.?
It requires a snail to complete its life cycle -- the snail dictates the epidemiology
Chronic Symptoms:
Tissue biopsies show large granulomas surrounding eggs, Inflammation in infected tissues due to soluble egg proteins, Portal hypertension
How is this transmitted, diagnosed, treated, and prevented?
Schistosome spp.
Transmission: Free-swimming cercariae (larval stage) penetrate the skin
Diagnosis: ID of eggs in stools or urine
Treatment: Praziquantel
Prevention: Avoid swimming in endemic areas and proper disposal of human waste
What chronic phase symptom of Schistosome spp. is specific to Mansoni?
Colonic polyps with bloody diarrhea
What chronic phase symptom of Shistosome spp. is specific to Haemotobium?
Bloody urine
Urinary Tract Infection
Cystitis
Bladder Neoplasms
What tissues does S. Mansoni target?
GI Tract
Liver
What tissues does S. Japonicum target?
GI Tract
Liver
What tissue does S. Haemotobium target?
Urinary Tract
Identify the Helminth:
Most infections of are asymptomatic.
Heavy infections can lead to:
Abdominal Pains
Bile Duct Obstruction leading to Cholangitis and Cholangiohepatitis
Rare incidence of Cholangiocarcinomas
How is this transmitted, diagnosed, treated, and prevented?
Clonorchis Sinesis
Transmission: Ingestion of cercariae from raw or undercooked fish
Diagnosis: Identification of eggs in stools
Treatment: Prazinquantal
Prevention: Prevent by eating properly cooked fish and proper disposal of human waste
How is this transmitted, diagnosed, treated, and prevented?
Fasciola Hepatica
Transmission: Ingestion of metacercariae larvae encysted in aquatic plants
Diagnosis: ID of eggs in stool
Treatment: Triclabendazole
Prevention: Prevent by not eating aquatic vegetables or raw sheep liver
Identify the Helminth:
Diarrhea
Abdominal Pain
Fever
Ascites
Intestinal Obstruction
How is it transmitted, diagnosed, treated, and prevented?
Fasciolopsis Buski
Transmission: Digestion of contaminated aquatic vegetables that contain cysts
Diagnosis: Eggs in stool
Treatment: Praziquantel
Prevention: Prevent by proper disposal of human waste
Inflammation of the liver caused by viruses, chemicals, drugs, alcohol, inherited diseases, or autoimmunity.
Hepatitis
These are possible acute symptoms what viral disease?
Symptoms:
Fatigue
Nausea
Loss of Appetite
Fever
Abdominal Pain
Jaundice
Itching
Dark Colored Urine
Light Colored Stools
Tender and Enlarged Liver
Hepatitis
These are some of the possible chronic symptoms associated with what viral disease?
Symptoms:
Usually presents no clinical symptoms
Loss of Energy
Fatigue
Gradually damage the liver (liver failure)
Typically lasts for years
Rarely resolves without treatment
Hepatitis
What is the histopathology of hepatitis?
Necrosis of hepatocytes
Framework of the reticulum is preserved
What labs are associated with hepatitis?
AST (normal range 5-40 units/liter serum)
ALT (normal range 7-56 units/liter serum)
What is the genome of Picornavirus?
Is it enveloped?
ssRNA '+' sense
No
Identify the Virus:
Distinguishing Features:
Single RNA, single polypeptide
IRES, vpG on RNA end essential for replication
Not Lytic (unique Hepatovirus)
Disease Manifestations:
Common Cold
Poliomyelitis
Mycocarditits
Meningitis/Encephalitis
Hepatitis
Picornavirus
What is the treatment and/or prevention of Picornavirus?
Supportive
Vaccine for Polio
What are the characteristics of Hepatitis A?
Picornavirus (Hepatovirus)
Icosahedral
Non-enveloped
ssRNA, + sense
Humans are the only reservoir
How is Hepatitis A diagnosed?
Detection of anit-HAV IgM
Detection of anti-HAV IgG in the absence of IgM indicates immunity (lifelong)
How is Hepatitis A transmitted?
HAV is shed into the GI and found in the stool of the infected person
Spread by fecal/oral route
Often found in raw shellfish which concentrate the virus
Blood exposure is rare but can occur
What is the diagnosis?
Symptoms:
Fatigue
Abdominal Pain
Loss of Apetite Nausea
Diarrhea
Fever
Jaundice
Dark Urine (often first indicator)
Pale Stools
Elevated Liver Enzymes (ALT, AST) in Sera
Hepatitis A
What is the most important determinant of severity in Hepatitis A?
Age -- patients older than 49 have substantially greater risk of fatality (2.7%)
How can Hepatitis A be prevented?
Vaccine -- 94-100% efficacious
Passive immunization with immune globulin -- up to 2 weeks after known contact or before travel to HAV-endemic area (protection will not last)
Hygiene and Sanitation
Is Hepevirus (HEV) enveloped?
No
What is the genome of Hepevirus (HEV)?
ssRNA '+' sense
Name the Virus:
Distinguishing Features:
Single RNA
Three distinct polypeptides
Icosahedral Symmetry
Lytic
Disease Manifestations:
Resolving Acute Hepatitis
More significantly pathogenic in pregs
Hepevirus
What is the treatment and/or prevention for Hepevirus (HEV)?
Vaccine -- not licensed in US bc dont see many cases
How is Hepevirus (HEV) transmitted?
Fecal-oral Transmission
Not commonly transmitted via person-to-person contact (gotta swallow)
What dictates severity of Hepevirus (HEV) infection?
Severity of disease is related to infectious dose
Pregnant women are at greatest risk
What is a key distinguishing feature between HAV and HEV?
Immunity to HEV is not life-long. One can be reinfected
Is Hepadnavirus (HBV) enveloped?
Yes
What is the genome of Hepadnavirus (HBV)?
Partial dsDNA/Partial ssDNA
Circular, but nicked
Identify the Virus:
Distinguishing Features:
Very small genome
Icosahedral
Replicates through an RNA intermediate
Causes tumors
Non-cytopathic Reverse transcriptase
Disease Manifestations:
Acute and Chronic Hepatitis
Transmission predominantly mother-to-child
Hepadnavirus (HBV)
What is the treatment and/or prevention for Hepadnavirus (HBV)?
Vaccine
In Hepadnavirus (HBV), what is an important antigen for replication that is derived from the same transcript as the core but has an alternate translational initiation and different structure?
HBV e antigen
What are the modes of transmission for Hepadnavirus (HBV)?
Blood
Sexual
Pernatal -- mother to neonate always results in chronic hepatitis
True or False:
Infection of HBV in adulthood generally results in protection.
True
There is a high incidence of what three diseases in chronic carriers of HBV, resulting in 5,000-6,000 deaths/year?
Progressive Hepatitis
Cirrhosis
Hepatocellular Carcinoma (HCC)
What is the most common mode of transmission of HBV in the US?
Sexual Transmission
In HBV, 90% of _______ infected individuals have chronically evolving hepatitis, whereas 90% of _____ infected individuals recover.
Vertically
Horizontally
How is Hepadnavirus (HBV) diagnosed?
Immunoassay for HBsAg -- present during prodrome and acute disease. Present for 6+ months = carrier state
"Window Phase" -- HBsAg has disappeared but anti-HBsAg can not be detected. During the window one can look for anti-HBc
Viral Load can be measured by PCR -- important in management of drug resistance
What is an important indicator of HBV virus production and transmissibility?
HBeAg presence during prodrome and acute disease
How is HBV treated and/or prevented?
Alpha-interferon for those already infected
Lamivudine (RT inhibitor) usually used after pts become sick. Resistance is a problem
Vaccine
HBlg -- for immediate protection in persons known to be exposed.
Identify the Virus:
Distinguishing Features:
Negative sense, closed circular, ssRNA
Satellite Virus: requires HBV to replicate
Smallest "virus" known to infect humans
Genome codes for no protein
Disease Manifestations:
More severe acute diseaseHigher risk of fulminant hepatitis
Hepatitis D Virus
What are the clinical characteristics of an HDV superinfection of HBV+ patient?
Usually develop chronic HDV infections
Greater potential for development of cirrhosis & HCC
How can HDV coinfection and superinfection be prevented?
Co-infection: use methods to prevent initial HBV infection
Superinfection: Education of HBV+ patient regarding risk factors to avoid
Monitor for sudden changes in hepatic disease in HBV infected patients
Is Hepacivirus (HCV) enveloped?
Yes
Identify the Virus:
Genome:
ssRNA + sense
Disease Manifestations:
Favivirus:
Yellow Fever
Dengue
West Nile Virus
Hepacivirus (HCV)
What is the most common blood-borne infection in the US?
Hepatitis C Virus
Identify the Virus:
Symptoms:
No clinical symptoms in 80% of infected
When present, same as for HAV
Long-term Effects: Chonic infection (60-80%), Chronic Liver Disease (60% of chronic infections -- HCC or Cirrhosis)
A leading indication for Liver Transplant
Hep C Virus
How is HCV transmitted?
Blood or Body Fluids
Permucosal (perinatal, sexual -- rare)
How is HCV diagnosed?
Detection of antibodies by anti-HCV ELISA (Test does not distinguish between acute, chronic, or resolved infection)
RIBA -- used after ELISA is positive due to false positives
RT-PCR: detects viral RNA in the blood to determine if disease is active
How is HCV managed?
Monitor liver function of infected patients
Interferon alpha + ribavirin or pegylated interferon alpha are treatments of choice
Infected individuals should avoid alcohol
Viral load should be monitored by RT-PCR in symptomatic phases
NO VACCINE
Viral infections are cleared by (lymphocytes or neutrophils)?
Lymphocytes
What are the two leading causes of cirrhosis in the US?
Chronic Viral Hepatitis
Alcohol
What is the sixth leading cause of adult deaths?
Cirrhosis
What is a serious complication of cirrhosis?
Portal Hypertension
What is the difference between a compensated and a decompensated form of cirrhosis?
Compensated: No portal hypertension complications
Decompensated: Have PH complications, die 1-5 yrs
What is a cirrhotic liver?
A liver that is unable to regenerate because it is encapsulated with fibrosis
What are the two clinical syndromes that cirrhosis leads to?
Portal Hypertension
Liver Insufficiency
Portal hypertension in cirrhosis leads to development of what three clinical complications?
Variceal Hemorrhage
Ascites
Encephalopathy
Liver insufficiency in cirrhosis leads to development of what two clinical complications?
Jaundice
Encephalopathy
What is this method used to measure?
Hepatic Venography
A balloon catheter is passed into the hepatic vein
and FHVP (free hepatic venous pressure) and WHVP (wedged hepatic venous
pressure) are measured.
Which type of varices are most difficult to stop bleeding?
Gastric Varices
The purpose of this is to correct portal hypertension by creating a communication between the hypertensive portal system and low-pressure systemic veins, bypassing the liver. What is it?
This is performed by advancing a catheter introduced through the jugular vein into a hepatic vein and into a main branch of the portal vein. An expandable stent is then introduced connecting hepatic and portal systems, and blood from the hypertensive portal vein and sinusoidal bed is shunted to the hepatic vein.
Fluid Restriction is not necessary unless there is hyponatremia
What are the indications for abdominal paracentesis?
New-onset ascites
Admission to hospital
Clinical deterioration
Fever
What are the main organismal culprits of spontaneous bacterial pericarditis?
Escherichia (43%)
Klebsiella Pneumoniae
Streptococcus Pneumoniae
Serum-Ascites Albumin Gradient (SAAG) is high in portal hypertensive causes of ascites. What SAAG score is indicative of the presence of sinusoidal hypertension as seen in cirrhotic and cardiac ascites?
A SAAG of 1.1 g/L or above
Do peritoneal causes of ascites have a low or a high SAAG value?
What is the leading cause of ACUTE liver failure in the US?
Acetaminophen
What dose of Acetaminophen can cause severe liver necrosis?
Single dose of 15-25 grams
Should liver patients ever be perscribed acetominophen?
Yes, liver patients can take in proper doses
What is the antidote for acetaminophen overdose?
N-acetylcysteine
What are the clinical variants of HAV infection?
Cholestatic Hepatitis
Relapsing Hepatitis
Fulimant Hepatic Failure
Globally, what is the most common type of Hepatitis infection?
Hep B
In HBV infection, does the risk of chronic infection increase or decrease with age?
Decreases
What agents are used to treat chronic HBV?
Peginterferon alfa-2a
Entecavir
Tenofovir
What are the stages of fibrosis in chronic hepatitis?
1. Portal
2. Periportal
3. Septal
4. Cirrhosis
What disease is characterized by this pathogenesis?
Increased intestinal iron absorption from birth
Period of asymptomatic iron accumulation
End-organ damage due to toxic iron effects
Hereditary Hemochromatosis
What are the classifications of Hemochromatosis?
Type 1: HFE
Type 2a: Hepcidin
Type 2b: Hemojuvulin
Type 3: Transferrin Receptor 2
Type 4: Ferroportin
In this type of Hereditary Hemochromatosis, a mutated HFE protein impairs Tfr2-linked serum iron entry in hepatocytes and immature enterocytes causing both to falsely "sense" an iron poor state. This causes DMT1, ferroportin to be upregulated, causing hepcidin secretion to be suppressed.
Type 1
These 2 types of Hereditary Hemochromatosis, known as Juvenile Types, are characterized by mutations that lead to lack of suppression of ferroportin-mediated enterocyte iron export into serum
Type 2a -- Hepcidin
Type 2b -- Hemojuvulin
What is the gene responsible for Type 1 Hereditary Hemochromatosis?
Homozygous: C282Y
Heterozygous: C282Y/H63D
What does a mutation in HFE-1 protein lead to?
An increase in intestinal iron absorption
What are the main serum iron tests?
Ferritin
Iron Saturation
For C282Y, penetrance variations are probably due to other "modifier" genes which interact with C282Y as well as female blood loss. The Beutler grading system is used to define penetrance. What are it's grades?
Grade 0: Normal Liver Tests
Grade 1: Increased TIBC
Grade 2: Plus Increased Ferritin
Grade 3: Plus Minor Symptoms
Grade 4: Plus Potentially Lethal Symptoms
The "Gestalt" System is a commonly used qualitative system to grade Iron. For Hepatocellular Hemosiderin, what is the Grading Scale?
Psychiatric Presentation: depression, psychosis, poor school performance
Hematologic Presentation: hemolytic anemia
Causes:
Decreased hepatic excretion of copper
Absorption remains normal
Copper Accumulation: in liver and brain -- damage through free radical formation
Wilson's Disease
What is the age of presentation and physical exam findings associated with Wilson's Disease?
Mean Age at Presentation: 12-23 years; pt rarely older than 50
Physical Exam Findings: Kayser-Fleischer Rings (copper ring in cornea); "Sunflower" cataracts
What is diagnostic of Wilson's Disease?
Lowered Ceruloplasm
Raised Urinary Copper
Kayser-Fleischer Rings
What is the definitive test for Wilson's Disease?
Quantitative Copper Analysis
Normal < 35 mcg/g dry weight liver
What is the cause of 44% of liver-related deaths?
Alcoholic Liver Disease
What are the minimum amounts of alcohol to cause cirrhosis?
Males -- 80 g/day X 10 years
Females -- 20-40 g X 10 years
What are the risk factors for alcoholic liver disease (5)?
Quantity
Gender
Hepatitis C
Genetics
Malnutrition
How is alcoholic hepatitis diagnosed (what are the associated labs)?
AST/ALT ratio > 2 (ETOH suppresses production of ALT)
ASH vs NASH -- repeat urine and blood alcohols, talk to spouse
How is asymptomatic alcoholic hepatitis characterized (3)?
Hepatomegaly
Biochemistry mildly abnormal
Needs histology for confirmation
How is liver failure in Alcoholic Hepatitis characterized (6)?
Bilirubin greatly increased
Alk Phos modest
PT increased
Albumin reduced
Neutrophilia
Ascites
What are the medication recommendations for Cirrhosis?
Acetaminophen is ok
Tramadol when acetaminophen is not enough
No NSAIDS
Trazodone or Hydroxyzine for insomnia rather than benzos
Should Corticosteroids be used for severe Alcoholic Hepatitis?
