First Pass Miss Flashcards
What forms the endothelial cells of the liver sinusoids?
Remnants of the yolk sac circulation -> vitelline and umbilical vessels
Stellate (Ito) cells, fibroblasts, Kupffer cells, hematopoietic stem cells, and connective tissue formed by mesenchyme of septum transversum
Biliary tract system + parenchyma formed by hepatic diverticulum foregut at week 4
What zone of hepatocytes are most susceptible to drugs / toxins / hypoxia / ischemia?
Hypoxia / Ischemia - zone 3, furthest from blood supply
Drugs / toxins - Zone 3 as well, due to phase 1 reactions (ethanol and acetaminophen toxicity causes centrilobular necrosis)
Zone 1 most susceptible to hemochromatosis
What are the symptoms of acute liver failure and why?
80-90% loss of liver function in weeks, most commonly caused by fulminant hepatitis
Encephalopathy -> increased nitrogen wastes
Hypoglycemia -> decreased glucose homeostasis maintenance by liver
Coagulopathy -> decreased production of coagulation factors
Renal failure -> not well understood
What is the hallmark of mild chronic hepatitis pathologically?
Inflammation of portal tracts, but minimal detectable hepatocyte injury
-> for viral hepatitis, will be lymphocytes which don’t really leave the portal tract area (chronic inflammatory infiltrate)
Chronic will show inflammation leaking out of portal triad, with piecemeal necrosis, interface (portal vein / liver) hepatitis, and bridging necrosis
What are the unique features of HBV vs HCV chronic hepatitis?
HBV - eosinophilic ground glass appearance of hepatocytes due to accumulated HBsAg
HCV - focal macrovesicular fatty change, and large periportal lymphoid aggregates
Autoimmune - plasma cells in portal tracts
How does acute hepatitis appear pathologically?
Lobular disarray - disruption of architecture
Random hepatocyte injury w/ ballooning degeneration, cytolysis, apoptosis
Inflammatory infiltrate, reactive Kupffer cells, and hepatocyte regeneration
What are the clinical manifestations of cholestasis?
- Pruritis - from retention of bile salts / acids
- Jaundice / icterus -> conjugated bilirubin increases
- Xanthomata / xanthelasma - lipid-laden Macs deposit in dermis due to increased serum cholesterol
- Fat / fat-soluble vitamin malabsorption
- Coagulopathy - failure to absorb vitamin K
- Osteoporosis - failure to absorb vitamin D
Describe the general pathogenesis of cirrhosis.
Chronic liver injury -> cytokine production by Kupffer cells, lymphocytes, and endothelial cells
Ito cells become myofibroblast-like cells due to cytokines, which causes contraction and synthesis of Types I and III collagen into space of Disse
Fibrosis impairs blood flow and diffusion of metabolites -> formation of fibrous septae and portosystemic shunts, impaired endothelial fenestrations
What are some etiologies of cirrhosis?
Alcohol abuse
Non-alcoholic fatty liver disease -> associated with metabolic syndrome + insulin resistance
Viral hepatitis (HBV/HCV)
Cholestasis
Metabolic disorders (hemochromatosis, Wilson’s, A1AT deficiency)
Cryptogenic (idiopathic)
What will happen to hepatocytes in terms of injury pattern in cholestasis disorders?
Feathery degeneration - actually doesn’t look that different, but we call it feathery degeneration when it is in the presence of dilated bile ducts and smooth green to golden-brown globular pigment
Why does portal venous blood flow increase in cirrhosis?
Circulation becomes hyperdynamic
- > cardiac output increases due to peripheral vasodilation which is not fully understood, mediated by nitric oxide and decreased response to vasoconstrictors
- > mesenteric / splanchnic arterial vasodilation -> increased blood flow to portal system
- > systemic arterial vasodilation also decreases effective arterial volume -> increased RAA activation -> sodium and water retention
What are the complications of cirrhosis due to portal hypertension?
- Ascites (due to increased fluid congestion in portal system leading to pressure backflow through capillies) -> peritonitis
- Extrahepatic portosystemic shunts can lead to significant hemorrhage
- Hypersplenism / congestive splenomegaly
- Hepatic encephaloathy - intrahepatic shunts avoid hepatic parenchyma for waste removal
What are the consequences of loss of hepatic function in cirrhosis?
- Hypoalbuminemia
- Coagulopathy
- Hepatorenal / hepatopulmonary symptoms
- Hyperestrogenism
- Jaundice / icterus with cholestasis
- Hepatic encephalopathy
Why does hyperestrogenism happen in liver disease and what are the clinical signs / symptoms
Decreased sex hormone binding globulin and decreased inactivation of estrogen and testosterone leads to more formation and maintenance of estrogen levels.
- Spider angiomas and palmar erythema (not well understood)
- Gynecomastia
What are the two shitty categories of cirrhosis?
- Micronodular - uniform, small nodules separated by thin fibrous septae -> hepatocytes replicating from a single lobule or portion of a lobule, forming nodules
- everything else - Macronodular - variably-sized, often larger nodules encircled by irregular bands of broad connective tissue, originating from multiple lobules
- viral
Why does sinusoidal vascular resistance increase?
- Active vasoconstriction -> stellate cell contraction, and increased endothelial production of endothelin
- Circulatory compression from fibrous tissue and regenerating parenchymal nodules
What is the clinical definition of acute liver failure?
Severe hepatic dysfunction progressing to encephalopathy within 8-12 weeks from initial onset of liver disease (no history of pre-existing liver dz, otherwise acute on chronic)
What are physical signs of cholestasis disorders?
Icterus
Skin excoriation - due to pruritis
Ecchymoses - coagulopathy (prolonged PT)
Xanthomas and xanthelasmas
Acholic (gray) stools
Gallbladder may be enlarged / palpable if obstructed
What are three special modalities used to check for hepatobiliary disease?
- ERCP - endoscopic retrograde cholangio-pancreatogram, inject dye into ampulla of vater
- PTC - percutaneous cholangiogram, find a bile duct through the skin and check for obstruction
- MRCP - Magnetic resonance cholangiopancreatogram
What are the treatments for medical jaundice / cholestasis?
Bile salt binding resins such as cholestyramine -> treat the pruritis
Ursodeoycholic acid - binds cholesterol and protects against gallstones
Vitamin K / Vitamin D supplementation
Medium chain triglycerides - can be absorbed without bile salts
What are the treatments for portosystemic collaterals (varices)?
- Transfusion - for blood loss if bleeding
- Endoscopic injection - sclerose the vessels closed
- Rubber band ligation -> suck them closed
- Pharmacologic agents to lower portal pressure
- Decompression
- > i.e. TIPS
What are the three types of portosystemic encephalopathy? How do they differ broadly in terms of reversibility?
Acute type -> not due to portal HTN/ shunting, irreversible:
Type A - Acute - delirium + convulsions, commonly progress to coma -> BBB and cerebral edema
Chronic types -> usually due to shunting problem, usually reversible:
Type B - Bypasses -> Occurs in patients with portosystemic bypasses
Type C - Cirrhosis / Chronic liver disease - functional hepatocellular failure with large shunting / portal HTN component
What factors precipitate worsening of hepatic encephalopathy?
Increased NH3 production or absorption:
- Excess oral protein intake -> ammonia builds
- GI bleed -> increased protein to gut microbes
- Constipation / infection
Decreased NH3 removal:
- Alkalosis / hypokalemia -> Increased K+ reabsorption stimulates H+ excretion via ammonia, but ammonia ends up returning to blood so it just exacerbates the issue
- Renal failure
- Diuretics -> hypokalemia
- TIPS procedure
- Benzos / sedatives
What pharmacologic agents are useful in reducing portal pressures and thus are useful in treating acute variceal bleeds?
Octreotide -> somatostatin analogy which decreases secretion of splanchnic vasodilators
Vasopressin -> constrictor of vascular beds
What lab tests are helpful in determining the etiology of the ascites fluid?
- Protein content
- WBC’s and type - monocytes elevated in TB, PMNs in bacterial peritonitis
- Malignant cells - diagnostic of cancer
- Amylase - elevated in pancreatitis
- > pancreatitis is a cause of ascites because malnutrition leads to decreased protein and hence oncotic pressure - Gram stain and culture - diagnostic of infection
How does protein content help determine the etiology of ascites and what is the cutoff?
Protein content:
High in chronic infection and tumor (exudate)
Low in portal hypertension - transudate
If serum minus ascities albumin is greater than 1.1 g/dL -> portal HTN is very likely
What are the problems associated with ascites?
- Spontaneous bacterial peritonitis
- Umbilical hernia with rupture -> Flood syndrome!
- Can lead to pleural effusions and generally diaphragm harder to move -> breathing difficulties
- Drug dilution due to increased volume of distribution
What are the two types of hepatorenal syndrome?
Type 1 - rapid development of kidney failure in less than two weeks, worst prognosis
Type 2 - Slower onset -> diuretic resistant or unresponsive ascites
Patients will have oliguria but no ultrasound or urine sediment signs of ATN
Must rule out pre-renal azotemia by trying volume expansion with saline to see if kidney function improves
What are some other non-hepatic causes of ascites?
Peritoneal infections, i.e. TB Cancer - primary or metastatic to peritoneum Nephrotic syndrome Pancreatitis CHF, constrictive pericarditis
How does alcoholic hepatitis appear pathologically?
Swollen and necrotic hepatocytes with a NEUTROPHILIC inflammatory infiltrate.
Mallory-Denk bodies -> alcoholic hyaline - eosinophilic cytoplasmic inclusions which are inclusions of damage keratin filaments
Can be some centrilobular fibrosis
What are the laboratory findings of alcoholic hepatitis?
Mild to moderate increase in serum transaminases, especially AST > ALT. “Make a toAST with alcohol”
Elevated bilirubin, alkphos, GGT with cholestasis, and mild leukocytosis due to neutrophils
Where does iron tend to accumulate in hemochromatosis and what are the consequences?
Bronze diabetes
Liver - micronodular cirrhosis and HCC
Pancreas - diabetes mellitus
Myocardium - restrictive -> dilated cardiomyopathy
Joint synovial tissue - arthropathy
Pituitary - hypogonadism
Skin - increased melanin in epidermis, increased hemosiderin in dermis
What is the pathogenesis of Wilson disease?
Defective transport of copper in liver -> decreased incorporation of copper into ceruloplasmin -> decreased excretion of excess copper into bile -> toxic copper accumulation
What are the consequences of copper excess in all liver and CNS in Wilson disease?
Liver - fat and glycogen accumulation -> hepatitis -> cirrhosis
CNS - neuronal injury -> neurologic and psychiatric manifestations.
Basal ganglia involvement: Temors, rigidity, dysarthria
Elsewhere: depression, anxiety, psychosis
What is the cause of primary biliary cholangitis (PBC) and who tends to get it?
Probably an autoimmune disease characterized by progressive T-cell mediated destruction of small to medium sized intrahepatic ducts
As it is autoimmune, it is classically seen in middle-aged women with other autoimmune disorders (i.e. Sjogren’s, RA, Hashimoto)
Pathognomonic is florid duct lesion: giant cell neck to ducts
-> starts as granulomatous inflammation in portal tract and worsens to biliary cirrhosis
What is seen in the lab values / tests for PBC?
Cholestatic lab profile (increased alk phos, GGT, cholesterol, conjugated bilirubin)
Increased IgM levels -> antimitochondrial antibodies and lipoprotein X (type of LDL only seen in bile diseases)
What is the treatment for PBC?
Ursodeoxycholic acid -> protects against bad bile acids, and symptomatic treatment of complications (i.e. vitamin D, cholestyramine, portal HTN treatments like octeotide)
What ducts are destroyed in primary sclerosing cholangitis (PSC) and who tends to get it?
Progressive destruction of large intrahepatic and extrahepatic bile ducts
Found mostly in middle-aged men, strongly associated with ulcerative colitis, p-ANCA+
Complications: Gallbladder cancer, cholangiocarcinoma, biliary cirrhosis
How does pathology appear in PSC?
Think sclerosing + targetting bile ducts
Alternating areas of stricture (concentric, “onion-skin” fibrosis around ducts) and dilatation “beads”.
Basically strictures of fibrosis that look like hyperplastic arteriolosclerosis of ducts, and dilations that are like “beads” - seen on barium study via ERCP
Representative examples of liver injury types:
Acute hepatitis - phenytoin
Chronic hepatitis - alpha-methyldopa, nitrofurantoin
Cholestasis - estrogens
Cholestasis/hepatitis - amox/clav, chlorpromazine
Macrovesicular fatty liver - corticosteroids
Microvesicular fatty liver - tetracycline overdose
Dose-related cirrhosis - methotrexate, need multiple liver biopsies
Granulomatous - allopurinol
What liver injury does pre-marrow-transplant chemotherapy cause?
Hepatic veno-occlusive disease
-> a cause of intrahepatic portal HTN
What determines if acetaminophen is toxic or not and how does the antidote work?
Phase I - toxic
Phase II - safe
N-acetylcysteine works to replenish intracellular glutathione stores involved in dealing with toxic NAPQI accumultation. These are also depleted in alcoholism and malnutrition
What is the type of DILI accounted for by most hepatic drug reactions? What is the clinical course?
Unpredictable, idiosyncratic
-> occurs rarely for any drug, includes herbals
- > long latent period (sensitization?) for several weeks before reaction
- > rechallenge with same drug will lead to rapid reaction
- > associated with fever, rash, eosinophilia (suggesting hypersensitivity)
-> drug acts as a hapten for immunologic response, or produces toxic metabolites
What drug reaction does phenytoin usually cause?
Acute hepatitis with delayed onset
May cause DRESS syndrome though:
Drug Reaction with Eosinophilia and Systemic Symptoms
-> fever, rash, eosinophilia, lymphadenopathy
-> mechanism unclear
What is the course and presentation of CMV hepatitis?
Generally causes hepatitis in children, or immunosuppressed adults.
Anicteric hepatitis with no chronic phase propensity, may be lethal in immunosuppressed
What atypical hepatitis occurs in immunosuppressed individuals and is associated with high mortality? How is it seen? What is the treatment?
HSV -> seen by inclusion bodies on light microscope
Treatment is acyclovir or vidarabine
Is acute liver failure common in HBV? What drugs are used to treat chronic infection?
No -> chronic carrier state can be though.
Drugs: Think NRTI wielding mace and lamb (lamivudine), as well as IFN-alpha antenna
Most commonly used are entecavir and tenofovir, suppressing virus
How is hepatitis E virus transmitted and why is it unique? What type of virus is it?
Fecal-oral, especially from contaminated water
RNA hepevirus
Unique - only human hepatitis virus with an animal reservoir (swine)
Who is considered at highest risk for HBV?
Men who have sex with men (trauma during sex), people born in areas with high rates of chronic HBV (especially Asia), and those with multiple sex partners
What is a Von Meyenburg Complex and what causes it?
Bile duct hamartoma - caused by persistence of embryonic bile duct structures
-> presence of multiple with intervening connective tissue may look like metastatic adenocarcinoma, need to differentiate based on lack of cellular atypia
Who tends to get focal nodular hyperplasia and how is it found?
Occurs in young adults, especially with oral contraceptives in women, or anabolic steroids in men
Usually found as an incidental finding -> looks like an oncocytoma of kidney, with a central scar and radiating bands of fibrous tissue
What are the microscopic features of focal nodular hyperplasia, and what are the clinical consequences?
Central scar, with abnormally large arterial branches accompanied by bile ductular proliferation (which don’t drain anything) and chronic inflammation, with no well defined portal triads
Hyperplasia grows between radial spokes of fibrosis
There are no clinical sequellae -> just need to differentiate between important masses
Proliferations occur due to alterations in blood flow leading to increased oxygenation by hepatic artery and thus release of growth factors causing reactive hyperplasia
What are the gross and microscopic features of nodular regenerative hyperplasia? What is it difficult to differentiate from?
Gross - diffuse, pale, fine nodularity of the liver
Microscopic - Regenerative nodules WITHOUT fibrosis (check trichrome stain), often with obliterated portal vein branches
Lack of fibrosis will help differentiate from cirrhosis
Arise in individuals with a predisposition for decreased blood flow to liver: i.e. hematologic / neoplastic disorders. Possible consequence: may develop portal HTN
How does cavernous hemangioma appear microscopically?
Frequently subcapsular - most common benign liver tumor
Large, thin-walled, blood-filled spaces lined by normal-appearing endothelial cells, separated by scarce fibrous connective tissue
What benign liver neoplasm is most associated with oral contraceptive or estrogen use, and almost never arises outside of this context? How does it present clinically?
Hepatocellular adenoma
Present in young women on oral contraceptives. May cause an acute abdomen due to rupture and intraperitoneal hemorrhage
Subcapsular, green, well-circumscribed, but more likely to bleed than cavernous hemangioma
How does hepatocellular adenoma appear microscopically?
Sheets and cords of relatively normal-looking hepatocytes, containing glycogen or triglycerides (functioning properly) but with NO portal tracts and scattered arteries and veins which are prone to hemorrhage.
What are the early vs late lab elevations in metastasis to liver?
Spread from colon, pancreas, lung (hepatic artery), breast (after lung)
Early - elevated Alk Phos (indicates metastasis to liver) and LDH (nonspecific for cell death)
Late - increased serum bilirubin and transaminases - due to necrosis of hepatocytes from ischemia and blockage of bile drainage = HEPATOMEGALY
What are the three major risk factors for development of HCC? Which is most common in US?
- Asymptomatic HBV carrier state
- Cirrhosis (repeated cycles of necrosis and regeneration is progressively mutagenic) - most common in US
- Exposure to aflatoxin
- > stored grains and peanuts from Aspergillus flavus, induces p53 mutations
What are the clinical consequences of venous invasion by HCC?
Portal vein -> portal hypertension
Hepatic vein -> Budd-Chiari syndrome, can even extend to right atrium thru IVC
What is the clinical triad of Budd-Chiari syndrome? What is seen in the liver?
Sudden liver enlargement (hepatomegaly), pain, and ascites - due to acute hepatic venous occlusion
Centrilobular congestion and necrosis can be seen
How does HCC appear microscopically?
highly variable. May be trabeculated or pseudoacinar if more well differentiated.
Can be told apart from benign by presence of prominent nucleoli, eosinophilic cytoplasm, and lack of simple hepatocellular cords (tend to grow in clusters / acini)
Will cause elevated alpha-fetoprotein (fetal albumin)
What form of hepatocellular carcinoma is seen in young adults and has a good prognosis? Why is the prognosis good?
Hepatocellular carcinoma, fibrolamellar variant
Prognosis is good because it is well circumscribed and individuals often have no underlying liver disease (can resect just fine)
- > well-differentiated tumor cells in abundant fibrous stroma and parallel lamellae of collagen
- > appears grossly like oncocytoma
What is cholangiocarcinoma? What are the risk factors?
Carcinoma of the bile duct epithelium (intrahepatic or extrahepatic)
Risk factors: often absent, but include primary sclerosing cholangitis, congenital biliary tract abnormalites leading to stasis, Thorotrast exposure, and Clonorchis sinesis (liver fluke)
-> looks like regular desmoplastic adenocarcinoma, very poor prognosis if intrahepatic (detected late)
How does hepatoblastoma appear grossly and microscopically?
Grossly - Large, hemorrhagic, necrotic nodular mass
Microscopically - small, round, blue-cell tumor with evidence of epithelial (embryonal to fetal hepatocellular) differentiation +/- mesenchymal differentiation (may even have random bone deposits)
Expresses alpha-fetoprotein
-Aggressive but treatable malignancy of children
What is the fate of bilirubin once it enters the intestine?
Bacteria in the gut deconjugate it to urobilinogen.
Urobilinogen can be excreted in stool after being made into stercobilin -> gives the stool its brown color.
Some urobilinogen is reabsorbed -> can be excreted again in bile, or transported to kidneys where it is oxidized to urobilin -> gives the urine its yellow color.
What is the most common congenital anomaly of the gallbladder?
Phrygian cap -> fundus (body, as opposed to neck and cystic duct) of the gallbladder folded inward
What gallbladder pathology is commonly seen with cholesterol stones and what is the cause? How does it appear grossly and microscopically?
Cholesterolosis - aggregates of foamy macrophages within the subepithelium of gallbladder (looks a bit like Whipple’s disease, but in gallbladder). Grossly -> little yellow deposits within the mucosa.
Increased bile cholesterol increases cholesterol absorption by gallbladder mucosa -> accumulate in subepithelium
What are the risk factors for pigment gallstones?
- Chronic hemolysis -> increased biliary excretion of conjugated bilirubin, and a small percentage always becomes UNconjugated
- > forms black stones which conjugate with Ca+2 and are radioopaque - Biliary tract infections -> microbial deconjugation of bile acids
- >forms brown stones which are soft and soap and radiotranslucent - Gallbladder hypomotility -> thickens bile
What are the four F’s of cholelithiasis risk factors?
Female
Fat
Fertile (pregnant)
Forty
+ Native American
-> cholesterol stones
What are the possible complications of cholelithiasis?
- *Acute cholecystitis
- Hydrops of gallbladder due to chronic obstruction - gallbladder filled with mucin
- Choledocholithiasis -Obstruction of the common bile duct
- Chronic cholecystitis
- Gallstone ileus
- Carcinoma of the gallbladder
What is the most common type of cholecystitis and its pathogenesis?
Calculous cholecystitis - obstruction of neck of gallbladder via a stone = retention of bile, gallbladder distention, and vascular compression in the wall (venous congestion, causing hemorrhagic infarct overtime)
Acalculous happens in critically ill patients with hypoperfusion or hypomotility
What are the predisposing factors to chronic cholecystitis, and what are the characteristic microscopic features?
Chronic cholelithiasis and bacterial contamination
Chronic inflammation - lymphocytes, macrophages, plasma cells, and fibrosis
Rokitansky-Aschoff sinuses - mucosal diverticula seen in gallbladder wall due to contraction against thick gallbladder wall
-> Porcelain gallbladder is most well-recognized variant
What is a Klatskin tumor and what are its risk factors?
A type of carcinoma of the extrahepatic bile ducts, which is located at the origin of the common hepatic duct (before it merges with cystic duct)
Risk factors for all adenocarcinomas of extrahepatic bile ducts:
Older males, biliary tract infections, PSC, choledochal cysts
What stimulates the release of the contents from duct cells and acinar cells?
Cephalic phase - Vagus nerve - acetylcholine
Gastric phase - Duct cells are stimulated by -> secretin, produced by S cells in duodenum
Intestinal phase - Acinar cells are stimulated by -> cholecystokinin, released by I cells, “I like fat”
What do the two buds of the pancreas form?
Ventral bud - forms off of the hepatic diverticulum (off the biliary tree endoderm which will induce formation of liver) -> will form the caudal portion of the head of the pancreas as well as the uncinate process
Dorsal bud - comes off of duodenum dorsally - forms the rostral portion of head of pancreas plus body and tail
