Exam 3
Risk factors for Cholelithiasis
"Female, Fat, Fertile, Forty" Female Increasing age pregnancy oral contraceptives obesity diabetes mellitus ethnicity: Native American Rapid weight loss
How does Non-alcoholic fatty liver disease "NAFLD" present microscopically?
**Steatofibrosis pattern Hepatic steatosis Inflammatory infiltrates: -due to ongoing hepatocyte oxidative/cellular injury Cell necrosis may eventually occur Early on, new collagen deposition will delicately encircel hepatocytes (right image) in a "chicken-wire fence"/sinusoidal pattern -this is seen in NAFLD and alcoholic steatohepatitis
Serous cystic neoplasm (Serous cystadenoma)
2x more common in women occurs in the tail of the pancreas Presentation: -non-specific abdominal pain
Acute large bile duct obstruction leads to?
Acute duct obstruction → inflammation in the obstructed area → inflammation spreading more proximally up the duct → ascending cholangitis and cholestasis in the liver Ascending Cholangitis: -occurs when bacterial overgrowth complicates obstruction -can evolve and extensive pus can be produced causing a suppurative cholangitis -pus may expand and spread out of the intrahepatic bile ducts causing liver abscesses or small bile-induced necrosis or infarcts Sepsis is a potential problem
What is considered the "generic" pancreatic cancer?
Adenocarcinoma
What lab values can be used to evaluate Hepatocyte Synthetic (not structural) function?
Albumin Coagulation factors Ammonia Normally found in the plasma Microscopy will show normal looking hepatocytes
A high AST/ALT ratio indicates?
Alcoholic liver disease when AST/ALT ratio is >1.5 (some say 2x), this is considered as highly suggestive that alcohol is the cause of the patient's liver injury FA: "Make a toAST with alcohol"
Explain the idea behind testing for aminotransferases as a component of liver function tests
Aminotransferases are normally intracellular -only low lvls normally found in the plasma which represents intracellular enzymes released during cell turnover Elevated plasma lvls of aminotransferases indicates damage to tissues rich in these enzymes (liver)
What lab values can be used to evaluate Hepatocyte Integrity/Structural function?
Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Lactate dehydrogenase (LDH) Not normally found in the plasma Steatosis may be seen microscopically
Wilson Disease
Autosomal recessive 10-20 years old range **BEFORE age 40** Results in copper dysmetabolism Mutations in the ATP7B gene, encoding a trans-membrane copper-transporting ATPase in hepatocytes --> decreased copper secretion into bile/blood with spillage of non-ceruloplasmin-bound copper that is picked up in certain tissues Symptoms of copper accumulation: -liver failure or cirrhosis -neurologic disease, including movement disorders and dystonia -Kayser-Fleisher rings in descemet membrane of the eye -Hemolytic anemia Treatment: -copper chelation can alter course of disease, but cirrhosis is a permanent process [Picture: copper accumulation w/in hepatocytes, seen with a special copper stain (Rhodanine)]
a-1 Antitrypsin Deficiency
Autosomal recessive disorder results in abnormal lvls of a1-antitrypsin, causes significant lung and liver disease (cirrhosis and emphysema) due to mutations in SERPINA1 gene Liver: -accumulation of mutated gene products results in round/oval protein inclusions, best seen w/ PAS stain (image) -most effected hepatocytes are generally periportal regions (Zone 2-3) -eventually fibrosis and cirrhosis result Lungs: -a protease-antiprotease imbalance can result in emphysema (permanent breakdown in alveolar septae/walls) -this imbalance occurs b/c a1-antitrypsin is an anti-protease (inactivates proteases) -a1-antitrypsin deficiency leads to increased protease activity, and proteolytic enzymes like elastase can break down alveaolar walls
Insulinoma
B cell tumor most common PanNET most are benign (90%) may induce significant hypoglycemia in episodes, promptly relieved by ingestion of glucose Tx: -surgical removal
Describe the microscopic findings of Cholestasis
Canaliculae expand w/ accumulated bile Excess bile/bile pigments collect w/in and stain hepatocytes -Some spill out of hepatocytes and are picked up in Kupffer cells Eventually, hepatocytes undergo apoptosis Cholestasis is evident early on as green-brown-gold plugs of bile w/in bile canaliculae, w/in heptocytes, and w/in Kupffer cells Longer standing cholestasis can develop bile plugs biliary stasis will incite the ductal cells to undergo hyperplasia
The liver expresses the enzyme y-glutamyl carboxylase. What is it's function?
Catalyzes the vitamin K-dependent modification of certain glutamate (Glu) residues on Factors II, VII, IX, and X This results in y-carboxyglutamate (Gla) residues on the inactive precursor clotting factors and facilitates its own activation Ex: Factor II (prothrombin) to Factor IIa (thrombin) conversion is vitamin K dependent
Cholelithiasis Causes, symptoms and complications
Causes: -develop when there is TOO MUCH cholesterol and NOT ENOUGH bile salts Symptoms: -biliary colic - RUQ or epigastric abdominal pain that is episodic, more pronounced after eating fatty or greasy foods, with accompanying nausea/vomiting -biliary colic occurs because a gallstone temporarily blocks the cystic duct, and then decreases in severity when the blockage temporarily stops Complications: -cholecystitis -jaundice/cholangitis -pancreatitis
hepatocellular carcinoma (HCC)
Chronic disease/infection → chronic inflammation → abundant mediators/signals for cellular regeneration, proliferation, activation, etc → slow and random acquisition of mutations in mitotically active cells → increased risk for dysplasia → increased risk for malignancy Risk factors: -Hep B virus (HBV) -Hep C virus (HCV): typically in the setting of liver cirrhosis -Chronic alcohol use -Alfatoxins: produced by certain mold species (Aspergillus) and regularly found on stored foodstuffs or staple foods Clinical presentation; -vague symptoms -abdominal fullness -weight loss, fatigue -grows larger until it interferes significantly w/ hepatic function causing general failure to thrive/tumor-induced cachexia or metastasis Diagnosis: -a-fetoprotein may/may not be elevated (inconsistent and non-sensitive for screening test)
How does chronic Hepatitis C characteristically present microscopically?
Chronic hepatitis causes portal triaditis Abundant interface hepatitis occurs with lymphocytes surrounding the portal triad Triaditis and its presence involving multiple portal regions is characteristic of Hepatitis C virus (Picture: arrow indicates region of portal triad)
What is the most common cause of ACUTE liver failure?
Drug induced liver injury ("DILI") On biopsy, pathology may show any histologic pattern of injury **Acetominophen results in mass necrosis Two patterns of DILI occur: I. Drugs that cause predictable, dose-dependent rxns in most ppl II. Idiosyncratic rxns, independent of dose only occuring in rare ppl
Type I Autoimmune hepatitis genetics
HLA-DRB1 alleles Middle aged-women with Anti-Nuclear (ANA) * Anti-smooth muscle (ASMA or anti-SMA autoantibodies)
What are the most common causes of Acute pancreatitis?
Gallstones Alcohol ingestion
How are Cholethiasis and Cholecystitis related?
Greater than 90% of the time, acute cholecystitis is due to blockage of the cystic duct by a gallstone (cholelithiasis).
Causes and Manifestations of Prehepatic obstruction
Impaired blood inflow Main cause= portal vein obstruction Causes of Portal vein obstruction: • Sepsis-induced thrombophilia • Inherited thrombophilias • Initiation of thrombosis due to inflammatory states, such as pancreatitis • Propagation of portal vein thrombosis from a splenic vein thrombosis • Trauma-related issues • Cirrhosis (responsible for about 25% of cases of portal vein thrombosis) Manifestations: -esophageal varices -splenomegally -intestinal congestion
Causes, forms and manifestations of Intrahepatic obstruction
Impaired intrahepatic blood flow Main cause= Cirrhosis -inhibits blood flow from entering and exiting the liver parenchyma Manifestations: -Ascites (cirrhosis) -Esophagesal varices (cirrhosis) -Hepatomegally -Elevated aminotransferases Ascites pathogenesis: -Increased pressure within hepatic sinusoids → collateral vein formation, splanchnic vasodilation (of inferior and superior mesenteric veins/systems) → increased capillary hydrostatic pressure and capillary permeability → fluid leaving portal system for abdominal cavity (ascites)
PanNET tumor (Pancreatic Neuroendocrine Tumor)
Involves Islets of Langerhans- endocrine portion of the pancreas may occur in any part of the pancreas (even outside of it in the peripancreatic soft tissue) Can be functional (hormone-producing) or non-functional Not common
Describe the pathogenesis of Cirrhosis from a microscopic/cellular level
Kuppfer cell activation begins cascade w/ release of cytokines Stellate cells (Ito cells) in space of Disse become activated in response to hepatic injury and inflammation and change their phenotype to allow for collagen production **Fibrogenesis is stimulated via TGF-B release from Kupffer cells**
What are the main causes of Chronic Pancreatitis?
Long standing alcohol use Long-standing duct obstruction, typically by a stone or a neoplasm Autoimmune or hereditary pancreatitis (ex., CFTR gene in cystic fibrosis)
Describe the morphology of Primary Biliary Cirrhosis (PBC)
Major diagnostic feature= florid duct lesion -abundant lymphocytes and plasma cells that surround and destroy bile ducts, particularly in the portal tracts -process may be patchy (Image on the Right) A granulomatous process is also possible (Image on the Left)
Explain the purpose behind measuring Prothrombin time as a component of liver function tests
Measures the extrinsic pathway clotting factors (Factors I, II, VII, and X.) Prothrombin is a clotting factor made by the liver PT (prothrombin time; in seconds) measures how long it takes a plasma sample to clot after a mixture of thromboplastin (Factor III) and calcium ions (top of the extrinsic pathway) is added. Explanation: -When the PT is high, it takes longer for the blood to clot (17 seconds, for example). -This usually happens because the liver is not making the right amount of blood clotting proteins, so the clotting process takes longer. -A high PT usually means that there is serious liver damage or cirrhosis. -A high PT may indicate there is a higher risk for internal bleeding from the upper part of the GI tract (esophagus, stomach).
Describe the pathogenesis of Acute Pancreatitis tissue injury
Pancreatic enzymes break down adipose → fatty acids released from adipocytes → fatty acids + calcium form chalky white calcium salts = saponification (fat necrosis)
a1-antitrypsin polymorphisms
PiMM phenotype is most common/wild type PiMZ phenotype has intermediate levels of α1-AT PiZZ phenotype has severe reduction in α1-AT (PiZ allele frequency 4%)
Risk factors, Symptoms, complications of Acute Cholecystitis
Risk factors: -cholelithiasis, in which case it's called calculous cholecystitis -when it occurs w/o stones= acalculous cholecystitis Symptoms: -biliary colic Complications: -gallbladder rupture -gangrene -fistula into the GI tract (gallstone ileus) -chronic cholecystitis with Rokitansky-Aschoff sinuses (dilated, epithelial-lined cystic structures)
Serous vs Mucinous cystic lining
Serous lining (upper image) - flattened to cuboidal epithelium; almost uniformly benign Mucinous lining (lower image) - columnar cells with apical mucin; precursors to invasive carcinoma
How do you screen for Autoimmune Cholangiopathies (PBC and PSC)`
Serum studies appear 'cholestatic': -increased alkaline phosphatase & GGT
How does a liver that has undergone cirrhosis appear grossly?
Smaller in weight Contracted appearing, distinct nodules are usually present Texture is very firm (filled with fibrosis) Often discolored toward the yellow-green spectrum (depending upon how much steatosis or bile accumulation is present, respectively)
How does acute pancreatitis present, how do you diagnose it, and what are complications?
Symptoms: -Stabbing epigastric abdominal pain radiating to the back -nausea/vomiting -evolving shock/systemic inflammatory response syndrome Diagnosis: -elevated amylase and lipase Complications: -ARDS -DIC -pseudocyst formation -abscess -calcifications -hypocalcemia
In what instance can a Kasai procedure be used to treat Biliary Atresia?
The Kasai procedure can be used in pts with EXTRAhepatic biliary atresia **not effective for intra-hepatic biliary atresia a portion of the neonate's small intestine is sewn to the liver to act as the new conduit for the biliary system, effectively trying to correct a surgically removed extrahepatic biliary obstruction
Describe "direct" vs "indirect" bilirubin tests. What are they used for?
These tests quantitatively distinguish the conjugated from the unconjugated bilirubins, based on their differential solubility. Direct Bilirubin: -When assay is carried out in citrate buffer (pH 3) - only conjugated bilirubin is soluble to react -the measurement represents a direct determination of conjugated bilirubin "direct biliruben" Indirect Bilirubin: -when the assay is carried out in citrate buffer (pH 3) containing detergent - the unconjugated bilirubin can now react, along w/ the conjugated bilirubin -This determination is designated as "total bilirubin." Therefore, "indirect bilirubin" = unconjugated bilirubin = "total bilirubin" - "direct bilirubin". Use: -the quantitative determination of conjugated vs unconjugated bilirubin often provides clues to possible causes of jaundice -Jaundice refers to the deposition of bilirubin and yellowish coloration of skin, nail beds, and sclerae
What is the function of Aminotransferase enzymes? (ALT & AST)
They catalyze the transfer of -NH2 groups from a DONOR a-amino acid to an ACCEPTOR a-keto acid Two functions: I. Make an aa needed in a cell: -by acquiring the NH2 group from glutamate II. Get rid of a particular amino acid: -by transferring the NH2 to a-ketoglutarate making glutamate -glutamate then funnels the amino group nitrogen into urea for excretion
Malignancies in the liver are much more likely to be?
a metastasis rather than a primary neoplasm often multifocal nodules of variable size and distribution Most commonly from the: -lungs -breast -colon
hepatocellular carcinoma (HCC) has the tendency for invasion of which vessels?
portal and hepatic veins, leading to hematogenous spread
Hepatic adenoma
benign clonal proliferation of hepatocytes more common in women associated with oral contraceptive use (increased risk by 30-40x)- anabolic steroid use also increases risk Associated w/ Mutations in Hepatocyte nuclear factor 1-a and B-catenin Chronic inflammatory infiltrates in the liver due to non-alcoholic fatty liver disease increase incidence have the potential to progress/transform into hepatocellular carcinoma.
Grey Turner's sign
bruising in flank area (lower back area) develops due to retroperitoneal hemorrhage tracking along fascial planes into these locations.
Describe the Necrosis (submassive or massive) hepatic pattern of injury
hepatocyte cell death in a large, obvious manner due to injury capable of killing hepatocytes (image: central vein at arrow with zone 3 hepatocyte death due to acetaminophen)
Describe the Triaditis hepatic injury pattern
inflammation (of different cell types depending upon the specific disease) filling and expanding the portal triad region, and may spill over into adjacent periportal hepatocytes and cause injury to them (interface hepatitis or piecemeal necrosis)
Describe the Cholangitis/Cholestatis hepatic injury pattern
inflammation in and around bile ducts; bile ducts may have bile inspissated in them (the process of cholestasis) or large accumulations of bile (so-called bile lakes) may be present
Cholangiocarcinoma
malignancies arising in the intrahepatic or extrahepatic biliary tree Risk factors= chronic inflammatory processes -recurrent biliary stones -primary sclerosing cholangitis -infection w/ liver flukes (Opishorchis & Clonorchis species)
What is an Activated partial thromboplastin time (aPTT) used for?
measures the time it takes a plasma sample to clot from the activation of Factor XII (top of the intrinsic pathway). factors I, II, VIII, IX, X, XI, and XII
Intraductal papillary mucinous neoplasm
more common in men head of pancreas Involves large ducts that communicate w/ the general ductal system Intraductal papillary growth
Hemangioma
most common BENIGN neoplasm of the liver typically subcapsular in location Asymptomatic presentation -pain can occur if they grow large in size More common in women Grossly: -appear hemorrhagic and/or blood filled -located just beneath the capsule
What is Cholestasis?
occurs when the biliary system undergoes dysfunction for any reason, causing buildup of bile and bile pigments. Mechanisms: -decreased or defective bile secretion -obstruction of bile channels, either intrahepatic or extrahepatic **Cholestasis doesn't indicate a specific disease, but is sometimes the predominant finding in certain conditions (cholestasis of pregnancy, cholestasis of sepsis, etc.).
Cullen's sign
periumbillical ecchymosis associated with acute pancreatitis develops due to retroperitoneal hemorrhage tracking along fascial planes into these locations.
Fibrolamellar variant of hepatocellular carcinoma (HCC)
rare (5% of HCC) usually arises in ppl <35 No associated risk factors No cirrhosis No gender association has dense fibrous bands that run through the tumor, creating a hard mass.
How does chronic Hepatitis B characteristically present microscopically?
virus infects a cell → hijacks cellular machinery → creates more of itself → packages itself within the cell and may be visible as an inclusion abundant hepatitis B surface antigen packing endoplasmic reticulum and imparts a homogenous, lightly eosinophilic quality to the cytoplasm - so-called ground glass inclusions or ground glass hepatocytes.
Describe the pathogenesis of steatosis in alcoholic liver disease
when ethanol is broken down into acetaldehyde by alcohol dehydrogenase, NAD+ is converted to NADH NADH in excess prevents fatty acid oxidation, causing a buildup of intracellular triglycerides
Mucinous cystic neoplasm
95% women 40's-50's occurs in the tail of the pancreas Cyst fluid is thick and mucinous Characteristic "ovarian-like" stroma Presentation: -non-specific do not arise from larger ducts or communicate with the ductal system Up to 1/3 have an invasive mucinous adenocarcinoma component on presentation
Which aminotransferases (specifically) are tested for with liver function tests?
AST and ALT ALT = more specific for ALT for liver disease (higher specificity) "L=liver" AST = higher concentration in the liver, so easier to detect (higher sensitivity) "S=sensitive"
Characteristics of Primary Biliary Cirrhosis (PBC)
Age: 30-70 -median age= 50 Gender: 90% female Clinical course: progressive Associated conditions: -Sjogren syndrome (70%) Serology: -(+)Anti-mitochondrial autoantibodies (AMA's) are sensitive and specific for PBC, particularly at high titers Radiology: -normal Duct lesion: -Florid duct lesions and loss of SMALL ducts only **Apparently this is associated with CREST syndrome: -calcinosis -Raynaud's phenomenon -esophageal dysmotility -sclerodactyly -telangiectasia
Characteristics of Primary Sclerosing Cholangitis
Age: median age= 30 years Gender: 70% male Clinical course: Unpredictable but progressive Associated conditions: -Inflammatory bowel disease (70%) -It's theorized that ulcerative colitis-induced activation of T cells leads them to cross-react against bile duct cell antigens, possibly accounting for the very high incidence of IBD in patients with PSC Serology: -(+) ANCA (65%) Radiology: -Strictures and beading of LARGE bile ducts- "beads on a string" on cholangiography` -pruning of smaller bile ducts Duct lesion: -"onion-skin" bile duct fibrosis -inflammatory destruction of extrahepatic and large intrahepatic ducts- -fibrotic obliteration of medium and small intrahepatic ducts
Describe the pathogenesis of Cirrhosis
Inflammatory cells become activated due to injury and begin to damage hepatocytes The parenchyma begins to collapse New collagen is laid down leading to a scar The scar bridges portal regions and central vein regions leading to encircling fibrosis/cirrhosis Cirrhosis= the end-stage of severe functional and structural damage to the liver
What lab values can be used to evaluate Bile Duct Function?
Bilirubin, total and direct Alkaline Phosphatase (alk phos) γ-glutamyl transpeptidase (GGTP) Microscopically, Cholestasis may be seen, with bile present in bile canaliculus and hepatocytes
How does a liver that has undergone cirrhosis appear microscopically?
broad bands of fibrosis will be subdividing the hepatic parenchyma into nodules, with abnormal and proliferating bile ducts and vessels present in the fibrous bands. nodules become rounded over time due to hepatocyte regeneration and hypertrophy- pushing out against the fibrous bands Fibrous bands can bridge portal-portal regions, portal-central vein regions, or central ven-central vein regions
Describe the morphology of Primary Sclerosing Cholangitis (PSC)
Characteristc= Large duct inflammation and scarring Cholangiogram may show large ducts alternating b/w dilation and narrowing/stricture This may lead to ascending cholangitis w/ abundant duct-centered neutrophils Characteristic concentric, "onion skin" fibrosis due to portal tract bile duct involvement eventually leading to potential cirrhosis
Characteristics and clinical manifestations of Chronic pancreatitis
Characteristics: -chronic inflammation -acinar cell atrophy -fibrosis of previously cellular parenchyma Clinical manifestations: -variably severe attacks of abdominal pain • Pancreatic insufficiency • Malabsorption • Pancreatic calcifications • Pseudocyst formation • Secondary diabetes mellitus (late complication)
Type II Autoimmune hepatitis genetics
Children/young adults Anti-liver kidney microsomal autoantibodies (anti-LKM1)
How does acute hepatitis present microscopically?
can range from minimal findings w/ only serologic evidence of infection to submassive hepatice necrosis Mononuclear infiltrate: -T lymphocytes, plasma cells, macrophages (very rarely neutrophils- not good for viruses) Lobular hepatitis: -inflammation and necrosis involing lobules where the liver cells live Necrotic or apoptotic hepatocytes (aka: Councilman body): -due to inflammation Steatosis/cholestasis: either possible
Gastrinoma
cell of origin is uncertain- may be endocrine cell in the peripancreatic soft tissue or nearby gut Excess gastrin production leads to hypersecretion of gastric acid and severe peptic ulcer formation (Zollinger-Ellison Syndrome) 50% are locally aggressive or metastatic at presentation; liver failure can be precipitated 25% arise in association with MEN-1 syndrome and are often multifocal
Chronic bile duct obstruction leads to?
chronic duct obstruction → on-going upstream inflammation as above → bile duct hyperplasia and ductal luminal expansion → on-going wound healing with collagen remodeling → biliary-induced cirrhosis outflow obstruction (blood or bile) leads to upstream injury, wound healing, remodeling and fibrosis/cirrhosis. Image: biliary-type cirrhosis, with nodules that are irregular or 'jig-saw' puzzle shaped.
What is the function(s) of Albumin?
Function as transporters in the blood for a variety of molecules -particularly hydrophobic molecules that have limited solubility in aqueous plasma These include: I. Free fatty acids II. Bile acids (derived from cholesterol) III. Bile pigments (derived from breakdown of heme) Transport of non-conjugated bilirubin to the liver for conjugation Plays a key role as a stabilizer of extracellular fluid volume
Describe the pathogenesis of Hemochromatosis
Epidemiology: males>females; northern European ancestry; **AFTER age 40** (Wilson disease= before age 40) Massively increased iron levels leads to iron deposition in tissues. Mutations to the HFE gene on chromosome 6 leads to a mutated gene product that results in decreased Hepcidin synthesis Hepcidin (produced by the liver) normally binds to intestinal epithelial cell ferroportin (a transmembrane iron efflux channel) inactivates it, and traps iron inside the cell Decreased Hepcidin synthesis allows for membrane-located ferroportin to freely efflux iron into the circulation **Presentation- classic triad of: -cirrhosis -diabetes mellitus -skin pigmentation "Bronze Diabetes"
Gross and microscopic presentation of Pancreatic Adenocarcinoma
Gross: -head more common (65%) -affected areas are white, firm, and poorly defined in terms of boundaries -invasion into peripancreatic soft tissue and abundant desmoplasia are seen Microscopically: -gland-forming -moderately poorly-differentated -distinct tendency for perineural invasion -continue to grow along the nerve sheath to exit the native tissue -desmoplasia evident as abundant fibrosis -lymphatic invasion
Which hepatitis viruses cause acute liver disease
Hep A, B, E
Which hepatitis viruses cause chronic liver disease
Hep B, C, D
Causes, forms and manifestations of Posthepatic obstruction
Hepatic vein outflow obstruction Most common cause= Hepatic vein thrombosis (Budd-Chiari Syndrome) Causes of Hepatic vein thrombosis: • Hematologic neoplasia, such as polycythemia vera • Pregnancy or the post-partum state • Oral contraceptive use • Disorders of coagulation/thrombophilic states Manifestations: -Ascites -Hepatomegaly -Abdominal pain -Elevated aminotransferases -Jaundice **High mortality rate**
What are the components of a Liver Function Test?
I. Enzymes such as aminotransferases (previously called transaminases) II. Serum proteins (secreted by the liver) such as albumin III. Catabolic intermediates that are processed by the liver, such as billirubins IV. Blood clotting factors produced by the liver V. Other components such as alkaline phosphatase and y-glutamyl transpeptidase
What are the two types of Autoimmune Cholangiopathies? How do they present?
I. Primary biliary cirrhosis (PBC) II. Primary sclerosing cholangitis (PSC) Leads to Fibrous obliteration of at least intrahepatic small ducts (like those in the portal triad) -PSC will also cause inflammatory destruction of large intrahepatic and extrahepatic ducts Symptoms: -jaundice -fatigue -pruritis **PSC more likely to present w/ ascending cholangitis: jaundice, fever, abdominal pain
Hemoglobin consists of?
I. the globin polypeptides (two each of a and B chains) II. one heme associated w/ each polypeptide The heme prosthetic group= Fe bound to N-containing porphyrin rings
Describe Post-hepatic venous induced cirrhosis
In some cases of acute hepatitis, necrosis can occur, and when it does, it's usually centered around central veins. if pt survives acute process, fibrosis will replace the necrotic veins and hepatocytes This leads to impaired venous outflow, leading to post-hepatic, venous induced cirrhosis (Image: many pale nodules around central veins (zone 3 hepatocytes) in acute viral hepatitis)
Symptoms of Cholestasis
Jaundice Pruritis Malabsorption (particularly or fat-soluble vitamins)
List some processes that may cause Large Bile Duct Obstruction
Lithiases/stones in the large ducts (choledocholithiasis). **most common** -ducts can develop unwanted stones Maligancies: -cholangiocarcinoma of the large extrahepatic ducts or pancreatic adenocarcinoma obstructing the common bile as it passes through Iatrogenic causes: -surgical disruption with scarring or stricture Biliary atresia: -a condition in infants in which the bile ducts outside and inside the liver are scarred and blocked. -Bile can't flow into the intestine, so bile builds up in the liver and damages it. Primary sclerosing cholangitis: - an autoimmune large duct obstructive process
Accumulation of iron is directly toxic to tissues and may cause what symptoms/diseases?
Liver (cirrhosis or signs of failure) Heart (dilated cardiomyopathy) Pancreas (diabetes) Skin (hyperpigmentation) Joints (arthropathy) Pituitary (signs of failure) **Image: Prussian blue stain (for iron) shows iron in both hepatocytes and Kupffer cells
How does Chronic Hepatitis present microscopically?
Much more dominated by inflammation, not in the lobules, but in the portal tracts (triaditis) Mononuclear infiltrate: -T lymphocytes, plasma cells, macrophages (very rarely neutrophils- not good for viruses Inflammation spills over into adjacent periportal hepatocytes causing interface hepatitis (and possible necrosis) Over time, portal inflammation/triaditis induces fibrosis and scarring, causing fibrous septa to extend towards other portal tracts or central veins Adjacent fibrous septa hook up and form complete bridging septa/fibrosis Bridging septa thicken, nodules of hepatocytes are created, and cirrhosis sets in
Plasma levels of aminotransferases (AST specifically) may be elevated in which non-liver disorders/problems?
Myocardial infarction Muscle disorders other enzyme markers (or tissue specific isozymes) can be used to distinguish hepatic versus non-hepatic problems.
How does passive congestion due to Right cardiac failure present in the liver? (Cardiac-induced cirrhosis)
Right heart failure → backup within venous return, such as vena cavae → backup within hepatic veins → backup within hepatic venules/central veins → central vein dilation and passive congestion → blood/hemorrhage spilling over/backing up into sinusoids → increased pressure exerted on hepatocytes (particularly in zone 3) → necrosis of these hepatocytes surrounding central veins (centrilobular necrosis) Grossly: "nutmeg liver" -darker areas represent hemorrhage and possible necrosis surrounding congested central veins Microscopically: -nutmeg liver w/ central vein dilation and spillage of hemorrhage into surrounding sinusoids -this causes hepatocyte injury and pressure-induces (centrolobular) necrosis
Risk factors, Symptoms, complications of Chronic Cholecystitis
Risk factors: -cholelithiasis and repeated bouts of acute cholecystitis Complications: -more bouts of acute cholecystitis, and the cycle of persistent inflammation continue
Which organ may be removed if a TAIL Pancreatic Neuroendocrine Tumor is found?
Spleen these tissues share a common vascular supply - the splenic artery.
What pattern of hepatic injury is often the first visible?
Steatosis steatosis is a common hepatocyte reaction pattern to injury, and may cause hepatocyte structural problems, leading to the leakage of the measurable cytoplasmic proteins: AST, ALT, LDH steatosis (fatty liver) occurs any time liver metabolism shifts away from triglyceride breakdown, causing it to build up.
How does alcoholic liver disease present microscopically?
Steatosis: -almost always present to some degree Mallory bodies "AKA: Mallory's hyaline/Mallory Denk bodies): -intracytoplasmic masses of tangled, cytoskeletal keratin proteins Neutrophilic infiltrate Hepatocyte swelling (aka: Ballooning Hepatocytes) Necrotic Hepatocytes: -often surrounded by neutrophils, which are killing them
What occurs when RBC's die (after about 120 days)?
they are broken down along with the Hemoglobin molecules Heme is separated from globin polypeptides, and undergoes oxidation-reduction to yield Bilirubin and Fe -Fe is reused in the iron pool of the body Unconjugated(free) Biliruben is hydrophobic (limited solubility in aqueous solution)- it is transported as bilirubin-albumin complexes in the plasma to the liver for conjugation In the liver, one glucuronic acid is attached to each of the two proprionic acid groups of the biliruben molecule forming biliruben diglucuronide (conjugated bilirubin) Conjugated bilirubin is much more water soluble, therefore easier to transport and excrete
What causes a plump belly in pts with Kwashiorkor "protein starvation"?
decreased plasma concentration of albumin leads to lack of adequate plasma proteins and an inability to maintain the distribution of water b/w blood and tissues (oncotic pressure)
Pancreatic adenocarcinoma
derived from PanIN 1-3 (pancreatic intraepithelial neoplasia) develops from ductal epithelial cells accounts for 85% of pancreatic malignancies Risk factors: -smoking -red meat consumption -obesity Presentation: -vague signs, presents later in disease process -abdominal pain radiating to back -migratory thrombophlebitis -obstructive jaundice (head located tumors obstruct the common bile duct) **VERY POOR PROGNOSIS (5% five year survival rate)**
Autoimmune Hepatitis presents how?
disease can range from indolent to rapidly progressive left untreated, 40% die within 6 months, and 40% develop cirrhosis Diagnosis: I. Labs: -(+) ANA, or ASMA Ab's II. liver biopsy -shows standard hepatitis features: cell swelling, inflammation, triaditis, interface hepatitis, hepatocyte necrosis, bridging fibrosis -characteristic feature= presence of plasma cells Treatment: immunosuppression (Image: arrows are pointing to plasma cells characterized by eccentric nucleus)
Pseudocyst
inflammation induces sequela of pancreatitis or pancreatic injury (trauma) -pancreatic enzymes leak into intestinal/extracellular spaces causing necrosis, hemorrhage and inflammation -the body attempts to contain the injury by developing incomplete fibrosis around the area Characteristics: -not lined by epithelium "pseudo" -comprise ~75% of all imaging-identified pancreatic cysts -can compress or erode adjacent structures or become infected -more likely to form after acute pancreatitis in a chronic alcoholic
Describe the Hepatitis/Hepatitic hepatic injury pattern
inflammation that surrounds and induces necrosis or apoptosis in hepatocytes; sometimes described as 'lobular inflammation' or 'lobular hepatitis' because the hepatocytes are located throughout the substance of the 'lobular model' in liver histology (recall lobular model: central vein at center, hepatocytes throughout the lobule, and multiple portal tracts around the lobular periphery) note: this description differs from the more general clinical or colloquial usage of any liver inflammation being 'hepatitis'
Focal nodular hyperplasia (FNH)
not a true tumor (no monoclonality at the genetic lvl) mass-like, presents similar to a true neoplasm arises as a mismatch in the # and quality of artery-vein connections in a localized region of hepatic parenchyma, resulting in hepatocyte hyperplasia Asymptomatic- found by imaging No malignant potential MUST DISTINGUISH from hepatic adenoma (via imaging) Gross: -nodule w/ a prominent central, stellate scar (arrow) -when growth is multifocal, it is called nodular regenerative hyperplasia Microscopic: -nodules separated by fibrous bands w/o normal portal regions (vaguely resembles cirrhosis)
Biliary atresia
partial or complete biliary obstruction at any level or location of the biliary tree Embryonic/fetal form: -biliary tree doesn't develop properly in utero Perinatal form: -normal biliary tree for some unknown reason undergoes destruction during infancy **Most common cause of neonatal jaundice and cholestasis **Most frequent cause of liver transplantation in the neonatal period Can effect either intrahepatic or extrahepatic ducts Microscopy: -inflammation, fibrosis, stricture involving intra- or extrahepatic ducts -when severe, portal tracts may lack visible bile ducts
Zones of the liver
zone 1: periportal zone which is affected first in viral hepatitis zone 2:intermediate zone zone 3: pericentral vein which is affected first by ischemia and contains p450 system