Liver and Biliary Tract

Question 1

Hepatic Failure

Answer 1

• when 80-90% of hepatic function is lost.
• mortality is 80%.
• presentation: jaundice, hypoalbuminemia with systemic edema, hyperammonemia, fetor hepaticus (odor from mercaptan formation), hyperestrogenemia from impaired estrogen metabolism (have palmar erythema, spider angiomata, hypogonadism, gynecomastia).
• complications: coagulopathy, multiple organ failure, hepatic encephalopathy (from porto-systemic shunting and loss of hepatocellular function. excess ammonia ⇒ brain edema, disturbances in consciousness, limb rigidity, hyperreflexia, asterixis), hepatorenal syndrome (↓ renal perfusion pressure, renal vasoconstriction, sodium retention, impaired free-water excretion), hepatopulmonary syndrome (from intrapulmonary vascular dilation and functional shunting from pulmonary arteries to veins, have hypoxia, V/Q mismatch).

Question 2

Acute Liver Failure

Answer 2

• liver illness associated with encephalopathy within 6 months of initial diagnosis.
• from hepatic necrosis from drug/toxin injury, viral hepatitis, autoimmune damage.

Question 3

Chronic Liver Disease

Answer 3

• most common cause of failure.
• ends in cirrhosis

Question 4

Hepatic Dysfunction without Overt Necrosis

Answer 4

• viable hepatocytes can’t perform normal metabolic functions.

Question 5

Liver Cirrhosis

Answer 5

• from alcohol abuse, viral hepatitis, non-alcoholic steatohepatitis. biliary disease and hemochromatosis less common.
• 20% are cryptogenic cirrhosis = unknown cause.
• characteristics = bridging fibrosis (links portal tracts with central veins), parenchymal nodules (hepatocyte regeneration when encircled by fibrosis), disrupted hepatic parenchymal architecture.
• pathogenesis: hepatocyte death, ECM deposition, vascular reorganization.
  
  • types I and III collagen deposited in space of Disse. sinusoidal endothelium loses fenestration. new vascular channels link portal triads to central veins.
  • fibrosis from proliferation and activation of stellate cells, promoted by PDGFreceptor beta. causes ↑ collagen synthesis and ↑ intrahepatic vascular resistance.
  • stellate cells and fibroblasts activated by: TNFalpha and IL-1beta, TFG-beta, direct toxin stimulation, disruption of ECM.
• presentation: silent until advanced. anorexia, weight loss, weakness, debilitation. precipitated by infection or GI hemorrhage.
  
  • death from progressive liver failure, complication of portal HTN, hepatocellular carcinoma.

Question 6

Portal Hypertension

Answer 6

• from ↑ flow into portal circulation and/or ↑ resistance to portal blood flow.
• prehepatic = from thrombosis, portal vein narrowing, ↑ splanchnic arterial circulation, massive splenomegal with ↑ splenic vein blood flow.
• intrahepatic = cirrhosis, schistosomiasis, massive fatty change, granulomatous disease, or nodular regenerative hyperplasia.
• posthepatic = right-sided heart failure, constrictive pericarditis, hepatic vein obstruction.
• consequences: ascites, portosystemic shunts, splenomegaly
  
  • ascites = have hypeatic sinusoidal hypertension from hypoalbuminemia, hepatic lymph in peritoneum, splanchnic vasodilation causes hypotension so retain sodium and water, have intestinal capillary transudation.
  • portosystemic shunts = from ↑ portal pressure. flow reversed from portal into systemic circulation. usually at esophagogastric varices, can rupture and have massive hematemesis. also at rectum (hemorrhoids), and falciform ligament/umbilicus (caput medusa).
  • splenomegaly = from long-standing congestion. can get thrombocytopenia from hypersplenism.

Question 7

Bilirubin and Bile Formation

Answer 7

• heme degraded to biliverdin to bilirubin, then bound to albumin, delivered to liver, conjugated to glucuronic acid by **UGT1A1 **⇒ water soluble bilirubin glucuronides excreted in bile, deconjugated in gut, degraded to urobilinogen and fecally eliminated.
• 20% urobilinogen reabsorbed and go to liver.

Question 8

Icterus

Answer 8

• yellow sclera discoloration.

Question 9

Jaundice

Answer 9

• yellow skin discoloration.
• bilirubin production exceeds hepatic uptake, conjugation, and/or excretion.
• unconjugated hyperbilirubinemia = excess production or diminished uptake and/or conjugation.
• conjugated hyperbilirubinemia = defective excretion

Question 10

Unconjugated Bilirubin

Answer 10

• water insoluble. usually bound to albumin.
• small amount circulates free and can diffuse into tissues (neonatal brain).
• unbound fraction increases with severe hemolysis or when drugs displace from albumin.

Question 11

Conjugated Bilirubin

Answer 11

• water-soluble, non-toxic, loosely bound to albumin.
• excess is renally excreted.

Question 12

Neonatal Jaundice

Answer 12

• transient, mild unconjugated hyperbilirubinemia until 2 weeks of age.
• hepatic metabolic machinery doesn’t develop until about 2 weeks.
• exacerbated by breast-feeding from bilirubin-deconjugating enzymes in breast milk.

Question 13

Crigler-Najjar Syndrome Type 1

Answer 13

• autosomal recessive.
• total absence of UGT1A1 causes jaundice with high serum levels of unconjugated bilirubin, normal liver histology.
• need liver transplantation or will get kernicterus (fatal neurologic damage).

Question 14

Crigler-Najjar Syndrome Type 2

Answer 14

• autosomal dominant.
• less severe UGT1A1 deficiency.
• not usually lethal but can get kernicterus.

Question 15

Gilbert Syndrome

Answer 15

• autosomal recessive. 6-10% population.
• mild, fluctuating unconjugated hyperbilirubinemia, 30% ↓ UGT1A1 activity.
• exacerbated by infection, strenuous exercise, fasting.

Question 16

Dubin-Johnson Syndrome

Answer 16

• autosomal recessive.
• defective hepatocyte secretion of conjugated bilirubin from absent MDR2 (does bilirubin glucuronide transport).
• liver is brown, accumulated pigment granules.
• jaundiced but have normal life expenctancy.

Question 17

Rotor Syndrome

Answer 17

• autosomal recessive.
• defective hepatocellular bilirubin uptake or excretion.
• jaundiced with normal life expectancy.

Question 18

Cholestasis

Answer 18

• impaired bile formation or flow ⇒ accumulation of intrahepatic bile pigments.
• extrahepatic = duct obstruction
• intrahepatic = hepatocellular dysfunction or canalicular obstruction.
• consequences: jaundice, pruritus, xanthomas (skin accumulations of cholesterol), intestinal malabsorption, ↑ serum levels alkaline phosphatase and GGT.
• morphology: bile pigment accumulates in hepatic parenchyma ⇒ dilated bile canaliculi and hepatocye degeneration.
  
  • obstruction ⇒ distended proliferating bile ducts in portal tracts, edema, periductular neutrophils.
    
    • prolonged ⇒ bile lakes, portal tract fibrosis, and cirrhosis.

Question 19

Progressive Familial Intrahepatic Cholestasis (PFIC)

Answer 19

• autosomal recessive disorders from mutated ATP-dependent transporter proteins.
• PFIC-1 = Bylder disease or Benign recurrent intrahepatic cholestasis.
• PFIC-2 = mutated ABCB11 gene for bile salt export pump in canaliculi.
  
  • have cholestasis, extreme pruritus, growth failure, progession to cirrhosis in 1st decade.
  • GGT levels normal.
• PFIC-3 = mutated ABCB4 gene for MDR3 protein for biliary phosphatidycholine secretion.
  
  • ↑ GGT levels from biliary epithelium damage by bile salts.

Question 20

Byler Disease

Answer 20

• PFIC-1. mutated ATP8B1 gene impairs bile secretion.
• cholestasis in infancy, progesses to liver failure by aduthood.
• no damage to canaliculi or biliary tree, normal GGT, normal bile ducts.

Question 21

Benign Recurrent Inrahepatic Cholestasis

Answer 21

• mild form of PFIC-1. affects ATP8B1 gene.
• intermittent attacks of cholestasis, doesn not progress to chronic liver disease.

Question 22

Hepatitis A Virus

Answer 22

• aka HAV. related to picornavirus.
• 25% acute hepatitis.
• ssRNA virus causing benign, self-limited disease.
• transmission: fecal-oral
• incubation: 2-4 weeks.
• damage from CD8+ T cell response.
• does not progress to chronic liver disease.
• detection: anti-HAV IgM in acute infection. IgG remains with immunity.

Question 23

Hepatitis B Virus

Answer 23

• aka HBV. hepadnavirus.
• dsDNA virus,causes acute, self-limited hepatitis, non-progressive chronic hepatitis, progressive chronic disease with cirrhosis, fulminant hepatitis with massive liver necrosis, asyptomatic carrier state.
• Dane particle with outer surface protein and lipid envelope encasing electron-dense core.
• 4 reading frames: HBcAg (core antigen), HBeAg (into bloodstream), HBsAg (surface antigen), HBx (for viral replication).
• strong response by CD4+ and CD8+ IFN-gamma for resolution. damage via CD8+ cells.
• related to cancer development (hepatocellular carcinoma).
• transmission: parenteral, sexual contact, perinatal.
  
  • high prevalence = from childbirth.
  • intermediate-prevalence = minor cuts or breaks in mucus membranes.
  • low prevalence = IV drug abuse, unprotected sex.
• incubation: 1-4 months.
• 10% get chronic liver disease.
• morphology: finely granular ‘ground-glass’ cytoplasm with HBsAg.
• detection: HBsAg before symptoms (anorexia, fever, jaundice). HBeAg and HBV DNA after HBsAG and before disease onset, persistence of HBeAg means chronic disease. Anti-HBcAg IgM first, then anti-HBeAg IgM and anti-HBcAg IgG. anti-HBsAg means end of acute disease and immunity.
  
  • chronic carrier = HBsAg in serum for 6 months.
  • detect by HBsAg or Ab to HBcAg.

Question 24

Hepatitis C Virus

Answer 24

• aka HCV. flaviridae.
• ssRNA, enveloped. substantial genomic variability (quasispecies).
• E2 envelope protein targeted by Abs, also most variable.
• antibodies don’t cause immunity.
• 80-85% go on to chronic liver disease. cirrhosis in 20-30%.
• damage is immune mediated.
• transmission: parenteral, intransal cocaine.
• risk groups: IV drug abusers, multiple sexual partners.
• incubation: 7-8 wks.
• morphology: portal lymphoid aggregates, bile duct reactive changes, lobular regions of macrovesicular steatosis.
• detection: HCV RNA in blood for 1-3 wks during active infection with transaminase elevation. anti-HCV Ab in 50-70% in acute, 90% in chronic.
  
  • PCR for HCV RNA.
• tx: for chronic use IFN-gamma and ribovarin.

Question 25

**Hepatitis D Virus**

Answer 25

* aka HDV. * **circular defective ssRNA**, **requires host RNA polymerase activity.** * only replicates and infects when encapsulated by HBsAg, so only when **with HBV**. * ranges mild to fulminant, **chronicity rare (5%** for co-infection, \<70% with superinfection). * high prevalence in Africa, Middle East, Italy, and Amazon basin. * **Dane-like particle** with HBV envelope. makes **delta antigen**. * _incubation_: **1-4 months**. * _detection_: HDV RNA in blood and liver during infection, recent exposure has **anti-HDV IgM**, **anti-HBcAg IgM = co-infection, HBsAg = superinfection** * have a **vaccine**.

Question 26

**Hepatitis E Virus**

Answer 26

* aka HEV. Calicivirus. * **non-enveloped ssRNA**, self-limiting, **does not become chronic liver disease.** * _transmission_: water-borne enteric infection (**fecal-oral**) via monkeys, cats, pigs, dogs. * epidemic in Asia, Africa, Mexico. * endemic in India = 30-60% acute hepatitis. * **high rate of fatal fulminant hepatitis in pregnant women**. * _incubation_: **4-5 wks**. * _detection_: **HEV antigen** in hepatocytes (PCR), RNA and **virions in stool and serum** before onset. * **IgG anti-HEV** = immunity.

Question 27

**Hepatitis G Virus**

Answer 27

* aka HGV. * **non-pathogenic RNA** virus in 1-4% blood donors. * replicates in **marrow and spleen**.

Question 28

**Acute Asymptomatic Viral Hepatitis with Recovery**

Answer 28

* **identified by ↑ transaminases or anti-viral Ab titers**. * HAV and HBV frequently subclinical.

Question 29

**Acute Symptomatic Viral Hepatitis with Recovery**

Answer 29

* **asymptomatic pre-icteric phase, symptomatic icteric phase, convalescence**. * peak infectivity during last few days of asymptomatic days and first few symptomatic days.

Question 30

**Chronic Hepatitis**

Answer 30

* symptomatic disease with biochemical or serologic evidence of **ongoing heptaic damage of more than 6 months.** * **HCV**\>\>HBV or HDV * **younger patients** more likely to develop this, **maternal-fetal transmission**. * causes ongoing **liver injury, cirrhosis, hepatocellular carcinoma, immune complex disease with vasculitis and glomerulonephritis**. * 35% chronic HCV develop **cryoglobulinemia**. * _morphology_: mild to severe cirrhosis. mild = limited to portal tracts. * extension of **chronic inflammation from portal tracts with interface hepatitis**, linking of portal-portal and portal-central regions = **bridging necrosis**. * continued loos of hepatocytes ⇒ **fibrous septum formation**, associated **hepatocyte regeneration causes cirrhosi**s. * major cause of morbidity and mortality in HIV pts. second most common cause of death in AIDs.

Question 31

**Carrier State (viral hepatitis)**

Answer 31

* harbors and tramsits hepatitis **without symptoms**. * patients with chronic disease and few/no symptoms, and those with few or no adverse effects (**healthy carriers**). * for HBV, **healthy carriers lack HBeAg but have anti-HBeAg, normal aminotransferase levels, low serum HBV DNA, no significant necrosis or inflammation**.

Question 32

**HIV and Chronic Viral Hepatitis**

Answer 32

* 10% HIV pts have HBV, 30% have HCV causing aggressive liver disease.

Question 33

**Acute Hepatitis Morphology**

Answer 33

* **injured hepatocytes are eosinophilic and rounded with shrunken or fragmented nuclei** (apoptosis). * **ballooning degeneration** = swollen hepatocytes. * when severe = **bridging necrosis** btw portal and central regions of adjacent lobules. can have cholestasis. * **Kupffer cell hyperplasia**, macrophage aggregates mark site of hepatocyte loss. * **portal tracts have mononuclear cell inflammation**, spillover into adjacent parenchyma. associated with periportal apoptosis (**interface hepatitis**).

Question 34

**Fulminant Hepatic Failure**

Answer 34

* **hepatic insufficiency with hepatic encephalopathy occuring within 2-3 wks after symptom onset**. * 12% from virus (HBV\>HAV\>HCV) * \>50% from **drug or chemical toxicity**. * 15% unknown cause. * in **HBV type, have massive hepatocyte apoptosis**. * mortality is 80% without transplant, 35% with transplant. * _morphology_: can involve portions or entire liver. can shrink liver. areas are **soft and muddy-red or bile-stained.** * destroys lobules ⇒ **cellular debris and collapsed reticulin network**. * regeneration is disorderly when substantial. leaves **scar ring** that produces lobulated pattern of cirrhosis.

Question 35

**Bacterial/Parasitic/Helminthic Infections of Liver**

Answer 35

* **extrahepatic sepsis** ⇒ hepatic inflammation, some degree of cholestasis from kupffer cell and endothelial cell production of cytokines to endotoxin. * biliary obstruction and intra-biliary proliferation ⇒ severe acute inflammatory response (**ascending cholangitis**). * parasitic infection ⇒ hepatic **abscesses** in developing countries. * **abscesses** in developed countries rare. from bacterial or candidal infection. * associated with **fever, RUQ pain, tender hepatomegaly, jaundice**. * **morality 30-90**%. * **rupture of echinoccal cysts** ⇒ spread of organisms and severe immune-mediated **shock**. * _morphology_: **parasitic fragments or fungal organisms in abscess**. * **cystic structures with laminated/calcified walls**, **hooklets**, and intact organisms in echinococcal infections.

Question 36

**Autoimmune Hepatitis (AIH)**

Answer 36

* **chronic, progressive hepatitis from T cell mediated autoimmunity** (cytotoxic T cells and production of IFNgamma). * triggered by **viral infections, drugs**, or from other **autoimmune diseases**. * **female** predominance with **↑ serum IgG** but no markers of viral infection. * **_type 1_** = **autoAb** to **nuclear, smooth muscle, actin, soluble liver Ag/liver-pancreas Ag**. associated with **HLA-DR3** haplotype. * **_type 2_** = **autoAb** to **liver kidney microsome-1 and liver cytosol-1 Ag.** * _morphology_: hepatitis picture with **clusters of periportal plasma cells.** * _presentation_: **acute onset liver failure** in 40%. show **substantial liver destruction and scarring**. * untreated ⇒ mortality of 40%, 40% survivors get cirrhosis. * _tx_: immunosuppression, transplant later on. * **22-42% recurrence** in transplants.

Question 37

**Drug and Toxin Induced Liver Disease**

Answer 37

* considered in any form of liver disease. * can be **immediate or develop over wks to months**. * _mechanisms_: **direct** toxicity, **hepatic conversion** to toxin, **immune-mediated** injury. * **acetaminophen** = uniformly hepatotoxic, **leading cause of drug-induced acute liver failure.**

Question 38

**Reye Syndrome**

Answer 38

* rare, potentially fatal syndrome of **mitochondrial dysfunction.** * **massive microvesicular steatosis**. * occurs in **kids taking aspirin for febrile illness**.

Question 39

**Alcoholic Liver Disease (ALD)**

Answer 39

* leading cause of liver pathology in West. * _morphology_: **_hepatic steatosis_** (fatty liver) = **micovesicular lipid droplets in hepatocyes**. chronic alcohol ⇒ droplets displace nucleus. becomes **enlarged, soft, greasy, yellow**. little to no fibrosis, reversible. * **_alcoholic hepatitis_** = **ballooning degeneration and hepatic necrosis**. **Mallory body formation** (intracellular aggregates of intermediate filaments), **neutrophilic reaction** to degenerating hepatocytes, **portal/periportal mononuclear inflammation, fibrosis**. * **_alcoholic cirrhosis_** = irreversible final outcome. **brown and shrunken, nonfatty liver**. **regenerative nodules** prominent or obliterated by fibrous scar. * _pathogenesis_: in 10-15% alcoholics. **F**\>M; **AA**\>whites. * polymorphisms in metabolizing enzymes or cytokine promotors. * iron overload or viral hepatitis increases severity. * **steatosis** from: impaired lipoprotein assembly and secretion, ↑ peripheral catabolism of fat, shunting of substrates from catabolism to lipid biosynthesis. * **acetaldehyde **⇒ lipid peroxidation and acetaldehyde protein adduct formation. * **induced cytochrome P450** ⇒ ROS and toxic metabolites. * **impaired methionine metabolism** ⇒ ↓ glutathione levels. * **malnutrition and vitamin deficiency**. * **↑ inflammatory response** from alcohol mediated release of bacterial endotoxins in GI. * cirrhosis from **collagen deposition by perisinusoidal stellate cells**. deranges hepatic blood flow from fibrosis and endothelins. * _presentation_: **_hepatic steatosis_** ⇒ **hepatomegaly with ↑ serum bilirubin and alkaline phosphatase**. treat by abstention and diet. * **_alcoholic hepatitis_** ⇒ acute **after heavy drinking. malaise, anorexia, tender hepatomegaly**. **↑ bilirubin and alkaline phosphatase**, with **neutrophilic leukocytosis**. leads to cirrhosis in 1/3. treat by abstention and diet. * **_alcoholic cirrhosis_** = irreversible, same symptoms as cirrhosis. * death from hepatic coma, massive GI hemorrhage, intercurrent infection, hepatorenal syndrome, and hepatocellular carcinoma.

Question 40

**Nonalcoholic Fatty Liver Disease (NAFLD)**

Answer 40

* hepatic steatosis in absence of heavy alcohol consumption. * from **obesity**. * most pathologic = nonalcoholic steatohepatitis (**NASH**) = **steatosis** plus hepatocyte damage and **inflammation**. goes to cirrhosis in 10-20%. * **associated with metabolic syndrome** of dyslipidemia, hyperinsulinemia, and insulin resistance. * _pathogenesis_: from **hepatocyte fat accumulation** and **↑ hepatic oxidative stress** ⇒ **↑ lipid peroxidation and ROS.** * _morphology_: **hepatocytes filled with fat vacuoles with or without inflammation**. varying degrees of fibrosis. * _presentation_: steatosis = asymptomatic. NASH = **fatigue, malaise, RUQ discomfort, ↑ transaminase levels.** * morbidity and mortality from cardiovascular disease. * _tx_: correct obesity, hyperlipidemia, and insulin resistance.

Question 41

**Hemochromatosis**

Answer 41

* **excessive iron accumulation in parenchymal cells** of organs (liver and pancreas). * **_hereditary_** = primary = homozygous recessive heritable disorder from excessive iron absorption. * **_hemosiderosis_** = secondary = associated with parenteral iron administration (transfusions, intake, chronic liver disease). * _pathogenesis_: damage from **direct iron toxicity** via **free radicals, stimulation of collagen formation, and/or iron and ROS-DNA interactions**. * hepcidin lowers plasma iron, deficiency causes iron overload. * **mutation of HFE** on chromosome 6. cysteine to tyrosine at C282Y inactivates HFE ⇒ **↓ hepcidin** * _morphology_: iron accumulates in: **liver, pancreas, myocardium, endocrine glands, joints, skin**. get **cirrhosis** and **pancreatic fibrosis**. * _presentation_: **micronodular cirrhosis, diabetes mellitus and skin pigmentation** in 75-80%. symptoms appear **after age 40**. usually **men**. * death from cirrhosis, hepatocellular carcinoma, cardiac involvement. * _tx_: phlebotomy.

Question 42

**Wilson Disease**

Answer 42

* **autosomal recessive** by mutated **ATP7B gene** that codes for **canalicular copper-transporting ATPase**. * **↓ copper excretion in bile, copper not incorporated into ceruloplasmin, inhibited ceruloplasmin secretion into blood**. * **copper accumulation in liver** ⇒ injury via ROS. * also affects **cornea and brain**. * _morphology_: **fatty change, acute and chronic hepatitis** (Mallory bodies), **cirrhosis**, massive necrosis (rare). * CNS toxicity **affects basal ganglia** ⇒ atrophy and cavitation. * **Kayser-Fleischer rings** - eye lesion from neurologic involvement, green-brown coper deposits in Descemet's membrane of corneal limbus. * _presentation_: **acute or chronic liver disease before age 40**. neuropsychiatric disorders: **behavioral changes, psychosis, Parkinson-like symptoms.** * _diagnosis_: **↓ serum ceruloplasmin, ↑ hepatic copper, ↑ urinary copper excretion**. * _tx_: copper chelation therapy, transplantation.

Question 43

**alpha1-Antitrypsin Deficiency**

Answer 43

* **autosomal recessive** marked by **very low serum levels of protease inhibitor** ⇒ **emphysema** and **hepatic disease**. * _pathogenesis_: alpha1-AT made by hepatocytes by PiMM. **PiZZ homozygotes have \<10% normal levels.** * causes **misfolding and prevents egress from ER** ⇒ ER stress response: **autophagy, mitochondrial dysfunction, NF-kB activation** ⇒ hepatocyte damage. * overt liver disease in 10-15% PiZZ. * _morphology_: **PAS-positive cytoplasmic globules in periportal hepatocytes**. ranges from cholestasis to hepatitis to cirrhosis. * _presentation_: **neonatal hepatitis with cholestatic jaundice** in 10-20% of newborns with alpha1-AT deficiency. later presentation from **acute hepatitis or complications of cirrhosis**. * hepatocellular carcinoma in 1-2% of PiZZ. * _tx_: liver transplant

Question 44

**Neonatal Cholestasis**

Answer 44

* **prolonged conjugated hyperbilirubinemia**. * caused by cholangiopathies (primarily **biliary atresia**) and **neonatal hepatitis**. **50% unknown**, 15% alpha1-AT deficiency. * _morphology_: hepatocyte death, **lobular disarray**, **hepatocyte giant cell formation**, prominent **cholestasis**, **portal tract inflammation, extramedullary hematopoiesis**. * _presentation_: **jaundice, dark urine, light stools, hepatomegaly**.

Question 45

**Secondary Biliary Cirrhosis**

Answer 45

* **due to uncorrected obstruction of extrahepatic biliary tree**. * causes: **cholelithiasis**, malignancies of biliary tree or ancreatic head, strictures, **biliary atresia, cystic fibrosis, choledochal cysts**. * prolonged cholestasis ⇒ inflammation ⇒ **periportal fibrosis and cirrhosis**. * subtotal obstruction promotes secondary bacterial infection (ascending cholangitis) that aggravates inflammatory injury.

Question 46

**Primary Biliary Cirrhosis (PBC)**

Answer 46

* **autoimmune** destructive disorder of **intrahepatic biliary tree ⇒ portal inflammation ⇒ cirrhosis**. * usually **middle aged women**. * _morphology_: varying degrees of severity. **dense chronic portal tract inflammation** with focal **non-caseating granulomas** along with interlobular **bile duct destruction and generalized cholestasis**. * intrahepatic biliary obstruction ⇒ upstream damage with **ductular proliferation, inflammation/necrosis of periprotal hepatocytes.** * end stage = same as all cirrhosis. * _presentation_: insidious with **pruritus, hepatomegaly, jaundice, and xanthomas**. with cirrhosis have **variceal bleeding and encephalopathy** * **↑ serum alkaline phosphatase and cholesterol**. * **↑ antimitochondrial Ab** in 90-95%. * can have **extrahepatic autoimmune manifestations** (Sjogren, scleroderma, thyroiditis, Raynaud, membranous glomerulonephritis). * cause of mortality: **liver failure**, variceal bleeding, intercurrent infection. * **↑ risk hepatocellular carcinoma**.

Question 47

**Primary Sclerosing Cholangitis (PSC)**

Answer 47

* **chronic cholestatic disease having inflammation and obliterative fibrosis of both extrahepatic and intrahepatic biliary tree**. * dilation of preserved segments ⇒ **beading of injected radiologic material**. * 70% have **ulcerative colitis**, circulating autoAb (ANA and anti-smooth muscle Ab, RF, atypical pANCA) = **autoimmune**. * _morphology_: **periductal inflammation and concentric fibrosis (onion-skin)**, progressive atrophy and **luminal obliteration**. get **biliary cirrhosis and hepatic failure.** * _presentation_: middle aged **men**. takes 5-15 yrs. severe disease ⇒ **weight loss, ascites, variceal bleeding, encephalopathy**. * ↑ incidence **chronic pancreatitis** and **hepatocellular carcinoma**. * 7% get **cholangiocarcinoma**. * _tx_: liver transplant

Question 48

**Von Meyenberg Complexes**

Answer 48

* aka **bile duct hamartomas**. * associated with polycystic kidney disease from **PKD1 mutation.** * **small clusters of dilated bile ducts or cysts within a fibrous stroma**. * very **common** * can present as hepatosplenomegaly and portal HTN or be silent.

Question 49

**Polycystic Liver Disease**

Answer 49

* **handful to hundreds of biliary epithelium-lined lesions**. * usually associated with **PKD1 mutation** (polycystic kidney disease). * if not, the have **mutated PRKCSH** that encodes **hepatocystin** (substrate for protein kinase C). * can be silent or present as hepatosplenomegaly and portal HTN.

Question 50

**Congenital Hepatic Fibrosis**

Answer 50

* **from incomplete involution of embryonic ductal structues with ensuing portal tract fibrosis ⇒ portal HTN.** * strongly associated with **PKHD1 mutation** of autosomal recessive polycystic kidney disease. * can be silent or present as hepatosplenomegaly and portal HTN.

Question 51

**Caroli Disease**

Answer 51

* **segmental dilation of larger ducts of intrahepatic biliary tree with bile inspissation**. * complicated by **cholelithiasis** and **hepatic abscesses**. * ↑ risk of **cholangiocarcinoma**. * associated with **mutated PKD1** of polycystic kidney disease. * can be silent or present as hepatosplenomegaly and portal HTN.

Question 52

**Alagille Syndrome**

Answer 52

* aka syndromatic paucity of bile ducts or arteriohepatic dysplasia. * rare, **autosomal dominant.** **absence of intrahepatic bile ducts.** * **mutated Jagged 1 - Notch signaling pathway**. * have chronic cholestasis, extrahepatic anomalies: **peculiar facies, vertebral and cardiovascular defects**. * may be silent or present with hepatosplenomegaly and portal HTN.

Question 53

**Hepatic Artery Compromise**

Answer 53

* infarct is rare but **thrombosis or compression of intrahepatic arterial branches** can cause **localized pale infarct.** * occasionally made hemorrhagic by portal blood suffusion.

Question 54

**Portal Vein Obstruction and Thrombosis**

Answer 54

* extrahepatic portal vein obstruction can be insidious/well tolerated or catastrophic and lethal from variceal bleeding. * causes: **neonatal umbilical vein infection, intra-abd sepsis causing pylephlebitis, coagulopathies, trauma, pancreatic lesions causing thromboses, cirrhosis**.

Question 55

**Sinusoidal Occlusion**

Answer 55

* caused by DIC, sickle cell disease, metastatic tumors, sarcoidosis.

Question 56

**Passive Congestion and Centrilobular Necrosis**

Answer 56

* systemic hypoperfusion ⇒ hepatocyte necrosis around central vein (**centrilobular necrosis**). * **_passive congestion_** = hemorrhage and hepatocyte necrosis around central vein = **centrilobular hemorrhagic necrosis. nutmeg liver**. * **_cardiac sclerosis_** = chronic passive congestion and pericentral fibrosis from right-sided heart failure ⇒ cirrhosis.

Question 57

**Peliosis Hepatitis**

Answer 57

* **reversible hepatic sinusoid dilation** associated with malignancy, AIDS, TB, post-transplant immunosuppression. * also from anabolic steroids, oral contraceptives, danazol.

Question 58

**Hepatic Vein Thrombosis and Inferior Vena Cava Thrombosis**

Answer 58

* **_Budd-Chiari syndrome_** = two or more major hepatic veins are obstructed. * in setting of primary myeloproliferative disorders (**polycythemia vera**), heritable **coagulopathies**, **pregnancy, anti-phopholipid Ab syndrome, paroxysmal nocturnal hemoglobinuria, and intra-abd cancers.** * can get obstruction from membranous inferior vena cava valve. * need porto-systemic shunting.

Question 59

**Veno-Occlusive Disease (VOD)**

Answer 59

* aka sinusoidal obstruction syndrome. * in **Jamaican drinkers of pyrrolizidine alkaloid-containing bush tea**. now from toxic injury to sinusoidal endothelium by **chemo**. * mortality = 30%. * _morphology_: **patchy obliteration of smaller hepatic vein radicles** by endothelial swelling and collagen deposition. * **_acute_** = **centrilobular congestion with hepatocellular necrosis** * **_progressive_** = **venule lumen obliteration** with dense **perivenular fibrosis and hemosiderin** deposition. * _presentation_: **tender hepatomegaly, ascites, weight gain, jaundice.**

Question 60

**Graft-Versus-Host Disease**

Answer 60

* from bone marrow or stem cell transplantation. * have **direct lymphocyte attack on liver cells, particularly bile duct epithelium**. * **_acute_** = **hepatitis** (parenchymal inflammation and hepatocyte necrosis), chronic vascular inflammation and intimal proliferation (**endothelialitis**), and **bile duct destruction.** * **_chronic_** = **portal tract inflammation, bile duct destruction** or loss, and **fibrosis**.

Question 61

**Rejection of Liver**

Answer 61

* **_acute_** = **portal tract inflammation with eosinophils, bile duct damage, endothelialitis**. * **_chronic_** = months or years later, **bile duct loss** and **arteriopathy** with eventual failure.

Question 62

**Preeclampsia and Eclampsia**

Answer 62

* in 3-5% of pregnancies. * **_preeclampsia_** = **HTN, proteinuria, peripheral edema, coagulation abnormalities**, varying degrees of **DIC**. * **_eclampsia_** when have **hyperreflexia** and **convulsions**. * primary manifestation preeclampsia = HELLP syndrome = **hemolysis, elevated liver enzymes, low platelets.** * _morphology_: **small red hemorrhagic patches** with **yellow-white areas of infarct**. **perportal sinusoidal fibrin deposition, periportal necrosis, hemorrhage**. * coalesced blood forms **hepatic hematomas** that can rupture.

Question 63

**Acute Fatty Liver of Pregnancy (AFLP)**

Answer 63

* rare. ranges from subclinical hepatocyte dysfunction to hepatic failure, coma, death. * usually has **mitochondrial dysfunction**. * **congenital fetal deficiency in long chain 3-hydroxyacyl coenzyme A dehydrogenase** ⇒ toxic levels of fetal metabolites, cause maternal hepatotoxicity. * have **microvesicular steatosis**. * **_severe cases_** have **portal inflammation, hepatocyte dropout, lobular dysarray**. * _tx_: terminate pregnancy.

Question 64

**Intrahepatic Cholestasis of Pregnancy (ICP)**

Answer 64

* from **altered hormonal state of pregnancy**. * _presentation_: **pruritus and jaundice in 3rd trimester with mild cholestasis.** * pruritus can be severe, can get maternal gallstones or malabsorption.

Question 65

**Nodular Hyperplasia**

Answer 65

* **solitary or multiple benign** hepatocellular nodules in **absence of cirrhosis**. * from **focal hepatic vascular obliteration with compensatory hypertrophy of adjacent well-vascularized lobules**. * **_focal nodular hyperplasia_** = **young to middle aged adults**. **irregular, unencapsulated mass** with **central stellate fibrous scar**. * **_nodular regenerative hyperplasia_** = **diffuse nodular transormation without fibrosis**. from conditions affecting intrahepatic blood flow (solid-organ transplants, bone marrow transpants, vasculitis).

Question 66

**Cavernous Hemangiomas**

Answer 66

* **most common benign liver tumor**. * identical to blood vessel tumors.

Question 67

**Hepatic Adenomas**

Answer 67

* **benign** hepatocyte neoplasms **up to 30cm** in diameter. in **young women, associated with oral contraceptives**. * mutation in **beta-catenin** and transcription factor **HNF1alpha**. * made of **sheets of hepatocytes containing arteries and veins**. **portal tracts with bile ducts are absent**. * rupture is rare but with massive hemorrhage and rarely have hepatocellular carcinoma.

Question 68

**Hepatocellular Carcinoma (HCC)**

Answer 68

* **most common primary liver cancer** * more common in developing countries, **high rates HBV.** * 2.4:1 **M**:F. * 4 major factors: **HBV or HCV, chronic alcoholism, NASH, and food contaminants**. * also hemochromatosis, tyrosinemia, and alpha-1 antitrypsin deficiency. * HBV-related = key events are integration of HBV DNA into host genome and presence of viral proteins. * HCV core and NS5A viral proteins may participate in HCC onset. * in high prevalence areas with vertical transmission of HBV, cirrhosis absent in 50% and carcinoma presents btw ages 20-40. * _morphology_: **solitary mass, multifocal nodules, or diffusely infiltrative cancer with massive liver enlargement and cirrhosis**. * **intrahepatic spread and vascular invasion**. * range from well differentiated to highly anaplastic. * **_fibrolamellar carcinoma_** = 5% HCC, **single scirrhous, hard tumor occuring btw age 20-40yrs without chronic liver disease**. **well-differentiated cells in cords or nests** and separated by **dense lamellar collagen bundles**. * _presentation_: **hepatomegaly, RUQ pain, weight loss, ↑ serum alpha-fetoprotein**. * mortality from cachexia, GI or esophageal variceal bleeding, liver failure with hepatic coma, or tumor rupture and fatal hemorrhage.

Question 69

**Angiosarcomas**

Answer 69

* associated with **exposure to vinyl chloride, arsenic, or Thorotrast** (contrast agent). * **malignant** and in liver.

Question 70

**Hepatoblastoma**

Answer 70

* **most common liver tumor of early childhood**. * activation of **Wnt/beta-catenin pathway**. * associated with **familial polyposis syndrome** and **Beckwith-Wiedemann syndrome**. * **_epithelial type_** = recapitulates liver development. * **_mixed epithelial and mesenchymal type_** = foci of mesenchymal differentiation including osteoid, cartilage, or striated muscle. * **fatal if untreated**. * 80% survival with resection and chemo.

Question 71

**Cholangiocarcinoma (CCA)**

Answer 71

* **arises from elements of intra- and extrahepatic biliary tree**. * **50-60% are perihilar** (**_Klatskin tumors_**), 20-30% distal, 10% intrahepatic. * _pathogenesis_: can be associated with **primary sclerosing cholangitis, congenital fibropolycystic lesions, HCV infection, and Thorotrast administration.** * in SE Asia, protracted biliary tree parasitic infection by **Opisthorchis sinensis**. * **IL-6 overexpression** ⇒ **AKT activation and ↑ production of anti-apoptotic protein MCL-1**. * p53 expression is ↓. * _morphology_: **single large mass or multifocal nodules, can be diffusely infiltrative. pale**. * variably differentiated bile duct elements that **resemble adenocarcinomas**. markedly **desmoplastic with dense collagenous stroma**. * mixed variants of hepatocellular-cholangiocarcinoma are rare. * outlook **dismal**. rarely resectable.

Question 72

**Metastatic Tumors**

Answer 72

* most common: **colon, breast, lung, and pancreas**. * multiple implants with massive hepatic enlargment. * large implants have **central necrosis**. * massive involvement before hepatic failure develops.

Question 73

**Congenital Anomalies of Biliary Tract**

Answer 73

* gallbladder can be absent or in different locations (within liver). * **phrygian cap** = folded fundus. * duplicated or bilobed gallbladder. * agenesis of common or hepatic bile ducts * hypoplastic narrowing of biliary channels.

Question 74

**Cholelithiasis**

Answer 74

* afflict 10-20% of adults. * **90% of calculi are cholesterol stones** (\>50% **cholesterol monohydrate**), rest are **bilirubin calcium salts.** * _risk factors_: ↑ hepatic cholesterol uptake or synthesis or to ↑ biliary cholesterol secretion. * **Native Americans**, industrialized countries, ↑ age, **female**, oral contraception, pregnancy, obesity, metabolic syndromes, hypercholesterolemia, **rapid weight loss**, gallbladder stasis (spinal cord injury). * **D19H variant of ATP-binding cassette transporter** using ABCG5 and ABG2 genes. * _pathogenesis_: cholesterol stones = cholesterol supersaturated. nucleates into cholesterol monohydrate crystals. * _4 conditions_: **supersaturated cholesterol, gallbladder hypomotility, accelerated cholesterol nucleation in bile** (promoted by calcium salts), and **mucus hypersecretion in gallbladder traps crystals**. * **_pigment stones_** = in setting of **unconjugated bilirubin (chronic hemolytic conditions) and precipitate calcium bilirubin salts.** * underdeveloped areas = **infection** (E.coli, Ascaris lumbricoides, Opisthorchis sinesis) **promotes bilirubin glucuronide deconjugation**. * _morphology_: **_cholesterol stones_** in gallbladder, **hard and pale yellow**. bilirubin salts are **black**. having **10-20% calcium carbonate makes radiopaque**, if mostly cholesterol then radiolucent. **single stones are ovoid**, multiple stones are **faceted**. * **_pigmented stones_** can be **black (sterile)** or **brown (infected)**. soft and multiple. **50-75% stones radiopaque.** * _presentation_: **70-80% asymptomatic**. 1-4% get symptomatic per year. **spasmodic colicky pain** from passage, **RUQ pain**. potential empyema, perforation, fistulas, biliary tree inflammation, obstructive cholestasis or pancreatitis, erosion into bowel. * mucocele when clear mucinous secretions obstructed in gallbladder and it distends. * **↑ risk gallbladder carcinoma.**

Question 75

**Acute Cholecystitis**

Answer 75

* acute inflammation of gallbladder **precipitated by gallstone obstruction**. 10% without gallstones * _pathogenesis_: with gallstones (**_calculous_**) = **chemical irritation by retained bile acids, release lysolecithin and prostaglandins, develop dysmotility**. * severe cases = distention, luminal pressures compromise mucosal blood flow ⇒ ischemia * **_acalculous_** = without stones. f**rom ischemia due to diminished flow in end arterial cystic artery circulation**. in setting of sepsis with hypotension and multiorgan failure, immunosuppression, major trauma/burns, diabetes mellitus, or infections. * _morphology_: **enlarged, tense, bright-red to blotchy green-black gallbladder with serosal fibrinous exudate**. contents can be turbid to purulent. * severe = **gangrenous cholecystitis with multiple perforations**. * mild = **edema and hyperemia**. * _presentation_: **RUQ or epigastric pain, fever, anorexia, tachycardia, diaphoresis, and nausea and vomiting. Jaundice** = common bile duct obstruction. * self-limited ones resolve over a few days.

Question 76

**Chronic Cholecystitis**

Answer 76

* repeated bouts of acute cholecystitis but often without. * 90% have gallstones. * **chronic bile supersaturation with cholesterol permits cholesterol suffusion and inflammation and gallbladder dysmotility**. * _morphology_: can be small, normal, or large. wall variably thick, **mucosa preserved but atrophied**. cholesterol-laden macrophages in lamina propria (**cholesterolosis**) and gallstones. **Rokitansky-Aschoff sinuses** = inflammation with mucosal outpouchings. * mural **dystrophic calcificatio**n (**_porcelain gallbladder_**) rare. * **_xanthogranulomatous cholecystitis_** = rare. **fibrosed, nodular gallbladder** with marked **histiocytic inflammation**. * _presentation_: **recurrent** attacks of steady or **colicky epigastric or RUQ pain**. * complications = superinfection, perforation, abscess formation or peritonitis, formation of biliary enteric fistulas.

Question 77

**Choledocholithiasis**

Answer 77

* **stones within biliary tree**. in 10% of pts with cholelithiasis. * in West, almost all stones are cholesterol. * **in Asia**, usually in biliary tree and are **pigmented**. * symptoms **due to obstruction, pancreatitis, cholangitis, hepatic abscess, secondary biliary cirrhosis, acute calculous cholecystitis**.

Question 78

**Cholangitis**

Answer 78

* **bile duct bacterial infection**. * in setting of choledocholithiasis. * **due to enteric bacteria entering biliary tract through sphincter of Oddi**. * _presentation_: **fever, abd pain, jaundice**. * sepsis can be fatal.

Question 79

**Biliary Atresia**

Answer 79

* causes **1/3 neonatal cholestasis**. * extrahepatic biliary tree obstruction **within first 3 months of life.** * **most frequent cause of death from liver disease in early childhood** and most liver transplantation in kids. * _pathogenesis_: **_severe early fetal form_** (20%) due to **aberrant intrauterine development of biliary tree**, associated with other anomalies. * **_perinatal form_** = **secondary to viral infections and/or autoimmunity**, from destruction of normal biliary tree. * _morphology_: **inflammation and fibrosing stricture of extrahepatic biliary tree**, goes into intrahepatic biliary system. liver shows: **bile duct proliferation, portal tract edema, fibrosis going to cirrhosis within 6 months.** * **_early severe form_** = aberrant intrahepatic biliary morphology, paucity of bile ducts. * 90% that extends above porta hepatis not amenable to surgery. * _presentation_: **infant** of normal birth weight and postnatal weight gain. **untreated ⇒ death by age 2yrs.**

Question 80

**Choledochal Cysts**

Answer 80

* **congenital dilations of common bile duct**. * in **kids \<10yrs**, nonspecific symptoms of **jaundice, recurrent colicky abd pain.** * **F**\>M * **predispose to stones, stenosis and stricture, pancreatitis, obstructive biliary complications, and bile duct carcinoma in adult.**

Question 81

**Gallbladder Tumors**

Answer 81

* primary = **epithelial**. * **adenomas** = benign. * **_inflammatory polyps_** = sessile mucosal projections containing chronic inflammation and lipid-laden macrophages. * **_adenomyosis_** characterized by muscle hyperplasia.

Question 82

**Carcinoma of Gallbladder**

Answer 82

* more common in **women, usually \>70yrs**. * risk factor: **chronic gallbladder infection**. * less common in Asians. * _morphology_: **_infiltrating_** = diffuse thickening and induration. * **_exophytic_** = grow into lumen as irregular, **cauliflower mass**. * most common = **adenocarcinomas**. * can be papillary to infiltrating, **moderately to undifferentiated.** * rare: squamous, adenosquamous, carcinoid, or mesenchymal. * **spread by local invasion, extension to cystic duct and portohepatic lymph nodes, metastatic seeding of peritoneum, viscera, and lungs**. * _presentation_: insidious, **indistinguishable from cholelithiasis.** * usually unresectable.