Hepatic Disorders Flashcards

Question

Bilirubin Synthesis & Transport

Answer 1

* **Heme derived end product** * 85% from senescent RBCs * 15% from other sources * Breakdown of other hepatic hemoproteins * Cytochrome P-450 enzymes * Premature RBC breakdown in bone marrow * **RBC** **phagocytosed by MΦ** in reticuloendothelial system (RES) * Heme porphyrin ring → biliverdin by microsomal heme oxygenase * Biliverdin → bilirubin by biliverdin reductase * **Unconjugated BRN is released into the plasma** * **Majority bound to albumin** * Insoluble in water ⇒ cannot be excreted in urine or bile * Transported to the liver * BRN released by albumin and taken up by hepatocytes * **Unbound (free) bilirubin** * Toxic to brain of newborns ⇒ **kernicterus** * Drugs competing w/ bilirubin for albumin binding sites ↑ free bili

Answer 2

* _Hepatic BRN metabolism__:_ * **Uptake**: * Bilirubin dissociates from albumin in the space of Disse * _Carrier mediated transport_ of unconjugated BRN across hepatocyte membrane * **Glutathione-S-Transferase (ligandin)** binds bilirubin in the cell * **Conjugation**: * BRN _conjugated w/ glucuronic acid_ by ***UDP glucoronyltransferase (UGT)*** in the ER * Forms **BRN mono- and diglucuronide** ⇒ both water soluble * **Excretion into the bile**: * **Conjugated BRN** _excreted into bile canaliculus_ via active transport by ***MRP2 transport protein*** * Rate limiting step for transhepatic transport of bilirubin * _Transport of conjugated BRN__:_ * Bile → biliary system → ampulla of Vater → 2^nd portion of the duodenum → large intestine (colon) * Bacteria convert **conjugated BRN** **→** **colorless urobilinogens** → **excreted in the feces** * Urobilinogens → colored **urobilins** ⇒ gives stool its color * 20% of urobilinogens _deconjugated by colonic bacteria_ and **reabsorbed by enterohepatic circulation** * **1% is excreted in the urine**

Answer 3

* **Total bilirubin** = 0.1-1.5 mg/dL * **Unconjugated or “indirect”** = 0.1-1.0 mg/dL * Not soluble in water * Not measured directly in serum * Indirect BRN = Total – Direct BRN * **Conjugated or “direct”** = 0-0.3 mg/dL * Water soluble * Small amount leaks out from liver * Directly measured in the serum

Answer 4

* **Hyperbilirubinemia**: ↑ bilirubin concentration in blood (\> 1.0 mg/dL) * **Jaundice** (icterus): yellow skin and sclerae (\> 2-2.5 mg/dL) * **Cholestasis**: visible bile plugs and bile by microscopic examination of liver * **Cholestatic jaundice**: Cholestasis and hyperbilirubinemia

Answer 5

**“Icterus”** * **Yellow discoloration of skin, sclera and mucous membranes** * **Excess serum bilirubin** **⇒** **deposited in tissues** * Tissues w/ high [elastin] ⇒ ↑ affinity for serum bilirubin * E.g., sclera of the eye * Normal serum bilirubin 0.3-1.5 mg/dL * **↑ BRN** **becomes clinically evident when \> 2-4 mg/dL** * _Other conditions can cause yellow discoloration of the skin but not scleral icterus_ * Carotenemia (excess serum carotene from carrots) * Tanning products * Side effects of medication (e.g., quinacrine or busulfan)

Answer 6

Disorders are not usually ass. w/ significant hepatic disease * **Displacement of BRN from albumin by drugs** * Rifampin * _Overproduction__:_ * *Overproduction of BRN** ⇒ exceeds hepatic conjugative capability * **BRN rarely \> 5mg/dL** * Jaundice usually mild * **Hemolytic disorders** * Sickle cell anemia, thalassemia, G6PD deficiency, paroxysmal nocturnal hemoglobinuria * **Ineffective erythropoiesis** * Fe deficiency, vitamin B12 deficiency, sideroblastic anemia, lead toxicity * **Resorption of large hematomas** * _Impaired uptake__:_ * 1°: **Gilbert’s syndrome** * 2°: Certain drugs, e.g., rifampin, may compete w/ BRN uptake * _Impaired conjugation__:_ * 1°: **Crigler-Najjar syndrome** * 2°: Acquired defects in conjugation * Drugs (e.g. chloramphenicol)

Answer 7

* AD disorder, 3-8% of population * **Mutation of bilirubin UDP-GT** * **↓ Uptake of unconjugated BRN by hepatocytes** * **Partial defect in BRN conjugation (50% of normal)** * _Mild unconjugated hyperbilirubinemia_ * **BRN levels ≤ 6mg/dL** * No other biochemical/histological abnormalities * Pts asymptomatic at baseline * **Occasionally exhibit jaundice** w/ illness, stress, fatigue, premenstrual state and alcohol abuse * Liver biopsy is not indicated, no specific therapy

Answer 8

Unconjugated Hyperbilirubinemia **Impaired conjugation of BRN caused by ∆ UDP glucoronyltransferase activity.** * **Type 1** * AR disorder * **No UDPGT activity** * **Fatal for neonates** * Severe unconjugated hyperbilirubinemia (**\> 20 mg/dL**) * Often die by 18 m/o w/ kernicterus * Tx: phototherapy, plasmapheresis, liver transplantation * **Type 2** * AD disorder * **↓** **UDPGT activity (10% of normal)** * BRN levels **10-16 mg/dL** * No kernicterus * Tx: Phenobarbital to induce UDPGT activity

Answer 9

* Seen in **70% of full-term newborns** * **Physiologic in first 5 days of life** * D/t incompletely developed hepatic BRN metabolism * **↓ Ligandin and ↓ UGT** * Result in **unconjugated hyperbilirubinemia** * UGT ↑ by 2 wks of life to adult levels * Bilirubin crosses placenta and is dealt w/ by mom in utero * _Other factors:_ * **RH and ABO blood incompatibilities**: hemolytic anemia ⇒ pathologic + physiologic jaundice in newborn * **Hypothyroidism** * **Breast milk jaundice** resulting from an inhibitor of UDPGT activity in maternal breast milk

Answer 10

* _Definition_: **conjugated BRN level \> 30% of total BRN** * _Congenital causes:_ * **Dubin-Johnson syndrome** * **Rotor’s syndrome** * **Progressive familial intrahepatic cholestasis (PFIC) (“Byler’s disease”)** * _Acquired causes:_ * **Cholestasis:** impaired formation or excretion of all components of bile

Answer 11

Conjugated Hyperbilirubinemia * AR condition * **Mutated MRP2 transporter** * **Impaired storage and excretion of BRN** * Serum BRN levels **2-5mg/dL** * Histological exam reveals a **darkly pigmented (black) liver** * No specific therapy

Answer 12

Conjugated Hyperbilirubinemia * AR condition * **Impaired intracellular storage of BRN** * Bile salt excretion is normal * BRN levels **2-5mg/dL** * Liver is not pigmented * Liver function unaffected * No specific therapy

Answer 13

Conjugated Hyperbilirubinemia * AR condition * **Defective hepatic secretion of bile acids across the canalicular membrane** * Particularly affecting the **Amish** **kindred** * Pts present w/ **severe watery diarrhea, cholestatic jaundice, fat-soluble vitamin deficiency and occasionally pancreatitis**

Answer 14

* **Impaired formation or excretion of all components of bile** * ↑ Serum and tissue bilirubin * _2 major mechanisms:_ * Defect in excretion of BRN from hepatocytes into bile ⇒ **intrahepatic cholestasis** * Mechanical obstruction to the flow of bile through the bile ducts ⇒ **extrahepatic cholestasis** * _Biochemical pattern:_ * ↑ Serum BRN (usually conjugated) * ↑ ALP * ↑ GGTP * Mild ↑ AST/ALT (≤ 2x ULN)

Answer 15

* Considerable overlap in biochemical pattern seen in intrahepatic and extrahepatic causes * Additional testing to look for an **extrahepatic** cause * **Abdominal US** * **CT** * **MRCP** (magnetic resonance cholangiopancreatography) * MRI of the biliary and pancreatic trees * **ERCP** (endoscopic retrograde cholangiopancreatography) * Endoscopic contrast study of the biliary tree * **Obstruction in the biliary tree** (gallstone, pancreatic tumor or malignant biliary tract CA) ⇒ **bile ducts will appear dilated** on imaging

Answer 16

* _Bile canaliculus_ * **Hepatocellular injury** * Viral and alcoholic hepatitis * Sepsis * Prolonged total parenteral nutrition * Congestive hepatopathy (from right heart failure) * Infiltrative disorders (sarcoidosis, amyloidosis, lymphoma etc.) * Graft-versus-host disease (after bone marrow transplant) * **Drugs** * Steroid hormones, chlorpromazine, OCP, NSAIDs etc. * **Benign post-operative cholestasis** * **Pregnancy** * _Bile ductule_ * ? Drugs * _Portal tract bile duct_ * **Primary biliary cholangitis (PBC)** ("Primary biliary cirrhosis") * Intrahepatic biliary atresia * _Medium and large interlobular bile ducts_ * **Sclerosing cholangitis** * Cholangiocarcinoma * Parasite * Vanishing bile duct syndrome (idiopathic adulthood ductopenia, chronic rejection)

Answer 17

**Cholestasis & cell necrosis** * _Early cholestasis_ * **Preferential localization in zone 3** * **See bile in hepatocytes** * _Late cholestasis_ * **Bile plugs in zone 1** * **Feathery degeneration** * Swelling * Bile pigment * Reticulation of cytoplasm * **Mallory hyaline** * **Fibrosis/Cirrhosis**

Answer 18

* **Choledocholithiasis** (gallstones impacted in common bile duct) * **Sclerosis and strictures of biliary tree** * Sclerosing cholangitis * Secondary causes * **Neoplasia** * Cholangiocarcinoma (bile ducts) * Pancreatic adenocarcinoma * Ampullary carcinoma * Duodenal neoplasm * Metastases to hepatic hilum * Portal LN involvement by any neoplasm * **HIV cholangiopathy** * **Haemobilia** (blood clots in biliary tree) * **Infectious cholangiopathy**: worms impacted in bile ducts (Clonorchis, Ascaris, Fasciola) * **Chronic pancreatitis** * **Benign biliary strictures** (post-cholecystectomy, post liver transplant, related to PSC, ischemic) * _Pediatric pts_ * **Extrahepatic biliary atresia** * **Choledochal cysts**

Answer 19

**Cholestasis & Cell Necrosis** _Plus_ * Portal tract edema * Bile duct proliferation * Neutrophils * Bile infarct * Extravasated bile

Answer 20

* **Dark urine** ⇒ “tea colored” * **Light stools** ⇒ “clay colored” * **Pruritus** * D/t retention of bile salts and other products * Tx w/ bile salt binders (cholestyramine) * **Abd pain** * **Weight loss** * **Fat malabsorption** (steatorrhea) * **Fat soluble vitamin deficiency states:** * Vit A ⇒ **night blindness** * Vit D ⇒ **osteomalacia** * Vit K ⇒ **coagulopathy** * **High cholesterol** ⇒ xanthomas * **Secondary biliary cirrhosis**

Answer 21

* Fundamental property of toxin * Injury in majority of people * **Dose dependent** * **Zonal necrosis** * Two mechanisms: * **Direct** * **Indirect**

Answer 22

* Idiosyncratic reaction * Host dependent * **Non-dose dependent** * **Non-zonal** * Two mechanisms: * **Hypersensitivity** * **Metabolic aberration**

Answer 23

* Viral * Drug/Toxin * Alcohol * Non-Alcoholic Fatty Liver * Autoimmune Related Disorders * Metabolic Disorders * Ischemic/Congestive * Extrahepatic biliary obstruction

Answer 24

* **Bridging**: Bands of necrosis linking landmark structures (portal tracts and central veins) * **Submassive**: Necrosis of entire lobules or groups of lobules * **Massive**: Necrosis of virtually all the hepatocytes

Answer 25

_Similar in all forms of viral hepatitis:_ * **Lobular disarray** * **Liver cell necrosis** * Apoptosis * Ballooning degeneration * **Inflammation** * Lymphocytes * Macrophages * Neutrophils * **Regeneration** * **± Cholestasis and phlebitis**

Answer 26

* Definition: **Presence of necrosis and inflammation in the liver for \> 6 months** * Liver biopsy can be done to establish degree of disease * Expressed as ‘grade’ and ‘stage’ * **Grade** describes the _amount of acute disease_ and takes into account: * Interface necrosis * Lobular activity * Portal inflammation * **Stage** describes the _level of fibrosis_: * No fibrosis * Portal fibrosis * Bridging fibrosis * Cirrhosis

Answer 27

**Chronic hepatitis of unknown cause** * ~20% of all cases of chronic hepatitis in Western countries * **More common in women**, usually **middle age** * Ass. w/ circulating auto-Ab and high levels of immunoglobulins * Ass. w/ other autoimmune diseases * _Suspected mechanism of injury:_ * **Ab-dependent cell-mediated cytotoxicity** * **Defective suppressor T cell function** * **Type I**: Anti-smooth muscle, Anti-actin, anti-asiaoglycoprotein receptor Ab * **Type II**: Liver/kidney microsomes and anti-liver cytosolic protein Ab * **_Patholog_**y: Like chronic viral hepatitis, often plasma cell rich infiltrate * _Clinical features_: Ranges from **asymptomatic** to **fulminant disease** * _Treatment_: **steroid and immune suppression responsive** * Must distinguish from other causes of chronic hepatitis

Answer 28

* Many drugs reported to cause chronic hepatitis * May be indistinguishable from viral and autoimmune disease histologically * Requires exclusion of other causes serologically and clinical history

Answer 29

* **Fatty Liver (Steatosis)** * **Yellow, enlarged, heavy liver** * Fat first accumulates in _zone 3_ * Enlarged mitochondria, SER hyperplasia * If discontinue drinking, can lose the fat * Cause of progression to next step is unclear * **Steatohepatitis** * 10-30% mortality * \> 30% who continue to drink for 1-2 yrs more will develop next step * **Necrosis of hepatocytes** * Neutrophilic infiltrate * **Mallory hyaline and fat** * Perivenular and pericellular fibrosis * **Cirrhosis** * **Thin and thick bands of fibrosis circumscribing nodules of regenerating hepatocytes** * Central and pericellular fibrosis Important to realize that any of these manifestations may coexist Do not need to see one to proceed to the next

Answer 30

* Obesity * Diabetes * Drug related: corticosteroids * Metabolic disease/disorder * Wilson’s disease * Kwashiorkor

Answer 31

“Primary Biliary Cirrhosis” **Chronic progressive cholestatic liver disease** characterized by **destruction of intrahepatic bile ducts** * Autoimmune disease (presumably) * \> 85% have **at least one other autoimmune disease**: * Chronic thyroiditis, RA, scleroderma, Sjogren’s, SLE * \> 95% have **elevated antimitochondrial Ab** * Elevated Ig, other Abs present * Presumed attack of ducts by cytotoxic T cells * **Middle age women** (range 30-65yrs) * **F:M ratio is 10:1** * Other labs: **elevated alkaline phosphatase, ↑ serum cholesterol**

Answer 32

* _Stage I_: **Destruction of small and medium sized bile ducts (focal, segmental)** * **Granulomas** are the characteristic portal infiltrate * All types of inflammatory cells are seen * **Plasma cell and eosinophils** may be prominent * _Stage II_: **Periportal inflammation and ductular proliferation** * _Stage III_: **Bridging fibrosis** * Mallory hyaline * ↑ Copper deposition * _Stage IV_: **Cirrhosis**

Answer 33

Chronic cholestatic liver disease of unknown cause **Inflammatory and fibrosing process narrows and eventually obstructs _intrahepatic and extrahepatic bile ducts_** * _Associations_: * Ulcerative colitis (seen in 2/3) * Less commonly: Crohn’s disease, lymphoma, retroperitoneal fibrosis * **Hypergammaglobulinemia** * **Antineutrophilic cytoplasmic Ab (ANCA)** * More common in men in 3-4th decade * **↑ risk of cholangiocarcinoma** * Up to 10% of PSC patients * Liver transplant is curative

Answer 34

* _↑ Iron absorption_ * **HHC** * **Chronic liver disease** * Porphyria cutanea tarda * Congenital diseases * Dietary iron overload * Excess medicinal iron * _Parenteral iron overload_ * Multiple blood transfusions * Injectable medicinal iron * _Focal iron overload_ * Idiopathic pulmonary hemosiderosis * Renal hemosiderosis

Answer 35

* **Inherited disorder of iron metabolism** * Iron deposition toxic to involved organs * Autosomal recessive * **HFE gene** on short arm of _chromosome 6_ * Linked to the HLA locus of the MHC * 70% of homozygotes have **HLA-A3**

Answer 36

* ↑ Iron absorption in duodenum * **↑ Serum iron, ferritin, and transferrin saturation** * _Clinical manifestations:_ * **Diabetes** * **Skin pigmentation** * **Cardiac failure** * **Cirrhosis**

Answer 37

Genetic disorder in which **excess copper builds up in the body**. Symptoms are typically related to the **brain and liver.**

Answer 38

* **Tenacious bile** due to CF * Similar change in viscosity seen in other bodily secretions * Newborns may present w/ **obstructive jaundice** * 15% of young adults w/ CF have **symptomatic liver disease**, can develop **cirrhosis**

Answer 39

* **Defective secretion of mutant protein made in the liver** * **Co-dominant inheritance**: \> 75 variants * PIMM normal * PIZZ phenotype ⇒ abnormal folding * **Liver and lung disease** * **Emphysema**: due to lack of protease inhibitor * **Hepatitis, Cholestasis and Cirrhosis**: due to accumulation of abnormal protein * Seen as globules in hepatocyte * **↑ risk of hepatocellular carcinoma** * _Most common genetic cause of liver disease in infants and children_ * 1/2000 live births * Only 10-15% of those develop liver dz * Liver transplant curative

Answer 40

* **Cardiac disease**: any disease ass. w/ _right heart failure_ * **Congestive heart failure** (most common cause) * Tricuspid valvular disease * Constrictive pericarditis * **Venous obstruction** * **Budd-Chiari:** occlusion of intra and/or extrahepatic veins w/ congestive liver damage * Hypercoagulable states * **Hepatic veno-occlusive disease**: occlusion of the central venules and small branches of the hepatic veins * Bush tea * Chemotherapeutic agents

Answer 41

* _Definition_: **Liver cannot perform metabolic, synthetic, detoxifying activities sufficiently for body’s needs** * **Usually end-stage of chronic progressive damage** * Steady destruction of hepatocytes * Repetitive waves of parenchymal damage * Rarely d/t sudden, massive liver destruction ⇒ **fulminant hepatic failure** * _Criterion_: **Need to lose 80-90% of liver functional capacity** * Without a transplant, 80% of pts w/ hepatic failure will die

Answer 42

* **Acute liver illness** w/ **encephalopathy** _within 6 months after dx_ * **Fulminant** if within 2 weeks jaundice onset * **Sub-fulminant** if within 3 months of jaundice onset * Caused by **massive hepatic necrosis** * Mechs include **direct toxic damage** or **combo of toxicity and immune-mediated hepatic destruction** * Etiologies: * Usu. from drugs or toxins * Halothane, antimycobacterial drugs, chemicals * Hepatitis A, Hepatitis B, autoimmune hepatitis

Answer 43

**Most common route** End point of **chronic hepatitis** that ends in **cirrhosis**

Answer 44

**Hepatocytes are viable**, but **can’t function normally** Examples: Tetracycline toxicity, pregnancy

Answer 45

* **Fatty liver disease** * Alcohol (ASH), Non-alcoholic steatohepatitis (NASH) / Non-alcoholic fatty liver disease (NALD) * **Viral hepatitis** * Hep C, B (w/ or w/o D) * **Autoimmune diseases** * Autoimmune hepatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis * **Genetic liver diseases** * Hemochromatosis, Wilson’s disease, α-1 anti-trypsin deficiency, cystic fibrosis * **Vascular causes** * R heart failure, Budd Chiari syndrome, veno-occlusive disease * **Rare causes** * Drugs * Methotrexate, amiodarone, methyldopa * Toxins, herbal supplements * Secondary biliary cirrhosis * Ass. w/ chronic cholestasis * **Cryptogenic** (unknown) * 10-15% of cases

Answer 46

* **Irreversible end result of chronic liver disease** * **Death of hepatocytes**, **ECM deposition, vascular reorganization** * Characterized histologically by **regenerative nodules** surrounded by **fibrous tissue** * Caused by a variety of _inflammatory, toxic, metabolic and/or congestive insults_ * Hepatitis, hepatopathy, cholestasis

Answer 47

* _Pathologically_ ⇒ gross pattern of architectural distortion * **Micronodular** * Regenerative nodules \< 3 mm * Often due to alcoholic cirrhosis * **Macronodular** * Nodules \> 3 mm * Commonly related to chronic viral hepatitis * **Mixed** * _Clinically_ * **Compensated** * No complications * **Decompensated** * One or more complications (ex. ascites, encephalopathy or variceal bleeding) * Liver transplantation considered

Answer 48

* May be dx @ at the asymptomatic stage * **General decline in health** (most ubiquitous feature) * _Non-specific complaints:_ * **Anorexia, wt loss, malaise, fatigue, weakness** * _Loss of normal bile flow_ * **Jaundice** * **Pruritus** * _Loss of detoxification_ * **Neurological sx** * **Hepatorenal** * _Loss of synthetic function_ * **Albumin** * **Clotting factors** * Advanced disease may present w/ _complications of portal HTN_ * **Esophageal varices** * **Ascites** * **Splenomegaly** * **Portosystemic shunting (varicosities)** * **Encephalopathy** * _Cancer risk_ * **Hepatocellular Carcinoma**

Answer 49

_Cutaneous stigmata and endocrine features_: * **Jaundice** * **Splenomegaly and ascites** ⇒ suggest portal HTN * **Spider angiomata** * **Palmar erythema** * **Leukonychia (white nails)** * **Gynecomastia** * **Testicular atrophy** * **Caput medusae**

Answer 50

* _Hepatic insufficiency_ (synthetic dysfunction): * **Low serum albumin** * **Prolonged prothrombin time (INR)** * **High bilirubin** * _Portal HTN_ (due to hypersplenism): * **Thrombocytopenia** * **Anemia** * **Leukopenia**

Answer 51

US, CT, and MRI may all be used _Characteristic features include:_ * **Small, shrunken, nodular liver** * **Recanalized paraumbilical vein** * **Enlarged caudate lobe** of the liver * Prominent vessels (**varices**) around the esophagus, stomach or in the mesentery * **Splenomegaly** * Free abdominal fluid (**ascites**) * **Enlarged portal vein**

Answer 52

* _Non-invasive:_ * **Bloodwork** * HCV – fibrosure * NASH – fibrosure * **Imaging** * US w/ elastography * Fibroscan * MR elastography * _Invasive:_ * **Liver biopsy** * Gold standard * Often not necessary if complications (e.g. varices or ascites) present or radiologic imaging diagnostic * Performed _percutaneously_ or via _trans-jugular_ route (allows for measurement of portal pressures)

Answer 53

* Cirrhosis = end histological stage resulting from chronic liver injury of various etiologies * Initially, **cirrhosis is compensated** * Median survival 10-12 yrs * **Decompensated stage** marked by onset of **variceal hemorrhage, ascites, hepatic encephalopathy and/or jaundice** * 60% risk over 10 yrs * Ascites most common * ↑ risk of death from liver disease * Median survival 2-4 yrs

Answer 54

* **Portal HTN** * **Hepatic encephalopathy** * Variety of neurological signs and sx in pts who suffer chronic liver failure or in who the portal circulation is diverted –has 4 stages, ending in coma * **Hepatorenal syndrome** * Renal failure featuring renal hypoperfusion: oliguria, azotemia and ↑ plasma creatinine levels * Usually kidneys function normally * Seems to be d/t ↓ in renal blood flow * **Hepatopulmonary Syndrome** * Clinical liver disease, hypoxemia, intra-pulmonary vascular dilations

Answer 55

* Portal circulation follow Ohm’s Law: **P = R x F** * Portal venous system ⇒ low-pressure system * _Cirrhosis_: * **Nodular regeneration and fibrosis in the space of Disse** * ↑ resistance to flow * **↓** **tone in the splanchnic arterioles** (possibly related to nitric oxide) ⇒ ↑ splanchnic blood flow * ↑ portal venous inflow * **Portal pressure gradient** = effective intrasinusoidal pressure * Difference between hepatic vein and portal vein pressure * Normally \< 5 mmHg * Clinically significant elevation: **\> 12 mmHg** * Not all PHTN is due to cirrhosis * PHTN is classified according to the **site of increased resistance**

Answer 56

* _Pre-hepatic causes:_ * Portal vein thrombosis, splenic vein thrombosis, splenomegaly, arterioportal fistula * _Intra-hepatic causes:_ * Presinusoidal (Schistosomiasis), sinusoidal (cirrhosis), post-sinusoidal (veno-occlusive disease) * Primary Biliary Cirrhosis (pre-cirrhosis) * Congenital hepatic fibrosis * Cystic disease of the liver * Nodular transformation * Metastatic or primary carcinoma * Toxins * _Post-hepatic causes:_ * Budd-Chiari syndrome (thrombosis of hepatic v.), IVC web/obstruction, constrictive pericarditis, right heart failure * Idiopathic

Answer 57

* **Portal HTN** ⇒ dilation of pre-existing connections ⇒ **portal-systemic collaterals** * _Most important:_ **Esophago-gastric collaterals** (Esophagogastric varices) * Coronary vein ↔︎ esophageal veins * Drains blood into azygos vein * Could cause life-threatening hemorrhage * _Other sites of portosystemic collaterals:_ * **Umbilicus (caput medusae)** * Splenic bed via short gastric veins (gastric fundic varices) * Retroperitoneum * **Rectum (rectal varices)** * **Small and large intestine (ectopic varices)**

Answer 58

* \> 50% of pts w/ cirrhosis develop gastroesophageal varices * Varices form and enlarge at a rate of 7-8%/year * **Endoscopy** to ID pts w/ medium-large varices @ high risk for bleeding * **Primary prophylaxis** (prevention of first bleed) * Non-selective **β****-blocker** (e.g. nadolol or propranolol) ⇒ ↓ intra-variceal pressure * **Endoscopic banding**

Answer 59

* Medical emergency * 10-30% of pts every year * Each episode associated w/ up to **50% mortality** * _Presentation:_ * **Hematemesis** * **Melena and/or hematochezia** * Typically leads to hemodynamic compromise * _Predictors of bleeding:_ * Larger variceal size * Red signs on the varices * More advanced liver disease (Childs B-C) * _Treatment:_ * **Hemodynamic resuscitation** w/ IV fluid * **Blood and/or FFP transfusion** * **Pharmacologic therapy** * **Somatostatin** or its synthetic analog (**octreotide**) * Abx * _Endoscopic therapy_ * **Band ligation or injection sclerotherapy** * **Transjugular intrahepatic portosystemic shunt** (**TIPS stent**) * Creates a communication between portal (portal vein) and systemic (hepatic vein) circulation * For refractory bleeding

Answer 60

* **Pathological accumulation of excess fluid in the peritoneal cavity** * Cirrhosis causes 75% of cases * Classification: **serum ascites-albumin gradient (SAAG)** * _Elevated SAAG \> 1.1 g/dL_ ⇒ portal HTN, right heart failure, massive liver metastases * **Clinically detectable w/ \> 500 mL** * Shifting dullness to percussion * Fluid wave * Bulging of the flanks * Everted umbilicus * Umbilical hernia * **Detectable w/ US @ \> 250 mL**

Answer 61

_Cirrhosis (portal HTN):_ * **Hepatic venous outflow block** * _Anatomical_: fibrosis and regenerative nodules * _Functional_: ↑intrahepatic vascular tone, predominantly post-sinusoidal ⇒ ↑ sinusoidal pressure * **Splanchnic and systemic arteriolar vasodilation** * Decreased effective arterial blood volume * Upregulation of sodium-retaining hormones * Sodium and water retention * Plasma volume expansion * Dilutional hyponatremia and renal failure from hepatorenal syndrome * **Sinusoidal hypertension** * Drives fluid out of the sinusoids and into peritoneal cavity * Intravascular fluid continuously replenished by plasma volume expansion

Answer 62

* **Sodium restriction** (\< 2g/day) * **Fluid restriction** [when hyponatremia (Na \< 125mEq/L) occurs] * **Diuretics** * Spironolactone (aldosterone antagonist) * Furosemide (loop diuretic) * **Refractory ascites** (~10% of pts w/ cirrhosis) * Fluid overload that recurs rapidly after therapeutic paracentesis * Unresponsive to high dose diuretic treatment and sodium restricted diet * Treatment includes **repeated large-volume paracentesis, TIPS or liver transplantation**

Answer 63

* **Ascitic fluid infection** w/ growth of a **single organism** and **ascitic fluid neutrophil count \> 250 cells/****μ****L** w/o e/o a surgically remediable intra-abd cause * Dx by _paracentesis_ w/ analysis of fluid cell count and culture * For all practical purposes, SBP occurs _only in the setting of liver disease_

Answer 64

* Severe liver disease ⇒ **failure of local and systemic immune defenses** ⇒ **↑ bacterial translocation** * RES = main defense system vs bacteremia and other hematogenous infectious * Most RES activity located in the liver * Kupffer cells (tissue MΦ) are the major components * Cirrhosis ⇒ **↓** **bactericidal activity of Kupffer cells** and **impaired reticuloendothelial system (RES) activity** * Porto-systemic shunting bypasses the liver * Escaping the action of the RES * Impaired RES ⇒ **prolonged bacteremia** * In the presence of ascites, **bacterial colonization occurs** * In pts w/ **↓** **local defense mechanisms** (e.g. low ascites complement levels) ⇒ **overt ascites infection develops** (SBP)

Answer 65

* _Predominant sx_: **fever, jaundice and abdominal pain** * Pts can present **atypically** w/ **encephalopathy, shock or renal failure** * Up to ⅓ of pts may be e**ntirely asymptomatic** * _Treatment:_ * Third generation cephalosporin (e.g. **cefotaxime**) IV for 5 days * **High rates of SBP recurrence** (70% at 1 year w/o abx) * **Secondary prophylaxis w/ long-term abx** is indicated

Answer 66

* Occurs in pts w/ **advanced cirrhosis** * **Functional renal failure** * Extreme peripheral vasodilatation ⇒ **renal vasoconstriction** * Kidneys w/o significant histological abnl * _Renal dysfunction characterized by:_ * **↓ GFR** * **Oliguria** * **Low urine sodium (\<10mEq/L)** * Absence of intrinsic renal disease or other renal insults ⇒ nl urinary sediment & nl renal US * _Tx:_ * Withdrawing diuretics and nephrotoxins * Volume expansion w/ saline or albumin * **Liver transplantation is the only effective cure** * If liver transplant is done early enough, kidneys should begin working properly again

Answer 67

**Neuropsychiatric manifestations of hepatic cirrhosis** * _Proposed pathogenesis:_ * ↓ Clearance of gut-derived neurotoxins, including **ammonia** * Ammonia ⤭ BBB ⇒ **↑** **astrocytic peripheral-type benzodiazepine receptors** * Most potent stimulants of neurosteroid production * **Neurosteroids** ⇒ major modulators of GABA * **GABA** ⇒ **cortical depression and hepatic encephalopathy** * _Dx_: based on hx and PE findings * Ammonia levels are unreliable * Poor correlation b/t stage of encephalopathy and serum [ammonia] * _Clinical features_: subtle changes in personality/affect → deep coma * Flapping tremor or “**asterixis**” ⇒ cardinal feature * Due to inability to maintain posture of the outstretched hands * Treatment: * ID and address precipitating factors * GI hemorrhage, infections, electrolyte abnl, new-onset renal insufficiency, TIPS placement, medication non-compliance * Therapy is directed at **altering the colonic microenvironment** * **↓ ammonia production in the gut** * **Lactulose** * Non-absorbable abx such as **rifaximin**

Answer 68

* **98% of Hepatic Malignancies in US** * _Carcinoma_ * **Lung, Breast, Colon, Pancreas** * _Hematopoietic Malignancies_ * **Non-Hodgkin lymphoma** * **Hodgkin lymphoma** * **Leukemia** * **Sarcoma**

Answer 69

**Malignant tumor that arises from hepatocytes** * _Low incidence regions_: Western industrialized countries * Age of onset: **6-7th decade** * **M:F ratio: 3:1** * % CA deaths: 0.5-2 * _High incidence regions_: Sub-Saharan Africa, Southeast Asia, **Japan** * Age of onset: **3-5th decade** * **M:F ratio: 9:1** * % CA deaths: 20-40% * Worldwide – Hepatocellular Carcinoma is either the #1 or #2 most common malignancy

Answer 70

Incidence of HCC ↑↑↑ in pts w/ cirrhosis * _Viral_ * **Hepatitis B Virus** * **Hepatitis C Virus** * HCC in 1-3% of HCV-infected pts over 20-30 yr follow up * _Metabolic disorders_ * **Hemochromatosis** * **α****-1 antitrypsin** * _Exposures_ * **Alcohol** * **Thorotrast** * **Aflatoxins** * **Anabolic steroids**

Answer 71

* _Symptoms_ * Abdominal pain * Fullness * Mass * Decompensated cirrhosis * Paraneoplastic sx * _Serology_ * **↑ alpha-fetoprotein** * _Outcome_ * Poor * 50% have metastases @ autopsy

Answer 72

Microtrabecular vs Macrotrabecular

Answer 73

* **Screen at-risk individuals w/ US every 6 months** * _Treatment:_ * Pts w/ well-compensated disease ⇒ **surgical resection** * Pts w/ advanced cirrhosis ⇒ **liver transplantation** * Non-surgical options: * **Microwave** or **radiofrequency ablation** * **Trans-arterial chemotherapy**

Answer 74

**Variant of HCC w/ unique features** * Arises in **normal liver** (not a cirrhotic liver like other HCC) * Affects **adolescents** and **young adults** * **Not ass. w/ elevated AFP** * Better prognosis * _Histology:_ * **Large eosinophilic hepatocytes** * **Delicate collagen in lamellar arrangement**

Answer 75

* **Adenocarcinoma of bile duct origin** * Affects primarily **6th-7th decade, M=F** * Location: * **Intrahepatic** (Peripheral): within the liver * **Extrahepatic**: outside the liver * R & L hepatic duct * If @ convergence ⇒ **hilar or Klatskin tumor** * CBD * Cystic duct * Differential diagnosis (microscopic look-alikes, i.e. other adenocarcinomas) * Pancreatic carcinoma * Ampullary carcinoma * Gallbladder carcinoma

Answer 76

* _Signs and symptoms related to site:_ * **Painless jaundice** * **Pruritus** * **Palpably enlarged gallbladder** * **Pancreatitis** * **Anorexia, weight loss** * _Clinical course_ * Similar to gallbladder carcinoma * _Outcome_ * Dismal

Answer 77

* _Biliary disease_ * PSC/UC * Chronic biliary infection * C. sinensis (liver fluke) * Choledochal cysts * Caroli’s disease * Congenital hepatic fibrosis * _Other exposures_ * Hemochromatosis * Thorotrast

Answer 78

* _Intrahepatic_ * **Glands within desmoplastic stroma** * May combine w/ HCC, results in **cholangiohepatocellular carcinoma** * _Extrahepatic_ * **Small sclerosing tumor obliterating lumen** * Tumor spreading along wall of duct * Intraductal papillary variant

Answer 79

* **Malignant tumor of the liver** * **Seen mainly in young children, age 0-3 yrs** * _Clinical manifestations:_ * Abdominal enlargement * Vomiting * Failure to thrive * Paraneoplastic syndromes * **Elevated AFP** * **May be cured by resection** * _Pathology_ * **Hemorrhagic, circumscribed mass, up to 25cm** * **Epithelial cells** * Embryonal appearance * Fetal appearance * **Mesenchymal component** * **Extramedullary hematopoiesis**

Answer 80

* **Rare (\< 1% of all hepatic malignancies)** * **Angiosarcoma** * Malignant neoplasm of blood vessels * _Risk factors (present in ~ 1/3)_ * Thorium dioxide * Vinyl chloride * Inorganic arsenic * Anabolic steroids * _Clinical:_ * **Peak: 6-7th decade** * **Rapidly fatal**

Answer 81

**Benign neoplasm of blood vessels**

Answer 82

**Benign neoplasm of hepatocytes** * **Women in reproductive yrs** * **Highly ass. w/ oral contraceptives** * Incidence ↓ w/ low dose oral contraceptives * Rare cases in men w/ **anabolic steroid use** * _Complication:_ * **Bleeding into peritoneal cavity** * _Treatment:_ * **Resection** * **May disappear w/ discontinuation of OCPs**

Answer 83

* 75% solitary, 25% multiple * Up to 40cm size * Mass lesion composed of **compressed benign hepatocytes without normal portal areas** * **Prominent vascular spaces**

Answer 84

* **Non-neoplastic nodular lesion** that _looks like cirrhosis_ * Mass lesion: must be distinguished from others * **F\>M** * _Pathology:_ * **Central fibrous scar** containing **large vessels** w/ r**adiating septa** * No portal areas, **proliferating bile ductules** * _Treatment:_ None required

Answer 85

**Hyperplastic nodules without fibrous scarring** * _Two forms:_ * **Partial nodular transformation** * Partially involves liver * Located predominantly in hilar region * **Nodular regenerative hyperplasia** * Diffuse involvement of liver * _Clinical Importance:_ * **Portal Hypertension in the absence of cirrhosis**

Answer 86

**Bile duct microhamartomas** Anomalous, small cystic bile ducts in stroma

Answer 87

**Solitary or multiple simple cysts** (Polycystic Liver Disease) Sporadic or can be ass. w/ adult polycystic disease of the kidney

Answer 88

* Autosomal recessive * **Enlarged portal tracts w/ extensive fibrosis** _w/o regenerative nodules_ * **Numerous bile ductules** that communicate w/ the biliary tree * Complication: portal hypertension

Answer 89

* Larger ducts are **segmentally dilated** * May contain **thickened bile** * **↑ risk of cholangiocarcinoma**

Answer 90

* **Highly successful procedure in pts w/ advanced liver disease** * _Indications:_ * Cirrhosis (all causes) * Intrahepatic malignancy (ex. localized hepatocellular carcinoma) * Acute liver failure * Metabolic diseases (ex. Wilson’s disease) * 1-year post transplant pt survival is ~90% * LT evaluation includes detailed medical and psychosocial assessment * Several prognostic indicators have been developed

Answer 91

* **Rejection** * _Early_ * Cholangitis * Cholestasis * Endothelialitis (inflammatory response within endothelium of vessels) * _Late_ * Paucity of bile ducts * Arteropathy * Subintimal foam cells * Myointimal hyperplasia * **Infection** * CMV * HSV * **Disease recurrence** * **EBV ass. lymphoproliferative disease**