Blood flows from the triad, through the sinusoids to the central vein; outside of lobule to inside

into the canaliculi and is collected in the bile ducts; 

from inside of lobule to outside (note: opposite of blood flow)

• the pancreatic duct to form the ampulla of Vater
• There, the two ducts are surrounded by of the Sphincter of Oddi

• glucose homeostasis
• fatty acids converted to triglycerides and secreted as lipoproteins
• amino acid metabolism

• glycogen
• triglycerides
• Fe, Cu
• lipid soluble vitamins

• Jaundice
• Portal hypertension (in liver)
• Hepatic failure

leak out of damaged liver cells–

• AST (Aspartate aminotransferase; SGOT); 
• ALT (alanine aminotransferase)

actively produced by damaged bile duct cells,

• e.g., alkaline phosphatase
• gamma glutamyltransferase

The majority of bilirubin comes from degradation of RBC within the macrophages of the spleen

(Hgb–>Heme–>biliverdin–>bilirubin)

first, dissociated at the hepatocyte surface, bilirubin crosses the membrane via

carrier mechanism

• Hyperbilirubinemia, unconjugated jaundice
• due to 
  • hemolysis
  • hemolytic anemia
  • multiple transfusions 
• Path-Phys: 
  • liver can not handle the overload the excess of unconjugated bilirubin

• Hyperbilirubinemia unconj bilirubin jaundice
• due to 
  • liver cell injury
  • viral hepatitis
  • drugs

• Crigler - Najjar syndrome
• Gilbert syndrome

• Hyperbilirubinemia; mix of conj/unconj bilirubin; jaundice 
• Due to:
  • hepatocellular injury
  • viral or alcoholic hepatitis
  • impairment of canalicular or ductal bile flow 

Portal Hypertension

• what is it?
• What is it due to?
• Breakdown of liver blood supply?
• The blood is what THREE things?

• Sustained increase in the portal venous pressure
• Due to:
  • obstruction of the blood flow somewhere in the portal circuit
• 2/3 of the liver blood supply is portal venous 
• 1/3 is from the hepatic artery
• The blood:
  • low in oxygen 
  • high in nutrients 
  • other toxins that need to be detoxified

Portal hypertension:

Etiology and Pathogenesis: 

• prehepatic obstruction
• intrahepatic obstruction 
• posthepatic obstruction
• acute or chronic

• splenomegaly and hypersplenism
• opening of collaterals to the inferior vena cava 
• ascites
• heart failure
• encephalopathy 

• Due to accumulation of fluid in the abdominal cavity which has the nature of transudate. 
• The mechanism is complex + involves:
  • increase in the portal pressure, 
  • pooling of blood in the mesenteric capillary bed
  • exudation of lymph from the liver
  • decreased oncotic pressure in association with a decrease in albumin production by the liver
  • increased renal absorption of sodium and water.

Hepatic Failure

• what is it?
• What is it in response to?

• Syndrome of end-stage liver disease that occurs when the mass of liver cells, or their function, is inadequate to sustain vital metabolic, detoxifying, and synthetic activities in the liver
• In response to injury:
  •  viral hepatitis
  •  cirrhosis
  • toxic liver injury

• Jaundice-conjugated or unconjugated hyperbilirubinemia
• metabolic insufficiency–hypoglycemia, decreased production of albumin, globulin and prothrombin
• hypoprothrombinemia
• altered synthesis and catabolism of hormones which may result in testicular atrophy and gynecomastia in males; 
• neurologic disorders-lethargy, coma, personality changes, confusion, flapping tremor of the outstretched hand
• respiratory, circulatory and renal failure; 
• ascites
• peptic ulcers
• It is often, but not always, irreversible.

Cirrhosis of the liver:

• what is it?
• results from?

• End-stage chronic liver disease resulting in destruction of normal hepatic architecture by fibrous bands that surround regenerating nodules of hepatocytes
• Results from persistent liver necrosis.

Alcoholic hepatitis 

• associated with?
• Type of cirrhosis?
• Involves what three changes?
• description of the fibrosis?

• Associated with: alcohol consumption
• Type of cirrhosis: Micronodular cirrhosis 
• Involves:
  • fatty change
  • alcoholic hepatitis (necrosis, Mallory bodies in the hepatocellular cytoplasm, neutrophils)
  • fibrosis in response to the toxic effect of alcohol
• The fibrosis surrounds small nodules of cells and destroys the architecture, and thus the function, of the liver.

• Micronodular cirrhosis
• Ascites, washed-out appearance, jaundice, esophageal varices, hepatic failure, heart failure, predisposition to gram negative infections, renal failure, central nervous system derangements, increased tendency for peptic ulcers, increased incidence of hepatocellular carcinoma. 
• Many patients progress to end- stage disease.

• Micronodular cirrhosis 
• Scarring throughout the liver which begins at the interlobular bile ducts and later involves the portal triads. 
• Primary form: 
  • autoimmune; 
  • mostly in women; 
  • both humoral and cell mediated immune destruction of tissues; 
  • 95% have anti-mitochondrial antibodies - AMA
  • fibrosis follows tissue destruction. 
• The liver is swollen and bile stained; 
• Dilated ducts may rupture and form bile lakes
• followed by inflammation and fibrosis

• Micronodular cirrhosis 
• Depends on the etiology and amount of tissue destruction
• Cholestasis enzymes: 
  • actively produced by damaged bile duct cells
  • e.g., alkaline phosphatase, gamma glutamyltransferase are elevated.

• Micronodular cirrhosis 
• Excessive accumulation of iron due to: 
  • 1) increased absorption from the intestine, e.g., hereditary hemochromatosis
  • 2) secondary: due to diet, supplements, multiple transfusions, hematologic disorders (thalassemia), alcoholism. 

• common autosomal recessive disorder of iron metabolism resulting in excessive iron absorption and accumulation in the parenchyma of the liver, heart, and pancreas
• In this disease, 20-40 g of iron may accumulate in the body
• The clinical hallmark of advanced HHC is cirrhosis (micronodular), diabetes (bronze diabetes), skin pigmentation, and cardiac failure.
• The patient is usually male, 40-60 years old. 
• Hepatocellular carcinoma is a significant complication of hemochromatosis induced cirrhosis.

• AKA postnecrotic cirrhosis
• Large tracks of connective tissue surrounding more than a single hepatic lobule. 
• It is classically associated with chronic active hepatitis or hepatotoxic agents. 
• Increased incidence of heparocellular carcinoma.

• Liver cell adenoma: rare, associated with the use of oral contraceptives. 
• Hemangioma: most common benign tumor seen in all ages

a. Hepatocellular carcinoma

b. Cholangiocarcinoma (Bile duct carcinoma)

• From hepatocytes. 
• Etiology associated with 
  • history of HBV infection
  • history of HCV infection
  • alcoholic or postnecrotic cirrhosis
  • exposure to aflotoxin B
• The clinical presentation may include: 
  • hepatomegaly
  • ascites
  • portal vein thrombosis
  • occlusion of hepatic veins
  • esophageal varices
  • cachexia
  • hepatic failure
  •  elevated levels of alpha- fetoprotein (an oncoprotein).

• From biliary epithelium any where in the duct system. 
• Usually in older individuals of both sexes.

• More common than primary neoplasia 
• The liver and lungs are most often involved in the metastatic spread of cancers.
• The most common primary sources producing hepatic or liver metastases are those of the colon, breast, lung, and pancreas. 
• Any cancer in any site of the body may spread to the liver, including leukemia, melanoma, and lymphoma. 
• Typically, multiple nodular metastases are found that often cause striking hepatomegaly and may replace over 80% of existent hepatic parenchyma. Thus, metastatic tumors to the liver are a major cause of hepatomegaly.

• Occupies a fossa on the inferior surface of the liver
• Serves to store, concentrate, and release bile (conjugated bilirubin, bile salts, phospholipids, cholesterol)
• Dilute bile from the hepatic duct passes via the cystic duct to the GB where it is concentrated.

• Stones within the lumen of the GB or extrahepatic biliary tree
• 20-30% of American population older than 75 years of age has gall stones.
• play role in: etiology of cholecystitis, result in obstructive jaundice through obstruction of the common bile duct
• may predispose to carcinoma of the GB.

• Female preponderance
• Most frequently affected: fat, female, fertile, and forty (the 4F population)
• Other factors: 
  • heredity, e.g., 75% of Pima Indian women affected by age of 25 and 90% by age of 60; 
  • estrogen- increases secretion of cholesterol and may decrease the secretion of bile acids; 
  • pregnancy-GB empties slowly in last trimester
  • obesity-via increase in biliary cholesterol secretion
  • hemolytic disease- favors pigmented stone formation (bilirubinate stones).

• Cholesterol 
• Calcium bilirubinate 
• Brown pigmented stones

• Most common stones (3/4 of all)
•  If the bile contains excess cholesterol, or it is deficient in bile acids, the bile becomes supersaturated and cholesterol precipitates as solid crystals
• The stones are usually round, yellow to tan color, single or multiple and contain over 50% cholesterol

• Composed of calcium bilirubinate (pigmented stones)
• Pathogenesis - increased concentration of unconjugated bilirubin in the bile which precipitates as calcium bilirubinate
• associated with hemolytic diseases, e.g., sickle cell anemia, thalassemia
• The stones are usually multiple and jet black in color

• Contain calcium bilirubinate mixed with cholesterol; 
• found most commonly in the intrahepatic and extrahepatic bile ducts
• almost always associated with bacterial cholangitis in which E. coli is the predominant organism

• Bacterial infections
• chemical injury, e.g., bile stasis
• stones

Acute-

• GB is enlarged, tense, edematous, and red
• wall is thickened
• 90-95% of cases has stones
• may perforate in severe cases.

Chronic-

• The most common disease of the GB
• persistent inflammation invariably associated with longstanding stones
• the wall is fibrotic

Acute form:

• Abdominal pain in the right upper quadrant (RUQ)
• biliary colic
• mild jaundice
•  fever and leukocytosis
• nausea
• vomiting

Chronic form:

• presents mildly with non specific abdominal symptoms

• Benign tumors - rare
• Adenocarcinoma is the most common malignant tumor
• it affects more females than males
• it is associated with cholelithiasis and chronic cholecystitis
• the 5-year survival rate is 3%

• Mixed exocrine-endocrine gland
• Located transversely in upper abdomen
• The head lies in the concavity of the duodenum, 
• The body includes most of the gland
• The tail ends in the hilum of the spleen
• retroperitoneal and inaccessible to physical examination
• The major pancreatic duct usually drains into the common bile duct immediately proximal to the ampulla of Vater. 
• The acinar cells (exocrine funx) synthesize some 20 different enzymes secreted into the duodenum following hormonal (cholecystokinin, secretin) and neural (vagal) stimulation
• The major hormones produced endocrine pancreas are insulin and glucagon

• Starts abruptly, usually following a heavy meal or excessive alcohol intake
• Associated with alcoholism (more commonly in men) or biliary disease (more commonly in women)
• Seen in middle age with peak incidence at 60 years of age
• Pathogenesis: 
  • Injury of acini or ducts results in the release of pancreatic enzymes which autodigest the tissues and induce inflammation
  • often hemorrhagic
• Causes: 
  • gallstones, bile reflux, ethanol, viruses, drugs, blunt trauma, etc. 
• Clinical: 
  • severe epigastric pain, nausea, vomiting; 
  • the enzymes released from the acinar cells enter the blood and the abdominal cavity and lead to peripheral vascular collapse and shock
• Elevation of serum amylase after 24-72 hrs of onset is diagnostic of acute pancreatitis.

• Progressive destruction of the parenchyma with fibrosis
• Major cause is alcohol abuse. 
• Chronic calcifying pancreatitis is the most common form. 
• Presents with persisting abdominal pain radiating to the back. 
• Complications include diabetes, malabsorption, weight loss.

Pancreatic Neoplasms:

Benign

• male predominance in younger groups; same male: female incidence in the older; highest incidence in the world is in New Zealand among the Maoris; in the USA more common among Native and African Americans. 
• Etiology
  •  smoking (it is dose-dependent)
  •  exposure to chemical carcinogens
  • high dietary fat consumption
  • diabetes mellitus
  • chronic pancreatitis
• pathogenesis 
  • k-ras mutations, overexpression of erbB2, deletions on chromosome #18 in 90% of the cases. 
• Most frequent location is in the head (60%)
• Clinical: 
  • weight loss, pain radiating to the back, jaundice
• Tumors in the head 
  • biliary obstruction
  •  tend to be smaller and with limited spread at time of diagnosis;
• tumors in the tail - more advanced and less symptomatic
• Half of the patients die within 6 weeks of diagnosis; the 5-year survival rate is 1%. 

• Zollinger-Ellison syndrome from G cells
• secrete gastrin
• may be benign but the majority are malignant; 
• associated with increased gastric hypersecretion and peptic ulceration

• Jaundice: Conjugated (more often) or unconjugated hyperbilirubinemia 
• Generalized edema 
• Ascites (Hydroperitoneum) 
• Neurologic disorders: confusion, lethargy, coma, personality changes 
• Fetor hepaticus (smell of breath- due to mecaptans) 
• Abnormal bleeding (coagulation factors/Vitamin K absorption) 
• Osteomalacia (Vitamin D absorption) 
• Esophageal varices

• Neurologic disorders: confusion, lethargy, coma, personality changes 
• Ascites 
• Peptic ulcers
•  Respiratory, circulatory and renal failure (hepato-renal syndrome)

• Function: Stores, concentrates and releases bile (conjugated bilirubin, bile salts, phospholipids, cholesterol) 
• Cholelithiasis: Stones within the lumen of the gall bladder or extraheptic biliary tree 
• Common Types: Cholesterol, Calcium bilirubinate
• Cholecysitis: Acute or chronic inflammation of the gall bladder 
• Etiology: bacterial infections, chemical injury, stones 
• Neoplasms 
• Benign tumors are rare 
• Adenocarcinoma is the most common malignant tumor (F>M)

• Normally a person has 3 to 4 g of iron, 2/3 of which is in the form of Hgb; 
• the rest is stored as soluble feritin in the cytoplasm of all cells
• most of the iron storage is in the bone marrow and liver
• Hemosiderin is a product of degradation of feritin; it is insoluble.

• Secondary form: 
  • extrahepatic biliary obstruction associated with gallstones
  • cancer
  • external compression by enlarged lymph nodes
• The liver is swollen and bile stained; 
• Dilated ducts may rupture and form bile lakes
• followed by inflammation and fibrosis

• obstruction of hepatic vein (Budd-Chiari syndrome) by tumor or thrombosis in association with polycythemia, myeloproliferative disorders, bacterial infections
• compression or obstruction of inferior vena cava
• severe right- sided heart failure