Exam III Liver / Gall Bladder II

Question 1

Liver and Gallbladder diseases PT II

Answer 1

Liver

_{Nonalcoholic Fatty Liver Disease (NAFLD)}

_{Hepatocellular Carcinoma (HCC)}

Gallbladder

_{Cholelithiases}

_{Cholecystitis}

_{Carcinoma of gallbladder}

Question 2

NAFLD

Answer 2

NAFLD represents a spectrum of disorders that have in common the presence of hepatic steatosis in individuals who do not consume alcohol

Types

1. NAFL: nonalcoholic fatty liver: hepatic steatosis is present without evidence of inflammation.
2. NASH: nonalcoholic steatohepatitis may progress to cirrhosis

Question 3

Natural HX of NAFLD

Answer 3

Cirrhosis - Develops when simple steatosis progresses to steatohepatitis and then fibrosis.

Clinical Significance - PTs with simple steatosis on biopsy are at low risk for developing significant fibrosis, whereas those with nonalcoholic steatohepatitis are at higher risk

Some PTs with fibrosis show regression of their disease

Question 4

Pathogenesis of Inflammation in NAFLD

Answer 4

Free Cholesterol accumulation leads to liver injury in NASH/NAFLD through the activation of:

Kupffer Cells

_{<em>Secretion of pro-inflammatory mediators and pro-fibrotic factors</em>}

Stellate Cells

_{<em>Increased liver fibrogenesis</em>}

• Hepatocytes*
• I_{nduces itself lipid peroxidation and lipotoxicity -> cellular dysfunction and death}*

Free Cholesterol accumulation in the mitochondria causes:

Mitochondrial dysfunction and induces an increase in ROS

Question 5

Insulin Resistance in NAFLD

Answer 5

Insulin resistance causes hepatic steatosis:

Increased release of free fatty acids (FFA) from adipose tissue

Increased fatty acids in Liver-> accumulation of triglyceride and steatosis, over-secretion of VLDL and increased glucose production

Increased fatty acids in muscle-> decreased glucose uptake

The net result of increased glucose production and decreased glucose uptake:

_{<strong><span>Hyper</span>glycemia and <span>hyper</span>insulinemia </strong>further increase hepatic de novo <strong>lipogenesis</strong>}

Question 6

Clinical Features of NAFLD/NASH

Answer 6

Individuals with steatosis are generally asymptomatic

Clinical presentation is often related to insulin resistance or diabetes mellitus

Serum AST and ALT are elevated in about 90% of PTs with NASH

Because of the association between NASH and the metabolic syndrome, cardiovascular disease is a frequent cause of death in PTs with NASH

Question 7

Recap of NAFLD

Answer 7

The main factors that contribute to the initiation/perpetuation of hepatic injury

_{Insulin resistance}

_{Chronic inflammatory state}

Question 8

Cholestatic Liver Disease

Answer 8

Definition:

A decrease in Bile flow

Mechanism:

_{<strong>Hepatocellular</strong>: an impairment of bile formation}

_{<strong>Obstructive:</strong> abnormal bile flow occurs after it is formed}

Tissue deposition of bile becomes clinically evident as:

_{Yellow discoloration of the skin: <strong>Jaundice</strong>}

_{Sclera: <strong>Icterus</strong> due to retention of bilirubin}

Question 9

Pathogenesis of Pruritis in Cholestatic Disease

Answer 9

Symptoms associated with cholestasis:

Pruritis (itching), which can range in severity from mild, to moderate, to extreme.

Pruritogens act on itch receptors:

• Bile acids and its metabolites*
• Histamine*
• Cytokines*

Question 10

Hepatocellular Carcinoma (HCC)

Answer 10

It is most common primary malignancy of the liver and occurs predominantly in PTs with underlying chronic liver disease with or without cirrhosis.

Tumors progress with local expansion, intrahepatic spread and distant metastases

Question 11

Risk Factors of HCC

Answer 11

Cirrhosis of almost any cause:

Inflammation, necrosis, fibrosis, and ongoing regeneration of the cirrhotic liver can contribute to HCC

HBV infection:

Viral Load

_{High serum levels of HBV DNA -> greater risk}

Active Replication:

_{HBeAG positivity, which indicates active replication}

HCV Infection:

In the setting of rapid cellular turnover and the chronic inflammatory state

Hereditary Hemochromatosis:

Free Iron -> rapid formation of ROS metabolites -> DNA damage, abnormal protein synthesis, and cell proliferation -> cell injury and fibrosis

Question 12

HCC Pathogenesis

Answer 12

Chronic exposure to liver Injury -> repeated hepatocyte damage -> sets up a vicious cycle of cell death and regeneration which eventually results in cirrhosis -> genomic instability -> initiation of HCC

Stepwise accumulation of multiple genetic events -> tumor progression and metastases

Question 13

The Gallbladder

Answer 13

Gallbladder:

Stores and concentrates bile 5 to 20-fold

Most abundant solute in bile is bile salts

Bile:

Fate emulsification and absorption

Medium for excretion of bilirubin and cholesterol

Bile Salts:

Amphipathic nature enables bile salts to:

_{Emulsification of lipids: Detergent action -> digested effectively}

_{<strong>Transport of lipids: </strong> Bile salts carry lipids (monoglycerides, fatty acids, cholesterol, others) to intestinal wall in the form of micelle}s

Question 14

Gallbladder Physiology

Answer 14

Question 15

Cholelithiasis (Gallstones)

Answer 15

The Presence of Gallstones within the Common Bile Duct

There are 3 general classes of Gallstones:

_{<strong>Pure cholesterol stones</strong> containing at least 90% cholesterol}

_{<strong>Pigment stones</strong> composed predominantly of bilirubin}

_{<strong>Mixed composition stones</strong> varying proportions of cholesterol, bilirubin, as calcium carbonate, calcium phosphate}

The Major Risk Factors are:

_{<strong>Age and sex. </strong>Age 40 appears to represent the cutoff between relatively low and high rates of cholecystectomies}

_{<strong>Environmental Factors. </strong>Estrogen exposure}

_{<strong>Acquired disorders.</strong> Gallbladder stasis}

_{<strong>Hereditary factors. </strong>Genes encoding transporters that carry biliary lipids}

Question 16

Pathogenesis of Cholelithiasis

Answer 16

Four conditions appear to contribute to formation of cholesterol gallstones:

_{Supersaturation of bile with cholesterol}

_{Hypomotility of the gallbladder}

_{Defective conversion of cholesterol to bile acids}

_{Hypersecretion of mucus in the gallbladder}

Pathogenesis of pigment stones:

_{<strong>Elevated levels of unconjugated bilirubin in bile</strong>}

_{Infection of the biliary tract with E coli}

Question 17

Cholelithiasis Clinical Features

Answer 17

70-80% of PTs remain asymptomatic throughout their lives

Most common symptom is biliary colic that may be excruciating

Pain is localized to right upper quadrant or epigastrium that may radiate to the right shoulder or the back

Cholecystitis in association with stones also causes pain

Question 18

Cholecystitis

Answer 18

Inflammation of the Gallbladder

Types:

Acute Cholecystitis

Acalculous Cholecystitis

Chronic Cholecystitis

Acute Cholecystitis: acute calculous cholecystitis caused by obstruction of the neck of the cystic duct by a stone

Question 19

Cholecystitis Pathogenesis

Answer 19

Acute calculous cholecystitis

By chemical irritation and inflammation of a gallbladder obstructed by stones

Glycoprotein mucus layer is disrupted, exposing the mucosal epithelium to the direct detergent action of bile salts

Prostaglandins released within the wall of the gallbladder causes mucosal and wall inflammation

Acute acalculous cholecystitis

Caused by ischemia

Inflammation and edema of the wall, gallbladder stasis, and accumulation of biliary sludge -> cystic duct obstruction

Chronic cholecystitis

It is mainly associated with the presence of gallstones

Mechanical or recurrent attacks of acute cholecystitis -> fibrosis and thickening of the gallbladder

Question 20

Carcinoma of the Gallbladder

Answer 20

Gallbladder cancer is uncommon but highly fatal.

Clinical presentations:

_{Early invasive GBC are often asymptomatic or they have nonspecific symptoms}

_{Symptomatic PTs: Pain, followed by anorexia, nausea, or vomiting}

Risk Factors:

_{<strong>History of gallstones</strong>}

_{Chronic infection: salmonella, H. Pylori}

_{Carcinogen exposure}

The common thread between gallstones or chronic infections with gallbladder cancer is chronic inflammation

Question 21

Pathogenesis of Gallbladder Carcinoma

Answer 21

Chronic Cholecystitis -> Intestinal Metaplasia -> Dysplasia -> In Situ Carcinoma -> Invasive cancer

Two Key pathways in PTs with:

Cholelithiasis

_{It is hypothesized that <strong>chronic irritation</strong> of the gallbladder mucosa over a period of years may predispose to malignant transformation or act as a promoter for carcinogenic exposure}

Anomalous pancreaticobiliary duct junction

_{P53 mutation}