Liver and Gallbladder Part II Flashcards
Nonalcoholic Fatty Liver Disease (NAFLD) is defined as ?
Nonalcoholic Fatty Liver Disease (NAFLD) is defined as a spectrum of disorders that have in common the presence of hepatic steatosis in individuals who do not consume alcohol.
What are the two types of NAFLD? Describe them?
- NAFL: nonalcoholic fatty liver: hepatic steatosis is present without evidence
of inflammation - NASH: nonalcoholic steatohepatitis may progress to cirrhosis
Describe the natural progession of simple steatosis to cirrhosis? What is the clinical significance of this
• Cirrhosis develops when simple steatosis progresses to steatohepatitis and then fibrosis
• Clinical significance: Patients with simple steatosis on biopsy are at low risk for developing
significant fibrosis, whereas those with nonalcoholic steatohepatitis (b/c of added inflammation and scarring) are at higher risk
• Some patients with fibrosis show regression of their disease
How does the pathogenesis of inflammation in NAFLD occur ?
*Inflammation is the main culprit and the most important risk factor
Pathogenesis of inflammation:
- Free cholesterol accumulation leads to liver injury in NASH/NAFLD through the activation of:
- Kupffer cells
- secretion of pro-inflammatory mediators and pro-fibrotic factors
- Stellate cells
- increased liver fibrogenesis
- Hepatocytes
- induces itself lipid peroxidation and lipotoxicity which leads to cellular dysfunction and death
- Kupffer cells
- Free cholesterol accumulation in the mitochondria causes:
- mitochondrial dysfunction and induces an increase in ROS which leads to liver damage
Describe the process of Insulin Resistance and NAFLD
** Insulin hormones are usless because they aren’t doing their jobs on the target cells by opening the gate and allowing glucose to enter through the cells
Insulin resistance causes hepatic steatosis:
• increased release of free fatty acids (FFAs) from adipose tissue
- increased fatty acids in the 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:
• Hyperglycemia and hyperinsulinemia further increase hepatic de novo
lipogenesis
- This leasds to increase triglyceride synthesis, increased lipolysis and increased triglycerid uptake by the liver
Name 4 Clinical Features of NAFLD/NASH?
*NASH = Diabetes + Obesity
- • Individuals with simple 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 patients with NASH
- • Because of the association between NASH and the metabolic syndrome, cardiovascular disease is a frequent cause of death in patients with NASH
Recap of NAFLD
What are the main factors that contribute to the initiation/perpetuation of the
hepatic injury?
• Insulin resistance
• Chronic inflammatory state
Cholestatic Liver Disease is defined as ?
• Definition: a decrease in bile flow
What are the two MOA of Cholestatic Liver Disease?
- hepatocellular: an impairment of bile formation
- obstructive: abnormal bile flow occurs after it is formed
What are some physical symptoms that happen to the skin and eyes of cholestatic liver disease
• Tissue deposition of bile becomes clinically evident as:
• yellow discoloration of the skin: jaundice
• Sclera: icterus due to retention of bilirubin
- also pruritus
Pathogenesis of Pruritus in Cholestatic Disease
Pruritogens act on itch receptors:
- • Bile acids and its metabolites
- • Histamine
- • Cytokines→
- act on C-fiber→Thalamus→ pruritis
- Mu receptors-
- promote itiching @ periphery and CNS level
- Kappa receptors-
- Inhibit itching at peripheray and CNS level
Hepatocellular Carcinoma (HCC) is defined as ?
Hepatoceullular Carcinoma tumors progress with…? (3 things)
- It is a most common primary malignancy of the liver and occurs predominantly in patients with underlying chronic liver disease with or without cirrhosis
- Cirrhosis is the primary risk factor
- Tumors progress with local expansion, intrahepatic spread and distant metastases
Hepatocellular Carcinoma (HCC) risk factors?
- Cirrhosis of almost any cause
- Inflammation, necrosis, fibrosis and ongoing regeneration of cirrhotic liver can contribute to HCC
- HBV infection
- Viral load:
- High serum levels of HBV DNA lead to great risk
- Active viral replicaiton
- HBeAg positivity, which indicates active viral replication
- Viral load:
- 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
Name two facts about the gall blader
- stores and concentrates bile 5 to 20-fold
- most abundant solute in bile is bile salts
Gallbladder Physiology
- Acidic, fatty chyme entering duodenum causes release of cholecystokinin an secretin from duodenal wall enteroendocrine cells
- Cholecystokinin and secretin enter bloodstream
- Bile salts and secretin transported via blood stream stimulate liver to produce bile more rapidly
- Vagal stimulation causes weak contractions of gallbladder
- Cholecystokinin (via blood stream causes gallbladder to contreat and hepatopacreatic spnhincter to relax; bile enters duodenum
Pathogenesis of pigment stones
- elevated levels of unconjugated bilirubin in bile
- infection of the biliary tract with E coli
What are 4 Clinical Features of Cholelithiasis ?
• 70% to 80% of patients 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
