12. GI pathopharmacology 2

portal hypertension

ascites

hepatic encephalopathy

jaundice

Pressure ↑ from 3 to 10 mmHg

Main Causes:

Liver Cirrhosis

Portal Vein Thrombosis (blockage)

Right-Heart Failure → Back-up into venous

circulation → Portal Hypertension

Main Complications:

Varices (in esophagus or rectum) → Rupture = Life-Threatening

Blood Vomiting

Splenomegaly → ↓ Clotting Platelets

Respiratory Dysfunctions

fluid retention in peritoneum (layer of fat around organs)

cirrhosis (complete loss of liver functions)

portal hypertension

decline in albumin synthesis -> decreased capillary oncotic pressure -> increase in renal absorption of sodium and water to try and maintain it

Abdominal Distention

↓ Lung Capacity (pushing on diaphragm)

Peritonitis → Fever & Pain • Death@1year=25%

liver is so damaged it doesn't work and toxins accumulate in brain

- especially ammonia (NH3)

- ↑ Ammonia & GABA → ↓ Neurotransmission

- there could be a shunt formed to bypass liver

Manifestations:

• Irritability, Memory Loss, Lethargy

• Confusion & Convulsions• Coma & Death

Types of Onset

Fulminant (Type A): appears out of nowhere

Porto-systemic Shunt (Type B) : formation of shunt

Slow/Chronic (Type C): not necessarily shunt

#1 symptom associated w/liver impairments

- you become yellow because of bilirubin accumulation

1. hepatotoxicity: any damage to hepatocyte cells leads to decrease ability of liver to excrete bilirubin

2. gallstones: obstruction of bile duct, bilirubin accumulates in liver + overflows into blood

3. hemolytic anemia: excessive RBC destruction, hepatocytes cannot metabolize bilirubin fast enough

4. Gilbert disease: bilirubin conjugating enzyme deficiency

Yellow Pigmentation (sclera or skin)

Dark Urine & Light Stool

Others depend on

Pathology

Physiologic:Within first few weeks of life → resolves on its own

Pathologic: Within first 24 hoursImmature liver unable to excrete bilirubin → Bilirubin in Brain → Kernicterus (Encephalopathy)

Complications: Cerebral palsy + Speech/Hearing deficit

Treatment = Phototherapy

UV & Blue Light metabolises bilirubin in water-soluble constituents

very common systemic disease of liver

- cause of several liver complications

Hallmark Hepatocyte Lesions

Cell-Mediated Hepatocyte Necrosis

Fibrosis & Phagocyte Infiltration

Kupffer Cell Hyperplasia

1.incubation = asymptomatic infection

2. prodromal = 2 weeks post exposure

- very contagious

- Sx: fatigue, nausea, vomiting, hyperalgesia, low fever

- ends with jaundice

3. icteric = 1-2 weeks post prodromal, lasts 2-6 weeks

- hepatocelullar necrosis + cholestasis -> severe jaundice

- liver enlargement + pain

4. recovery = 6-8 weeks post exposure

- begins with jaundice resolution

- symptom ↓ except for chronic cases (HBV + HCV)

- chronic carrier = non-contagious

RNA

1 month

Fecal-Oral

Acute/Mild

NO

Hygiene & Vaccine

DNA/RNA - Hep D requires prior infection with Hep B

2-6 months

Blood-Borne, mother-infant transmission possible, STI

Insidious/ Severe

YES

Hygiene & Vaccine

RNA

1-2 month

blood borne

insidious/severe

YES

Hygiene

RNA

0.5-2 month

fecal oral

acute/severe in pregnant women

NO

Hygiene

cirrhosis

hepatocelullar carcinoma

disease that can lead to chronic liver damage then evolve into hepatitis and cirrhosis

Severity ∝ Amount & Duration of Alcohol Intake + Acetaldehyde Formation (toxic metabolite)

Associated Malnutrition → ↓ Liver Regenerating Capacities

1-2 drinks/day chronically

Cessation → Reversible ↓ Hepatocyte Function → Fat Deposition

can transition into hepatitis -> Cirrhosis Precursor

Acetaldehyde + Inflammatory mediators -> Tissue Necrosis

More Severe with HCV≈35% of Alcoholics will transition into cirrhosis

↑↑ Acetaldehyde = Very Toxic Lead to Oxidative Damage + Fibrosis

Chronic Damage + Fibrosis-Regeneration Cycles → Cobbly Regenerating Nodules

micro nodular cirrhosis

macro nodular cirrhosis

When cells are damaged +die -> tissue becomes fibrotic

o   Thickened + form scar tissue

-   When liver has problem (alcohol, Hep, hepatocyte destruction, inflammation)

o   Liver becomes seriously scarred and damaged to a point it is no longer reversible -> fibrotic

- when cells are injured they form nodules

= cirrhosis

o   Portal hypertension

§  Fluid gets pushed into peritoneal cavity

· ASCITES

· Congestive splenomegaly

·  Portosystemic shunt

o   renal vasoconstriction

o   Low kidney blood flow + filtration

o   Hepatorenal failure

o   Decreased liver function

§  Decreased detoxification

·  Toxins can get in brain -> ammonia

§  Asterixis (tremors) + coma

§  decreased estrogen metabolism

· gynecomastia, spider agiomata, palmar erythema

§  decreased bilirubin conjugation

· increased unconjugated bilirubin = jaundice

§  decreased albumin production

§  decreased clotting factor production

o   Early = some fibrosis -> compensated, still does its job

§  Asymptomatic

§  Non-specific (weight loss, weakness, fatigue)

o   Later = excessive fibrosis-> decompensated, can’t function

§  Jaundice + pruritus

§  Ascites

§  Hepatic encephalopathy (confusion)

§  Easy bruising

o   Liver biopsy

o   Lab findings

§  Elevated bilirubin

§  Elevated enzymes = AST, ALT, ALP, GGT

§  Thrombocytopenia

o   Fibrosis is generally irreversible

o   Prevent further damage by treating underlying cause

§  Stopping alcohol

§  Antiviral treatment for hepatitis C

o   Liver transplant

Gallbladder Duct Obstruction -> Mostly Asymptomatic

Cholesterol Stones:

Supersaturated Bile

↓

Cholesterol Crystal Formation

↓

Cystic/Common Duct Occlusion

Pigmented Stones

Hemolytic Anemia or Infection

↓

Hyperbilirubinemia

↓

Cystic/Common Duct Occlusion

Risk Factors:

Obesity; Low HDL Pancreatic/Gallbladder/Ileal Disease

Upper Abdominal Pain + Intolerance to Fatty Food

Jaundice → from Common bile duct obstruction

Cholecystitis (gallbladder inflammation) → Fever

inflammation of pancreas

gallstones -> duct obstruction -> edema, ischemia -> activation of enzymes = auto digestion

acing cell injury (can be ALD, causes chronic pancreatitis)-> activation of enzymes = auto digestion

Upper Abdominal Pain

Nausea + Vomiting

Fever & Neutrophil Infiltration

Sepsis or Multisystem Shock

pancreatic abcess -> acute hemorrhagic pancreatitis (rare but life-threatening)

Insufficient Caloric Intake → Weight ↓

Ex.: Therapeutic (Desired) vs. Pathologic (Lack of Resources)

Inadequate intake of calories, vitamins, proteins

Ex.: Malabsorption Syndrome; Starvation

short term

Dietary Abstinence for Several Days (Intermittent Fasting)

Depletes Carbohydrate stores; Minimal Protein Catabolism

long term

Dietary Abstinence > Several Days (Famine)

Severe Fat & Protein Catabolism: ↓ Muscle Mass & Adipose Tissue

Glucose Depletion↓Lipid Depletion↓Proteolysis↓Electrolyte Imbalance (Na+/K+-Pump Failure)↓

Renal/Pulmonary/Heart Failure

↓Death

Cachexia

Inflammation-Induced Body Wasting

Ex.: Cancer; AIDS; Tuberculosis

No Metabolic Adjustments!!

Kwashiorkor

Protein Insufficiency

Normal Body Fat

Looks like ascites

Refeeding Syndrome!! ≈ Reperfusion Injury

Nutrient Absorption Disorder:

• Malabsorption/Maldigestion or Both

Pancreatic Enzyme Insufficiency

No lipase in saliva or brush border -> Fat Maldigestion

Causes:

Pancreatitis or Carcinoma;

Cystic Fibrosis

Lactase Deficiency

Defective/Absent Lactase -> Lactose Maldigestion

Causes:

(1◦) Genetic /(2◦) Intestinal Disorder

lactose accumulation -> osmotic diarrhea, painful cramps

Bile Salt Deficiency

↓ Micelle Concentration Fat Malabsorption

Causes:

Severe Liver & Ileal Disease; Gallstones; ↑ Microbiome Bile Salt Deconjugation

Vit. A: Night blindness

Vit. D: Osteoporosis

Vit. K: Clotting Issues

DSM-IV-TR Criteria:

Irrational fear of obesity

Irrational perception of body

Caloric Restriction → Severe Weight Loss

Behavioral resistance to weight gain

DSM-IV-TR Criteria:

Recurrent binge eating episodes

1 episode/week for 3 months

Behaviors to oppose binge eating

Irrational influence of weight on self-confidence

Does not meet criteria for Anorexia Nervosa

Weight Gain = Caloric Input-Output Imbalance

Adipocytes

• Fat (Energy) Storage Cells + Endocrine Cells• Release Adipokines (Ex.: Leptin & Adiponectin)

metabolic changes -> chronic low grade inflammation + adipokine pattern alterations -> associated pathologies = T2DM, cancer, PCOS, cardiovascular disease

section in hypothalamus called the arcuate nucleus that has 2 pathways:

1. anabolic pathway: stimulates appetite and triggers eating while decreasing metabolism + energy usage in the body

- activated when you're hungry

2. catabolic pathway: reduced appetite and desire for eating, time to use energy you have ingested

orexins (Ghrelin, endocannabinoids) = activate anabolic + inhibit catabolic

anorexins (leptin, insulin) = inhibit anabolic + activate catabolic

Anorexin acting on Hypothalamus

↓ Appetite & ↑ Energy Expenditure

Secretion Regulation:Eat: Adipocytes full of fat → ↑ Leptin → Full

Fast: Adipocytes empty → ↓ Leptin → Hungry

Weight-Gain Mechanism:↑ Adipocytes → ↑↑ Leptin →Leptin Resistance → Overeating → Weight Gain

Hyperleptinemia → ↑ Sympathetic Activity → HTN

Anti-Inflammatory & Anti-Atherogenic

↑ Insulin Sensitivity

Weight-Gain Mechanism:

↓ Adiponectin Release↓↑ Insulin Resistance → T2DM+↑ Inflammation & Atherosclerosis

when fridge is empty, you feel hunger -> so you eat and fill your fridge = more fat in adipocytes

when you overeat, there is no more space in your fridge -> you get a bigger fridge = adipocyte hypertrophy

but now, adipocytes are so big, they feel empty even though there is food inside -> hunger signal continues despite fact there is food in them

adipocyte hyperplasia = more of them

- hunger signal keeps going up, but cuz u have more adipocytes the # of calorie is divided across all of them, so they all feel more empty. So you got to keep eating some more -> self-reinforcing

Profit from fat-shaming culture

Marketed as efficient & safe

Once on market, widespread use & abuse

Many approved then withdrawn b/c of serious toxicity discovery

95% failure rate + weight cycling = Serious Health Risks

Lipase Inhibitor, ex. Orlistat

GLP-1 Agonist, ex. Liraglutide

5-HT2C Receptor Agonist, ex. Lorcaserin

Cannabinoid Inhibitor, ex. Rimonabant

Sympathomimetic Amines, ex. Phentermine, Diethylproprion

Combination Products, ex. Phentermine + Topiramate ex. Naltrexone + Buproprion

Rimonabant

cannabinoid receptors in the brain can regulate appetite + in GI tract can regulate the food signals sent to the brain to regulate appetite

Marketed in 2006

Withdrawn in 2008

Therapeutic window too narrow

High risk of CNS depression & psychosis

phentermine + topiramate

naltrexone + bupropion

phentermine:

• Sympathomimetic amine• ↓ appetite at the hypothalamus

topiramate:

• Anticonvulsive drug

• ↑ satiety feeling

Adverse Effects• Common: Dry mouth, dizziness, insomnia

• Serious: hypertension, tachycardia, birth defects

Interactions

• ↑ hypoglycemia risk with antidiabetic agents

• Inhibits oral contraceptives• MAO inhibitors are contraindicated

naltrexone

• Opioid antagonist• ↓ appetite at hypothalamus

buproprion

• Dopamine/Norepinephrine reuptake inhibitor

• ↓ reward feeling of food

Adverse Effects• Common: Nausea, vomiting, constipation, dizziness

Serious: Depression, mania, suicidal ideation

Interactions

• Strong CYP2D6 inhibitor• Opioids & MAO inhibitors are contraindicated