BMS150 - Wk 12

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Questions and Answers

What is the primary function of bacteria in the terminal ileum and colon regarding bilirubin?

They eliminate biliverdin from the bloodstream.

They synthesize bilirubin from cholesterol.

They convert bilirubin into urobilinogen. (correct)

They store bilirubin in the liver's hepatocytes.

Which substance is primarily responsible for the brown color of feces?

Cholesterol

Stercobilin (correct)

Bilirubin

Urobilinogen

What role do hepatocytes play in nutrient management after absorption?

They exclusively release nutrients into the liver circulation.

They synthesize nutrients without regulating their absorption.

They can store, release, or bind nutrients for circulation. (correct)

They only metabolize carbohydrates for energy.

What is one of the main functions of bile produced by the liver?

Eliminate waste products such as bilirubin. Signup and view all the answers

Which of the following substances is NOT synthesized by the liver?

Red blood cells Signup and view all the answers

Which process occurs first in the liver after importing compounds from the blood?

Import of compounds across the basolateral membrane Signup and view all the answers

What is a primary function of the Na-K pump at the basolateral membrane of hepatocytes?

Providing energy for active transport of solutes Signup and view all the answers

Which of the following is an example of a Na-independent transporter involved in hepatocyte function?

Organic anion-transporting polypeptides (OATPs) Signup and view all the answers

What role does the Na/taurocholate co-transporting polypeptide (NTCP) play in liver function?

Responsible for the uptake of bile acids Signup and view all the answers

In which cellular location do the chemical modifications or degradations of products primarily occur?

Within lysosomes or through biotransformation reactions Signup and view all the answers

What is the primary role of insulin in energy homeostasis?

Facilitating the uptake of glucose by cells Signup and view all the answers

What triggers the release of glucagon from the pancreas?

Low blood glucose levels Signup and view all the answers

Which cells in the pancreas are responsible for producing glucagon?

Alpha cells Signup and view all the answers

How does insulin affect blood glucose levels after a meal?

It facilitates glucose uptake, lowering levels Signup and view all the answers

What happens to glycogen in the liver when glucagon is released?

It is broken down into glucose Signup and view all the answers

What components result from the cleavage of proinsulin during its processing?

Mature insulin and C-peptide Signup and view all the answers

Which type of cellular compartments are involved in the packaging of mature insulin?

Secretory vesicles Signup and view all the answers

What triggers the secretion of insulin from beta cells?

Increased blood glucose levels Signup and view all the answers

What is the function of C-peptide in relation to insulin?

It is helpful in measuring endogenous insulin secretion Signup and view all the answers

How does a low glucose concentration affect the membrane potential in beta cells?

Results in the opening of K+ channels, causing hyperpolarization Signup and view all the answers

What is the primary reason for the majority of acute pancreatitis cases?

Excessive alcohol intake and cholelithiasis Signup and view all the answers

Which of the following is considered a mechanical etiologic factor for acute pancreatitis?

Gallstones Signup and view all the answers

What is a common drug known to incite acute pancreatitis?

Azathioprine Signup and view all the answers

What is a possible consequence of mutations in trypsinogen and trypsinogen inhibitors?

Understanding of pancreatitis pathology Signup and view all the answers

Which is NOT a vascular etiologic factor associated with acute pancreatitis?

Hyperlipoproteinemia Signup and view all the answers

What is the main function of acinar cells in the pancreas?

Secretion of digestive enzymes Signup and view all the answers

Which part of the pancreas does the main pancreatic duct join?

Common bile duct Signup and view all the answers

What type of gland system is the exocrine pancreas classified as?

Compound tubulo-acinar gland Signup and view all the answers

What is the approximate length of the pancreas?

25 cm Signup and view all the answers

Which artery supplies the head of the pancreas?

Gastroduodenal artery Signup and view all the answers

What is the primary cause of Type 1 diabetes?

Autoimmune destruction of pancreatic beta cells Signup and view all the answers

What is the normal fasting blood glucose level in healthy individuals?

Less than 5.6 mmol Signup and view all the answers

Which laboratory test indicates possible diabetes with a hemoglobin A1c level?

Level greater than 6.5% Signup and view all the answers

What type of diabetes is most commonly associated with insulin resistance?

Type 2 diabetes Signup and view all the answers

What does the term 'hyperglycemia' refer to in the context of diabetes?

Elevated blood glucose levels Signup and view all the answers

Study Notes

Vitamin D Hydroxylation and Thyroid Hormone Deiodination

Initial hydroxylation of Vitamin D occurs primarily in the liver and kidneys.
T4 (thyroxine) is converted to T3 (triiodothyronine) through deiodination, which is critical for metabolic regulation.

Biotransformation and Degradation in the Liver

Hepatocytes receive a vast array of compounds from portal and systemic circulation.
Process involves four major steps: import, transport, chemical modification, and excretion into bile.
Basolateral membrane of hepatocytes is closest to blood supply, facilitating compound entry.
Na-K pump creates a low intracellular Na+ concentration to drive active transport of solutes.

Transport Mechanisms in Hepatocytes

Na+-driven transporters include Na-H exchanger and Na/HCO3 cotransporter, essential for solute uptake.
Na/taurocholate co-transporting polypeptide (NTCP) is key for bile uptake.
Na-independent transporters include organic anion-transporting polypeptides (OATPs) that handle diverse amphipathic compounds like bile acids and drugs.

Bilirubin Conjugation and Metabolism

Conjugated bilirubin is converted back to bilirubin in the intestine by bacteria.
Bilirubin is further transformed into urobilinogen, which can become stercobilin (the primary fecal pigment) or be reabsorbed into circulation.
Urobilinogen contributes to the yellow color of urine.

Nutrient Storage and Synthesis in the Liver

Hepatic portal vein delivers absorbed nutrients to the liver for metabolism.
Nutrients may be stored, released unbound, or bound to carrier molecules based on metabolic needs.
The liver synthesizes essential substances like albumin, coagulation factors, and plasma proteins.

Bile Production and Function

Bile serves to eliminate waste products and facilitates digestion and absorption of lipids.
Synthesized from cholesterol and modified by bacteria in the ileum and colon.
Secondary bile salts formed from dehydroxylation are reabsorbed and conjugated before bile secretion.

Composition and Flow of Bile

Bile contains phospholipids, IgA, cholesterol, bilirubin, lipophilic drugs, and trace minerals.
Flows from hepatocytes through bile canaliculi, ducts, and finally into the duodenum.

Cirrhosis: Pathogenesis and Clinical Features

Activated stellate cells in the liver deposit fibrous extracellular matrix, leading to structural fibrosis and regenerative nodules.
Often asymptomatic until advanced stages; symptoms can include anorexia, weight loss, and weakness.
Complications may lead to liver failure, characterized by jaundice, encephalopathy, and bleeding.

Cholelithiasis: Overview and Risk Factors

Common biliary tract disease affecting 10-20% of adults in high-income countries.
Two types of gallstones: cholesterol stones (made of crystalline cholesterol) and pigment stones (made of bilirubin calcium salts).
Major risk factors include age, sex (more common in females), obesity, and rapid weight loss.

Pathogenesis of Cholelithiasis

Cholesterol stones form when bile is supersaturated with cholesterol, leading to crystal nucleation.
Pigment stones arise from excessive bilirubin production, ileal disease, or gallbladder infections.

Clinical Features and Complications of Gallstones

Biliary pain can range from excruciating to "colicky," often linked to obstruction or inflammation.
Complications include acute cholecystitis, which can lead to emergency surgical interventions and increased carcinoma risk.

Jaundice: Definition and Etiology

Jaundice refers to yellowing of the skin, while icterus signifies yellowing of the sclera due to elevated bilirubin.
Causes categorized as pre-hepatic, intra-hepatic, and post-hepatic, including hemolytic anemias and liver disease.

Overview of Energy Homeostasis

Energy homeostasis maintains stable energy levels in the body, regulated by the endocrine pancreas.
Islets of Langerhans consist of hormone-secreting cells: alpha (glucagon), beta (insulin), and delta (somatostatin).

Insulin and Glucagon Functions

Insulin is released by beta cells when blood glucose levels rise, facilitating glucose uptake and energy production.
Glucagon is released by alpha cells when blood glucose levels drop, stimulating liver glycogen breakdown and glucose release.

Insulin Synthesis and Processing

Proinsulin, the precursor to insulin, has three domains: A chain, B chain, and C-peptide.
In the endoplasmic reticulum and Golgi, proinsulin is cleaved to produce mature insulin and C-peptide.

Insulin Secretion Mechanism

Increased blood glucose triggers insulin secretion via exocytosis of insulin-containing vesicles from beta cells.
Membrane potential changes due to the ADP:ATP ratio influence potassium conductance, leading to insulin release.

Insulin Receptor Activation

Insulin binding causes receptor dimerization and activates tyrosine kinase, triggering a phosphorylation cascade.
Key pathways involved include the PI3K pathway (Akt and mTOR activation) and Ras-Raf-MEK-MAPK pathway for protein synthesis.

Insulin Resistance and Desensitization

Chronic high insulin levels lead to a decrease in insulin receptor expression through reduced synthesis and increased endocytosis.
Down-regulation of signaling pathways contributes to insulin resistance.

Regulation of Insulin Secretion

Nutrient stimulators: Major - glucose; Minor - amino acids (arginine, lysine), free fatty acids.
Hormonal stimulators include CCK, GIP, GLP-1, and parasympathetic innervation.
Inhibitors include somatostatin, epinephrine, and sympathetic nervous system activation.

Importance of Incretins

Incretins like GLP-1 enhance insulin release from the intestines, significantly affecting glucose metabolism.
Intravenous glucose does not stimulate incretin release, thus showing a smaller insulin response compared to glucose ingested orally.

Glucose Transport Mechanisms

Insulin promotes GLUT4 translocation to the membrane, crucial for glucose uptake in skeletal muscle and adipose tissue.
Insulin-independent transporters (SGLT-1, SGLT-2, GLUT-1, GLUT-2) are involved in various tissues.

Effects of Insulin on the Liver

Promotes glucose uptake and conversion to G-6-P, enhancing glycogenesis and glycolysis, while reducing glycogenolysis.

Glucagon Synthesis and Secretion

Proglucagon yields multiple peptides, including glucagon and incretins (GLP-1, GLP-2), depending on cleavage points.
Glucagon is secreted in response to low blood glucose, high serum amino acids, cortisol, and sympathetic activation.

Effects of Glucagon on the Liver

Increases glucose output through glycogenolysis and gluconeogenesis.
Results in enhanced beta-oxidation and ketogenesis due to ketone body production from fatty acids.

Acute Pancreatitis Basics

Severity varies from life-threatening to mild-moderate abdominal pain.
Characterized by acute, reversible injury and inflammation of the pancreas.
Incidence ranges from 10-20 cases per 100,000 individuals.
Major risk factors: excessive alcohol intake and gallstones (cholelithiasis); account for 80% of cases.

Etiologic Factors in Acute Pancreatitis

Metabolic Factors:
- Alcoholism, hyperlipoproteinemia, hypercalcemia.
- Certain drugs (e.g., azathioprine) can also trigger pancreatitis.
Genetic Factors:
- Mutations in cationic trypsinogen (PRSS1) and trypsin inhibitor (SPINK1) genes can lead to pancreatitis.
Mechanical Factors:
- Gallstones, trauma, and surgical endoscopic procedures can obstruct ducts.
Vascular Factors:
- Shock, atheroembolism, and vasculitis can impair blood flow.
Infectious Factors:
- Infections like mumps can contribute.

Role of Trypsinogen Activation

Trypsinogen activates other zymogens and may lead to autodigestion of the pancreas.
Knock-out studies indicate local/systemic inflammation resembling chronic pancreatitis, suggesting other mechanisms at play.

Pathophysiology of Acute Pancreatitis

Alcohol Ingestion:
- Results in excessive protein in secretions, duct blockage, and direct toxicity to acinar cells.
Biliary Obstruction:
- Gallstones or sludge causes retention of pancreatic secretions in ducts.
Common pathway: duct blockage leading to acinar injury and pancreatic damage.

Inflammatory Response

Cytokines such as IL-1β, IL-6, and tumor necrosis factor increase inflammation and edema.
Activation of complement and clotting cascades, and heightened interstitial pressure impair blood flow.
Can trigger systemic inflammatory response, causing leukocytosis, hemolysis, and acute respiratory distress syndrome (ARDS).

Pathological Features

Microvascular leakage and edema, fat digestion by lipolytic enzymes, acute inflammation, and proteolytic destruction of pancreatic tissue.
Severe cases show interstitial hemorrhage and necrosis with potential for saponification, leading to hypocalcemia.

Clinical Features

Abdominal pain: constant, intense, can refer to the upper back or shoulder.
Accompanies symptoms: anorexia, nausea, and vomiting.
Severe cases may lead to systemic complications, shock, and kidney failure.

Complications of Acute Pancreatitis

Potential complications include pseudocysts, chronic pancreatitis, infection of necrotic tissue, hemorrhage, and 5% mortality due to shock in the first week.

Chronic Pancreatitis

Results in irreversible destruction of exocrine and late-stage endocrine parenchyma.
Commonly caused by repeated episodes of acute pancreatitis and chronic alcohol abuse.
Other causes include cystic fibrosis and pancreatic tumors.

Pathophysiology of Chronic Pancreatitis

Ductal obstruction due to calcified protein plugs, oxidative stress from alcohol, damaging pancreatic cells.

Pathology of Chronic Pancreatitis

Characterized by parenchymal fibrosis, reduced acinar size/number, dilation of pancreatic ducts, and chronic inflammation around ducts.

Clinical Findings in Chronic Pancreatitis

Symptoms: repeated mild to moderately severe abdominal or back pain.
Disease can be silent until developing pancreatic insufficiency or diabetes, with a 50% mortality rate after 25 years.

Pseudocysts

Localized collections of necrotic-hemorrhagic material, without epithelial lining; account for 75% of pancreatic cysts.
Often follow acute pancreatitis or result from chronic pancreatitis.

Pathogenesis of Pseudocysts

Typically solitary; can occur within the pancreas or in surrounding areas (e.g., lesser omentum, retroperitoneum).
Formed by necrotic material walling off with fibrous tissue, varying in size from 2 to 30 cm.

Clinical Features of Pseudocysts

Symptoms mimic the underlying condition, often arising post-pancreatitis.

Anatomy and Histology of the Pancreas

Composed of four parts: head and uncinate process, neck, body, tail.
Main pancreatic duct merges with the common bile duct at the hepatopancreatic ampulla (Ampulla of Vater).
Accessory pancreatic duct drains into the minor duodenal papilla.
Measures approximately 25 cm in length, 5 cm in width, and 1-2 cm in thickness; considered a retroperitoneal structure.
Covered by a thin capsule with septa dividing it into lobes and lobules.

Pancreatic Arterial and Venous Supply

Arterial Supply:
- Head supplied by pancreaticoduodenal branches of the gastroduodenal artery and superior mesenteric artery.
- Neck, body, and tail supplied by branches of the splenic artery.
Venous Supply:
- Blood drains into the splenic vein and superior mesenteric vein.

Exocrine Function and Histology

Acinar cells are the functional units of the pancreas, forming a compound tubulo-acinar gland system.
Produce approximately 1200 ml of bicarbonate-rich fluid containing digestive enzymes daily.
Acinar cells are pyramidal-shaped columnar cells; they secrete inactive enzymes (zymogens) and are rich in rough endoplasmic reticulum (RER).
Centroacinar cells line the acinus’ lumen and secrete bicarbonate-rich fluid; stimulated by secretin.

Bicarbonate Secretion Mechanism

CO2 diffuses from blood into cells, forming bicarbonate (HCO3-) through a reaction catalyzed by carbonic anhydrase.
HCO3- is actively transported into ducts, sodium ions (Na+) follow into the ducts due to the negative charge of HCO3-.
This ion exchange creates osmotic pressure, drawing water into the duct.

Phases of Pancreatic Secretion

Cephalic Phase: Initiates via vagal nerve stimulation, contributing 20% of pancreatic secretion.
Gastric Phase: Nervous stimulation accounts for 5-10% of enzyme secretion.
Intestinal Phase: Triggered by the entry of chyme into the small intestine, leading to significant pancreatic secretion influenced by secretin and cholecystokinin (CCK).

Regulation of Pancreatic Secretion

Neural control: Cephalic and gastric phases primarily regulated by the nervous system.
Hormonal control: The intestinal phase is primarily regulated by hormones like secretin and CCK.
Secretin: Released when acidic chyme enters the duodenum, stimulating secretion of bicarbonate-rich fluid to neutralize gastric acid.
CCK: Released when fats and amino acids are present, stimulating enzyme secretion and gallbladder contraction.

Pancreatic Secretions Pathway

Secretions combine and flow through the pancreatic duct, joining the common bile duct before entering the duodenum at the major duodenal papilla, regulated by the sphincter of Oddi.

Proteolytic Enzymes of the Pancreas

Major types and activation:
- Pepsin (origin: stomach) activated by low pH; cleaves aromatic/hydrophobic amino acids.
- Trypsin (origin: pancreas) activated by entero-kinase; cleaves bonds next to lysine/arginine.
- Chymotrypsin, elastase, and carboxypeptidases further digest proteins into smaller peptides and single amino acids.

Proteolytic Enzymes Classification

Endopeptidases: Cleave peptide bonds within the chain (e.g., pepsin, trypsin, chymotrypsin).
Exopeptidases: Cleave peptide bonds at the carboxy-terminal end (e.g., carboxypeptidases A and B).

Protection Against Auto-Digestion

Trypsin inhibitor, secreted from acinar cells, prevents premature activation of trypsin, protecting pancreatic tissue from auto-digestion.

Overview of Type I Diabetes Mellitus

Diabetes is characterized by hyperglycemia due to defects in insulin secretion or action.
The term "diabetes" means excessive urination, while "mellitus" means sweet, referring to the sweet-smelling urine of patients.

Laboratory Diagnosis of Diabetes

Diagnosis is based on:
- Random blood glucose (RBG) > 11.1 mmol with classic symptoms.
- Fasting blood glucose (FBG) > 7.0 mmol on multiple occasions.
- Abnormal oral glucose tolerance test (OGTT) > 11.1 mmol after 1 hour on multiple occasions.
- Hemoglobin A1c > 6.5%.
Normal fasting glucose should be < 5.6 mmol.

Classification of Diabetes

Type 1 Diabetes (5-10%):
- Autoimmune destruction of pancreatic beta cells, often diagnosed in childhood or young adulthood.
Type 2 Diabetes (90-95%):
- Involves insulin resistance and inadequate insulin secretion.
Monogenic and Secondary Causes:
- Rare and can include single-gene disorders or secondary effects from infections or pancreatic damage.

Insulin Actions and Blood Glucose Regulation

Insulin is released when blood glucose rises, facilitating glucose uptake by tissues (muscle, liver, adipose) for energy or storage.

Pathology of Type I Diabetes

Reduction in islet number and size, with leukocytic infiltrates (primarily T-cells).
The immune response leads to inflammation and destruction of beta cells.

Pathogenesis of Type I Diabetes

Characterized by chronic metabolic disorder where the pancreas fails to produce adequate insulin.
Leads to inability of cells to use glucose, resulting in elevated blood glucose levels.

Honeymoon Phase

Remaining beta cells may exhibit hyperproductive activity, partially compensating for insulin deficiency initially.
Once remaining cells fail, deterioration of health occurs rapidly.

Clinical Features of Type I Diabetes

Rapid progression following significant beta-cell loss.
Initial presentation often includes diabetic ketoacidosis (DKA) characterized by:
- Symptoms of polyphagia, polydipsia, and polyuria.
- Severe dehydration and emaciation as glucose is not utilized for ATP production.
- Ketoacidotic state arises from fatty acid metabolism, lowering blood pH and affecting consciousness.

Volume Depletion in DKA

Elevated blood glucose causes osmotic diuresis leading to dehydration.
Increased thirst response due to higher blood osmolarity.
Potassium loss occurs from reduced function of Na+/K+ ATPase due to insulin deficiency.

Complications of Long-Term Hyperglycemia

Associated with small vessel disease (microangiopathy) and large vessel disease (macroangiopathy).
Can lead to diseases such as diabetic nephropathy, retinopathy, and neuropathy.

Advanced Glycation End Products (AGEs)

Formed from non-enzymatic linkage of glucose to protein, impacting vascular health.
Contribute to inflammation, oxidative stress, and coagulation issues.
May lead to decreased artery elasticity, atherosclerosis, and vascular complications in diabetes.

Diabetic Microangiopathy

Characterized by hyaline arteriolosclerosis and diffuse thickening of capillary basement membranes.
Increased permeability of diabetic capillaries leads to leakage and underlies complications like nephropathy and retinopathy.

Neuropathy in Diabetes

Loss of both small and large axons leads to diminished pain sensation.
Other sensory losses include vibration, proprioception, and fine touch.
Autonomic neuropathy can cause complications such as postural hypotension and sexual dysfunction.

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This quiz covers the processes involved in liver function, focusing on the biotransformation and degradation of various compounds. Key topics include the initial hydroxylation of Vitamin D and the deiodination of T4 to T3. Test your knowledge on how hepatocytes manage and transform these compounds.