Phases of Digestion

Digestion is divided into 3 phases, namely cephalic, gastric, and intestinal.

Cephalic phase

• Begins when the brain receives stimulatory sensory inputs about food from the chemo- and mechanoreceptors located in the oral and nasal cavities
• Sensory inputs capable of stimulating gastric activity include:
  • Seeing, smelling, tasting, or thinking about food
  • Chewing and swallowing
• Induces higher brain centers to stimulate the dorsal vagal complex (DVC)
• The vagus nerve (parasympathetic) releases acetylcholine (ACh), which leads to:
  • ↑ Salivary secretions
  • ↑ Gastric secretions ( HCl HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia, pepsinogen) → chemical digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption
  • ↑ Gastric motility → mechanical digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption

Gastric phase

• Begins when swallowed food enters the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach
• Stimuli include:
  • Chemical stimuli: e.g., the presence of proteins, peptides, and amino acids
  • Mechanical stimuli: e.g., stretching
• Stimuli trigger several reflexes → ↑ gastric secretions and motility
  • Short reflexes (local reflexes):
    • Contained within the enteric nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System (ENS)
    • Sensory signals travel to cell bodies in the ENS (located within the gut wall).
    • ENS coordinates the response → sends out a signal via the ENS efferents → ACh stimulates ↑ gastric secretions and GI motility
  • Long reflexes (vago-vagal reflexes):
    • Response is coordinated in the brain.
    • Sensory signals are transmitted to vagus nerve afferents → travels to the DVC in the medulla
    • DVC coordinates a response → sends out a signal via vagal nerve efferents to the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach → ACh stimulates gastric secretions and motility

Intestinal phase

• Begins when food leaves the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach and enters the duodenum
• Duodenum:
  • Modulates gastric activity via hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and neural reflexes:
    • Initially, the signals stimulate gastric activity.
    • Soon, the signals inhibit gastric activity.
  • Secretes signaling molecules (e.g., cholecystokinin) that stimulate secretions from the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas and gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract
• Absorption of nutrients begins.

Salivary Secretions

Functions of salivary secretions

• Protection of the oral cavity
• Lubrication
• Digestion of carbohydrates Digestion of carbohydrates Carbohydrates store energy and are used as a source of nutrition. To be used as energy by humans, most carbohydrates must be metabolized. Carbohydrate metabolism involves transforming complex starches into glucose, a monosaccharide that can subsequently be absorbed by the body. Digestion and Absorption of Carbohydrates and lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids

Salivary glands

There are 3 primary salivary glands Salivary glands The salivary glands are exocrine glands positioned in and around the oral cavity. These glands are responsible for secreting saliva into the mouth, which aids in digestion. There are 3 major paired salivary glands: the sublingual, submandibular, and parotid glands. Salivary Glands (all with a tubuloacinar structure), which together produce a combination of serous and mucous secretions.

• Parotid glands: serous secretion
• Submandibular glands: both serous and mucous secretions
• Sublingual glands: mainly mucous secretions, with a small serous component

Constituents of saliva

Saliva consists of:

• Water
• Mucus
• Electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes:
  • K⁺: assists in the reabsorption of Na⁺ and water
  • HCO₃^–: buffers acid
• Enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
  • Salivary amylase: starch digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption
  • Lingual lipase: lipid digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption
• Antimicrobial agents:
  • Muramidase: lysozyme (an enzyme that can destroy cell walls of certain bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview)
  • Lactoferrin: binds iron, which helps prevent bacterial growth
  • IgA: immune mediator (secreted antibody)

Saliva production

Overview:

• Saliva is produced by acinar cells in the salivary glands Salivary glands The salivary glands are exocrine glands positioned in and around the oral cavity. These glands are responsible for secreting saliva into the mouth, which aids in digestion. There are 3 major paired salivary glands: the sublingual, submandibular, and parotid glands. Salivary Glands as a filtrate.
• Modified by ductal cells as it moves through the ducts
• Salivary glands secrete approximately 1‒1.5 L of saliva daily.

Acinar cells:

Acinar cells secrete a filtrate containing Na⁺, K⁺, Cl^–, HCO₃^–, water, and other substances.

• Na⁺/K⁺ ATPase pump keeps:
  • K⁺ concentrated within acinar cells
  • Na⁺ concentrated in the interstitial space
• Movement of Na⁺:
  • Na⁺ moves paracellularly to the acini lumen down its concentration gradient → Na⁺ is secreted in saliva
  • Brought into acinar cells via the Na⁺/Cl^– cotransporter on the basolateral membrane → Na⁺ is transported to the interstitial space with H⁺
• Movement of water:
  • Water follows Na⁺ into the lumen through the aquaporin channels in acinar cells.
  • Isosmotic movement
• Movement of K⁺:
  • Concentrated within acinar cells due to the action of the Na⁺/K⁺ ATPase pump
  • Moves via K⁺ channels down its concentration gradient into the lumen
• Movement of Cl^–, H⁺, and HCO₃^–:
  • CO₂ is produced during metabolism → CO₂ combines with H₂O → carbonic acid (H₂CO₃) → splits into H⁺ and HCO₃^–
  • H⁺ and Na⁺ are transported into the interstitial space via the H⁺/Na⁺ cotransporter on the basolateral membrane.
  • HCO₃^– (from metabolism) and Cl^– (from the Na⁺/Cl^– basolateral cotransporter) are secreted via the HCO₃^–/Cl^– cotransporter on the apical (lumenal) membrane
• Produce and secrete other substances (e.g., mucin, enzymes) into the acini

Ductal cells:

Ductal cells modify the filtrate as it moves through the ducts, ultimately reabsorbing Na⁺ and Cl^– and secreting more K⁺ and HCO₃^–.

• Reabsorption of Na⁺ and secretion of K⁺:
  • Na⁺ and H⁺ are reabsorbed across the apical membrane via the Na⁺/H⁺ cotransporter.
  • Na⁺ is pumped out across the basolateral membrane into the interstitial space via the Na⁺/K⁺ ATPase pump.
  • H⁺ is recycled back into the lumen while K⁺ is secreted: H⁺ and K⁺ are moved across the apical membrane via the H⁺/K⁺ cotransporter.
• Reabsorption of Cl^– and secretion of HCO₃^–:
  • CO₂ is produced during metabolism → CO₂ combines with H₂O → H₂CO₃ → splits into H⁺ and HCO₃^–
  • HCO₃^– is exchanged for Cl^– on the apical membrane (HCO₃^– is secreted and Cl^– is reabsorbed into the ductal cell) via the HCO₃^–/Cl^– countertransporter.
  • Cl^– is reabsorbed into the interstitial space via Cl^– channels.
  • H⁺ (left over from the carbonic anhydrase reaction) is removed across the basolateral membrane via the H⁺/Na⁺ countertransporter (Na⁺ is moving down its concentration gradient into the cell).
• As water is not reabsorbed (but some ions are), the resulting saliva is hypotonic.

• 

Control and regulation of salivary secretions

• Involved in the cephalic phase of digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption:
  • Sensory input capable of stimulating salivation:
    • Thinking about food
    • Seeing, smelling, or tasting food
  • Induces higher brain centers to stimulate the ANS (primarily the parasympathetics)
• Parasympathetic stimulation increases salivary secretions via:
  • ACh: increases salivary secretions
  • Vasoactive intestinal peptide (VIP): increases blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure to salivary glands Salivary glands The salivary glands are exocrine glands positioned in and around the oral cavity. These glands are responsible for secreting saliva into the mouth, which aids in digestion. There are 3 major paired salivary glands: the sublingual, submandibular, and parotid glands. Salivary Glands
• Sympathetic stimulation: increases salivary secretions to a lesser degree via norepinephrine release

Clinical relevance of salivary secretions

Xerostomia, or dry mouth, is the clinical term used to identify impaired salivary secretion, which occurs commonly as part of Sjögren syndrome, as an adverse effect of some medications (such as antidepressants, antihypertensives, or anticholinergics), and in individuals undergoing radiation therapy for head and neck cancers.

Gastric Secretions

Functions of the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach

• Protecting the rest of the GI system by killing most microbes
• Preparation of chyme for the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine via:
  • Mechanical breakdown
  • Chemical digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption by acid and pepsinogen
• Absorption of lipophilic substances
• Storage and gradual release of material into the duodenum (regulates food entering the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine)

Gastric oxyntic glands: cells and their secretions

Gastric oxyntic glands are found below (and emptying into) the gastric pits. The glands contain numerous cell types, including:

• Surface mucous cells:
  • Line the gastric pits
  • Secrete bicarbonate and insoluble mucus:
    • Form a protective barrier against the acidic environment of the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach
    • Concentrate bicarbonate in the mucus
• Mucous neck cells:
  • Located in the neck of the glands where they join the gastric pits
  • Secrete soluble mucus
• Stem cells:
  • Found between the pits and the entrance of the glands
  • Produce new cells to replace both surface mucous cells in the pits and the glandular cells below
  • Stomach epithelial cells are replaced every 3‒6 days.
• Parietal cells:
  • Located in the lower-middle region of the glands
  • Secrete:
    • HCl HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia
    • Intrinsic factor: important for vitamin B12 Vitamin B12 Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
• Chief cells:
  • Most numerous glandular cells
  • Located in the lower-middle region of the glands
  • Secrete:
    • Pepsinogen → converted to its active form pepsin by HCl HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia → breaks down proteins
    • Gastric lipase → breaks down fats
• Enteroendocrine cells:
  • Located in the base of the glands
  • D cells secrete somatostatin:
    • Inhibition of many secretions
    • Released in response to H⁺ (the natural way to “turn off” acid production)
  • G cells secrete gastrin:
    • Stimulates parietal cells to secrete HCl HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia
    • Has trophic/growth effects on the GI mucosa
    • Released in response to proteins, peptides, and amino acids
  • Enterochromaffin-like (ECL) cells secrete histamine (which stimulates parietal cells to secrete HCl HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia).
  • Other chemical messengers secreted by enteroendocrine cells:
    • Substance P
    • VIP
    • Secretin
    • Neuropeptide Y

• 

• 

Production and secretion of acid in parietal cells

• Normal metabolism produces CO₂ → combines with H₂O → H₂CO₃ → splits into H⁺ + HCO₃^–
• H⁺ is pumped out to the lumen in exchange for K⁺ by H⁺/K⁺ ATPase:
  • 1 K⁺ molecule is brought into the cell.
  • K⁺ leaves the cell through the basolateral membrane down its concentration gradient through a K⁺ channel.
• HCO₃^– is exchanged with Cl^– across the basolateral membrane:
  • HCO₃^– is moved into the interstitial space.
  • Cl^– is brought into the cell → moves into the lumen through its own channel
• End result:
  • H⁺ and Cl^– are secreted into the lumen.
  • K⁺ and HCO₃^– are moved into the interstitial space.

Control and regulation of gastric secretions

Gastric secretions are heavily influenced by parasympathetic signaling via the vagus nerve (cranial nerve X), which releases ACh that induces acid production by several pathways.

• Production of secretions:
  • 40% in the cephalic phase
  • 50% in the gastric phase
  • 10% in the intestinal phase
• HCl HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia secretion from parietal cells is stimulated by:
  • ACh from the vagus and myenteric nerves (long and short reflex pathways, respectively)
  • Gastrin from G cells in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach
  • Histamine from ECL cells in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach
• HCl HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia secretion is inhibited by:
  • Somatostatin
  • Prostaglandins

Acid-stimulation pathways

• Direct pathway (direct activation of parietal cells):
  • ACh stimulates the muscarinic (M₃) receptors of parietal cells.
  • Activates G_q (a G protein)
  • G_q activates phospholipase C (PLC).
  • PLC cleaves phosphatidylinositol-4,5-bisphosphate (PIP₂) to produce:
    • Inositol trisphosphate (IP₃) → calcium (Ca²⁺) release from the ER
    • Diacylglycerol (DAG) → phosphorylation of protein kinase (PK) C
  • Both Ca²⁺ and PKC activate the H⁺/K⁺ ATPase to secrete H⁺.
• Gastrin pathway:
  • ACh stimulates G cells to release gastrin.
  • Gastrin activates cholecystokinin B receptors on parietal cells.
  • Cholecystokinin B activates PLC → cleaves PIP₂ into IP₃ + DAG → ↑ Ca²⁺ + PKC → ↑ H⁺/K⁺ ATPase activity
• Histamine pathway:
  • ACh stimulates ECL cells to release histamine.
  • Histamine activates H₂ receptors on parietal cells.
  • H₂ receptors activate G_s (a G protein).
  • G_s activates adenylate cyclase (AC).
  • AC converts ATP to cAMP.
  • cAMP phosphorylates/activates PKA.
  • PKA stimulates H⁺/K⁺ ATPase to secrete H⁺.
• The effects of these pathways are potentiating/synergistic in nature → ACh + gastrin + histamine activity simultaneously results in greater HCl HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia secretion than the sum of HCl HCL Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia secretion if they each acted alone

• 

• 

Acid-inhibition pathways

Somatostatin and prostaglandins:

• Somatostatin (released from D cells in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach) and prostaglandins activate the inhibitory G_i protein.
• G_i inhibits AC → cAMP levels fall → ↓ activation of PKA → ↓ H⁺/K⁺ ATPase activity

Clinical relevance of gastric secretions

• GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease: occurs when the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach acid frequently flows back into the esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus. The backwash (acid reflux) can irritate the lining of the esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus, causing symptoms such as retrosternal burning pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain (heartburn) and may eventually lead to inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation ( esophagitis Esophagitis Esophagitis is the inflammation or irritation of the esophagus. The major types of esophagitis are medication-induced, infectious, eosinophilic, corrosive, and acid reflux. Patients typically present with odynophagia, dysphagia, and retrosternal chest pain. Esophagitis), metaplasia (Barrett esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus), and progression to esophageal cancer Esophageal cancer Esophageal cancer is 1 of the most common causes of cancer-related deaths worldwide. Nearly all esophageal cancers are either adenocarcinoma (commonly affecting the distal esophagus) or squamous cell carcinoma (affecting the proximal two-thirds of the esophagus). Esophageal Cancer. Uncomplicated GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease can be managed with lifestyle changes and over-the-counter medications.
• Barrett esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus: a condition characterized by metaplastic changes in the normal stratified squamous epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium of the esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus to columnar epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium. The change is a consequence of chronic GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease and is considered premalignant.
• Medications to reduce gastric acid secretions: Drugs include proton pump inhibitors (PPIs) and H₂ receptor antagonists and are most commonly indicated in treating peptic ulcer disease Peptic ulcer disease Peptic ulcer disease (PUD) refers to the full-thickness ulcerations of duodenal or gastric mucosa. The ulcerations form when exposure to acid and digestive enzymes overcomes mucosal defense mechanisms. The most common etiologies include Helicobacter pylori (H. pylori) infection and prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs). Peptic Ulcer Disease ( PUD PUD Peptic ulcer disease (PUD) refers to the full-thickness ulcerations of duodenal or gastric mucosa. The ulcerations form when exposure to acid and digestive enzymes overcomes mucosal defense mechanisms. The most common etiologies include Helicobacter pylori (H. pylori) infection and prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs). Peptic Ulcer Disease), GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease, and dyspepsia. The mechanism of action of PPIs in reducing gastric acid is by inhibiting the H⁺/K⁺ ATPase in parietal cells, whereas that of H₂ blockers is by inhibiting the stimulatory effects of histamine on parietal cells.
• Zollinger-Ellison syndrome (ZES): a gastrin-secreting tumor (often malignant) arising from the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas, stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach, duodenum, jejunum, and/or lymph nodes, which is characterized by recurrent/refractory peptic ulcers, gastroesophageal reflux, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea. Diagnosis is based on elevated fasting serum gastrin levels. Treatment is with surgical resection of the tumor and/or symptomatic management.

Pancreatic Secretions

Types of pancreatic tissue

There are 2 types of pancreatic tissues:

• Exocrine (85% by mass):
  • Release pancreatic enzymes into the duodenum
  • Arranged as clusters of acini draining into a ductal system → main and accessory pancreatic ducts → duodenum
• Endocrine:
  • Releases hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview into the bloodstream
  • Cells are located in clusters known as islets.
  • α cells: secretion of glucagon
  • β cells: secretion of insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin
  • 𝛿 cells: secretion of somatostatin

Exocrine pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas secretions

The exocrine pancreas Exocrine pancreas The major component (about 80%) of the pancreas composed of acinar functional units of tubular and spherical cells. The acinar cells synthesize and secrete several digestive enzymes such as trypsinogen; lipase; amylase; and ribonuclease. Secretion from the exocrine pancreas drains into the pancreatic ductal system and empties into the duodenum. Pancreas secretes a mixture known as pancreatic juice, which contains water, enzymes, zymogens (inactive proteins), HCO₃^–, and electrolytes:

• Buffer (neutralizes acid from the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach): HCO₃^–
• For carbohydrate digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption: pancreatic amylase
• For lipid digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption:
  • Pancreatic lipase
  • Phospholipase A₂
  • Cholesterol esterase
• For protein and peptide digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption (secreted primarily as zymogens):
  • Trypsinogen → activated by enterokinase (a glycoprotein bound to the brush border) to trypsin
  • Chymotrypsinogen → activated by trypsin to chymotrypsin Chymotrypsin A serine endopeptidase secreted by the pancreas as its zymogen, chymotrypsinogen and carried in the pancreatic juice to the duodenum where it is activated by trypsin. It selectively cleaves aromatic amino acids on the carboxyl side. Pancreatic Parameters
  • Procarboxypeptidase → activated by trypsin to carboxypeptidase
  • Proelastase → activated by trypsin elastase
• For nucleotide digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption:
  • Ribonuclease (RNAse)
  • Deoxyribonuclease (DNAse)

Ion concentrations in pancreatic juice

• HCO₃^–:
  • Actively secreted: concentration in pancreatic juice > that in plasma
  • Secretion increases as flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure rate increases.
• Cl^–:
  • Actively reabsorbed: concentration in pancreatic juice < that in plasma
  • Reabsorption drops as flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure rate increases.
• Mechanism of HCO₃^– secretion and Cl^– reabsorption:
  • CO₂ enters cells → combines with water to form H₂CO₃ → splits into H⁺ and HCO₃^–
  • H⁺ is moved back across the basolateral membrane into the interstitial space via the H⁺/Na⁺ exchanger.
  • HCO₃^– is secreted across the apical membrane into the lumen via the HCO₃^–/Cl^– exchanger.
  • Cl^– can be recycled back into the lumen through the Cl^– channel.
  • Na⁺ is removed from the cell to across the basolateral membrane via the Na⁺/K⁺ ATPase exchanger.
• Na⁺ and K⁺ are neither actively secreted nor reabsorbed:
  • Concentration in pancreatic juice is similar to that in the plasma.
  • Some Na⁺ moves paracellularly into the lumen.
  • Water follows Na⁺ into the lumen.

• 

• 

Control and regulation

Percentage of secretions produced:

• 25% in the cephalic phase, stimulated primarily by ACh released from the vagus nerve
• 10% in the gastric phase, stimulated primarily by vago-vagal reflexes
• 65% in the intestinal phase, stimulated by secretin and cholecystokinin, both of which are hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview released in the duodenum

Secretion stimulation:

• Release of secretin and cholecystokinin from the duodenum:
  • Acidic content in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach induces the release of secretin.
  • Amino acids and fats induce the release of cholecystokinin.
  • Secretin and cholecystokinin enter the bloodstream and are transported to the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas.
• Neural stimulation:
  • Direct stimulation by the vagus nerve (ACh)
  • Stimulation via other neurotransmitters:
    • VIP
    • Gastrin-releasing peptide (GRP)
• 2 major intracellular pathways trigger the secretion of pancreatic juices:
  • ↑ In intracellular cAMP, which is caused by:
    • Secretin
    • VIP
  • ↑ In intracellular Ca²⁺:
    • ACh
    • Cholecystokinin
    • GRP
  • Both pathways result in phosphorylation of structural and regulatory proteins → induce docking and fusion of secretory granules → proteins are secreted into acini

Clinical relevance of pancreatic secretions

• Acute pancreatitis Acute pancreatitis Acute pancreatitis is an inflammatory disease of the pancreas due to autodigestion. Common etiologies include gallstones and excessive alcohol use. Patients typically present with epigastric pain radiating to the back. Acute Pancreatitis: occurs when pancreatic enzymes are retained within the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas, resulting in self- digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption. Acute pancreatitis Acute pancreatitis Acute pancreatitis is an inflammatory disease of the pancreas due to autodigestion. Common etiologies include gallstones and excessive alcohol use. Patients typically present with epigastric pain radiating to the back. Acute Pancreatitis can occur due to obstruction (e.g., gallstones, cancer in the head of the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas) and can be seen in cases of cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis.
• Cystic fibrosis: an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder caused by mutations in the CFTR gene. Mutations lead to dysfunction of the Cl^– channels, resulting in the formation of hyperviscous mucus. Hyperviscous mucus obstructs the flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure of pancreatic juice and bile in the GI tract, resulting in maldigestion Maldigestion Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion, malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion, and progressive liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and pancreatic disease. Common presentations include chronic respiratory infections, failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive, and pancreatic insufficiency (due to loss of exocrine function).

Hepatobiliary Secretions (Bile)

Bile

• Synthesized by hepatocytes
• Transported to the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract (via the hepatic and cystic ducts) for storage
• Primary function: emulsification (rather than digestion Digestion Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Digestion and Absorption) of fats

Components of biliary secretions (i.e., bile)

• Bile salts
• Cholesterol
• Lecithin
• Bilirubin
• Ions

Bile concentration in the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract

The primary function of the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract is the storage and concentration of bile. Bile can be concentrated in the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract by about 5%‒20% through dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration:

• Na⁺:
  • Reabsorbed from the lumen in exchange for H⁺ via the Na⁺/H⁺ exchanger in the apical membrane
  • Na⁺ within the cell is then pumped across the basolateral membrane into the interstitial space in exchange for K⁺ via the Na⁺/K⁺ ATPase.
• Cl^–:
  • Reabsorbed from the lumen in exchange for HCO₃^– via the HCO₃^–/Cl^– exchanger in the apical membrane
  • Cl^– within the cell moves to the interstitial space through the Cl^– channels in the basolateral membrane.
• Water follows NaCl:
  • Moves from the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract lumen into the interstitial space
  • Via transcellular Transcellular The movement of one cell into, through, and out of another cell. The Tubular System and paracellular movement

Control and regulation

Bile is continuously produced by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver; thus, regulation is via release from the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract.

• The primary mediator is cholecystokinin, which has 2 main effects:
  • Gallbladder contraction
  • Relaxation of the sphincter of Oddi
• Other regulators:
  • Vagus nerve: weak stimulator of gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract contraction
  • Inhibitors of bile release:
    • Somatostatin
    • Norepinephrine

Intestinal Secretions

• Intestines secrete about 1‒2 L of intestinal juice per day.
• Secretions released into the lumen:
  • Mucus
  • Serous fluid
• Functions of intestinal juice:
  • Protection of the intestinal walls
  • Regulation of GI function
  • Minimal secretions for digestive functions (i.e., secretions contain very few enzymes)
• Secretions released into the blood (i.e., hormonal signaling molecules):
  • Secretin
  • Cholecystokinin
  • GIP
  • Motilin
  • Small amounts of gastrin