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Flashcards in GI Midterm Deck (223):

What are the fat soluble vitamins? Describe their storage and digestion


2) stored in liver and adipose tissue, can be stored for a long time and released as needed

3) Vitamins released when proteins are degraded into small peptides in the stomach (first step of digestion same for water- and fat- soluble vitamins)--> in jejunum, vitamins form micelles with bile salts --> passively transported to intestinal enterocytes (intestinal absorptive cells) --> packaged into chylomicrons and released into lymphatic system --> Travel up thoracic duct --> enter left subclavian vein --> blood circulation

*as opposed to water soluble vitamins, which are directly absorbed into the bloodstream*


Vitamin A:
1) biologically active form(s)
2) sources
3) functions
4) transport
5) excretion

1) Retinyl ester (food) --> retinol --> retinal --> retinoic acid; beta-carotene (food) --> retinal *(retinol, retinal, and retinoic acid are all forms of Vit A)*

2) Sources: retinyl ester from animal foods e.g. liver, beta-carotene from orange root vegetables e.g. sweet potatoes, carrots, retinol from milk and milk products

3) Functions: Retinol --> supports reproduction; Retinal --> vision *esp important for night vision*; Retinoic acid --> acts as transcription factor for proteins involved in cell differentiation of epithelial and goblet cells, growth, and embryonic development; Beta carotene --> antioxidant (immunity)

4) transported bound to retinol-binding proteins

5) small amount excreted in the urine


Describe the pharmacological uses of retinoids (Vitamin A)

-treatment of anemia
-acne and age spots
-Accutane - oral medication for severe acne, *teratogenic so women need to be on birth control*


Describe Vit A deficiency including causes, symptoms,

1) Causes: primary - inadequate intake, develops over 1-2 years; secondary - poor absorption of fats due to liver disease, cystic fibrosis, etc.

2) Symptoms: night blindness, dry eyes (due to reduction in goblet cells), Bitot gray spots (due to keratin buildup), hyperkeratosis (skin becomes dry rough and scaly), inflammation (ulcers) and softening of the cornea --> eventually blindness, impaired immunity


Describe Vit A toxicity including causes, symptoms

1) Causes: frequent consumption of liver (Abali's example is polar bear liver), use of retinoic acid analogues e.g. Accutane during pregnancy to treat skin conditions

2) Symptoms: birth defects- craniofacial and defects of CNS, thymus, heart; reduced bone mineral density, liver + spleen enlargement, diarrhea, bone/joint pain, dermatitis

*beta-carotene excess not harmful, just turns skin yellow*


Vitamin D:
1) biologically active form(s)
2) sources
3) functions

1) Precursor derived from cholesterol in liver + UV light --> Calciferol/Vitamin D3 synthesized in skin --> hydroxylated in liver --> hydroxylated in kidneys by 1OHase --> active form = calcitriol = 1,25(OH)2D3

2) Source: need UV light (from sun) to activate, Vit D3 found in fish, fortified milk, mushrooms

3) Functions: acts as at transcription factor to increase Ca2+ absorption via CaBP from small intestine, kidney; works with PTH in bone resorption; inflammation reduction and bp regulation


Describe Vitamin D deficiency including causes, types, symptoms

1) Causes: dark skin, lack of sunlight, little dairy in diet, old people, vegans, exclusive breastfeeding (low levels of Vit D in breastmilk)

2) Types: rickets (infants) and osteomalacia (adults)

3) Rickets- bones do not calcify properly --> big head, bowed legs, growth retardation;
Ostomalacia- chronic kidney disease/anticonvulsants --> soft flexible brittle bones due to poor mineralization, + pain in legs, pelvis, lower back


Describe Vitamin D toxicity including causes, symptoms

1) Causes: occurs due to supplementation (not from excessive sunlight)

2) Symptoms: buildup of calcium which precipitates in blood vessels, kidney, heart, lungs --> can cause kidney stones, death


Vitamin E:
1) biologically active form(s)
2) sources
3) functions

1) Tocopherol (only 1 of 8 isomers is active)

2) Sources: nuts and vegetable oils, though Vit E is easily destroyed by frying

3) Function: primary defender against ROS and free radicals by donating H+ --> protects cell membrane integrity, primary lipid soluble antioxidant --> prevents platelet aggregation and monocyte adhesion; protects Vitamin A from oxidation

*after it donates its H+, vitamin E is regenerated by Vitamin C*; *Vitamin E works in concert with selenium*


Describe Vitamin E deficiency in terms of causes and symptoms

1) Causes: primary- inadequate intake (rare), secondary - fat malabsorption

2) Symptoms: hemolytic anemia due to oxidation of polyunsaturated fatty acids, nerve damage


Describe Vitamin E toxicity in terms of causes and symptoms

1) Causes: v high doses (nontoxic at low doses)

2) Symptoms: hemorrhage, since Vit E interferes with Vit K role in blood clotting


Vitamin K:
1) biologically active form(s)
2) sources
3) functions

1) Menaquinones, phylloquinones

2) Sources: menaquinones synthesized by bacteria in our gut, or found in fish oils and meats; phylloquinones found in green leafy vegetables, broccoli

3) Functions: Vit K is cofactor for Glu --> Gla (blood coagulation), rxn catalyzed by gamma-glutamyl carboxylase *know this enzyme*


Describe Vitamin K deficiency in terms of causes, symptoms

1) Causes: rare since gut bacteria synthesize K, secondary deficiencies due to antibiotics, infection, or malabsorption; newborns do not have the gut bacteria so given bolus of Vit K after birth

2) Symptoms: Hemorrhage, bruising, mucosal bleeding


Describe Vitamin K toxicity in terms of causes, symptoms

No toxicity known

However, patients on coumadin (Anticoagulant which inhibits Vitamin K) should be careful not to eat too many Vit K rich foods bc it will lessen effectiveness of warfarin --> potentially lead to clots


Describe the interrelationships between the fat-soluble vitamins

Vitamin E: protects A from oxidation, is regenerated by C (primary water-soluble antioxidant), and impairs activity of K (blood clotting)

A, D, K play roles in bone growth and remodeling


Describe the digestion and absorption of water-soluble vitamins

1) Vitamins bound to protein are hydrolyzed and degraded into small peptides in the stomach --> frees vitamins from protein partners

2) Absorbed in upper small intestine (Except for B12, which is absorbed in the ileum)

3) Absorbed into portal vein and transported into liver

4) B12 is stored in the liver, the other water soluble vitamins are sent directly into the bloodstream

5) Excess vitamins excrete in urine --> need daily consumption of vitamins


Describe the differences between water and fat soluble vitamins in terms of:
1) Absorption
2) Transport
3) Storage
4) Excretion
5) Toxicity
6) Intake requirements

1) Absorption: water vitamins directly into the bloodstream, fat vitamins into lymphatic system and then the bloodstream

2) Transport: water vitamins move freely, fat vitamins may be bound to protein carriers

3) Storage: water vitamins circulate freely in water-filled parts, fat vitamins stored in cells

4) Excretion: excess water soluble vitamins excreted, fat soluble vitamins tend to remain in fat storage sites

5) Toxicity: water rare unless mega dose supplements, fat more likely due to long-term storage

6) Intake: water needed frequently, fat vitamins needed in periodic doses


What are the B water-soluble vitamins?

*Many coenzymes are derived from water soluble vitamins*

The - Thiamine, B1
Rhythm - Riboflavin, B2
Nearly - Niacin, B3
Proved - Pyridoxine, B6
Fully - Folate, B9
Contagious - Cobalamin, B12


B1, Thiamine:
1) biologically active form(s)
2) sources
3) functions

1) Active form: TPP - Thiamin pyrophosphate *absorption reduced with alcohol consumption, folate B9 deficiency*

2) Sources: meats, sunflower seeds, fortified cereals

3) Functions: found in tissues with high metabolic rate e.g brain, skeletal muscle heart -- plays role in conversion of carbs to energy bc coenzyme for 4 enzymes: A) pyruvate dehydrogenase (PDH), B) alpha ketoglutarate dehydrogenase, C) branched chain alpha ketoacid dehydrogenase, D) transketolase


Describe B1 thiamine deficiency and toxicity in terms of causes, symptoms

1) Rare but found in homeless, people on Atkins, alcoholics (can progress to Wernicke-Korsakoff syndrome --> brain damage + psychosis)

2) Early symptoms: Poor appetite, weight loss, confusion, irritability

3) Late symptoms: beriberi- wet (edema, due to congestive heart failure) and dry (muscle wasting, neurological disorders)

4) No toxicity reported


B2, Riboflavin:
1) biologically active form(s)
2) sources
3) functions

1) Active form: Circulates bound to albumin, metabolized to active forms flavin mononucleotide (FMN) and FAD once taken up into the cells
*UV light, radiation destroy riboflavin but heat does not*

2) Sources: beef liver, milk producta

3) Functions: Prosthetic groups for enzymes participating in redox reactions by conversion between FAD FADH2


Describe B2 riboflavin deficiency and toxicity in terms of causes, symptoms

1) Causes: Inflammation of membranes

2) Symptoms: cheilosis (cracks at the corner of the mouth), glossitis (tongue inflammation), stomatitis (mouth inflammation), bloodshot eyes sensitive to light, flaky and scaly skin on the scalp and face

3) No toxicity reported


B3, Niacin:
1) biologically active form(s)
2) sources
3) functions

1) Active form: NAD and NADP, circulates in the blood as nicotinamide and can be made from tryptophan

2) Sources: protein-rich foods e.g. chicken, fish, peanut butter, also fortified cereal

3) Functions: coenzyme in redox rxns for breakdown of glucose, AA, fats, DNA


Describe B3 niacin deficiency and toxicity in terms of causes, symptoms

1) causes: corn-based diet, alcoholics

2) Early symptoms: loss of appetite, fatigue, weakness, depression

3) Late symptoms: Pellagra ("rough skin") - 4Ds: Diarrhea, dermatitis, dementia, and unresolved death

4) Toxicity: from supplementation to dyslipidemia (lower LDL), niacin flush which can be avoided by taking low dose aspirin or ibuprofen


B6, Pyrodoxine:
1) biologically active form(s)
2) sources
3) functions

1) Active forms: pyridoxal phosphate (PLP), converted from pyridoxal, pyridoxine, and pyridoxamine; stored in muscle tissue

2) Sources: oatmeal, banana, pistachios, pinto beans

3) Functions: Coenzyme for metabolism of amino acids and urea; conversion of tryptophan to niacin; synthesis of heme; synthesis of neurotransmitters e.g. serotonin, dopamine, norepi


Describe B6 pyridoxine deficiency and toxicity in terms of causes, symptoms. What are the pharmacological uses of B6?

1) Causes: alcoholics, women on OCPs, drug interactions (e.g. isoniazid for TB, penicillamine for Rheumatoid Arthritis)

2) Symptoms: cheliosis, glossitis, dermatitis (like in pellagra, since B6 deficiency can cause niacin B3 deficiency), depression, confusion

3) Toxicity: irreversible nerve degeneration

4) Pharma uses: treatment of carpal tunnel, asthma, depression, diabetic neuropathy


B9, Folate:
1) biologically active form(s)
2) absorption
3) sources
4) functions

1) Active forms: many active forms, including tetrahydrofolate

2) Absorption: Polyglutamate in food --> all glutamates but one removed in small intestine --> folate methylated in epithelial cells --> released into circulation as methyltetrahydrofolate (inactive) and taken up by cells --> B12 activates folate and in the process becomes activated

3) Sources: dark leafy vegetables, liver, fortified breads and cereals, orange juice, lentils

4) Functions: synthesis of DNA, RNA, some AA esp for rapidly dividing cells e.g. RBCs, epithelial cells


Describe B9 folate deficiency and toxicity in terms of causes, symptoms.

1) Causes: inadequate absorption e.g. Celiac's, Crohn's, increased utilization e.g. pregnancy, cancer therapy (antifolates prescribed), alcoholics, elderly with poor diet, antacids

2) Symptoms: megaloblastic anemia - weakness, fatigue, headache, palpitations; folate deficiency can lead to neural tube defects in babies e.g. spina bifida, anencephaly- so women should take folate supplements;
*B12 deficiency also leads to megaloblastic anemia, but there are neurotoxic symptoms involved*

3) Toxicity: Folate supplementation may mask B12 deficiency--> irreversible neurologic deterioration; give both folate and B12 supplements


B12, Cobalamin:
1) biologically active form(s)
2) absorption
3) sources
4) functions

1) Active forms: methylcobalamin, deoxyadenosylcobalamin

2) Absorption: salivary glands produce R protein --> B12 + R move to stomach where B12 is released from meat protein partner (bc of the acidity) and binds to R; intrinsic factor (IF) released from parietal cells --> in duodenum, pancreatic enzymes cleave R, and B12 binds to IF --> IF receptors at distal ileum allow internalization of B12 --> enters portal vein, delivered to liver --> can be stored for years

3) Sources: animal products (product of bacterial fermentation in animals) + fortified or fermented foods e.g. soy milk

4) Functions: works with folate to synthesize DNA, RNA, AA; metabolism of fatty acids to maintain nerve cells


Describe B12 cobalamin deficiency and toxicity in terms of causes, symptoms.

1) Causes: decreased uptake in vegans (bc found in animal products), malabsorption due to decreased IF (autoimmune disease that kills parietal cells, which produce IF), decreased gastric acid (due to antacids/PPI, need HCl to remove B12 from bound protein), bypass/removal of terminal ileum (eg gastric bypass surgery)

2) Symptoms: pernicious anemia (IF deficiency), megaloblastic macrocytic anemia (B12 + folate deficiency), nerve damage/neurotoxicity + and swollen tongue (just B12 deficiency)

3) Toxicity: N/A


Describe the function and deficiency of B7 biotin

1) Function - coenzyme in carboxylation rxns (Adds C02), required for metabolism of carbs, fats, and proteins

2) Defiency is rare but can be due to enzyme deficiency or consumption of raw eggs (egg whites contain avidin which binds to biotin) --> weak muscles, seizures, alopecia, lactic aciduria


Describe the source, form, function and deficiency of B5 pantothenic acid

1) Source: meat, milk, veggies

2) Active form: part of coenzyme A

3) Function: Activation of fatty acids --> important in lipid metabolism

4) Deficiency/toxicity: none reported


Vitamin C, Ascorbic acid:
1) sources
2) functions
3) deficiency
4) Toxicity

1) Sources: citrus fruits

2) Function: cosubstrate for 2 enzymes used collagen formation (anchoring teeth, wound healing, tissue repair) - proline hydroxylase and lysine hydroxylase, water soluble antioxidant (donates electrons to ROS), synthesis of neurotransmitters (e.g. norepi), synthesis of carnitine (fatty acid degradation), absorption of non-heme iron

3) Deficiency: Scurvy due to alcohol, smoking, burns, old age; symptoms --> muscle weakness, loose teeth, bleeding gums, joint pain, bruised skin

4) Toxicity: diarrhea + GI distress; Vitamin C metabolized to oxalic acid, so people with tendency to form kidney stones should avoid high levels of Vit C


What are minerals? What are the two groups of minerals and what are the differences between them?

1) Minerals - essential, inorganic elements required for maintaining normal body functions e.g. blood clotting, nerve impulses, bone health and growth, and as antioxidants and electrolytes; come from both plant and animal sources

2) Macrominerals - required in large amounts (greater than 100 mg/day), include Ca, P, K, S, Na, Cl, Mg;

Microminerals/trace minerals - need less than 100 mg/day


What is bioavailability? What factors affect positively or negatively

1) Bioavailability - extent to which amount of ingested nutrient is absorbed and available in the body

2) Factors that increase bioavailability: deficiency in a mineral increases absorption, cooking for legumes (breaks bond bw mineral and binders), Vitamin C for iron, zinc

3) Factors that decrease: binders including oxalates (found in veggies), phytates (Grains), polyphenols (Tea + coffee), goitrogens (iodine); too much of one mineral can affect absorption of competing minerals e.g. Zinc supplementation can reduce copper toxicity

Overall, absorption efficiency of minerals is low and tightly controlled


Iron (trace mineral):
1) Source
2) Forms
3) Functions
4) Transport

1) Source: clams, fish + meat + poultry, whole grains, legumes; Heme iron only from animal foods (e.g. meat, eggs, milk) - smaller % of daily iron intake but well absorbed; non-heme iron in both animal and plant foods - majority of iron intake but less well absorbed

2) Forms: In RBCs as part of hemoglobin, in heart/skeletal muscle as part of myoglobin, stored in intestinal mucosa cells and liver/spleen/bone marrow as ferritin or in liver/macrophages as hemosiderin (if iron levels are v high)

3) Functions: oxygen delivery, cofactor in redox rxns, part of electron carriers, prosthetic group in enzymes that destroy microorganisms

4) Free iron is toxic; transported in circulation bound to transferrin


Describe the absorption of iron and what factors affect non-heme absorption in particular

1) Absorption (duodenum): Fe3+ must be reduced to ferrous form Fe2+ to be transported into the intestinal cell --> either stored as ferritin in the cell or transported out of cell by ferroportin --> oxidized by ceruloplasmin into Fe3+ and bound to serum transferrin in the blood --> distributed to liver, muscle, bone marrow, other tissues
*if there is excess iron, it is not transported out of the cell but rather stays in the cell as ferritin and is excreted when the intestinal cells are shed*

2) Enhancing factor: increased demand, Vitamin C, Meat Protein Factor (MPF) in animal proteins, acids

3) Inhibiting factors: infections, low gastric acid or GI disease, binding agents e.g. phytates, oxalates, polyphenols, Ca Zn or Mn (bind to Fe), antacids + H+ pump inhibitors


Describe iron deficiency in terms of causes, symptoms, and diagnosis

1) Causes: *most common nutrition deficiency worldwide*- pregnancy/menstruation, infants/young children, inadequate intake through diet e.g. raw vegans, malabsorption e.g. Celiac's

2) Symptoms: fatigue, feeling cold or faint, shortness of breath (--> all due to iron deficiency anemia), low IQ (infants, due to altered neurotransmitter synthesis), pica (consumption of nonfood e.g. dirt), glossitis, koilonychia (spoon nails)

3) Diagnosis: decrease in serum iron and ferritin and increase in transferrin --> decrease in transferrin saturation; iron deficiency anemia i.e. hypochromic microcytic anemia


Describe iron toxicity in terms of causes, symptoms

1) Causes: excess ingestion, transfusion, hemochromatosis (genetic disease where iron is absorbed at high rate, also called "bronze diabetes"),

2) Symptoms: diabetes, skin darkening, arthritis


Zinc (trace mineral):
1) Source
2) Absorption and transport
3) Functions

1) Source: seafood e.g. oysters and crabs, meat, eggs, also veggies but they need to be cooked well to release zinc from phytates

2) Absorption: zinc absorbed into intestinal mucosal cells and binds to metallothionein (just as ferritin binds to iron) --> metallothionein releases Zn to albumin --> bound to serum albumin and transported in blood to the rest of the body --> pancreas use zinc to make digestive enzymes --> Secrete into the intestine
*if there is excess Zinc, it is not taken up but remains in the intestinal mucosal cell and is excreted when the cells are shed*

3) Functions: cofactor for hundreds of enzymes--> used for heme, DNA, RNA synthesis; gene expression (part of Zinc finger proteins); sexual maturation; sense of taste and smell and immune function


Describe zinc deficiency in terms of causes, symptoms

1) Causes: malabsorption disorders, alcoholics (promotes Zn excretion), lactating women, vegetarians, heavy smokers, patients with ulcers, genetic condition called acrodermatitis enteropathica (inflammation of skin + diarrhea)

2) Symptoms: changes in taste, anosmia (loss of sense of smell), poor appetite, poor wound healing, impaired immunity, hair loss, growth retardation/delayed sexual maturation in children


Describe zinc toxicity in terms of causes, symptoms

1) Causes: rare, can occur with supplementation

2) Symptoms: diarrhea, naseau, vomiting, depresses immune function, impairs copper absorption --> *give zinc supplementation to treat genetic condition Wilson's disease which results from increased copper storage*


Copper (trace mineral):
1) Source
2) Absorption and transport
3) Functions

1) Source: beef liver, shellfish e.g. oysters and lobster, nuts + seeds, lentils, soy, dark chocolate

2) Absorption: small intestine --> transported bound to albumin --> transported from liver as part of ceruloplasmin, increased in more acidic environment

3) Functions: component of lysyl oxidase --> production of skin + hair + connective tissue (e.g. elastin, collagen), cofactor for superoxidase dismutase --> removing ROS, maintenance of myelin sheath + nervous system, part of ceruloplasmin --> oxidation of iron so it can be bound to transferrin for transport


Describe copper deficiency in terms of causes, symptoms

1) Causes: rare, seen in premature infants, in individuals with Menke's syndrome (poor copper absorption), nutritional disorders e.g. kwashiorkor, anemia, Celiac's

2) Symptoms: anemia, connective tissue damage --> excessive bleeding; silver, brittle hair


Describe copper toxicity in terms of causes, symptoms, treatment

1) Causes: consumption of acidic beverages in copper containers, Wilson's genetic condition (Copper cannot be excreted in bile --> increased copper deposits in brain, kidney, cornea, liver + decreased blood copper levels)

2) Symptoms: abdominal pain, naseau, vomiting, diarrhea; Wilson's --> Kayser-Fleischer ring (Greenish discoloration of cornea), low blood copper levels but increased copper deposits in brain, kidney cornea, liver

3) Treatment: Zinc supplementation (to impair copper absorption), Copper chelation therapy through penacillamine


Selenium (trace mineral):
1) Source
2) Forms
3) Absorption and transport
4) Functions

1) Source: based on soil content, brazil nuts

2) Forms: selenocysteine (biologically active form), selenomethionine (Storage)

3) Absorption: regulated through urinary excretion, highest concentration in liver pancreas muscle kidneys thyroid; not much known about transport

4) Functions: component of 2 proteins, part of the antioxidant enzymes --> protect against ROS (works with Vitamin E) e.g. glutathione peroxidase (GPx) which breaks down peroxides to water, thyroid metabolism --> conversion of T4 to T3, immune function,


Describe selenium deficiency and toxicity in terms of causes, symptoms

1) Deficiency: rare, noted for Keshan disease (poor soil content) --> enlarged heart with poor cardiac function

2) Toxicity: also rare, caused by industrial accidents or supplementation; symptoms --> garlic odor breath, fatigue, joint pain, hair loss, GI upset


Fluoride (trace mineral):
1) Source
2) Function

*fluoride is NOT an essential nutrient*

1) Source: fluoridated water or toothpaste/mouthwash

2) Function: no natural metabolic function, but promotes tooth mineralization and healthy enamel and prevents development of cavities


Describe fluoride deficiency and toxicity in terms of causes, symptoms

1) Deficiency: accelerates formation of cavities

2) Toxicity: accidental swallowing; symptoms --> discolored teeth, enamel pitting, but no health risk


Iodine (trace mineral):
1) Source
2) Absorption
3) Functions

1) Source: seafood, iodized salt, plants from iodine rich soils

2) Absorbed in the small intestine, 40% of body iodine is in thyroid gland; goitrogens are vegetables (turnips, cabbage, cauliflower, broccoli) which decrease absorption of iodine in the gut *cooking destroys goitrogen activity*

3) Part of thyroid hormone --> regulates basal metabolic rate, growth, energy metabolism, blood cell production, growth, nerve and muscle function


Describe iodine deficiency in terms of causes, symptoms, treatment

1) Causes: deficient intake, excessive Calcium intake, tobacco/alcohol consumption, pregnancy

2) Symptoms: goiter and hypothyroidism since T3/T4 production declines and TSH secretion increases --> lethargy, dry skin, reduced muscle and skeletal growth, weight gain; cretinism (irreversible mental retardation, in infants)

3) Iodized salt, thyroid hormone


Describe iodine toxicity in terms of causes, symptoms

1) Causes: excessive dietary intake

2) Symptoms: body can adapt to higher intake, but can lead to goiter


Describe the sources and uses of chromium in the body and its relationship to diabetes.

1) Sources: egg yolks, whole grains, pork, mushrooms

2) Function: enhances insulin action

3) Chromium deficiency linked to glucose intolerance (DMII)


Describe the sources and uses of cobalt in the body and its relationship to megaloblastic anemia

1) Source: animal foods containing Vitamin B12

2) Function: part of Vitamin B12

3) Same symptoms as Vitamin B12 deficiency --> megaloblastic anemia, nerve damage, and swollen tongue


Define peritoneal and primary and secondary retroperitoneal organs + give examples + venous drainage

1) Peritoneal - contained within the peritoneal cavity and covered by visceral peritoneum e.g. stomach, liver, spleen, first part of duodenum, ileum, jejenum, cecum, transverse colon, sigmoid colon, tail of pancreas; drained via the hepatic portal system and connected to the parietal peritoneum via mesentary (conduit for vessels/nerves)

2) Primary retroperitoneal - lie between parietal peritoneum and the abdominal wall, covered by parietal peritoneum e.g. kidney, adrenals, ureter, aorta, IVC, lower rectum, anal canal; drained via the caval system

3) Secondary retroperitoneal - initially peritoneal and suspended in mesentary, but migrated behind the peritoneum during development e.g. head neck body of pancreas, rest of duodenum, ascending and descending colon; drained via the hepatic portal system


Describe the organs of the GI tract including components and function:
1) Esophagus
2) Stomach
3) Small intestine
4) Large intestine

1) Esophagus - conduit for ingested food, no digestion

2) Stomach - 3 muscle layers (others have 2) for churning and digesting food; pyloric sphincter guards entry into small intestine; mucosa has gastric pits that are continuous with gastric glands (Secrete HCl + enzymes)

3) Small intestine: duodenum (bw foregut and midgut), jejunum, ileum; responsible for digestion and nutrient absorption, have crypts + villi, epithelium contains enterocytes (intestinal absorptive cells) + goblet cells

4) Large intestine/colon: cecum, ascending colon, transverse colon, descending colon, sigmoid colon (continuous with rectum and anal canal); contain haustra outpocketing and taenia coli muscle bands; NO villi + increased # goblet cells


Describe the accessory digestive organs, including their development from the gut tube:
1) Salivary glands
2) Pancreas
3) Liver

*all accessory glands are outgrowths of the forming digestive tract*

1) Salivary gland: ducts emerge from gut tube --> terminate by generating acini; acini secrete digestive enzymes into the ducts to access the lumen of the gut

2) Pancreas: ducts emerge from gut tube --> terminate by generating acini; some acini which lose their connection to the ducts become the islets of langerhans (endocrine function) --> produce insulin, glucagon, somatostatin and secrete into the bloodstream

3) Liver: bud from duodenum --> branches to form gall bladder and liver --> hepatic branch encounters venous pool and develops into cords/lines of hepatocytes; sinusoids lying between hepatocytes are continuous with the portal system (Receive blood from portal vein and hepatic artery)


What is portal hypertension? Describe cause and symptoms

1) Hepatic portal system- blood from peritoneal and secondary retroperitoneal organs passes through liver en route to the heart; liver damage --> fibrosis (Scar tissue) --> blood cannot flow and backs up --> blood seeks alternate routes via anastomotic connections to the caval system

2) Increased blood flow in anastomotic veins --> veins enlarge and walls weaken
A) esophageal varices *patients can die from blood loss*
B) anorectal varices
C) caput medusae in abdominal body wall


Describe the arterial blood supply to the GI organs

*3 major arteries that arise from the aorta*

1) Foregut - celiac artery e.g. spleen, liver, stomach, pancreas

2) Midgut - superior mesenteric artery e.g. pancreas, small intestine (cecum, asending), large intestine

3) Hindgut - inferior mesenteric artery e.g. large intestine, (Transverse, descending, sigmoid), rectum


Define and describe:
1) Dietary Reference Intake (DRI)
2) Recommended Dietary Allowance (RDA)
3) Adequate Intake (AI)
4) Upper Limit (UL)
5) Estimated Average Requirement (EAR)
6) Estimated Energy Requirement (EER)

*established for HEALTHY individuals*

1) DRI - set of reference values to assess nutrient intake, include RDA, AI, and UL

2) RDA - goal to ensure that intake is adequate in an individual (sufficient intake for 97% of pop)

3) AI - likelihood that intake is adequate when no RDA is set for the nutrient

4) UL - likelihood of toxicity or excess

5) EAR - likelihood that intake is adequate in a population (sufficient intake for 50% of pop)

6) EER - average dietary energy intake to maintain energy balance - no upper level e.g. active 20 year old man requires 3000 kcal, sedentary requires 2500 kcal


What are the major nutrient categories? What are micronutrients vs macronutrients?

1) Water, Minerals, Vitamins, Carbs, Proteins, Lipids (can also argue Oxygen and Alcohol)

2) Macronutrients: need >1g/day, include water, carbs, proteins, lipids

3) Micronutrients: need less than 1g/day, includes minerals and vitamins


1) Essential nutrient
2) Conditionally essential nutrient

1) Essential nutrient - one the body cannot make, and we need to survive

2) Conditionally essential - depends on the condition e.g. choline for prenatal

*Whether something is nutritious depends on the dose*


What is the energy that can be yielded from the following nutrients:
1) Carbs
2) Protein
3) Fat
4) Alcohol

1) Carbs = 4kcal/g

2) Protein = 4 kcal/g

3) Fat = 9 kcal/g

4) Alcohol = 7 kcal/g (estimate)


What are the ABCD methods of nutritional assessment?

A) Anthropometry e.g. height, weight, circumferences

B) Biochemical measurements e.g. blood, urine

C) Clinical assessments e.g. medical history, visible signs or symptoms of illness

D) Dietary assessment e.g. food diary


Describe the three groups of polysaccharides (complex carbs) including sources and functions:
1) Starch
2) Glycogen
3) Fiber *elaborate on soluble vs insoluble and harmful effects of excessive fiber intake

1) Starch - found in corn, rice, wheat, legumes; glucose storage in plants --> amylose (unbranched chain of glucose molecules) and amylopectin (branched chain)

2) Glycogen - highly branched chain of glucose --> can be easily broken down for fast energy (fasting, exercise), storage in liver and muscle

3) Fiber - cannot be digested; promotes growth of beneficial intestinal bacteria --> protects against disease, binds dietary fat and cholesterol --> decreases blood cholesterol, promotes satiety
A) soluble = fermentable in water, found in apples, gums,; softens feces and relieves constipation
B) insoluble = non-fermentable, found in whole grains, green leafy veggies; increases bulk of feces and also releases constipation (though too much causes constipation)
C) Overintake: GI obstruction --> gas, diarrhea, too many phytates prevent absorption of minerals


1) Glycemic index
2) Glycemic load

1) Glycemic index - rise in blood glucose after eating 50g of carbs; 1=glycemic index of glucose

2) Glycemic load - rise in blood glucose based on how many carbs you actually eat; GL = (GI/100) x #carbs

*eating low GI and GL foods is associated with better health*


What are the simple vs complex carbs? How are carbs metabolized

1) Simple carbs: monosaccharides (glucose, fructose, galactose) + Disaccharides (lactose, sucrose, maltose)

2) Complex carbs: oligosaccharides (3-10 sugar units) + polysaccharides (>10 sugar units, glycogen, starch, dietary fiber)

3) Metabolized into glucose, stored as glycogen in liver + muscle --> fuels body's cells

*carbs are NOT essential nutrients*


Explain the protein-sparing action of complex carbohydrates

Need adequate dietary carbohydrate to prevent the breakdown of protein into amino acids --> glucose for energy


What are the functions of protein in the body?

1) Structural materials
2) Enzymes
3) Hormones
4) Fluid balance --> can cause edema
5) Acid-base balance
6) Transportation
7) Antibodies
8) Provide fuel, and glucose if needed
9) Other - fibrin for clotting, collagen for scars, opsin for vision


How is excess nitrogen excreted?

1) AA --> ammonia (NH3) *toxic*

2) 2 NH3 --> 1 Urea (NH2)2CO

3) Urea released into blood

4) Kidneys filter urea out of blood, excreted in urine


Define nitrogen balance and give examples of different states

Nitrogen balance = Nitrogen intake - nitrogen output

1) Positive nitrogen status - body synthesizes more N than it degrades --> protein added e.g. growing children, pregnancy, people recovering from illness, increased insulin/GH secretion

2) Negative nitrogen status - body degrades more N than it synthesizes e.g. starvation, stress, cancer, surgery, increased T4/cortisol secretion, deficiency of essential amino acids (e.g. PVT TIM HLL)


What is the PDCAAS method of ranking dietary proteins? Contrast protein quality bw animal vs plant sources. Explain the concept of protein complementation

1) PDCAAS - evaluating protein quality based on AA requirements (does it have essential AA? N-containing AA?) and digestibility

2) Animal proteins e.g. egg, milk protein, poultry have high PDCAAS ~1; plant proteins e.g. kidney beans, whole wheat bread, generally have lower PDCAAS scores although soy=1

3) Protein complementation = combining low-quality proteins to provide adequate levels of essential AA e.g. combining beans (Ile, Lys) with rice (Met, Trp)


Discuss the forms of protein-energy malnutrition including causes and symptoms:
1) Kwashiorkor
2) Marasmus

1) Kwashiorkor - wasting due to sudden and recent deprivation of food, or due to lack of protein but not calories (e.g. rice diet); symptoms: distended belly/edema, 60-80% body weight for age, poor appetite

2) Marasmus - wasting and stunting due to severe deprivation of food for long time, both calorie and protein deficit; symptoms: muscle wasting, less than 60% body weight for age, good appetite


What is the importance of dietary protein? What is the recommended intake

1) Need dietary protein bc its the only source of essential AA (mnemonic: PVT TIM HLL) and practical source of Nitrogen

2) RDA for adults: 0.8 g/kg body weight/day


Describe the structural features of fatty acids.

What are common foods rich in different types of fatty acids?

1) Carboxylic acid with long aliphatic chain that can be saturated (solid) or unsaturated (liquid) *fats spoil when exposed to 02*

2) 18-C fatty acids abundant in food: saturated from animal fats, coconut oil, butter; monounsaturated (1 double bond) in olive, canola oils; polyunsaturated (1+ double bonds): omega-6 in corn, soybean, sunflower oils; omega-3 in flaxseed and fish (salmon) oils

*double bonds are numbered based on distance from methyl end of carbon chain*


What is hydrogenation? What is the difference between saturated fatty acids and trans fats?

1) Hydrogenation - conversion of unsaturated fats --> saturated fats (trans-fats)

2) Trans fats are not found in nature, are worse for us than saturated fats, although both increase incidence of coronary heart disease

A) Sat fats: increase LDL, promote blood clotting

B) Trans fats: increase LDL, lower HDL, interfere with enzyme function, raise blood levels of atherogenic lipoprotein (which causes plaque formation)


Describe the structure, functions, and sources of the following lipids:
1) Phospholipid
2) Sterols
3) Triglycerides

1) Phospholipid - hydrophilic head, hydrophobic tails; lipid bilayer of cell membrane + emulsifiers; found in chocolate

2) Sterols - made in body, another component of cell membranes; found in cholesterol, plant sterols

3) Triglyceride=triacylglyceride=TAG - glycerol + 3 fatty acids; provide cells with energy, secrete hormones, skin insulation + shock absorption; found in foods high in cholesterol, saturated fats that lower HDL e.g. red meat, butter


What are the essential fatty acids, in what foods are they found, and what are their health benefits?

What are eicosanoids? What is their function?

Two essential FAs *(can be used to make other FAs)*:
linoleic acid and linolenic acid

1) Linoleic acid (omega-6) found in vegetable oils (corn, soybean, sunflower) and meats --> lower LDL, increase HDL, reduces risk of coronary heart disease

2) Linolenic acid, EPA, DHA (omega-3) found in flaxseed oil, fish (salmon) --> little effect on LDL, HDL, reduces risk of coronary heart disease + cancer

3) Eicosanoids are prostaglandins, leukotrienes etc. derived from omega-6 and omega-3 FAs (ideally in 2:1 ratio, though realistically its much higher); one major pathway is omega 6 linoleic acid--> arachidonic acid

4) "local hormones" with health benefits: regulate inflammation, immunity


What is the main driver of high cholesterol? What are ways to lower cholesterol

1) It is NOT dietary cholesterol (e.g. eggs, cheese), but rather saturated fats that are the top determinant of LDL cholesterol; sources include meats, whole milk products, tropical oils

2) Replace saturated fats with unsaturated fats, consume omega-3 fatty acid foods or supplements


What are the guidelines for fat intake?

~1/3 daily energy from fat, including essential FAs

limit intake of harmful fats: saturated fats, trans fat, cholesterol


Describe the four types of lingual papillae including histology, function, and whether or not there are taste buds:
1) Filiform
2) Fungiform
3) Foliate
4) Circumvallate

Papillae - mucosal projections on the tongue, formed by highly vascular CT core and covered by strat squamous epithelium

1) Filiform: narrow conical shape, smallest, most numerous, NO taste buds, keratinized stratified epithelium --> breaks up food into smaller particles

2) Fungiform: mushroom shape, taste buds on dorsal surface

3) Foliate: three fingers of dermal papillae sticking into epithelial layer, taste buds along a furrow/trench, von Ebner glands which flush material from the trench so taste buds can respond rapidly

4) Circumvallate: rectangle shaped, largest, taste buds along a furrow/trench, von Ebner glands


Describe the histology and function of the major salivary exocrine glands:
1) Parotid
2) Sublingual
3) Submandibular
*Which gland has the most common benign tumor?

*all salivary glands have myoepithelial cells*

1) Parotid: 95% serous secreting acini, has adipocytes, can sometimes see facial nerve VII
*clinical correlation: pleomorphic adenoma is most common benign salivary gland tumor- nodular mass, needs to be resected*

2) Submandibular: serous acini + adipocytes, also serous demilunes (mucous cell capped with serous cells, looks like mushroom)

3) Sublingual: 95% mucous secreting acini, lighter in color bc mucous doesnt stain, flattened basal nuclei
*much fewer intercalated and striated ducts bc mucous secretion doesnt need to be modified/buffered*


Describe the duct system in the salivary glands

1) Intralobular ducts (within lobule):
A) Intercalated ducts - connect acini with striated duct, modify serous secretion (which contains amylase) by secreting bicarb and absorbing Cl
B) Striated ducts - connect intercalated duct to interlobular duct, modify secretion by secreting K and bicarb and absorbing Na+, appear striated bc of infoldings with mt

2) Interlobular ducts (bw lobules):
A) Excretory ducts - transport saliva to exterior surface, surrounded by lots of CT, will see goblet cells


Describe the histology of the mucosa and the muscle layers of the organs of the GI tract and how it relates to their function: Esophagus

1) Mucosa: Stratified squamous epithelium, Large mucosa that allows bolus of food to fit in the lumen, submucosa has mucous glands to lubricate epithelium, and counteract the acidity of stomach

*only esophagus and duodenum have submucosal glands*

2) Muscle: large muscularis externa to move food down to the stomach- striated skeletal muscle closer to mouth, smooth closer to stomach


Describe the histology of the mucosa and the muscle layers of the organs of the GI tract and how it relates to their function: Stomach

1) Mucosa: Simple columnar epithelium with gastric pits that extend into glands, NO villi or goblet cells, Mucosa has transient folds called rugae which open up to expand stomach surface area

Pit:gland length ratio--> Cardia - 1:1, fundus/body - 1:3 (most colorful bc of chief and parietal cell staining), pylorus - 3:1 (NO chief or parietal)

2) Muscle: Thick muscularis externa bc three layers of muscle (all other organs have 2)


Describe the 6 types of cells that make up the epithelium of the stomach (in the gastric pit and gland):
1) Surface mucous
2) Neck mucous
3) Stem
4) Parietal *differentiate bw active and inactive
5) Chief
6) DNES *differentiate bw open and closed

1) Surface mucous - located in the gastric pit, cells produce bicarb & granules which contain glycoproteins that combine with the bicarb to form surface protective insoluble gel

2) Neck mucous - located at juncture of gastric pit --> gland, produce soluble gel eventually differentiate into surface mucous

3) Stem - need active stem cell pop bc cells die due to abrasion, takes 4-5 days to mature

4) Parietal - produce HCl (gastric acid) and intrinsic factor (for B12 absorption --> otherwise develop pernicious anemia);
A) Inactive cell has lots of mt and membrane reserve (tubules, vesicles) in the cytoplasm
B) Active cell - membranes coalesce to increase surface area, prominent intracellular canaliculus

5) Chief - located in basal half of gastric glands, produce pepsinogen and gastric lipase, v basophilic (stains v dark), stimulated by ACh and secretin

6) DNES - communication --> interact with other DNES cells, neurons, influence motility and digestion, secrete secretin, glucagon, other hormones into ECM --> blood circulation (NOT the lumen, so fenestrated capillaries are on basal side)
A) Open - extend to lumen, Closed - stay on basal side


What are the protective and destructive factors in the stomach?

1) Protective: bicarbonate rich mucous secretion, prostaglandins (increase local circulation and bicarb secretion), tight junctions, pepsinogen (not active form), pepsinogen, stem cells

2) Destructive: HCl, pepsin, stress + aspirin + NSAIDs (inhibit prostaglandins --> decreased bicarbonate production --> "heartburn" symptoms), H. pylori


Describe the histology of the mucosa and the muscle layers of the organs of the GI tract and how it relates to their function: Small intestine

1) Mucosa: Simple columnar epithelium with goblet cells, villi (evaginations) and crypts of Lieberkuhn (invaginations) --> increase surface area; plicae circularis = folds of submucosa that encircle the small intestine, covered by villi;
A) duodenum submucosa has Brunner's glands --> produce alkaline mucous to protect epithelium from acid that spills over from stomach
B) Jejunum has long villi
C) Ileum has short and fat villi, Peyer's patches (lymphoid nodules)

2) Muscle: 2 muscle layers, smaller than that of the stomach - inner circular and outer longitudinal

*only esophagus and duodenum have submucosal glands*


Describe the 6 types of cells found in the epithelium of the small intestine including histology, function, and where they are found:
1) Enterocytes
2) Goblet
3) Immune
4) Paneth
5) Stem

1) Enterocytes - absorptive cell located in villi and crypts; absorb lipids, sugars, AA, ions, etc., digest proteins and carbs, produce enzymes associated with glycocalyx

2) Goblet - located in villi; produce layer of mucous

3) Immune - located in villi e.g. lymphocytes, macrophages, M cells

4) Paneth- located at base of crypts; produce lysozyme (controls gut flora), TNF-alpha (pro-inflammatory), defensins (antimicrobial)

5) Stem - located at the base of crypts

6) DNES - located in villi and crypts, for communication


What is GALT, what is it composed of, how is it organized. Describe the immune process incl role of M cells

1) GALT = Gut associated lymphoid tissue; Well-developed lymphoid system associated with gut, esp prominent in the ileum of small intestine

2) T and B lymphocytes, both epithelial and in lamina propria; plasma + eosinophil + mast + macrophage, M cell - specialized epithelial cells found in FAE of Peyer's patches (in the ileum of small intestine)

3) Can be diffuse lymphatic tissue, solitary nodules, or aggregated nodules called Peyer's patches (the specialized epithelium of Peyer's patches is called follicle associated epithelium, FAE)

4) M cells take up antigen in the lumen --> carry it to the lymphocytes and macrophages lying beneath --> these cells are activated --> lymphocytes differentiate into cells that produce IgA, IgE antibodies--> IgA neutralizes bacteria/viruses by preventing them from adhering to the surface of the lumen


Describe the blood, lymphatic supply to the small intestine

1) Blood: capillary villus plexus at the tip of the villus + pericryptal capillary plexus at the base --> both drain into submucosal venule

2) Lymph: lacteal is a lymphatic vessel in the core of the villus that connects to plexus + lymphoid nodule (in submucosa), efferent lymphatic vessels of the lymphoid nodule anastamose with lacteal and leave with the blood vessels


Describe the histology of the mucosa and the muscle layers of the organs of the GI tract and how it relates to their function: Large intestine

Large intestine = cecum, appendix, colon, rectum, + anal canal

1) Mucosa: Simple columnar epithelium with goblet cells, NO villi but continue to have crypt invaginations (become more torturous as you descend), Submucosal folds called plicae semilunaris - also to increase surface area

Rectum (simple columnar) is continuous with anal canal (abruptly becomes stratified squamous)

2) Muscle: taenia coli is modified longitudinal muscle coat (straps that lie over the inner circular muscle)

muscle changes as you enter anal canal; internal anal sphincter --> circular layer of smooth muscle; external anal sphincter --> skeletal muscle


Describe the 5 types of cells found in the epithelium of the large intestine including histology, function, and where they are found:
1) Absorptive
2) Goblet
3) Immune
4) Stem

1) Absorptive - look like the enterocytes in the small intestine, absorb ions + water

2) Goblet - increase in # as you move down the large intestine --> create mucous which is important to move the feces as it becomes more solid

3) Immune - for protection, # of lymphocytes increases as you move down the large intestine

4) Stem - at the base of the crypts

5) DNES - for communication


Describe the components of the enteric nervous system and its mechanism of action

1) Enteric nervous system: intrinsic nervous system in the gut wall, can act autonomously to drive peristalsis, formed by migrating neural crest cells;
A) Myenteric plexus (Auerbach's plexus) - cell bodies lie between the 2 muscle coats of the muscularis externa: circular and longitudinal muscle layers
B) Submucosal plexus (Meissner's Plexus) - cell bodies at outer edge of submucosa, surrounded by CT, adjacent to muscularis externa

2) Food enters lumen --> stimulates nerve endings projecting into lamina propria --> neuronal cell bodies in submucosal plexus activated:
A) Muscularis mucosa - muscle strands can project into villi and wiggle it so it comes into contact with more nutrients in the lumen
B) Glands in submucosa or mucosa secrete more
C) Myenteric plexus activated --> innervates muscularis externa to contract and relax in response to presence of food


Describe the different layers of the GI tract

1) Mucosa: epithelium, lamina propria (thin layer of CT that sits below epithelium), muscularis mucosa (2 thin smooth muscle layers)

2) Submucosa: contains CT and submucosal plexus

3) Muscularis externa: inner circular layer, myenteric plexus, and outer longitudinal layer

4) Adventitia or serosa


Describe the relationship between food, digestible, and metabolizable energy

100% food energy --> 90-99% digested energy (losses to feces) --> metabolizable energy (minor losses to urine, sweat): 50% lost to heat (inefficiency), 10% lost to thermic effect of food (digestion, absorption, storage of nutrients), 40% trapped in ATP and other transport pumps


What are the basic 2 compartment model of body composition? Which uses most energy?

Body weight = Fat + FFM = lean tissues + glycogen *no way of measuring glycogen*

1) Lean body mass / Fat free mass - 20% protein, 80% water, accounts for the most energy expenditure (e.g. heart, kidney, liver, brain, muscle)

2) Fat - adipose tissue is 85% lipid, 15% water, accounts for ~2% of BMR


Describe methods to assess body composition:
A) Anthropometry
B) Hydrodensitometry
C) Bodpod
D) Bioimpedance

Body weight = Fat + FFM

Methods: *gold standard is cadaver dissection*

A) Anthropometry (height, weight, BMI, circumference)

B) Hydrodensitometry (underwater weighing)

C) Bodpod (sit in chamber, see amount of air displaced)

D) Bioimpedance (resistance to low electrical current)

E) DEXA (uses radiation to give 3 compartment model - bone, lean, fat)

F) MRI (can visualize muscle, fat distribution)

G) Total body water (labeled deuterium water given and amount measured in body fluid e.g. plasma, urine, saliva) - can estimate total daily physical activity

H) Total body potassium (calculate body cell mass through radioactive K in cells)


What is energy expenditure? What are the components? How do we measure it?

1) energy expenditure ~ heat production ~ 02 consumption/C02 production

2) Energy expenditure = physical activity (voluntary + spontaneous/NEAT) + thermic effect of food + basal metabolic rate
*energy expenditure is actually higher in obese people (bc they have more FFM to carry around all the fat*

3) Methods:
A) Direct calorimetry - measure heat produced, but takes forever;
B) Indirect calorimetry - Respiratory Quotient (RQ)= Co2 produced / O2 used =0.8-1 (oxidizing carbs), 1.1 (Fat synthesis, v rare) --> higher RQ means less fat burn (more carb burn), indicator of weight gain
*if RQ=FQ (food quotient) --> no weight gain*
C) Activity monitors


What are signals that promote or inhibit food intake? Explain the leptin mechanism in particular

1) Orexigenic signals: ghrelin, orexin, GABA, MCH

2) Anorexigenic signals: gastric distension, CCK, GLP-1 (type of incretin), insulin, lipids + protein/AA + glucose, leptin (produced by white fat)

3) In hypothalamus: Leptin stimulates POMC/CART neurons --> stimulates MC4 receptor --> stimulates catabolic system; leptin inhibits AgRP/NPY --> relieves inhibition of MC4R

*majority of obese people more likely to have leptin receptor resistance rather than leptin deficiency*


What is the Barker Hypothesis on the Fetal Origins of Chronic Disease?

What happens in utero and birth - as well as mothers metabolic health and programing - can affect later health status (e.g. low birthweight babies have increased catchup growth after birth, but then higher risk for obesity and DMII later on in life)

Dutch famine during WWII, babies in early gestation later had higher rates of glucose intolerance, heart disease, breast cancer; those in mid and late gestation also had negative effects (e.g. glucose tolerance) but not as many

Mechanism: epigenetics e.g. histone modification, DNA methylation


Describe the three types of fat cells

1) WAT - one single lipid droplet

2) BAT - multiple smaller lipid droplets, well-vascularized and lots of mitochondria, + UCP1 protein expressed (uncouples electron flow from ATP --> just heat with no ATP production)

normally high levels of ATP inhibit UCP1, activated with cold temperatures, high T3/T4, norepi, more prevalent in slimmer, younger, and women

3) BRITE/Beige - BAT present within WAT, contains UCP1, but we dont know whether progenitor is BAT or WAT


What is the difference between visceral and subcutaneous fat?

1) Visceral fat in the abdominal cavity (omentum and mesentery), drains into portal vein --> more Beta adrenergic receptors + less sensitive to insulin --> increased risk of diabetes, cardiovascular disease

2) Subcutaneous fat located under the skin, drains into systemic circulation --> fewer beta adrenergic and more alpha2 receptors --> increased response to insulin, increased direct FFA uptake


Describe the different types of GI pain

1) Visceral pain - midline discomfort, poorly localized

2) Referred pain - felt at spinal level where visceral afferents enter spinal cord, more localized (abdomen wall)

3) Parietal pain - parietal peritoneum involved, highly localized and intense pain with guarding


Describe the neurotransmitters in the ANS

1) PSNS: (preganglionic) Ach, nicotinic subtype of cholinergic receptor; (postganglionic) Ach

2) Somatic: (preganglionic) Ach, nicotinic subtype of cholinergic receptor; (postganglionic) Ach *only to skeletal muscles*

3) SNS: (preganglionic) Ach, nicotinic subtype of cholinergic receptor; (postganglionic) norepi, adrenal medulla --> epi, *exception is sweat glands which use Ach, muscarinic subtype of cholinergic receptor


Explain the neurocrine effect of SNS and PSNS innervation on the enteric nervous system in the GI tract

Neurocrine - specialized paracrine effect involving neurons and neurotransmitters *major paracrine substances are histamine and somatostatin*

1) SNS: norepi (mostly postgang neurons) --> relax smooth muscle, contract sphincter, reduce blood flow, reduce watery secretions *important for pain sensation - pain afferents run in pregang sympathetics (greater, lesser/least, and lumbar splanchnic nerves)*

3) PSNS: Ach (pregang neurons) --> synapse on enteric neurons in gut wall --> postgang Ach --> contracts smooth muscle, relaxes sphincters, increases salivary + gastric + pancreatic secretions

*vagus nerve passes through the prevertebral sympathetic ganglia, uses celiac trunk and superior mesenteric artery to distribute efferents and collect afferents*


Describe the functions of the neurotransmitters in the ENS:
1) Vasoactive intestinal polypeptide (VIP)
2) Substance P
3) Enkephalin (opiate)
4) Neuropeptide Y
5) GRP aka Bombesin

1) VIP - relaxes smooth muscle but increases secretions

2) Substance P - cosecreted with PSNS Ach, helps it out (contracts smooth muscle and increases secretions)

3) Enkephalin (opiate) - mess up the gut bc they contract the gut but also the sphincters --> constipation

4) Neuropeptide Y - relaxes smooth muscle and decreases secretions (acts like SNS norepi)

5) GRP / Bombesin - increases gastrin secretion (acts like PSNS Ach)


Describe the following GI hormone, including secretion, function, and regulation: Gastrin

1) Secreted by G cells in the stomach antrum, duodenum, and pancreatic islet; two forms: Little 17 AA one and big 34 AA form which is secreted at low levels between meals

2) Function: increases gastric acid secretion, grow gastric mucosa, increase gastric motility (via ERA stomach muscle contractions)

3) Positive regulation: Dietary peptides + vagus nerve --> GRP as neurotransmitter (NOT Ach) --> stimulates G cells to release gastrin --> (direct) activates CCKb receptor on parietal cell; (indirect) activates ECL cell --> Releases histamine --> activates parietal cell --> HCl released into stomach lumen via H+/K+ ATPase --> Gastric acid *indirect pathway is more powerful*

Negative regulation: Acid in antrum --> stimulates D cells to release somatostatin --> inhibits G cells --> no gastrin secreted; gastrin also inhibited by CCK, Secretin, and Incretins


Describe the phases of gastric acid secretion and what % they are of total secretion

1) Cephalic - the senses (Sight/smell/taste) --> vagal efferent output = 30%

2) Gastric - when there is food in stomach, vagus stimulates pepsinogen production (chief cells) and gastrin release (G cells) = 60%

3) Intestinal - food exits stomach and enters duodenum (digestion product)--> stimulates G cells to produce gastrin = 10%


How can gastrin be blocked pharmacologically through H2 blockers and proton pump inhibitors? What are the pros/cons of each

1) H2 blocker - block histamine which is involved in the more powerful indirect pathway --> work faster but less effective overall

2) Proton pump inhibitor - block the H+/K+ ATPase in the parietal cell --> block both indirect and direct pathways --> more effective but takes longer to act


Describe the following GI hormone, including secretion, function, and regulation: CCK (cholecystokinin)

1) Secreted from I cells in duodenum and jejunum; three forms; CCKa receptor binds just CCK while CCKb receptor binds both CCK and gastrin

2) Function: Contracts the gallbladder to empty it, mediates enzyme secretion from exocrine cells in the pancreas, relaxes sphincter of Oddi to let bile and pancreatic juice into the small intestine through Ampulla of Vater, promotes growth of exocrine pancreas + gallbladder, inhibits gastric emptying

3) Regulation: I cells activated in response to fatty acids and protein


Describe the following GI hormone, including secretion, function, and regulation: Secretin

1) Secreted by S cells in duodenum and jejunum, after gastrin + CCK have done their work

2) Function: Secretin stimulates ductal cells in the exocrine pancreas to secrete HC03- and stimulates CFTR in the small intestine to release Cl- and its coupled transporter to release HC03- --> bicarb neutralizes stomach acid, important for luminal protection and fat absorption bc pancreatic lipases denatured at low pH

3) Regulation: S cells activated in response to H+ and fatty acids, CCK and Ach increase activity of Secretin


Describe the following GI hormone, including secretion, function, and regulation: Incretin

1) Main ones are GIP (secreted from K cells in duodenum) and GLP-1 (Secreted from L cells in ileum and colon)

2) Function: Increase insulin release from pancreatic beta cells --> prevents hypoglycemia *insulin response greater following oral glucose compared to IV glucose load bc incretin can prepare body to make more insulin*

3) Regulation: Increased after glucose, protein, fat heavy meal, ONLY in presence of glucose


Describe the three types of GI reflexes:
1) Local
2) Extrinsic (gastrocolic, enterogastric, colonoileal)
3) Conscious

1) Local: distension causes contraction behind the bolus and receptive relaxation in front of the bolus; mediated by ENS

2) Extrinsic: act over a distance, are subconscious;
A) gastrocolic - signal from stomach distension promotes evacuating of colon (poop)
B) enterogastric - signal from small intestine inhibits stomach motility and secretion --> hormones (CCK, secretin, and GIP), short reflexes via enteric neurons, and long reflexes via SNS --> all inhibit gastric emptying
C) colonoileal - signal from colon inhibits emptying of ileum

3) Conscious reflexes:
A) Vomiting - centrally mediated via chemoreceptor trigger zone
B) Ileus - pain inhibits entire GI tract e.g. after surgery
C) Defecation - can voluntarily contract external anal sphincter to prevent pooping


Describe the positive and negative inputs for food intake

1) Positive hypothalamic input: appetizing sight/smell/taste signals from cerebral cortex, ghrelin from empty stomach

2) Negative hypothalamic input: afferents from stomach relaying fullness, GI hormones e.g. insulin, CCK, adipose tissue releasing leptin


Describe the functions, composition, secretion, and inhibitors/activators: Saliva

1) Functions: lubricate bolus for swallowing, dissolve substances for tasting, protection, facilitate speech, start carb and lipid digestion

2) Composition and volume varies but always hypotonic; compared to plasma: greater [K+], lower [Na+], [Cl-]

3) Secretion: PSNS --> Ach, VIP --> vasodilation, acinar cell metabolism --> saliva secretion by acinar cells in the salivary glands, modified by ductule epithelial cells (reabsorb more Na+, Cl- and secrete less K+, HC03-)

4) Neural control: Positive --> smell, taste, pressure, nausea; Negative --> fatigue, lack of sleep, dehydration, fear


Describe the functions, composition, secretion, and inhibitors/activators: Gastric juice

1) Functions: Liquefy bolus and form chyme, activate pepsinogen and lipase to initiate protein and fat digestion, absorption - HCl solubilizes minerals + IF required for B12 absorption, protect gastric mucosa

2) Composition depends on # and type of secreting cells, compared to plasma: greater [K+], [H+]

3) Secretion: *Gastric juice is mixture of two secretions from different (oxyntic and non) cells with different controls*
A) Oxyntic - HCl, IF, K+ (parietal cells);
B) Non-oxyntic - mucous, Na+, HC03- *transported from blood to cell* (mucous cells in response to PSNS via ENS); pepsinogen (chief cells)

4) Stimulates secretion --> eating/meal times (oxyntic>>>non-oxyntic);
Negative --> inhibition of secretin, mucous barrier disrupted by aspirin, ethanol, H. pylori


Describe the functions, composition, secretion, and inhibitors/activators: Pancreatic secretions

1) Functions: provides enzymes for digestion *(rate of digestion determined by rate of gastric emptying, since enzymes are in excess they are not limiting factor)*, provide alkaline activity for optimal enzymatic activity and to protect mucosa from acid

2) Composition depends on # and type of secreting cells + secretory rate

3) Secretion: acinar cells secrete proteins via fusion of zymogen granules with apical membrane; extralobular duct cells secrete alkaline bicarbonate fluid

4) Majority of secretion in intestinal phase, enzyme secretion activated by CCK, aqueous component by secretin (enhanced by CCK and Ach)

*pancreatic secretions = lipase, protease, amlyase*


Describe the functions, composition, and secretion: Intestinal secretions

What is the external fluid circuit? How do you manipulate it to treat diarrhea?

I. A) Functions: maintain isotonicity and fluidity of luminal contents, protect epithelial surface, aid digestion and absorption

B) Composition: mucous + fluids

C) Secretion: Small intestinal epithelial and crypt cells, mucous from Brunner glands and mucosal cells; CFTR (activated by PKA but constitutively activated by enterotoxins)

II. A) External fluid circuit: Absorption of Na, Cl, H20 at tip of villi and secretion of Na, Cl (via CFTR), H20 into lumen at base of crypt

B) Diarrhea due to oversecretion (e.g. active CFTR) --> dehydration; to treat: Add glucose, NaCl to drinking water --> absorbed via SGLT1 (Na+, glucose) + passive (H20, Cl-) --> increased absorption balances increased secretion --> no more dehydration


Describe the functions, chemical characteristics, secretion, and inhibitors/activators: Hepatic secretions

1) Functions: emulsify fats into smaller particles; solubilize hydrophobic things e.g. cholesterol, fat soluble vitamins; augment pancreatic secretions to maintain alkaline environment; excrete lipid soluble substances

2) Mixture of 2 solutions: organic substances (e.g. bile salts, phospholipids) + bicarb rich fluid

3) Secretion: Organic substances secreted by hepatocytes, bicarb fluid by epithelial ductular cells

4) Positive --> organic secretion by increased bile acid/salts, bicarb secretion by increased secretin


Describe bile flow, recycling and role of enterohepatic circulation, and regulation

1) Bile flows from liver --> common bile duct --> gallbladder OR duodenum (path of least resistance) --> more bile flows into duodenum during digestive bc muscle tone of Sphincter of Oddi decreases; more bile flows into gallbladder during interdigestive period

2) Bile acids and salts reabsorbed from ileum and returned to liver via enterohepatic circulation --> taken up by hepatocytes in the liver --> stimulates bile secretion and inhibits bile synthesis *bile recycled 6 times/day*

3) CCK --> more bile released into duodenum;
Lack of CCK --> more bile into gallbladder --> concentrated and stored --> lack of bile return to liver --> synthesis of primary bile salts by the hepatocyte (happens during interdigestive period when bile goes to gallbladder)


Describe the cells of the liver:
1) Hepatocytes
2) Endothelial cells
3) Macrophage/Kupffer cells
4) Lipocytes/Ito Cells

1) Hepatocytes - cells that have exocrine (bile secretion) and endocrine (hormone secretion e.g. IGF-1) functions, cell polarized

2) Fenestrated cells lining sinusoids facilitate exchange between blood and hepatocytes

3) Kuppfer cells - pseudo-fixed in sinusoid (no junctions but still dont move), macrophages that produce cytokines that stimulate fibrosis of Ito cells

4) Lipocytes/Ito cells/Hepatic stellate cells - located in perisinusoidal space (i.e. Space of Disse), store fat and Vitamin A, can contribute to cirrhosis by secreting collagen in pathologic condition


Describe the flow of blood and bile in the liver

*this is the exocrine function of the liver hepatocytes*

Blood flows from hepatic artery (25%) and portal vein (75%) --> mixes in sinusoids --> flows towards central vein

Bile produced by hepatocytes --> secreted into bile canaliculi between cells --> flows towards Canal of Hering (contains cholangiocytes which aid unidirectional bile flow) --> bile duct in the portal triad

*bile canaliculi are channels formed by retraction of plasma membranes of the hepatocytes*


Describe the different zones of the liver acinus

Zone 1 (perilobular)- hepatocytes are in the center of the acinus (and thus the edge of the liver lobule) --> receive blood rich in 02 and nutrients --> most active and healthy cells that synthesize bile (proteins, lipids, bile salts, cholesterol), glycogen, etc.

Zone 2- N/A

Zone 3 (centrolobular)- hepatocytes nearest edge of of acinus (and thus center of liver lobule near the central vein) --> receive blood low in 02 and nutrients --> first cells to die, least active, most detoxification happens here


Describe the exocrine and endocrine components of the pancreas by function and histology

1) Exocrine - synthesizes and secretes bicarb rich fluid containing enzymes e.g. trypsinogen into duodenum via Ampulla of Vater (where common bile duct from liver/gallbladder also enters) when stimulated by CCK; composed of centroacinar cells connected to intercalated ducts *therefore duct system begins IN the acinus, in salivary gland it begins outside* - NO striated ducts or myoepithelial cells

2) Endocrine - Islets of Langerhans secretes hormones (glucagon at glucose >70, insulin at glucose >70, somatostatin); discrete lighter-staining clusters separated from exocrine part by CT


Describe the causes, symptoms, and treatment for pancreatic cancer

Causes: obesity, high fat diet, diabetes, chronic pancreatitis, smoking

Symptoms: dark urine and clay colored stools

Treatment: Whipple procedure to remove head of pancreas + duodenum (lot of complications)


Describe the function and histology of the gallbladder

1) Function: storage, concentration (through absorption of H20 and NaCl through epithelial cells and into CT spaces), and release of bile into the duodenum

2) Lined with simple columnar epithelium with short villi and NO goblet cells, folded mucosa creates little bubbles/sinuses *(key histological feature)*
NO muscularis mucosa or submucosa


Describe the motility that occurs in terms of function and control: Mouth

Mouth --> mastication (chewing)

Functions: reduce particle size, lubrication --> increases ease of swallowing and maximizes exposure to salivary amylase (carb digestion) and lingual lipase (lipid digestion ONLY in newborns), enhance stimulation of taste buds

Control - primarily reflexive, can also be voluntary


Describe the phases of swallowing and the organs involved:
I. Oral
II. Pharyngeal
III. Esophageal

At rest - UES and LES are contracted (closed) and esophagus is flaccid

I. Oral phase - under voluntary control, bolus moved to back of tongue and oropharynx

II. Pharyngeal phase - involuntary, coupled to phase III; bolus --> Afferent impulses to swallowing center in brainstem --> UES relaxes --> pharyngeal peristaltic wave + airways close --> bolus propelled into esophagus --> UES contracts to prevent reflux

III. Esophageal phase - primary peristaltic wave initiated by swallowing center and mediated by vagus X;
high UES pressure --> primary esophageal peristaltic wave --> LES relaxes and stomach receptive relaxation (temporary inhibition of resting tone in the fundus, *neurotransmitter = NO*) --> bolus pushed towards stomach --> LES contracts to prevent reflux

*liquids may move through LES before peristalsis due to gravity*


What is the difference between primary and secondary esophageal peristalsis?

Primary - peristaltic wave initiated by pharyngeal activity phase and initiated by swallowing center

Secondary - initiated by distension in esophagus that stimulates stretch receptors --> mediated by vagus + ENS --> clears esophagus of retained food and/or refluxed gastric contents


Describe the 4 mechanisms for preventing gastroesophageal reflux (GERD)

1) Higher tone of LES (than stomach) - relaxes and contracts to prevent reflux

2) Secondary esophageal peristalsis - can move something that is stuck, clear any acid

3) Pinching of LES by diaphragm - reinforces the LES

4) Reflexes --> increase in intragastric and intraabdominal --> increased LES pressure

*infants only have #3, pregnant women only have #2*


Describe the general functions of gastric motility in the upper and lower stomach

1) Upper stomach - storage due to receptive relaxation (during swallowing) and accommodation (relaxation/volume expansion in response to food distension) *Storage allows for digestion of food and controlled gastric emptying*

2) Lower stomach - grinding and mixing (due to retropulsion of chyme back into stomach) during antral systole (contraction of antral muscle + pyloric sphincter) *chyme and liquids leave stomach prior to antral systole, when the pyloric sphincter is open*


1. What is gastric emptying?

2. Name the control of this process.

3. Name stimuli/inhibitors of gastric emptying.

1) Gastric emptying - chyme/liquids passing through pylorus prior to antral systole/closure of pyloric sphincter

2) Vagal tone + Gastrin--> stimulate upper stomach tone + lower stomach peristalsis --> gastric emptying --> peptides from duodenum (CCK, GIP, and Secretin) inhibit Gastrin + stretch receptors increase duodenal contractions and inhibit gastric activity (and therefore more emptying)

3) Mediators of gastric emptying:
A) Increase rate: increased gastric volume via stretch receptors, liquids>>solids, smaller particles, carbs>>proteins>>fats, neutral>>acid solutions, isotonic>>hypotonic>>hypertonic solutions

B) Decrease rate: CCK + GIP (incretin) + Secretin, duodenal chemo + pH + osmoreceptors, duodenogastric reflex (excessive distension activates stretch receptors), ileogastric reflex (ileal distension)


What are the differences between interdigestive and digestive motilities?

I. Digestive period: 4-8 hours; Motilities are constant, intermediate strength, optimize digestion and absorption:
A) stomach- receptive relaxation, accommodation, small pylorus to regulate gastric emptying;
B) small intestine- segmentation (nonperistaltic slow movement - bidirectional movement brings chyme into repeated contact with intestinal enterocyte to ensure digestion)

II. Interdigestive period: 10-18 hours; starts only after food has been cleared from stomach AND small intestine; intermittent and strong migrating myoelectrical complexes (MMC) that remove undigestible materials and prevent bacterial growth, lasts about 2 hours each (cause of stomach rumbling);
A) stomach - open, relaxed pylorus
B) small intestine - peristaltic waves
*motilin is the mediator and only available during interdigestive period, levels are highest at start of MMC*


Describe the functions of the small intestine motilities based on muscle types

1) Muscularis mucosa and villi muscle --> facilitates absorption and lymph flow

2) Muscularis externa --> housekeeping through MMC and intraluminal mixing and propulsion through segmentation/slow movement (stationary circular muscle contraction) --> optimizes digestion and absorption


1) Describe electrical control activities (ECAs) and how they are generated

2) Phases of an ECA

3) Distinguish between ECA and ERA

1) ECA = basal electric rhythm = slow waves = inherent (spontaneous + constant) rhythmical fluctuation in the resting membrane potential of muscle cells (due to changes in ion conductance)

Generated by pacemaker cells that lie between inner circular and outer longitudinal muscle layers (called interstitial cells of Cajal) - 3x/min in stomach, 12x/min in duodenum

2) Phases:
A) Depolarization - Ca2+, Na+ influxes
B) Plateau - Ca2+, Na+ influxes and K+ efflux
C) Repolarization - K+ efflux

3) Electrical response activity (ERA) - specialized ECAs that are big and have spike potentials that occur during plateau phase --> contraction of gastric smooth muscle


Describe the relationship among ECA, ERA, neuroendocrines and muscle activity

ERA - initiate muscle contraction (multiple ERAs --> stronger + longer contraction)

ECA - frequency = frequency of contractions, sets max rate for contractions

Neuroendocrines can modulate but NOT initiate ECAs;
Excitatory: Ach, gastrin, Substance P -- induce ERAs to increase #, strength, and length of contractions;
Inhibitory: Norepi, epi, VIP, NO, Neuropeptide Y -- reduce ERAs for weaker, shorter contractions or no contraction at all (if it falls below mV threshold)


Describe the process of peristalsis incorporating ERA/ECAs and neuroendocrine control

1) Proximal to/at the bolus: relaxation of outer longitudinal muscle and contraction of inner circular muscle (bc excitatory neurons stimulate ERAs)

2) Distal to the bolus: contraction of outer longitudinal muscle and relaxation of inner circular muscle

Propulsive force proximally, receptive force distally *muscle contraction and relaxation coordinated by interneurons*


Describe the functions and the reflexes of the ileo-cecal sphincter

1) Functions: Delay transit of chyme into colon --> increased time for absorption; prevent bacterial overgrowth in ileum

2) Reflexes: Ileal distension --> receptive relaxation --> allows chyme to go through;
Cecal distension --> contraction --> does not allow chyme to go through and reflux prevented


Describe the functions of the large intestine and muscle activities involved

1) Functions: mix chyme to facilitate reabsorption of water and salt; store and expulse feces

2) haustral shuttling (segmental nonperistaltic contractions) - reabsorb H20, slow fecal stream --> occasional peristaltic activity to push stool aborally/distally --> rare mass movement (sustained peristaltic wave 1-3x/day) to push stool to the rectum --> initiates defecation

*motility slower in colon due to taenia coli + haustra, picks up in sigmoid colon and rectum*


Describe the steps for defecation

Resting - rectum empty + relaxed, IAS contracted and EAS relaxed

1. Fecal material in rectum --> stretch receptors --> perceive urge to poop --> ENS + PSNS reflexes relax IAS --> SNS reflex contracts EAS *can voluntary contract EAS to prevent pooping*
2. Fecal material moves into anal canal --> EAS relaxes --> increased intraluminal pressure in rectum + increased intrabdominal pressure + descent of the pelvic floor driving force for expulsion of feces


Describe how the following factors increase constipation:
1) Low fiber diet
2) Low fluid intake
3) Delaying poop
4) Narcotics
5) Physical inactivity
6) Antibiotics
7) Old age

1) Low fiber diet - decreased baroreceptor stimulation, fewer microbes

2) Low fluid - decreased baroreceptor activity (reduced fecal volume)

3) Poop delay - decreased baroreceptor activity (reduced fecal volume)

4) Narcotics - inhibits fluid secretion, increased sphincter tones --> increased resistance

5) Inactivity --> decreased GI neuroendocrine activities associated with exercise

6) Antibiotics - lose gut microbiome-initiated ENS activities

7) Old age - reduced food intake, neuroendocrine activities, and physical activity


Describe the reflexes coordinating motility system-wide:
1) Stimulatory
A) Gastroileal
B) Gastrocolic
C) Colonocolic
2) Inhibitory
A) Duodenogastric
B) Ileogastric
C) Intestino-intestinal
D) Colonic-intestinal
E) Peritoneo-intestinal

1) Stimulatory:
A) Gastroileal - entry of food into empty stomach relaxes ileocecal sphincter --> ileum empties
B) Gastrocolic - entry of food into empty stomach OR chyme into duodenum --> increases aboral/distal propulsive movement in colon
C) Colonocolic - distension of one part of the colon leads to relaxation of other parts --> increases aboral movement

2) Inhibitory
A) Duodenogastric - duodenal distension decreases gastric emptying
B) Ileogastric - ileal distension decreases gastric emptying
C) Intesto-intestinal - overdistension of intestine segment results in overall inhibition of intestinal muscle activity
D) Colonic-intestinal - overdistension in colon results in overall inhibition of intestinal muscle activity
E) Peritoneo-intestinal - handling of intestine during abdominal surgery results in overall inhibition of intestinal muscle activity

*C, D, and E fall under adynamic ileus - inhibition of muscle activity*


Define alkaline tide

Alkaline tide - pH increase coupled to gastric acid secretion; this is because when parietal cells are producing and secreting HCl into the lumen of the stomach, they release HC03- into the blood in order to maintain plasma electrical balance

neutralized by secretion of H+ into the blood during HC03- secretion by pancreas

called postprandial alkaline tide after a meal (physiological),
but severe vomiting leads to sustained alkaline tide --> metabolic alkalosis (pathological)


List the symptoms of the classic cystic fibrosis profile

- Caucasian patient (most common genetic diseasE)
- autosomal recessive
- diagnosed via sweat test -- increased Cl- concentration in sweat


Describe the structure, function, and mechanism of action of CFTR

CFTR gene --> CFTR protein = ABC transporter-class ion channel

1) Structure: 2 transmembrane domains form the channel, 2 nucleotide binding domains (NBD) hydrolyze ATP, and 1 regulatory domain controls opening of channel

2) Function: Transfer of ions e.g. Cl- down concentration gradient, can work in tandem with ENaC which is Na+ reabsorption

3) Mechanism: R domain phosphorylated by PKA, ATP binds to both NBDs and is hydrolyzed at one --> channel opens


Describe the different mutations in CFTR and effects on the CFTR chloride channel

Most common mutation - deltaF508 (Class II); another one is G551D

delF508 mutation - prevents normal CFTR folding during and after translation --> CFTR does not get delivered to the plasma membrane

Class I-III mutations severe, associated with pancreatic + lung problems; Classes IV + V less severe, not associated with pancreatic insufficiency


Explain how defective CFTR leads to clinical symptoms of cystic fibrosis in:
1) Sweat
2) Airways
3) Pancreas
4) Other organs

1) Sweat: Defective CFTR cannot reabsorb Cl- into the cell --> increased concentration of both Cl- and Na+ in the lumen/sweat

2) Airways: Defective CFTR cannot secrete Cl- into airway --> increased Na+ and H20 reabsorption --> dehydrated mucous --> leads to airway obstruction and is more susceptible to bacterial infection

3) Pancreas: Defective CFTR reduces ductular bicarbonate secretion --> digestive enzymes precipitate and block the ducts --> lipase, amylase, and proteases don't reach small intestine to digest fat, carbs, protein --> CF patients need high caloric intake + coated capsules of enzymes with every meal (they also poop more because of decreased digestion of food)

4) Other organs that express CFTR include: uterus, testicle, epididymis --> male CF patients tend to be infertile; patients also have meconium ileus (bowel obstruction)


Describe treatment options for CF

1) Gentamicin antibiotic, Ataluren can suppress premature stop codons if that is the cause of CF

2) For deltaF508 CF, cause is improper folding of protein that means it doesn't get delivered to the plasma membrane

Corrector e.g. VX-809 increases amount of defective CFTR protein at the membrane, potentiator e.g. VX-770 increases activity of defective proteins at surface --> increase in Cl- transport


What are the basic structural and chemical features of cholesterol?

What are the fates of cholesterol in the body?

What is the equation for total cholesterol?

1) Cholesterol = 27C hydrophobic lipid produced in all cells; contains 4-ringed steroid nucleus + hydrocarbon tail + double bond at C5-6

2) Principal fates of cholesterol: steroid hormones (progestin, estrogen, androgen, glucocorticoid e.g. cortisol, mineralocorticoid e.g. aldosterone) in the adrenal cortex + ovary + testes, bile acids in liver *bile salts are the only way body can excrete cholesterol, small amount can also be excreted as free cholesterol* (another fate is Vitamin D)

3) Total cholesterol = HDL + LDL + VLDL (HDL and LDL carry cholesterol, and VLDL carries TAGs --> VLDL=total triglycerides/5)


What are the forms by which cholesterol enters, and then exits, the liver?

*cholesterol transported in plasma esterified and as part of lipoprotein*

1) Liver cholesterol sources:
A) Dietary cholesterol via chylomicrons (lipoprotein from intestine)
B) de novo synthesis
C) extrahepatic tissues via HDL/LDL (lipoprotein from liver)

2) Liver exports:
B) free cholesterol in bile
C) conversion to bile salts


Describe the biosynthesis of cholesterol incl. rate limiting step.

Describe cholesterol homeostasis/regulation by cholesterol, insulin, glucagon, SREBP2, and diet

1) All cholesterol synthesis starts with Acetyl CoA
Rate limiting/committed step: HMG-CoA --> Mevalonic acid, enzyme is HMG CoA reductase and cofactor is NADPH

2) Cholesterol homeostasis:
A) Excess cholesterol has negative feedback --> reduces levels of HMG CoA reductase (HMGR) by stimulating proteolysis and inhibiting transcription of the gene by RNA pol II;
B) Insulin activates HMGR by removing phosphates
C) Glucagon inhibits HMGR by causing phosphorylation via AMPK
D) when cholesterol levels are low --> SREBP2 sensor protein moves from ER to Golgi --> is cleaved and activated --> goes into nucleus and enhances transcription of HMGR
E) Diet: increasing dietary cholesterol will reduce de novo cholesterol synthesis in liver, and vice versa


Describe the 2 forms of esterification of cholesterol

Esterification - OH at C3 replaced with fatty acid --> more hydrophobic --> Easily stored, packaged, transported

1) free cholesterol (de novo or from diet)--> esterified by ACAT enzyme in intestinal epithelial cells --> cholesteryl ester stored in lipid droplets in hepatocytes/steroid producing cells *excess cholesterol activates ACAT*

2) peripheral tissue cholesterol --> Esterified by LCAT enzyme in blood --> stored in HDL and taken to liver (reverse cholesterol transport)


Describe the mechanism of action of statins

Statins = structural homologues of HMG CoA, competitive reversible inhibitors of HMGR--> reduced de novo cholesterol synthesis in liver --> liver has to more efficiently retrieve cholesterol from lipoproteins --> increased LDL receptors on hepatocytes --> decreases blood cholesterol levels while maintaining liver levels


Describe forms of cholesterol dysregulation (hypercholesterolemia):
1) coronary heart disease
2) xanthoma - distinguish between tendon and tuberous

1) CHD - leading worldwide cause of natural death; high LDL/low HDL levels --> atherosclerotic plaques form --> arteries narrow --> decreased blood and 02 supply --> MI, death

2) Xanthoma - cutaneous deposition of lipids (cholesterol-laden foam cells); high cholesterol --> tendon xanthoma on hands/feet; high cholesterol AND triglycerides (=TAGs)--> tuberous xanthoma over knees/elbows

3) SLOS - autosomal recessive genetic condition --> mutated gene for enzyme required for last stage of cholesterol synthesis --> ptosis, microcephaly, polydactyly


What are apo/lipoproteins, general structure, function

1) Lipoprotein - lipid-binding proteins in the blood responsible for transport, "apo" refers to just the proteins

2) Surface layer of amphipathic lipids (phospholipid, unesterified cholesterol) and proteins; anhydrous core of triacylglycerol TAGs and cholesterol ester

3) Functions: Structural, ligands for receptors, activators/coenzymes


Describe the different classes of lipoproteins including source, function, and major associated apolipoproteins

Classes based on protein:lipid density, from low to high: Chylomicron, VLDL, LDL, HDL

1) Chylomicron - from small intestine, largest size and lowest density, transports dietary TAG, contain Apo B48 *shortened N-terminal fragment of Apo B100*

2) VLDL - from liver, transports endogenously synthesized triglycerides = TAGs, contain Apo B100

3) LDL - formed in circulation, highest % CE compared to the other lipoproteins; delivers cholesterol to peripheral tissues, contains Apo B100 (acts as ligand for LDL receptors)

4) HDL - from liver, high density bc of high % proteins; removes used cholesterol from tissues (in the form of cholesteryl esters) and takes to liver, acts as reservoir for apolipoproteins, including AI and AII


Overview of the three pathways of lipid metabolism

1) Exogenous- chylomicrons deal with dietary lipids, originating in small intestine

2) Endogenous - VLDL/LDL dealing with de novo lipids, originating in liver

3) Reverse cholesterol transport - HDL, dealing with cholesterol in the peripheral tissues


Overview of the following apolipoproteins that reside in HDL:
1) Apo CII
2) Apo CIII
3) Apo E

1) Apo CII: made in liver, cofactor for lipoprotein lipase

2) Apo CIII: from liver, inhibits lipoprotein lipase

3) Apo E: from liver, ligand for receptor mediated clearance of chylomicron remnants and IDL, both of which bind to LRP1 on hepatocytes so remnants can be endocytosed


Describe the role of the following proteins in lipoprotein metabolism:
1) Lipoprotein lipase
2) Hepatic lipase

1) Lipoprotein lipase: *requires Apo CII as cofactor*
A) extracellular enzyme that is synthesized by skeletal muscle and adipose tissue; the protein is anchored to epithelium of blood capillaries;
B) Functions: cleaves TAGs from lipoproteins (chylomicron or VLDL) and hydrolyzes to FFA + glycerol --> FFA transported to heart, muscle, fat (80%) and 20% returned to liver

2) Hepatic lipase:
A) enzyme synthesized by hepatocytes, present in liver endothelial cells (also transported to capillary endothelium of adrenals + gonads)
B) Functions: processing of chylomicrons (hydrolyzes TAGs), processing of IDL --> LDL, conversion of cholesteryl ester-rich HDL2 --> HDL3 (hydrolyzes TAG + phospholipid)

3) CETP: transfer protein secreted in liver that circulates in blood; remodels HDL by transferring cholesteryl esters from HDL --> VLDL and TAG from VLDL --> HDL; CETP inhibitors increase HDL and decrease LDL


Describe the exogenous pathway of lipid metabolism including timeline

Exogenous pathway: Metabolism of Chylomicrons

(lumen of intestine) dietary cholesteryl esters hydrolyzed --> cholesterol enters micelle with bile salts, fatty acids, monoglycerides --> bind to NCP1L1 and taken up by jejunum epithelial cells via endocytosis --> incorporated into chylomicrons via MTP--> exported into lymphatic system --> chylomicrons enter circulation with Apo B48 and lots of TAGs

(blood) chylomicrons gain Apo CII and Apo E from HDL --> travel around circulation until they associate with lipoprotein lipase through Apo CII --> LL cleaves TAGs (of which FFA diffuse into local tissues) --> now they are chylomicron remnants, return Apo CII to HDL --> enter Space of Disse in the liver --> hepatic lipase removes more TAGs --> Apo E binds to LRP1 on hepatocytes --> remnants enter via endocytosis and are degraded in lysosomes (can also be repackaged or converted to bile salts) *dietary cholesterol inhibits cholesterol synthesis by the liver*

*chylomicrons also transport vitamins ADEK from small intestine to liver*

overall timeline - chylomicrons cleared from blood within hours of a lipid rich meal --> why we do fasting blood samples (chylomicrons in the urine cause it to appear cloudy)


Describe the endogenous pathway of lipoprotein metabolism:

Endogenous Pathway: Metabolism of LDL and VLDL

(liver) Liver synthesizes TAGs by esterifying FAs (from excess dietary carbs or from the blood) with glycerol --> packaged into VLDL with cholesterol esters, Apo B100, E, and CII (de novo lipid synthesis)

(blood) sent into circulation, where addl Apo E and CII donated by HDL --> travel around circulation until they associate with lipoprotein lipase through Apo CII --> LL cleaves TAGs (of which FFA diffuse into local tissues to be stored as fat or oxidized to form ATP) --> now they are VLDL remnants, or IDL, and return Apo CII to HDL

50% IDL cleared from circulation by liver (via Apo E binding to LRP1 on hepatocytes);
Other 50% remains in circulation and remodeled to LDL (via hepatic lipase which hydrolyzes more TAGs and phospholipids--> why LDL is so rich in cholesterol)

Takes longer to clear VLDL from blood (several hours)


Describe different mechanisms of clearance of LDL

Takes days to clear LDL from blood --> contains majority of blood-borne cholesterol

Circulating LDL taken up by cell via Apo B100 binding to LDL receptor; # LDL receptors expressed based on cholesterol concentration that SREBP2 senses in the ER membrane

2/3 of circulating LDL taken up by liver; 1/3 taken up by peripheral tissues --> significant source of cholesterol in peripheral tissues (in addn to de novo synthesis)

liver secretes PCSK9 enzyme - decrease # LDL receptors --> degrades LDL receptor so it can no longer remove LDL from blood --> inhibiting PCSK9 pharmacologically would lower blood LDL levels

Alternative receptor: Scavenger receptor SR-A, expressed on macrophages in various organs e.g. intestine, spleen- high affinity for damaged/oxidizes LDL --> endocytoses and releases free cholesterol into cytoplasm


Describe the reverse cholesterol transport pathway of lipoprotein metabolism

Reverse Cholesterol Transport: HDL Metabolism

Synthesis (in the blood of liver and intestine): Apo AI + lipid *(Apo AI activates LCAT)* --> ABCA1 transporter adds more cholesterol + phosphatidylcholine --> disc-shaped nascent HDL

(peripheral tissues) cholesterol taken up by HDL is esterified by LCAT (transfers fatty acids from phosphatidylcholine to cholesterol) --> HDL3 --> HDL2 (cholesteryl ester-rich molecule)

(liver) scavenger receptor SR-B1 selectively uptakes cholesteryl esters from HDL (protective mechanism against artherosclerosis)

Functions: remove excess cholesterol from peripheral tissues and returns it to liver; reservoir of apolipoproteins e.g. CII, E


Discuss the model for atherosclerosis. Why is LDL the most atherogenic lipoprotein?

I. Atherosclerosis:
A) Fatty streak formation: LDL enters the cell, is oxidized --> taken up by macrophages through SR-A receptor--> form foam cells --> recruitment of cytokines, more macrophages --> smooth muscle cell proliferation and collagen synthesis
B) Fibrous plaque formation: lesion extends into lumen --> foam cell necrosis + smooth muscle cell migration from media into intima
C) Complicated lesion formation: Endothelial cell layer lost --> thrombus encroaches into lumen of artery + debris accumulates --> calcification and damage to artery wall --> can lead to occlusion (infarction) or thrombosis (stroke)

II. *lipoprotein (a) is abnormal variant of LDL that is an independent risk factor for artherosclerosis*

LDL is small and is able to penetrate and bind in the subendothelial space between smooth muscle and endothelial cells, can be oxidized at which point it can no longer bind to LDL receptor, rather binds to scavenger receptor SR-A


Define hypertriglyceridemia.

Describe the effects of the following hyperlipoproteinemia conditions:

1) Familial hyperchylomicronemia --> Apo CII/lipoprotein lipase deficiency

2A) Familial hypercholesterolemia --> complete LDL receptor deficiency

2B) Familial hypercholesterolemia --> partial LDL receptor deficiency

3) Familial dysbetalipoproteinemia --> ApoE deficiency

I. Hypertriglyceridemia - total plasma triglycerides in fasting state > 150 mg/dl (due to high VLDL, chylomicrons, or both); increases risk for pancreatitis (treat by stopping food intake), xanthomas, and CVD

1) (manifests in childhood) lipoprotein lipase or Apo CII deficiency --> chylomicrons are not cleared from blood, even after fasting --> TAG>1000 mg/dl

2A) Completely defective LDL receptor --> increased LDL concentration with normal VLDL--> have early CHD, heart attacks

2B) Partial defects in LDL receptors --> increased LDL and also increased VLDL and TAG (due to increased B100 synthesis and overproduction of substrates e.g. TAG, AcetylCoA)

3) Apo E deficiency --> increased IDL + increased chylomicron remnants --> equal increases in plasma total cholesterol and TAG + increased VLDL:TAG ratio


Describe the effects of the following hypolipoproteinemia conditions:
1) Apo AI deficiency
3) LCAT deficiency
4) Tangier disease

1) Apo AI deficiency (plasma ApoAI = 0 mg/dl) --> decrease in HDL but normal levels of LDL and TAG --> corneal opaqueness

2) LCAT deficiency --> increased free cholesterol in peripheral tissues bc it cannot be converted to cholesteryl esters and sent back to liver --> inability to form HDL and rapid clearance of Apo AI --> low HDL and Apo AI and LDL but increased TAG (linked to decreased lipoprotein lipase activity)

3) Tangier disease = defective ABCA1 --> prevents HDL maturation and cholesterol efflux to liver --> decreased HDL and Apo AI and LDL but increased TAG --> cholesterol accumulates throughout the body --> atherosclerosis, large orange tonsils


Explain if the following are treatments for hypertriglyceridemia, hypercholesterolemia, or both:
1) Statin
2) Ezetimibe
3) Fish oil
4) Bile acid binding resins
5) Fibrate
6) Niacin B3

1) Statin: BOTH; HMG CoA analogue that reduces de novo cholesterol synthesis in liver --> reduces VLDL production and LDL plasma levels

2) Ezetimibe: CHOLESTEROL; inhibits absorption of dietary cholesterol in the intestine + increases LDL receptors in liver --> increases LDL clearance from circulation --> Reduced LDL levels

3) Fish oil: TAG; omega-3 fatty acids increases lipoprotein lipase activity --> decreases TAG in plasma

4) Bile-acid binding resins: CHOLESTEROL; increases shunting of cholesterol and bile acids to feces for excretion --> reduced LDL levels

5) Fibrate: BOTH; activate transcription factors for increased lipoprotein lipase activity and increased FA oxidation --> decreases TAG, VLDL, LDL

6) Niacin B3: BOTH; activates receptor that inhibits lipolysis (the release of FAs from tissues) --> decreased plasma lipids, both TAG and cholesterol


1) components of bile
2) how gallstones are formed
3) types of gallstones
4) risk factors

1) Typical composition in healthy humans: bile salt (70%), phospholipids e.g. lecithin (20%), cholesterol, protein, minute amount of bilirubin

2) balance of bile salt, phospholipid, cholesterol decides if you get gallstones --> If bile becomes supersaturated with cholesterol --> cholestasis promotes crystal formation --> cholesterol crystals clump to form stones

3) Two types: cholesterol stones (80%), pigment stones due to bilirubin excess (20%)

4) risk factors: fat, female, forties


Describe the tissues for synthesis, storage of bile salts

Describe the digestion and absorption of lipids in the small intestine + role of bile salts + CCK

bile acids/salts = amphipathic detergents, synthesized in liver, stored in gallbladder

Secretion: fatty acids in lumen of small intestine stimulate I cells to release CCK --> contracts smooth muscle of gallbladder + relax sphincter of Oddi --> bile released into duodenum --> bile salts emulsify fats (prevents lipids from aggregating and facilitates digestion) --> fats digested by pancreatic lipases + colipase --> create micelles with lipid fragments + bile salts, which bump up against the enterocytes --> lipids absorbed by enterocytes in the microvilli + bile salts recycled back to liver at terminal ileum via hepatic portal vein

*RLS in the absorption of lipids is the diffusion of mixed micelles*


Describe bile salts and their function.

What happens with bile salt deficiency

Discuss the importance of bile acid synthesis not only in the digestion and absorption of fats but also as a major excretory route for cholesterol

1) Bile salts are amphipathic (one face is hydrophilic, other is hydrophobic) --> makes them good detergents

Function: bile salts emulsify fats + fat-soluble vitamins by breaking down into smaller lipid droplets, which are broken down by lipase molecules into glycerols + fatty acids, which maintain association with bile salts to form micelles

Bile acids are important for fat absorption: micelles bump against border of the small intestinal enterocytes --> glycerols + fatty acids taken up by the cells

2) With bile acid deficiency (e.g. ileal resection) --> steatorrhea (fat in stool, due to bile deficiency or any defects in lipid digestion/absorption) + decrease in fats and fat-soluble vitamins (ADEK)

3) Secondary bile acids (dehydroxylated, deconjugated primary bile salts) are the only way body has of getting rid of cholesterol


Name the two main primary bile acids and salts found in mammals + outline the pathway by which they are synthesized from cholesterol in the liver.

Describe how secondary bile acids are produced from primary bile acids by intestinal bacteria

(Liver) Cholesterol is hydroxylated by 7alpha hydroxylase --> produce bile acids: 24-carbon cholic acid, chenodeoxycholic acid --> conjugated with glycine or taurine to produce bile salts: glycocholic acid and taurocholic acid (produced ONLY during the interdigestive period, since in digestive period bile salts are being recycled from the ileum) --> enhance hydrophilicity so fully charged at lower pH (in intestinal lumen) --> better detergents

(Colon) Bacteria deconjugate and dehydroxylate to secondary bile acids --> deoxycholic acid, lithocholic acid

*lith=stone --> gallstone formation

*biliary bile acids - conjugated form; fecal bile acids - nonconjugated


Describe the role of cholesterol 7α-hydroxylase in bile synthesis and its regulators

cytochrome p450 enzyme - 7 alpha hydroxylase i.e. cyp7a

committed step in bile acid synthesis of cholesterol --> cholic acid (primary bile acid); make molecule more hydrophilic by adding OHs, adding COO- to end of side chain, removing double bond (chenodeoxycholic acid has one fewer OH group)

enzyme regulation: product inhibition by cholic acid, substrate activation by cholesterol


What is the difference between bile acids and salts

primary bile acids: cholic acid, chenodeoxycholic acid

bile salts are conjugated: glychocholic acid, taurocholic acid (primary bile acids modified with amide linkages of glycine or taurine) --> bile SALTS can form micelles that solubilize lipids


Explain what is meant by “enterohepatic circulation” and why it is important.

Efficient recycling via enterohepatic circulation: Bile acids made and conjugated in the liver, stored in gallbladder --> released into intestine --> work on lipid digestion and absorption on the duodenum --> 95% reabsorbed at the terminal ileum --> return to liver via hepatic portal vein

the other 5% reach colon, where they are converted to secondary bile acids --> 15-30 g bile salts (0.5 g cholesterol) /day excreted in feces


Discuss the role of bile acid resins in reducing blood cholesterol levels

bile acid resins = pharmacological sequestrants

drugs that bind to bile acids so they cannot be reabsorbed into enterohepatic circulation at the ileum --> Reduces cholesterol within the liver --> upregulate LDL receptors at the hepatocytes --> decrease plasma LDL


Describe and differentiate the transporters of bile acids in enterohepatic circulation:
3) OSTalpha-OSTbeta

Bile acid export pump (BSEP): transports bile acid across canaliculi in the liver

bile duct: bile acids enter intestinal lumen

apical sodium dependent bile transporter (ASBT): reabsorbs 95% bile acids in the distal ileum (5% go to colon for excretion)

OSTalpha - OST beta: bile acids efflux basolateral membrane of ileum and nter enterohepatic circulation via portal vein

NTCP and OATP: transport bile acids across basolateral membrane of hepatocytes


Explain cholelithiasis - describe causes and morphological changes and treatment

I. cholelithiasis = yellow gallstones formation --> more cholesterol enters bile than is excreted
*dark heme gallstones also exist, much less common*

II. Causes:
A) severe ileal disease (not enough enterohepatic circulation --> reduces amount of bile acids --> increases proportion of cholesterol in the bile),

B) obstruction of bile duct (cholesterol hypomobility facilitates gallstones),

C) severe hepatic diseases (messes up homeostasis of cholesterol metabolism --> more secreted into bile),

D) genetic susceptibility (LITH "lithogenic" genes)

III. Morphological changes:
A) Kupffer cells (macrophages) accumulate bile
B) hepatocytes enlarge and accumulate bile -- see bile pigments
C) bile canaliculi enlarge
D) cells undergo apoptosis
E) bile obstruction due to bile plugs

IV. treatment: UDCA acid


Distinguish between intravascular and extravascular hemolysis

Extravascular (90%) - old RBCs engulfed by macrophages in spleen and liver; characterized by spherocytes (smaller cells that look like balls)

Intravascular (10%) - RBCs are lysed in the circulation and release hemoglobin and heme into plasma --> macrophages pick it up using haptoglobin (for Hb) and hemopexin (for heme); characterized by schistocytes (Fragments of RBCs can be seen on blood smear)


Explain the function of bilirubin

Describe overall pathway from heme --> bilirubin excretion

Bilirubin - metabolite of heme that is a means to excrete unwanted heme

(macrophage) Heme from destroyed RBC --> Biliverdin --> Bilirubin --> circulates in blood bound to albumin --> (liver) conjugated twice by UDPGT --> released back into gallbladder --> secreted into intestine with bile --> converted to urobilinogen --> 90% remains in colon and converted to urobilin (brown color of feces) + 10% reabsorbed and goes to kidney where it is converted to urobilin there (yellow color of urine)


What is the difference between direct and indirect bilirubin?

What is the van den Bergh reaction?

Total bilirubin = direct + indirect --> 0.3 to 1.9 mg/dl

van den Bergh: Indirect = total bilirubin - direct

expose to acid to find amount of Direct = conjugated --> 0-0.3 mg/dl (should be low since direct bilirubin is not in blood but in bile duct, only conjugated is what escapes via MRP3 transporter)

then add accelerator e.g. alcohol to find amount of Total bilirubin


Describe the conversion of heme --> bilirubin in the macrophage

Heme (purple) --> heme oxygenase enzyme --> biliverdin (antioxidant, green) + CO (vasodilator) --> bilirubin reductase enzyme --> bilirubin (red)


Predict the consequences of bilirubin metabolism due to UDPGT deficiency

UDPGT used to conjugate bilirubin in two steps: bilirubin --> bilirubin monoglucuronide (BG) --> bilirubin diglucuronide (BG2) *second rxn is rate-limiting*

bilirubin deficiency --> buildup of BG >> BG2


Lay out the bilirubin transporters

Unconjugated bilirubin in blood bound to albumin --> taken up at hepatocyte via OATP transporters --> bound to GSTB to prevent efflux --> conjugated bilirubin (BG/BG2) secreted at bile canaliculi via MRP2, small amounts secreted into plasma via MRP3


Explain causes of physiologic jaundice of newborns

*jaundice is not a disease - indicator of a problem* jaundice - yellowing of the skin; icterus - yellowing of the eye bc of bilirubin accumulation

low UDPGT activity in premature babies --> high indirect bilirubin levels (bilirubin is toxic in newborns but not kids/adults) --> kernicterus = yellow staining of deep nuclei of the brain

symptoms: extreme jaundice, lethargy, muscle rigidity, seizures

treatment: UV phototherapy to make bilirubin more soluble so it can be secreted in the urine


Describe the genetic conditions of bilirubin metabolism and their relative direct/indirect bilirubin levels:
1) Criggler-Najjar Type 1
2) Criggler-Najjar Type 2
3) Gilbert
4) Dubin-Johnson
5) Rotor

1) Criggler-Najjar Type 1: complete absence of UDPGT --> severe jaundice + kernicterus; increased indirect bilirubin

2) Criggler-Najjar Type 2: UDPGT mutation --> benign jaundice; increased indirect bilirubin

3) Gilbert: promoter mutation --> Reduction in UDPGT transcription --> UDPGT normal but at lower levels --> mild jaundice that manifests during stress (e.g. taking exams); increased indirect bilirubin

4) Dubin-Johnson: MRP2 mutation --> deposition of dark brown pigment in hepatocytes since they cannot be sent to bile canaliculi --> jaundice is only symptom; increased direct bilirubin

5) Rotor: OATP mutation (no activity) --> mild hyperbilirubinemia; increased direct bilirubin


Describe the types of jaundice and their relative direct/indirect bilirubin levels:
1) (Pre-hepatic) hemolytic
2) (Hepatic) neonatal
3) (Hepatic) hepatocellular
4) (Post hepatic) obstructive

How can you differentiate between 3 and 4 using LFTs?

1) (Pre-hepatic) hemolytic: massive RBC lysis --> increased amounts heme beyond liver's ability to process --> increased indirect (blood) and direct (bile canaliculi) bilirubin

2) (Hepatic) physiological/neonatal: low levels of UDPGT --> impaired bilirubin conjugation --> increased indirect bilirubin in the blood, direct in bile canaliculi decreased or 0

3) (Hepatic) hepatocellular: damage to liver cells --> cannot meet normal demand --> decreased bilirubin uptake and conjugation --> increased direct bilirubin in the blood (should normally be 0)

4) (Post hepatic) obstructive: biliary obstruction prevents direct bilirubin from draining into intestine --> increased direct bilirubin in the blood + poop is pale clay color

5) For hepatocellular jaundice: AST/ALT >>> Alk Phos; for obstructive jaundice: Alk Phos >>> AST/ALT


What are the normal lab values for LFTs and what direction indicates damage?

1) Transferases AST/ALT (hepatocyte): 0-40 IU/dl (HIGH suggests liver inflammation)

2A) Alkaline phosphatase (biliary tract): 0-120 units/dl (HIGH suggests cholestasis)

2B) Bilirubin (biliary tract): 0-1 mgm/dl (HIGH suggests cholestasis)

3A) Albumin (chronic disease): 4 g/dl (LOW- suggests loss of hepatocytes)

3B) Prothrombin time INR (chronic disease): 1.0 (HIGH suggests chronic liver disease)

4A) Amylase (pancreas): 40-140 units (HIGH suggests inflammation)

4B) Lipase (pancreas): 60-140 units (HIGH suggests inflammation)


What is the pattern for hepatocellular damage? How does alcoholic related liver disease affect this?

Hepatocyte damage: leakage of enzymes into the serum --> inflammation --> v high serum transaminases ALT/AST , somewhat high alkaline phosphatase + bilirubin

hepatic damage: ALT>>AST, but in alcoholic disease and NASH (nonalcoholic fatty liver disease): AST>>ALT


What is the pattern for biliary tract damage? How is bilirubin, alkaline phosphatase, and GGTP used to evaluate damage?

Biliary tract damage: increased expression in bile canalicular cells --> v high alkaline phosphatase and bilirubin, somewhat high AST/ALT *since alkaline p is found in several tissues, use GGTP to prove liver problem*

Bilirubin - fractionate (direct/indirect) only if it is 3), tracking flow of bilirubin with imaging helps figure out where obstruction lies


Describe the 4 factors important in devlpt of GERD.

What is the sequelae of GERD?

GERD is the most common cause of esophagitis, GERD can mimic CAD

Factors leading to GERD:
1) impaired LES pressure
2) Presence of hiatal hernia (weakens LES)
3) Impaired distal esophageal mucosal defense mechanisms (no longer prevents back diffusion of acid)
4) delayed gastric emptying (fatty meals, tobacco, alcohol, chocolate)

10% of GERD patients develop Barrett's esophagus (beefy red islands where normal mucosa is replaced by columnar intestinal epithelium)--> 10% of those develop dysplasia (enlargement)--> adenocarcinoma


What is acute cholecystitis, pathology, symptoms.

What is the difference between acute cholecystitis and biliary colic?

I. Cholecystitis - inflamed gallbladder due to obstruction of the cystic duct by a gallstone

Pathology of acute calculous cholecystitis (90% of cases): Phospholipids become toxic --> damage gallbladder mucus protective layer --> prostaglandins released into mucosa and cause inflammatory response --> gallbladder poor contractility --> distension and stasis

Symptoms: nausea, vomiting, RUQ > 4hrs, elevated WBC (due to inflammation), elevated ALT/AST (Affecting liver which is next to gallbladder), positive Murphy's sign

II. Biliary colic - gallstone lodged in cystic duct but falls back into fundus --> RUQ pain


Describe the causes and pathophysiology and lab values of acute pancreatitis

Causes: alcohol + gallstones

Pathology of alcohol: Alcohol alters balance between proteolytic enzymes and protease inhibitors --> triggers
activation of trypsinogen to trypsin in the pancreas

Pathology of gallstones: Gallstones block bile duct --> prevent pancreatic enzymes from entering small intestine and force them back into the pancreas --> disturbs balance between enzymes and inhibitors --> triggers activation of trypsinogen to trypsin

Once trypsin is activated --> Activates more trypsin + other zymogens --> acinar cell injury + destruction --> injured cells activate inflammatory cascade --> inflammation, interstitial edema, fat necrosis (lipase), breakdown of blood vessels (protease) --> hemorrhage

Lab values: amylase, lipase values ~3x normal; (~420 units)


What is dumping syndrome, pathology, symptoms, and treatment?

Dumping syndrome - rapid gastric emptying, common in gastric bypass patients where pylorus is bypassed, no longer there to regulate

Rapid loading of small intestine with hypertonic stomach contents--> increased osmotic pressure --> pulls water into lumen of GI tract --> distension increases motility --> Watery diarrhea

other symptoms: gassy, weakness + tachycardia (due to loss of blood volume to GI tract); hypoglycemia (dumping triggers insulin release)

treat by eating several bland low-carb small meals, limit high sugar foods (otherwise insulin oversecretion --> exacerbates hypoglycemia)



1) Where does digestion occur, what are the enzymes and end products

2) Where does absorption occur (Esp highlight glucose + lactose) and by what mechanism

*Carbs include amylose (plant starch), cellulose (dietary fiber), glycogen (animal starch), sucrose + lactose (disaccharides), and glucose + fructose + galactose (monosaccharides)

1) Partial digestion in mouth via salivary amylase, inactivated by gastric acidity

Luminal digestion in small intestine via pancreatic amylase --> disaccharide, trisaccharide and alpha limit dextrin (oligosaccharide)

Membrane/brush border (duodenum+jejunum) digestion by various enzymes e.g. lactase, maltase --> glucose, galactose, fructose (only monosaccharides are absorbed by intestinal cells)

Cellulose partially digested in the colon and then excreted in the feces

2) Absorption occurs in small intestine, glucose completely absorbed, mostly by the jejunum; wide range in lactose absorption bc of varying levels of lactase enzyme (also needs to be broken down into glucose + galactose)

Apical absorption: Fructose via GLUT5 by passive transport, glucose and galactose via SGLT1 Na+ symporter

Basal absorption: via GLUT2 --> portal circulation --> liver


Describe what happens during carb maldigestion.

Describe causes of maldigestion - genetic and nongenetic

1) Maldigestion: carbs reach the colon --> partially digested by bacteria --> produce short chain fatty acids + H2 + gas (can be measured on breath), lessen water loss in feces (less osmotic diarrhea)

2) Genetic: lactose intolerance, SGLT1 mutation; pancreatic insufficiency (less amylase); non-genetic: decreased surface area (bc resection, Celiac's), parasitic infections



1) Where does digestion occur, what are the enzymes and end products

2) Where does absorption occur and by what mechanism

1) Partial digestion in stomach via pepsin --> polypeptides and AA

Luminal digestion in small intestine via pancreatic peptidases - trypsin activated from trypsinogen via enterokinase- brush border enzyme of the intestinal epithelial cells; activates other proteases (chymotrypsin, elastase, carboxypeptidases) --> oligopeptides + AA

Membrane (brush border) peptidases further break down large peptides --> tri/dipeptides and AA

2) Absorption occurs throughout small intestine, 50% takes place in duodenum, although overall absorption is slow and incomplete

Apical absorption: Tri/dipeptide cotransported into cell with H+ via carriers, use NHE3 to set gradient; free AA transported in through facilitated diffusion; in the cell, cytoplasmic peptidases break down tri/dipeptides into free AA

Basolateral absorption into circulation: AA transporters, either Na+ independent or dependent, use Na/K ATPase to set gradient *no known transporter for acidic AA, used within the cell for energy*



1) Where does digestion occur, what are the enzymes and end products

2) Where does absorption occur and by what mechanism

Digestion: DNA and RNA denatured in stomach by the low pH--> denatured nucleic acids --> nucleases in small intestine break down to olignucleotides --> luminal digestion by pancreatic DNase and RNase and membrane digestion by nucleotidases/nucleosidases --> pyrimidine and purines

Absorption in small intestine: Nucleoside transporters --> sent to circulation OR purine can be metabolized to uric acid


Describe flux of electrolytes and water in the small intestine and how it leads to diarrhea

9L fluid enters GI tract every day, 8 L reabsorbed (7 by small intestine, 1 by colon)

Water enters cell via aquaporins and tight junctions (Cations can also move through tight junctions); Tight junctions are leaky in duodenum, get more tight as you go down the intestine

Water follows osmotic gradient set by ion transport: (luminal cells in small intestine) water enters cell bc glucose does via SGLT1; (crypt cells in intestine) CFTR - water LEAVES the cell bc Cl- is secreted; (colon) water enters cell bc Na+ does via ENaC


What nutrient from dietary fiber do colonic bacteria provide to their hosts?

What's the flip side?

Fermentation in the colon: Dietary fibers = undigestible polysaccharides --> short chain fatty acids e.g. propionate, butyrate, acetate --> we use for energy and immune functions

in general, microbiota increases nutritional efficiency, though can also facilitate malnutrition, obesity, DMI, or DMII (dysbiosis in patients - dont know if its cause or result, probably two way interaction)


Describe how motility, secretion and microflora affect the mucosal defense in the GI tract

1) motility and secretion: mechanic cleansing (to remove pathogens from our gut), mucin + lysozyme, acquired IgA antibody

2) microbiota upregulates:
A) endocytosis of pathogens via M cells

B) tight junctions between cells

C) granular leukocytes

D) epithelial cell turnover

E) GALT proliferation for immunity e.g. Peyer's patches (lymphoid nodules)

F) increased cell enzyme activity e.g. pancreatic lipase protein (also involved in T lymphocyte devlpt)

G) thicker muscle for improved motility


Describe potential role of microbiota in viral infections

1) competes with pathogens for nutrients + Adhesion sites

2) secretes antimicrobial factors e.g. bile acids, lactic acids

3) denegerates toxins generated by pathogens

4) general stimulation of immune functions e.g. phagocytosis, antibody production, GALT

5) BUT... potentially also helps pathogens... also associated with IBD, colorectal cancer


Describe the proposed etiology of Celiac disease

1) Multifactorial pathogenesis: genetic, environmental (intestinal permeability, innate immune response, microbiome)

Genetic mutation in HLA-DQ2 or 8 (40% heritability) and non-HLA genes on same locus (60% heritability) e.g. dermatitis herpetiformis, DMI

Trigger: gliadin (protein found in gluten) --> activated immune cells in lamina propria, T lymphocytes recruited, cytokine release --> intestinal enteropathy (inflammation)


Describe the presenting signs and symptoms of Celiac disease

What nutritional deficiencies are associated

I. Distended stomach hypertympanic upon percussion

stools bulky and foul smelling + steatorrhea + diarrhea

weight loss + gluteal wasting

II. Calcium malabsorption --> osteoporosis, osteoarthritis; iron deficiency --> anemia; neurological disorders, clubbed fingers, folate deficiency --> folic acid supplements for female patients


How do you diagnose Celiac? What are the the histological changes?

Diagnosis: Tests for presence of IgA-tTG, EMA antibodies; then small bowel biopsy

Histology - villi atrophy + walls thicken, crypt hyperplasia (become longer), increased # inflammatory cells (intraepithelial lymphocytes), mucosal inflammation


Describe the role of AMPK, mTOR and growth hormones in the regulation of energy metabolic homeostasis

1) AMPK - senses low ATP levels through the buildup of AMP from ADP (e.g. exercise) and makes more ATP for energy by stimulating catabolic pathways + GLUT4 muscle transporters and inhibiting anabolic pathways

2) mTOR - senses AA availability, regulates cell tissue + organ growth by stimulating protein synthesis and anabolic pathways

3) GH - stress hormone (along with cortisol and epinephrine) - stimulates growth through IGFs (increases transcription), raises blood glucose by decreasing uptake in fat, muscle; increases lipolysis and protein synthesis + other anabolic pathways


i. Structure of glucagon
ii. Regulation of glucagon secretion
iii. Metabolic effects of glucagon
iv. Mechanism of action of glucagon

i. Structure: single polypeptide chain - AA sequence is the same in all mammalian species; produced in pancreatic alpha cells

ii. Regulation: secretion stimulated by low blood glucose, AA (to prevent hypoglycemia bc of insulin secretion), epinephrine; inhibited by elevated blood sugar

iii. Metabolic effects: Hepatic glycogenolysis, gluconeogenesis (through uptake in AA)--> leads to immediate rise in glucose levels; promotes oxidation of fatty acids and lipase in adipose tissues

iv. Mechanism: Binds to membrane receptors on liver or fat --> activates cAMP cascade --> PKA phosphorylation of enzymes (epinephrine also operates through the same mechanism though it binds to a different receptor)

*caffeine inhibits phosphodiesterase enzyme that inactivates cAMP --> constitutively activated


i. Structure of Insulin
ii. Regulation of insulin secretion
iii. Metabolic effects of insulin
iv. Mechanism of insulin action

*Insulin is the most important hormone coordinating the use of fuels by body tissues*

i. Structure: A and B chains linked by disulfide bonds, + C-peptide (used clinically as marker of endogenous insulin production); produced in pancreatic beta cells

ii. Regulation: secretion stimulated by glucose (primary control), AA; inhibited by epi (trauma) - epi can override glucose control

iii. Metabolic effects: Anabolic, promotes storage of fuels and synthesis of complex molecules (glycogen, protein, fat), inhibits gluconeogesis + glycogenolysis + lipolysis

iv. Mechanism: insulin binds to tyrosine kinase receptors on cell membranes in tissues (liver, fat, muscle) --> signal transduction cascade --> ras (alters gene transcription) or PKB (dephosphorylation of enzymes)


Describe the similarities and differences among glucagon, epinephrine and cortisol

All work to oppose the actions of insulin, glucagon + epi use same signaling pathway (cAMP and PKA)

epi and cortisol are hormones, respond to STRESS, receptors on muscle + liver + fat

glucagon is a protein, responds to GLUCOSE, receptors on liver + fat but NOT muscle


At what level is enzyme expression regulated?

At what level is enzyme activity regulated?

Expression - mRNA synthesis and degradation

Activity - phosphorylation (glucagon) / dephosphorylation (insulin)


Describe the differences between GLUT2 and GLUT4 in terms of location and role in glucose uptake.

I. GLUT2 in liver and pancreatic beta cells, uptake of glucose in pancreatic cells leads to insulin secretion which activates GLUT4

GLUT4 is in muscle and fat, lower Km ensures these tissues extract glucose from blood faster

then liver can use GLUT2 to take up whatever glucose is leftover


Describe the first step in glycolysis. Why is glucose phosphorylated?

1st step: Glucose + ATP --> Glucose-6-P (irreversible)

enzyme: hexokinase or glucokinase (isozymes)

glucose moves acc to gradient --> phosphorylating glucose and making it negatively charged maintains downhill gradient for glucose entry into cell; also, it cannot be recognized/escape cell through transporters


Compare and contrast hexokinase and glucokinase including: tissue distribution, relative Km/Vmax, and regulation

Hexokinase - in all tissues, low Km and low Vmax, works at maximum rate all the time --> ensures glucose stores are quickly replenished when the body has glucose to spare; regulation: feedback inhibited by product (G6P)

Glucokinase - ONLY in the liver and pancreas, high Km and high Vmax, works best when blood glucose is HIGH--> liver has to wait until muscle has replenished glucose stores, but after that can take in much more glucose for glycolysis, glycogen storage (prevents hyperglycemia)

Regulation: In presence of F6P product, GKRP inactivates glucokinase by forming complex and sequestering in nucleus; GK is activated by F1P (dissociates GK-GKRP complex); allosterically activated by insulin and deactivated by glucagon (via increased/decreased transcription of the gene encoding the enzyme)


Describe the allosteric regulation of PFK1 (activators/inhibitors) in liver vs muscle

F6P + ATP + PFK1 --> F16BP + ADP step is fast in the liver when blood glucose is high (for glycolysis and glycogen storage) and fast in the muscle when ATP deficient (e.g. during exercise, need ATP replenishment)

Liver regulators: PFK1 activated by F2,6BP (created from F6P by PFK2 enzyme); PFK2 activated by insulin dephosphorylation and inhibited by glucagon phosphorylation via PKA --> ensures that the RLS proceeds only when the body is in fed, glucose rich state and has enough substrate (F6P); PFK2 also inhibited by epinephrine

*PFK2 is bifunctional - can either make F2,6BP (in kinase form) or break down F2,6BP (as FBP2, phosphatase form)*

Muscle regulators: PFK1 activated AMP (implying low energy state)

PFK1 inhibited by ATP, low pH, citrate (implying high energy state)


Compare aerobic and anaerobic glycolysis

Aerobic glycolysis - if there is available 02, pyruvate goes into the TCA cycle

Anaerobic glycolysis - pyruvate --> lactate, produces NAD+ to keep glycolysis going; occurs in cells with no mt (e.g. RBCs) and exercising muscle (produces lots of NADH) --> can lead to lactic acidosis

Cori cycle: lactate taken to liver via circulation and converted back to pyruvate


List the energy gains and expenditures of aerobic and anaerobic Glycolysis

Aerobic glycolysis: Glucose + 2P + 2ADP + 2NAD+ --> 2 pyruvate + 2ATP + 2NADH + 2H20 + 2H+

Anaerobic glycolysis: Glucose + 2P + 2ADP --> 2 lactate + 2ATP + 2H20


Describe the disorders of glycolysis incl cause, symptoms, and treatment:
1) PFK1 deficiency
2) Pyruvate kinase
3) GLUT1 deficiency
4) Glucokinase deficiency

1) PFK deficiency
A) Cause: mutation of M subunit --> Affects muscle cells + RBCs
B) Symptoms: muscle weakness, hemolytic anemia (from RBC loss)
C) Treatment: avoid exercise

2) Pyruvate kinase
A) Cause: Mutation in RBCs --> cannot maintain Na/K ATPase --> swollen burr cells --> hemolysis
B) Symptoms: hemolytic anemia, destruction of spleen, decreased hemoglobin, increased 2,3BPG (useful bc of improved 02 unloading)
C) Treatment: blood transfusion, folate supplementation

3) GLUT1 deficiency
A) Cause: decreased glucose uptake in the brain
B) Symptoms: devlpt delay, seizures
C) high fat, low carb ketogenic diet so body can burn ketones as alternate fuel soruce in the absence of glucose (brain can only use glucose or ketone bodies)

4) Glucokinase deficiency
A) Cause: autosomal dominant mutation; increased blood glucose --> increased insulin secretion
B) Symptoms: one allele leads to MODY (monogenic diabetes)
C) Treatment: diet


Describe the pyruvate dehydrogenase complex incl rxn + regulation

c is in the mt and catalyzes the irreversible linkage rxn bw glycolysis and TCA cycle: pyruvate + CoA + 2NAD --> AcetylCoA + 2C02 + 2NADH

ATP, Acetyl CoA + NADH (products) inhibit PDH in 2 ways: 1) direct allosteric effect and 2) activating a kinase which phosphorylates/inactivates it (covalent modification)

Insulin (fat), calcium (muscle) activate a phosphatase which dephosphorylates/activates PDH (covalent modification)

pyruvate + NAD + CoA (reactants) + dichloroacetate drug (pyruvate) analog activate PDH by inhibiting PDH kinase


Describe PDH components + cofactors, incl which 3 enzymes share E3

Structure: 3 subunits E1, E2, E3

E1- cofactor is TPP (Vit B1 thiamine)

E2 - cofactors are CoA (Vit B5 pantothenic acid) and lipoic acid; E2 inhibited by arsenic + mercury --> antidote is BAL (british anti-lewisite) chelator

E3- cofactors are FAD (Vit B2 riboflavin) and NAD (Vit B3 niacin); E3 common in 3 enzymes: 1) PDH 2) alpha keto glutarate dehydrogenase 3) branched chain keto acid dehydrogenase

*Can remember Tender Loving Care For Nancy


Describe PDH deficiency incl causes, symptoms, and treatment

1) PDH deficiency can be due to mutation e.g. E1 X-linked gene

2) PDH deficiency --> pruvate and lactate accumulate --> lactic acidosis + brain gray matter degeneration (delayed devlpt, seizures)

3) Treatment: thiamine supplementation (if E1 mutation), ketogenic (high fat, low carb) diet to create more ketone bodies that brain can use as fuel, dichloroacetate (inhibits kinase to PDH kinase to increase activity of whatever PDH is there)

*type of Leigh disease (Characterized by lactic acidosis)


What is the function, location, and activators/inhibitors of the TCA cycle?

What does it mean that Acetyl CoA cannot "fill" the cycle? What does?

TCA cycle = Krebs cycle = Citric acid cycle

1) occurs in mitochondria, runs all the time (Rate depends on energy status, only allosteric regulation NO hormones), aerobic pathway that provides energy for ATP synthesis

2) High energy molecules ATP, NADH, Succinyl CoA, and citrate inhibit the key regulatory enzymes and slow down pathway

Calcium and ADP speed up the pathway

3) Acetyl CoA has two carbons which leave the cycle as C02 -- so it cannot replenish the intermediates

in order for TCA cycle to continue, need anapleuritic rxns that fill in the cycle by replenishing intermediates e.g. citrate, glutamate, malate, aspartate


What are the three key regulatory enzymes of the TCA cycle and what is their role?

1) Citrate synthase: Acetyl CoA + oxaloacetate + H20 --> Citrate + C0A

2) isocitrate dehydrogenase *committed step*: Citrate + NAD --> alpha ketoglutarate + NADH + C02

3) alpha ketogluturate dehydrogenase complex (similar to PDH and branched chain alpha keto acid dehydrogenase in that it is an E1/E2/E3 complex): alpha ketoglutarate + NAD + CoA-SH --> succinyl CoA + NADH + C02


What are the TCA cycle products and what is their fate?

TCA cycle (2 turns for the 2Acetyl CoA from glycolysis) --> 2ATP, 6 NADH, and 2FADH2