BRS - Biochem Clinical Correlates Flashcards
Which cells produce HCl of the stomach?
What is responsible for producing acidic gastric fluid?
- parietal cells of the stomach produce HCl
- H+-K+ ATPase (the proton pump) in the cell membrane is responsible for producing as much as 2 L of acidic gastric fluid per day.
GERD:
pathology, symptoms, treatment
gastroesophageal refulx disease (GERD)
- results from reflux of HCl into the esophagus
- sxs: burning sensation in the chest, cough, SOB
- tx: proton pump inhibitors (PPI - omeprazole) to inhibit the H-K-ATPase/ “proton pump”
what drug is used to treat glaucoma and altitude sickness?
carbonic anhydrase inhibitor (acetazolamide);
blocks the reaction pictured
what can cause metabolic acidosis?
- accumulation of metabolic acids
- lactic acid or the ketone bodies, b-hydroxybutyric acid, and acetoacetic acid
- ingestion of acids or compounds that are metabolized to acids
- (e.g., methanol, ethylene glycol).
what can cause METABOLIC ALKALOSIS?
- due to increased HCO3-, (accompanied by an inc. pH)
- Acid-base disturbances –> compensatory responses –> attempt to restore normal pH.
- E.g. a metabolic acidosis causes hyperventilation & the release of CO2, which tends to raise the pH.
- During metabolic acidosis, the kidneys excrete NH4+, which contains H+ buffered by ammonia:
Glycoside digitalis:
mechanism of action, use
- MOA: inhibit the Na-K ATPase on cell membranes
- Tx: congestive heart failure
how do labs measure the amount of glucose in urine?
(highly specific test)
using a dipstick to measure glucose in urine;
measures oxidation of glucose by GLUCOSE OXIDASE
Gray Baby Syndrome:
define, physiology of infants –> pathology
- DEF: fetal shock-like syndrome (circulatory collapse); ashen-gray color, abdominal distention, vomiting, flaccidity, cyanosis, circulatory collapse, and death
- PHYS: infants have decreased ability to conjugate glucuronic acid onto drugs such as CHLORAMPHENICOL
- PATH: Admin of antibiotic during the neonatal period can result in elevated plasma levels of the drug
Benedict test for reducing sugars:
- why used?
- what does it detect?
- when is this used routinely?
- why: bc dipsticks ONLY detect glucose; this is another test for reducing sugars
- what: ALSO detects the presence of glucose, sucrose, galactose, and fructose
- when: most newborn and infant urine is routinely screened
- screened for reducing sugars to detect inborn errors in metabolism
Sorbitol:
def:
diffusion?
clinical correlate
- def: glucose is reduced to SORBITOL
- DOES NOT READILY diffuse out of cells
- CC: as sorbitol accumulates in cells –> causes osmotic damage to cells of the nervous system –> cataracts and neuropathy
Leukocyte adhesion deficiency (LAD) II:
pathology, sxs
- Path: pts w/ this type of congenital deficiency –> deficiency in ability to glycosylate ligands for cell surface selectins, which mediate immune cell migration
- Sxs: prone to recurrent life-threatening infxns
Heparin:
composition, MOA, use
- glycosaminoglycan
- important anti-coagulant found in the granules of mast cells
- tx myocardial infarction as well as preventing DVT during hospitalizations
Influenza virus:
MOA
infects cells by binding its viral hemagglutinin to SIALIC ACID on the surface of epithelial cells
Glycine:
function in the brain?
what antagnoizes it?
- Fxn: Glycine functions as INHIBITORY NEUROTRANSMITTER in the brainstem and spinal cord;
- Antagonist: RODENTICIDE STRYCHINE –> muscle spasm and twitching
Glutamate:
MOA,
Antagonist
Implications
- MOA: Amino acid of highest concentration in brain and fxns as neurotransmitter in brain and spinal cord; EXCITATORY
- Antagonist: MEMANTINE, used for tx of Alzheimer disease
- Glutamate antagonism implicated in SCHIZOPHRENIA, in which drugs of abuse, like ketamine & phencyclidine, affects glutamate binding to its receptor
Cholera toxin:
MOA, CC
it binds to the ganglioside GM1 receptor on cells and upon entry causes a potentially life-threatening water diarrhea
CYSTIC FIBROSIS TRANSMEMBRANE REGULATOR
(CFTR):
where, mutation, CC
Marfan Syndrome:
biochem/gross pathology; presentation
- biochem: mutations in gene for the highly alpha-helical fibrillary protein FIBRILLIN, which is a major component of fibrils found in extracellular matrix
- gross: patients have DEFECTIVE CONNECTIVE TISSUE, particularly in ligaments and aorta
- presentation: excessively long fingers and extremities; arachnodactyly, and predisposition to dissecting aortic aneurysms and valvular disease
Creutzfeldt-Jakob disease (CJD)
pathology, presentation
- path: prion disease; results from transmission of a proteinaceous agent that is capable of altering the normal alpha-helical arrangement of prion protein->
- replacing it with beta-pleated sheets and smaller alpha helices; similar to pathogenic form –>
- resulting misfolding protein is resistant to degradation, w/ death of the affected neurons
- presentation: pronounced involuntary jerking movements (startle myoclonus), and rapidly deteriorating DEMENTIA
Heat shock proteins:
function, pathology
- fxn: group of chaperones
- path: mutations in such proteins –> leads to human disease
- Charcot-Marie-Tooth disease (MC cause of inherited neuromuscular diseases ; found to have mutations in HSPS
alpha1- antitrypsin (AAT) deficiency:
path, presentation
- path: results in misfolded protein that gets trapped w/in the cell
- presentation: pts w/ decreased levels of this protease inhibitor manifest w/ cirrhosis and emphysema
Huntington disease:
pathology, presentation
- path: expansion of a region of POLYGLUTAMINE REPEATS w/in the Huntington protein –> protein aggregates and forms intranuclear inclusions –> neuronal cell death
- presentation:
- progressive movement disorders
- dementia
Bortezomib (Velcade)
purpose, function
- purpose: novel anticancer drug; used for treatment fo multiple myeloma and inhibits the proteasome
- function: thought is that cancer cells are more dependent on proteasomal degradation than normal cells for proliferation, metastasis, and survival
Chediak-Higashi syndrome:
pathology, presentation
- path: defect in the ability to transfer enzymes from lysosomes to phagocytic vesicles
- presentation: recurrent infections owing to a lack of microbial killing, anemia, and thrombocytopenia
Sickle Cell Anemia:
pathology, presentation
- path: mutation producing alterations in structure of hemoglobin
- beta chain of hemoglobin contains VALINE instead of GLUTAMATE at position 6
- Mutant hemoglobin (HbS), a hydrophobic amino acid replaces an AA w/ a negative charge –>
- allows deoxygenated molecules of HbS to polymerize –>
- RBCs contain large complexes of HbS –> sickle shape
- presentation: causes HEMOLYSIS –> anemia results
- painful vaso-occlusive crises
- end-organ damage may result
How does the affinity of hemoglobin for carbon monoxide differ from those of oxygen?
- Hemoglobin has about 250 times the affinity for carbon monoxide than it does for oxygen.
- Path:
- Prolonged or heavy exposure to carbon monoxide results in disorientation, headache, and potentially fatal asphyxiation.
- Patients may have ‘‘cherry-red mucous membranes’’ due to the accumulation of carboxyhemoglobin.
Osteogenesis imperfecta:
pathology, presentation
- path: synthesis of the Type I collagen; widespread clinical consequence
- presentation: BONE FRAGILITY (w/ predisposition to multiple childhood fractures), hearing loss, and distinctive blue sclera
Ehlers-Danlos syndrome:
pathology, presentation
- path: group of disorders characterized by a DEFECT in the synthesis or structure of collagen; Ehlers-Danlos type VI results from a defect in the enzyme lysyl hydroxylase
- presentation: hyperextensible skin, laxity of joints, defects in large blood vessels
C-peptide levels:
purpose,
- path: levels are used to differentiate the causes of high insulin in patients
- C-peptide is elevated in cases of tumors of pancreatic Beta cells: Low blood glucose/ due to inc levels of insulin via endogenous production
-
C-peptide is NOT ELEVATED in surreptitious insulin administration (purposeful injection of insulin)
- think: commercial insulin preparations have purified away this contaminant
Valacyclovir and Valganciclovir:
function
- nucleoside analogs; valine ester PRODRUGS of the antiviral acyclovir (treating HSV types 1 and 2 and varicella-zoster infxns)
ganciclovir and famciclovir:
function
-
ganciclovir: tx CMV retinitis in pts w/ AIDs
- a prodrug activated and converted by hepatic and intestinal enzymes to active drug and higher bioavailability and efficacy
- famciclovir: for shingles and recurrent outbreaks of HSV type 2
what is the optimal pH for pepsin?
Why?
- optimal pH for pepsin is 2,
- reflecting its need as a digestive enzyme in the acidic gastric juice of the stomach
what is the optimal pH for alkaline phosphatase?
why?
optimal pH for alkaline phosphatase is 9,
reflecting the basic pH environment in bone
Isoniazid:
use, function
- drug used in treatment of tuberculosis
- acetylated by an N-acetyltransferase
- Fast acetylators/metabolizers: clear the drug from blood about 300% faster than in the second group of individuals,
-
Slow acetylators/poor metabolizers, in
whom the presence of drug is prolonged, causing hepatotoxicity and neuropathy
- Km (affinity of isoniazid substrate) is normal, but the Vmax of ‘‘fast’’ N-acetyltransferase, is three times normal.
Hypersensitivity to alcohol:
pathology
- exists when drinking small amounts of alcohol causes
- *facial flushing and tachycardia (rapid heartbeat).**
- Alcohol dehydrogenase generates acetaldehyde, which is converted to acetate by aldehyde dehydrogenase. The latter enzyme exists in two forms, a high-affinity (low Km) form and a low-affinity (high Km) form.
- Those sensitive to alcohol lack the high-affinity form, resulting in excess acetaldehyde and, hence, vasodilation
Physostigmine:
pathology, use
- path: a competitive reversible inhibitor of acetylcholinesterase
- used to tx glaucoma (inc intraocular pressure) and myasthenia gravis (an autoimmune disease acting at the neuromuscular junction)
Angiotensin-Converting Enzyme (ACE) inhibitors:
examples, action
- captopril, enalapril, lisinopril
- MC used antihypertensive therapies that inhibit formation of angiotensin II, an octapeptide from angiotensin I
EDTA (ethylenediamine tetracetic acid):
path
- common noncompetitive inhibitor; result of chelation (metal binding) therapy
- resulting in removal of required divalent metal ions from active site of enzymes
- CC: blood of patients is collected with EDTA to inhibit both calcium-activated proteases and the blood coagulation pathway
Nerve gas:
path
- aka agents of chemical terrorism (tabun and sarin), alkylphosphate insecticides (malathion)
- path: irreversible inhibitors of acetylcholinesterase
- also called “suicide inhibitors”, creating a reactive group irreversibly reacting in the active site, forming an extremely stable intermediate
how are hemostasis and thrombosis mediated?
- mediated by enzymes along cascading steps of
the blood coagulation pathways. Inherited deficiencies of clotting factors result in uncontrolled bleeding. - Factor VIII deficiency causes hemophilia A, an X-linked disease rife in some European royal families
Where is CK-MM found?
Where is CK-MB found?
- CK-MM: makes up 99% of skeletal muscle distribution, and 75% of myocardium
- CK-MB: makes up 25% of myocardium, but it is not found in any other tissues;
- CK-MB is significant marker in a myocardial infarction (heart attack, MI)
- used in conjunction with another protein marker (troponin)
Serum amylase:
pathology
- elevated in cases of pancreatitis;
- the test to measure amylase is often ordered in patients to evaluate such a condition;
- however, serum lipase is another marker of pancreatitis that demonstrates higher sensitivity and specificity compared with amylase
ACARBOSE:
what, where, fxn
- alpha-glucosidase inhibitor,
- works in the intestine,
- fxn: to facilitate better postdigestive blood glucose control
- slowing down digestion of carbohydrates–>
- lengthening the time it takes for carbs to be converted to glucose
LACTASE DEFICIENCY:
epi, pathology, sxs
- epi: occurs in 80% of Native, African, and Asian Americans
- path: lactose is NOT digested at a normal rate and accumulates in the gut –> where it is metabolized by bacteria
- sxs: bloating, abdominal cramps, watery diarrhea
STEATORRHEA:
path
- occurs when excess lipids are excreted into the feces
- bc of lipid malabsorption from IMPAIRED LIPOLYSIS, MICELLE, OR CHYLOMICRON formation, or chylomicron transport
ORLISTAT:
fxn
- anti-obesity drug
- inhibits pancreatic and gastric lipase –> 30% blockage of dietary fat from digestion and absorption, –> REDUCTION IN BODY WEIGHT in some patients
OLESTRA:
fxn
- artificial fat, composed of a sucrose polyester and fatty acids
- NOT DEGRADED by gastric or pancreatic lipases and PASSES THROUGH THE BODY UNDIGESTED and unabsorbed –>
- excress use in foods may interfere with absorption of fat soluble vitamins
non-tropical sprue (ADULT CELIAC DISEASE)
path, sxs
- path: causes reaction to gluten (a protein found in grains) <– from intestinal epithelial cells are DAMAGED –> malabsorption results
- sxs: steatorrhea, diarrhea, weight loss
ACHLORYDRIA:
def, path
- def: lack of ability to produce HCl (usually due to autoimmune destruction of gastric parietal cells)
- path: deficiencies in protein digestion and absorption
SECRETIN:
fxn; clinical correlate
- Fxn: hormone that is released by cells lining the duodenum –> bicarbonate is released from pancreas
- CC: FAILURE TO FULLY NEUTRALIZE the acidic gastric contents results in PEPTIC ULCERS in the duodenum
HEREDITARY DEFICIENCY OF ENTEROKINASE:
path, sxs, tx
- Deficiency of this important zymogen activator
- Sxs: diarrhea, failure to thrive, and hypoproteinemia
- Tx:
- managed during infancy with pancreatic enzyme supplementation.
- When patients become adults, they no longer need such supplementation, owing to the decreased anabolic demands and the autocatalysis of digestive enzymes
CYSTINURIA:
path, sxs
- PATH: transport of cysteine and basic amino acids is defective in both
the intestine and kidney.- Cysteine cannot be resorbed from the glomerular filtrate and concentrates in the urine.
- Within the urine, the cysteine is oxidized to cystine, which can crystallize
- SXS: kidney stones
HARTNUP DISEASE:
path
transport of neutral amino acids is defective –> resulting in potential deficiencies of essential amino acids because they are not absorbed from the diet.
what is the function of gamma-glutamyl transferase (GGT)?
what causes elevated serum levels of GGT?
- fxn: mediates rranslocation of amino acids in the g-glutamyl cycle
- elevated serum GGT in:
- intrahepatic & posthepatic biliary obstructions –(indicating cholestasis)
- pancreatic cancer and alcohol-induced liver disease
RED BLOOD CELLS (RBCs):
path
- lack mitochondria –> completely reliant on glycolysis as source of energy
- deficiencies of glycolytic enzymes have a profound effect on RBC function
Hereditary deficiency of GLUT-1:
structure, sxs
- structure: an insulin-dependent transporter –> decreased glucose in the cerebrospinal fluid
- sxs: manifest with intractable seizures in infancy, developmental delay
Absence of A isoform of Aldolase:
where is it found, presentation
- where: aldolase is found in RBCs and muscles
- presentation: nonspherocytic hemolytic anemia
- episodes of Rhabdomyolysis (destruction of muscle cells)
- following febrile illness
Triose phosphate isomerase (TPI):
presentation
- neonatal-onset hemolytic anemia as well as progressive neurologic involvement
- children have progressive hypotonia with eventual diaphragm paralysis that requires ventilation, as well as cardiomyopathy
enolase inhibition
how, path
- enolase is INHIBITED BY FLUORIDE
- to prevent ongoing glycolysis in a patient’s blood samples collected for sensitive glucose tolerance tests, blood is collected in tubes containing fluoride
FETAL HEMOGLOBIN (HbF):
structure,
and maternal-fetal interface
- composed of two alpha subunits and two gamma subunits, has a lower affinity for BPG than does HbA, and therefore, HbF has a higher affinity for O2.
- The difference in maternal and fetal hemoglobin facilitates the unloading of O2 at the maternal–fetal interface (i.e., the placenta).
maturity-onset diabetes of the young (MODY):
path, sxs
- path: type 2 is an autosomal dominant disorder involving mutations in the glucokinase (GCK) gene
- sxs: nonprogressive hyperglycemia; usually asymptomatic at diagnosis, and is usually managed with diet alone
Phosphofructokinase deficiency
type, path, sxs
- a form of glycogen storage disease [TYPE VII]
- path: glycogen accumulates in muscles –> results in inefficiency use of glucose stores by RBCs and muscles
- Sxs: with hemolytic anemia, muscle cramping
pyruvate kinase deficiency:
path
- causes decreased production of ATP from glycolysis;
- RBCs have insufficient ATP for their membrane pumps, and a hemolytic anemia results
ARSENIC:
characteristics, pathology
- odorless and tasteless heavy metal, which has been used
throughout the centuries as a poison. - path: it inhibits one of the subunits of the PDHC –> resulting in impaired production of acetyl CoA and subsequent energy production via oxidative phosphorylation
PDHC Deficiency
(PDHC = pyruvate dehydrogenase complex)
path, sxs
- one of the MC neurodegenerative disorders associated with abnormal mitochondrial metabolism.
- sxs:
- Severe forms of the disease are lethal;
- mild forms exhibit ataxia and mild psychomotor delay and nonspecific symptoms (e.g., severe lethargy, poor feeding, tachypnea) related to lactate buildup
- (especially during times of illness, stress, or high carbohydrate intake.)
Fluoroacetate
(rat poison)
path, sxs
- path: reacts with oxaloacetate (OAA) to form fluorocitrate –> Fluorocitrate inhibits aconitase, leading to the accumulation of citrate.
- Ingestion may result in convulsions, cardiac arrhythmias, and eventually death.
fatal infantile mitochondrial myopathy
path, sxs
- path: involves decreased activity of the mtDNA-encoded respiratory chain complexes (I, III, IV, V)
- sxs: patients have early progressive liver failure and neurologic abnormalities, hypoglycemia, and inc lactate in body fluids
mutations in the mitochondrial encoded gene for
NADH:ubiquinone oxidoreductase (complex I)
path
- results in the disorder MELAS.
- MELAS is an acronym for the clinical manifestations of the disease mitochondrial encephalopathy, lactic acidosis, and stroke
mitochondrial DNA (mtDNA):
name, path, sxs
- name: Leber’s hereditary optic neuropathy (LHON)
- path: have point mtuations in the gene for cytochrome reductase
- sxs: pts are typically males in their 20s and 30s who develop loss of central vision
Kearns-Sayre syndrome:
path, sxs
- path: mtDNA defect –> mutations in the complex II of the ETC
- sxs: short stature, complete external ophthalmoplegia, pigmentary retinopathy, ataxia, and cardiac conduction defects
LEIGH DISEASE:
path, sxs
- path: mtDNA disorder (Mitochondrial DNA)
- sxs: present w/ lactic acidemia, developmental delay, seizure, extraocular, and hypotonia
- The disorder is usually fatal by the age of 2 years, with some patients exhibiting mutations in cytochrome oxidase
how do alcohol and certain drugs affect cytochrome mono-oxidases?
- Consumption of alcohol and certain drugs induces expression of various cytochrome mono-oxidases.
- Patients who abuse such substances are more prone to the deleterious effects of ROS formed by these P-450 enzymes.
Chronic granulomatous disease (CGD):
path, sxs
- path: results from a deficiency of NADPH oxidase and the inability to effectively kill engulfed microbes, especially bacteria.
- sxs: Patients with CGD present with serious recurrent bacterial infections.
H2O2-MPO-halide system:
fxn, path
- one of the most effective mechanisms for killing bacteria within neutrophils.
- However, patients with defects in this system have near-normal immune function because bacteria are killed, albeit slower, by superoxide produced by the action of NADPH oxidase.
carbon tetrachloride (CCl4):
use, mechanism
- use: organic solvent used in the dry cleaning industry
- mechanism: P-450 cytochrome system converts CCL4 to the free radical species CCl3.
- This highly reactive species causes a chain reaction of lipid peroxidation, particularly in the liver, that leads to hepatocellular necrosis.