FDN Exam 2 Clinical Correlations Flashcards
Define hyperglycemia and give its cause
Elevated blood glucose caused by decreased insulin action
Insulin action = [insulin] x insulin sensitivity
What is diabetes mellitus?
A family of disorders characterized by chronic hyperglycemia and the development of long-term (chronic) complications
List the acute and chronic complications of diabetes
Acute: polyuria, polydipsia, dehydration, weight loss, ketoacidosis (T1DM > T2DM), blurry vision (lens changes), infection (b/c phagocytes don’t work well during hyperglycemia)
Chronic: macrovascular disease (CAD, PVD, and carotid artery disease), microvascular disease (blindness, renal failure), neuropathy
Type 1 diabetes mellitus
Absolute insulin deficiency. The beta cells in the pancreas have been destroyed via an autoimmune response.
Typically seen in the young
Type 2 diabetes mellitus
Insulin resistance; relative insulin deficiency
Beta cells are making insulin but they cannot keep up with the demand
Typically see in older adults, but is skewing younger due to obesity trends
Note: gestational diabetes is like this
Affects of hypoglycemia?
Impaired CNS function (can occur acutely)
Decreased mentation, coma, seizure, apnea, death
Mechanism of action by Bordetella pertussis
Pertussis toxin is an ADP-ribosylating enzyme. Covalently modifies Gia (inhibitory G protein alpha subunit) and inhibits GDP/GTP exchange (stuck with GDP in the inactive form). Gi protein complex can no longer inhibit adenylyl cyclase and persistent cAMP formation ensues
Mechanism of action by Vibrio cholerae
Vibrio cholerae is an ADP-ribosylating enzyme. Covalently modifies Gsa (stimulatory G protein alpha subunit) and inhibits GDP/GTP exchange (stuck with GTP/in the active form). Persistent activation of adenylyl cyclase ensues.
Classic galactosemia: cause and clinical observations
Elevated galactose in the blood due to a deficiency in galactose-1-phosphate uridyltransferase enzyme
Clinical observations: FTT, vomiting & diarrhea after ingestion of breast milk, formula, or dairy. Less common is hepatomegaly and jaundice. Elevated galactose and galactose metabolites in blood & urine
Consequences of untreated galactosemia
Mental and growth retardation, impaired motor function, cataracts, hepatomegaly/impaired liver function
Impaired neurological functions & ovary deficiency can still occur even with treatment
The aggregation of what galactose-derivative in the eye causes cataracts?
D-Galactitol
Made from D-Galactose by the enzyme aldose reductase
What enzyme is galactose-1-phosphate a competitive inhibitor of?
What is the reaction this stops/slows?
Phosphoglucomutase (found in liver, brain & kidneys)
Glucose-6-phosphate —-> Glucose-1-phosphate
(Link between glycogen, glucose and glycolysis!)
Glycogen storage disease type 1a - von Gierke’s Disease (cause and underlying mechanisms of action/affects on the cell)
Deficiency in the liver enzyme glucose-6-phosphatase. Inability to mobilize glucose from glycogen or run gluconeogenesis. Levels of glucose-6-phosphate will increase in the cell.
Hypoglycemia will lead to the release of glucagon (glucagonemia) & then the mobilization of fats from adipose tissue (leading to hypercholesteremia and hypertriglyceridemia)
Glucagon will stimulate gluconeogenesis, making even more glucose-6-phosphate! Now it is driven into glycogen… and thus the glycogen storage blobs from histology slides.
** Final key mechanism is that NADH levels rise and push pyruvate to lactate. Causing lactic acidosis
Presentation symptoms of von Gierke’s Disease/glycogen storage disease type 1a
Severe hepatomegaly (due to glycogen and fat accumulation), growth retardation (carbohydrate starvation of tissues), hepatic adenomas that lead to hepatic carcinomas in adults
Treatment of glycogen storage disease type 1a/von Gierke’s Disease
Normalize hormones and metabolism with many small daytime meals that are high in carbohydrates (60-70%)
Supplement with grams of cornstarch (slow glucose release)
Can you maintain blood glucose from fat?
NO
just checking :
Steatorrhea
Excess fat in the feces. Can be caused by:
- Insufficient bile formation due to liver disease or biliary atresia
- Insufficient lipase secretion (pancreatitis, CF, pancreatic cancer)
- Intestinal inflammation like Crohn’s
- Other intestinal absorption deficiencies
What effect do dietary omega-6 PUFAs have on cholesterol?
Lowers total plasma cholesterol and LDL, BUT also lowers HDL
What effect do dietary omega-3 PUFAs have on cholesterol?
Little, BUT they can lower plasma TAG which will decrease heart arrhythmias, BP, and overall heart disease
What effect do dietary trans fats have on cholesterol?
Elevate LDL, lower HDL, and thus increase cardiovascular disease
What effect do MUFAs have on cholesterol?
Decrease LDL, maintain or increase HDL, lower incidence of coronary heart disease
What affect do saturated fatty acids have on cholesterol?
Increase LDL, little effect on HDL, increase risk of CHD, prostate and colon cancers
Alcoholic Fatty Liver Disease
Excessive alcohol use causes hepatic acetaldehyde formation that damages liver cells and promotes fat storage
Chronic alcoholic fatty liver can lead to fibrosis, hepatitis, and liver failure
Non-Alcoholic Fatty Liver Disease (NAFLD)
Exact mechanisms are unknown; often occurs with obesity, Type 2 Diabetes, steroid and other drug treatments, and hepatitis C
** Most severe form is called NASH (non-alcoholic steatohepatitis). Hallmark is liver inflammation
Type IIa hypercholesterolemia cause
defective LDL receptors, which leads to premature atherosclerosis
Other things that can cause hypercholesterolemia
- Defects in apo B-100
2. Increased activity of PCSK9 (protein) that promotes lysosomal degradation of the LDL receptor
Wolman Disease
lysosomal storage disease resulting from defects in hydrolysis of cholesteryl esters
Niemann-Pick disease
lysosomal storage disease resulting from defect in transport of cholesterol out of the lysosome
What is the primary cause of atherosclerosis?
Excess LDL-derived cholesterol
Tangier disease
rare deficiency of ABCA1 transporter characterized by the virtual absence of HDL particles
Note: cholesterol is exported from cells into plasma by ABCA1 transporter and then esterified by LCAT on nascent HDL particles
What two things raise HDL levels?
Exercise and estrogen
What do statins do?
Block the synthesis of cholesterol by inhibiting HMG CoA Reductase
Ex: Lipitor, Crestor, Zocor
What do bile acid binding resins do?
Bind bile acids in the intestinal lumen and increase excretion in feces. Lowers cholesterol by increasing conversion to bile acids
What do PCSK9 inhibitors do?
Promote LDL receptor recycling thus increasing liver LDL uptake and decreasing LDL cholesterol in the blood
Ex: Praluent, Repatha
What do cholesterol absorption inhibitors do?
Block cholesterol absorption in the small intestines
Ex: Zetia
What is one cause of night blindness?
hint: vitamin related
Deficiency in vitamin A - specifically 11-cis Retinal
Retinol or retinyl esters used to treat deficiency
What is retinoic acid used for?
To treat acne, skin aging, and promyelocytic leukemia
Which vitamin controls serum calcium and phosphate levels?
Vitamin D (1,25-dihydroxycholescalciferol)
Rickets
incomplete mineralization and soft bones in children due to a vitamin D deficiency
Osteomalacia
demineralization of existing bones (and thus increased fractures) in adults due to vitamin D deficiency
Warfarin
a synthetic analog of vitamin K that inhibits blood clotting
What type of antibiotic has warfarin-like side effects and requires vitamin K supplementation when administered?
cephalosporin
Abetalipoproteinemia
Defective formation of chylomicrons and VLDL resulting in severe vitamin E deficiency
What vitamin is used to slow the age-related vision loss due to macular degeneration?
Vitamin E
Vitamin A deficiencies and corresponding signs/symptoms
Night blindness, xerophthalmia, infertility, growth retardation
S/S: increased visual threshold, dryness of cornea
Vitamin D deficiencies and corresponding signs/symptoms
Rickets and osteomalacia
S/S: soft, pliable bones
Vitamin K deficiencies and corresponding signs/symptoms
Seen in newborns and rare in adults
S/S: bleeding
Vitamin E deficiencies and corresponding signs/symptoms
Very rare
S/S: red blood cell fragility; leads to hemolytic anemia
Aromatase inhibitors
Used to treat estrogen-responsive breast cancer along with estrogen receptor blockers like Tamoxifen
(Note: aromatase converts the weak precursor of estrogen to mature estrogen)
Congenital adrenal hyperplasia (CAH)
a group of genetic disorders that often result in decreased cortisol and increased androgen
Addison’s Disease
autoimmune destruction of the adrenal cortex leading to reduced cortisol and aldosterone
Cushing’s Syndrome
Results from excess production of adrenal cortisol or from excess medication
A pituitary tumor can cause CD by over-stimulating the adrenal cortex with excess ACTH
SGLT2 Inhibitors: function + examples
Inhibition of SGLT2 transporters results in increased renal glucose excretion and lower blood glucose levels. This is helpful in treating hyperglycemia (e.g. in diabetes)
Examples: Forxiga (dapagliflozin), Invokana (canagliflozin), and jardiance (empagliflozin)
All end in -agliflozin!
Hypoglycemia symptoms
Obtundation, coma, seizures, and even death
Define adrenergic symptoms and provide examples
Systemic effects of catecholamines (lay term: adrenalin) released from the adrenal medulla in response to various psychological and physiological stresses
Tachycardia, palpitations, sweating, anxiety, nervousness, feeling cold, sweating, tremulousness
Define neuroglycopenia and provide examples
Describes the consequences of low blood glucose on CNS function
Decreased consciousness, faintness, blurred or double vision, behavioral changes, headache, slurred speech, confusion, dizziness, incoordination, hunger, paresthesias (“pins and needles”), hemiparesis (loss of feeling on one side)
What is Whipple’s triad and what is it used to diagnose?
Used to diagnose hypoglycemia
Low blood glucose (generally under 45mg/dL), symptoms of hypoglycemia present, and beneficial response to glucose administration
What test is initially most important to asses in the differential diagnosis of hypoglycemia?
Insulin
Crucial because we can divide hypoglycemia into hyperinsulinemic hypoglycemia vs. non-hyperinsulinemic hypoglycemia
How is hyperinsulinemic hypoglycemia defined?
Insulin increased above reference interval
OR
Insulin/glucose ratio inappropriately elevated (i.e. > 0.3)
NOTE: Insulin may be within the reference interval for fasting yet still be too high for the plasma glucose level
Differential diagnosis of hyperinsulinemia hypoglycemia?
- Excess endogenous insulin (insulin from the patient’s own pancreas)
- Excess exogenous insulin (injected insulin)
Cause(s) of excess endogenous insulin?
Drugs that stimulate the beta cells and beta cell disorders like insulinoma
Cause(s) of excess exogenous insulin?
Injected insulin
What do we measure to distinguish injected insulin from endogenous insulin?
C-peptides
Remember proinsulin is cleaved into insulin + C-peptide, which are secreted in a 1:1 molar ratio into the portal vein
What are the major drugs that releases insulin from the pancreas?
The sulfonylurea class of medications (glipizide, glyburide, and glimepiride) and meglitinides
Both of these are used to treat type 2 diabetes
What is in the differential diagnosis list for NON-hyperinsulinemic hypoglycemia?
drugs (excluding those that raise insulin), hormone deficiencies, liver disease, renal disease, inborn errors of metabolism
How can drugs (excluding those that increase insulin) cause hypoglycemia?
By causing liver injury (aspirin or tylenol poisoning) or by interfering with gluconeogenesis (ethanol, malnutrition & starvation)
Pathophysiology behind alcohol-induced hypoglycemia?
Ethanol burning/conversion to acetaldehyde and then acetic acid requires NAD+. If there is a large amount of ethanol to process we could theoretically deplete NAD+ stores and be unable to run the Cori Cycle. Inability to run the Cori Cycle means a lack of lactate being converted back to glucose in the liver for re-use by muscle tissues
What is the normal osmolality range in the body?
275 - 295 mOsm/L
Normal fluid intake?
1500 mL/M^2/day
What is the difference between sensible and insensible losses?
You can measure sensible losses (urine and stool). you cannot directly measure insensible losses (sweat and exhaled H2O)
How can you clinically assess a patient’s volume status?
- Blood pressure and pulse. With severe dehydration a patient will have hypotension and tachycardia
- Body weight (before and after)
- Physical exam for skin turgor, sunken eyes, tears & saliva, and scaphoid abdomen (“sucked in”)
What are the laboratory assessments of a patient’s volume status?
- Volume of urine output (will decrease under dehydration)
- measurement of waste products - BUN and creatinine (both will increase when dehydration is present)
- GFR estimation (decreased when dehydration is present)
- Urine specific gravity (urine osmolality) - will increase
What is normal urine specific gravity?
1.002 - 1.030
What is normal urine output?
800 - 2000 mL/day
Oliguria is urine output less than 500 mL per day
In chronic respiratory acidosis is HCO3- typically elevated or decreased?
Elevated!
The kidney retains NaHCO3 as renal “compensation”
What are the sources of lost HCO3-?
Kidney (renal tubules) or intestinal tract (loss of pancreatic bicarb)
Renal tubular acidoses (RTA)
disorders where bicarb is lost in the renal tubules (resulting in metabolic acidosis or alkalotic urine)
What situations may cause an insulin-treated diabetic to present with hypoglycemia?
Taking excessive doses of insulin, skipping meals, and exercising more than usual
Venous plasma or serum glucose level for hypoglycemia?
Less than 45 mg/dL
applies to individuals regardless of age
What laboratory results are typically observed in hyperinsulinism?
- Urine negative for ketones
- Beta-hydroxybutyrate is not elevated and may be suppressed
- Normal FFA concentrations (aka not elevated)
- Normal branched chain amino acids (aka not elevated)
These reflect the suppressive effect of hyperinsulinism on the generation of alternative fuels like ketones and fatty acids
What are the most common types of drugs to produce hyperinsulinism?
Sulfonylureas or meglitides used to treat T2DM
What is the definition of hyperglycemic hyperosmolality?
Plasma glucose > 600mg/dL, effective serum osmolality > 320mOsm/kg, profound dehydration (up to 9L deficit), serum ph > 7.30, bicarb > 15mEq/L
“Characterized by significant hyperglycemia, some degree of mental status changes, usually little to no acidosis or ketosis”
What does “effective serum osmolality” mean?
It does not include urea because urea freely crosses cell membranes. It DOES contribute to extracellular osmolality, but it doesn’t cause water shifts
Bottom line for von Gierke’s Disease?
Liver cannot generate free glucose from gluconeogenesis or by glycogen mobilization
(because of glucose-6-phosphatase deficiency)
Can fatty acids contribute to net blood glucose levels?
Still nope!
What is the most common inherited Urea Cycle disorder? Describe its clinical phenotype.
Deficiencies in ornithine transcarbamoylase
This means the individual cannot produce citrulline
Clinical presentaiton: ranges from neonatal hyperammonemia (lethargy, ataxia, death) to asymptomatic adults.
What is Citrullinemia Type 1 (CLTN1)?
Issue with argininosuccinate synthetase
This means the individual cannot produce argininosuccinate
Untreated individuals will have hyperammonemia (1-3 mM vs. normal 20-30 uM). Plasma shows high levels of citrulline (1 mM vs. normal 50 uM)
What are the clinical signs of Citrullinemia Type 1 (CLTN1)?
Progressive lethargy, vomiting, and possible signs of increased intracranial pressure (ICP)
Mutations affecting argininosuccinate lyase can present in what two ways?
- Severe neonatal onset form (usually indistinguishable from other Urea Cycle disorders)
- Late onset form
How are deficiencies in argininosuccinate lyase treated?
Minimizing protein degradation, communicable diseases, IV steroids, and/or hepatotoxic drugs
Deficiencies in what urea cycle enzyme cause episodic hyperammonemia?
Arginase
Most often birth and childhood and normal for these patients because excess arginine is needed in times of growth
Describe molecular basis of phenylketonuria, the inheritance pattern, and what it does to the body
Autosomal recessive inheritance. Defunct phenylalanine hydroxylase enzyme (can’t make tyrosine; phenylalanine “backs up”)
We see high serum phenylalanine and high urinary phenylpyruvate. The elevated phenylalanine damages nerve function
What is Cystinuria?
Cause and treatment?
Buildup of cystine in kidneys and bladder. Leads to the formation of cystine crystals and/or stones that may block the urinary tract
Cause: mutations in the SLC3A1 and SLC7A9 genes that code for a cysteine transporter
Treatment: reduce methionine intake
Symptoms of cystinuria?
nausea, hematuria, pain, and frequency UTIs
What is gout?
The pathologic precipitation of excess uric acid
Crystals accumulate in the joint, activate and inflammasome response, and WBCs attack and lower the pH + product more acid crystals
How is gout treated?
With allopurinol, a xanthine oxidase inhibitor
What is Lesch-Nyhan Syndrome? Inheritance pattern?
Loss of function of the HGPRT gene (responsible for purine salvage!!)
Patients have severe gout + disorders of the nervous system (like chewing fingers and lips)
x-linked inheritance pattern
What is Severe Combined Immunodeficiency Disorder (SCID)? Deficiency in what leads ultimately to what?
Caused by a deficiency in adenosine deaminase (ADA). In the absence of ADA, deoxyadenosine is phosphorylated yielding high levels of dATP (50x normal)
High [dATP] inhibits RNR which stops other dNTPs from being produced.
Net effect is the inhibition of DNA synthesis & inhibition of immune response
Purine Nucleoside Phosphorylase Deficiency: inheritance pattern and mechanism of action
Autosomal recessive disorder where PNP, a key purine nucleoside degrading enzyme, is lacking
Ultimately leads to dGTP build-up, RNR inhibition, and then T-cell toxicity
PNP-deficiency also gives rise to autoimmune disorders like Lupus
What is the most common cause of peripheral neuropathy?
Diabetes
What is the underlying pathophysiology of T2DM?
Insulin resistance and relative insulinopenia (inadequate secretion)
What non-pharmacological options are available to increase insulin sensitivity in patients with T2DM?
Exercise and weight loss
How can you determine if a patient has hypoproliferative anemia?
Do a reticulocyte count. If there is a vitamin or nutrient deficiency then we will see less reticulocytes (i.e. hypoproliferative)
What is the most common type of microcytic anemia?
Iron deficiency anemia
What is the most common cause of anemia?
Iron deficiency
What is the most common single deficiency state worldwide?
iron deficiency
What is “anemia of chronic disorder”?
A type of microcytic anemia seen in patients with chronic illness
There is chronic inflammation present that causes anemia. Iron is present in the body but it is NOT available for Hb synthesis
What is the first thing you rule out when treating a patient with microcytic anemia?
Iron deficiency
After taking a history and performing a physical exam on a patient with microcytic anemia you determine that iron deficiency is present. Next steps?
Bleeding must be considered and then excluded
What is hemophagocytic syndrome?
Seen in infants; macrophages are phagocytosizing erythrocytes, leukocytes, platelets, and their precursors in the bone marrow
Describe what happens to serum iron, TIBC, Tf saturation and ferritin levels when a patient is iron deficient?
Serum iron, Tf sat and ferritin levels all decrease
TIBC increases (because there is less Fe bound - plenty of free transferrin waiting to bind Fe!)
