Metabolikos

Question 1

Hyponatremia

Answer 1

• *Hyponatramia**
• *Na<135, Severe Na<120**

_**FIRST Calculated Serum Osmolality (SO)_
CO = 2Na + BG + BUN (285-295mOsm/kg)
CO = Calculated Osmolarity
DKA and HHS raise the BG resulting in an increased CO.
For HHS, CO >320mOsm/kg.

Serum Osmolar Gap (OG = MO - CO)
OG = MO - CO
MO = Measured Osmolality
CO = Calculated Osmolality
Elevated in presence of Osmols that are not normaly present in the blood such as: Alcohol, Sugars, Lipids, Proteins. DKA results in high ketones raising the Osm gap.

Isosmolar (Pseudohyponatremia)
Lab error – old machines measured falsely proteins and lipids added to volume.

Hyperosmolar
Increase in Glu (DKA or HHS), BUN or another osmotic agent such as Mannitol.

Hyposmolar (90%)
1. Hypovolemic – Dry – losing Na and H2O
UNa<10 - kidney retaining Na
Meta]
Vomiting (losing Na and H2O)
Diuretics

Org (Adrenos)]
Adrenal Insufficiency (Addisons)
Rx: NS

2. Hypervolemic – Wet – gaining Na and H2O but more H2O than Na
UNa>20
Examples: CHF and Cirrhosis, Nephrotic syndrome
In the most direct pathway, volume depletion triggers intrarenal baroreceptors in the afferent arteriole to activate the release or renin from the afferent juxtaglomular cells. Renin leads to the release of ADH from the pitiutary and Aldoserone from the Adrenals.

Macula densa cells sense fluctuations in Na+, Cl- and filtrate flow. In reductions of filtrate concentration and flow, macula densa cells release prostaglandins to the afferent juxtglomular cells that release renin.

Sympathetic beta1 receptors on the juxtglomerular cells from sympathetic stimulation causes renin release.
Rx: H2O restriction

3. Isovolemic – Normal – no change in Na but increase in H2O (no change in volume status)
Examples: siADH
Rx: H2O restriction

HPI]
Fatigue, HA, N, V
Confusion, Seizures, Coma – when severe
Note: The reason for symtpoms is cerebral edema. The water goes into the cells due to less concentration outside.

O/E]

• *Wet** – raised JVP, mucous membranes full/moist, moist axilla, edema, weight gain.
• *Dry** – lowered JVP, mucous membranes dry, dry axilla, skin tenting, weight loss.

Question 2

Primary Hyperaldosteronism

Conns Disease
HTN and Hypokalemia (low K+)

Answer 2

ETIOLOGY]
Org (Adrenal)]
BIlateral Idiopathic(micronodular) Hyperplasia (IHA) 60-70%
Unilateral Aldosterone-producing Adenomas (APA) 30-40% (Somatic mutations in KCNJ5)

Less likely:
Org (Adrenal)]
Unilateral hyperplasia
Cong]
Familial hyperaldosteronism (FH) (Germline mutation in KCNJ5)
Oncos]
Pure aldosterone producing adrenocortical carcinoma
Ectopic aldosterone secreting tumours (ovary or kidney)

O/E]
HTN (Secondary to volume expansion)

INVESTIGATIO]
L(H)/Meta]
Hypokalemia
L(F)]
PAC/PRC (Plasma Aldosterone Concentration/Plasma Renin Concentration)
PAC is high/PRC is reduced

Imago] CT Adrenals

Biops] Adrenal Venous Sampling (AVS)

Question 3

Hypercortisolism

Cushings Disease/Syndrome

Answer 3

Glucocorticoids are steroids hormones that bind to cell surface receptors and easily cross the lipid cell membrane. After crossing the cell membrane, steroids bind to intracellular and nuclear receptors, then translate to the nucleus and bind to steroid response elements (sequences of DNA). After binding to the SREs, specific genes are upregulated and downregulated that results in cellular changes.

GCs have anti-inflammatory and immunosupression properties through by regulating differential gene expression. For instance, increased synthesis of Annexin A1 (lipocortin) and inhibiting sythesis of various cytokines having a variety of affects.

• *1. Anti-inflammatory:**
• *Eicosanides** – Increased synthesis of Annexin A1 in phagocytic cells. Annexin A1 inhibits phospholipase A2, and thereby COX and LOX. Inhibition of inducable COX2 at sites of inflammation by supression of NF-kB. GCs do not seem to affect constitutive COX1.

Reduced bradykinin – Upregulating the synthesis of angiotensin-converting enzyme and neutral-endopeptidase enzymes that degrade bradykinin, which is a vasodilatory peptide central to the generation of some forms of angioedema.

• *2. Innate immunity:**
• *Neutrophils –** GCs inhibit IL1 and TNF leading to decreased synthesis of L-Selectins and neutrophil detachment from the endothelium. Extravasation is reduced and there are reduced numbers of neutrophils to sites of inflammation and infection. GSs inhibit neutrophil apoptosis.

Eosinophils – GCs reduced synthesis of IL5, which promotes eosinophil apoptosis.

Monocytes and Marcophages – reduced production of inflammatory cytokines, eicosanides, IL1, TNF, and inhibits phagocytic function. Clearance of opsonized bacteria from reticuloendothelial system is reduced.

Mast cell and basophils – inhibition of mast cell degranulation in a time dependent manner by upregulation of inhibitory regulators.

• *3. Acquired Immunity:**
• *Marcophages and dendritic cells –** GCs suppress antigen presentation and number of circulating dentritic cells.

Cell-mediated immunity – GCs reduce the number of circulating T cells by the inhibition of IL2, a T cell growth factor. Immature T cells undergo apoptosis in the thymus (Bcl-2), in glucocorticoid induced apoptosis.
Note: T cells, by interacting with antigens presented on MHCII, need to differentiate self from non-self. The process of how T cells do this occurs beforehand through positive and negative selection in the thymus, called central tolerance.

Humoral immunity – B cells are less affected and antibody production is largely preserved, although a mild decrement in immunoglobulin G (IgG) and immunoglobulin A (IgA) levels may develop in some patients with chronic use. Immunoglobulin E (IgE) levels may increase.
Note: B cells go through negative selection, differentiate self from non-self called central tolerance, in the bone marrow.

Metabolic effects of GCs include increased protease and lipoprotein lipase activity to increase gluconeogenesis in the liver. Skeletal muscle is broken down to produce amino acids and lipoprotein lipase produces glycerol and fatty acids. Amino acids and glycerol are used in gluconeogenesis.

Note: There is a balance of GC induced lipoprotein lipase activity that causes the production of fatty acids and glycerol. Glycerol is used in gluconeogenesis. Fatty acids are deposited in ectopic tissue.

DDx]
Meta]
Exogenous glucocorticoids (Steroids)
Hor]
Pituitary Adenoma (Cushing disease)
Org (Adrenos)]
Adrenal Adenoma
Oncos]
Ectopic ACTH (from small cell lung cancer)
Adrenal carcinoma

Less likely:
Org (Adrenos)]
Hyperplastic Adrenal Glands (Cushings Syndrome)
Nodular Adrenal Hyperplasia

HPI]

• *Fat accumulation** and muscle weakness – Glucocortocoid induced increase in gluconeogenesis. Lipoprotein lipase expression is increased to produce glycerol used in gluconeogenesis, and free fatty acids. Free fatty acids deposited at ectopic sides. Protease expression is increased to produced amino acids used in gluconeogeneis, from the breakdown of muscle.
• *moon facies, facial plethora, hyperpigmentation (from increased ACTH), hiurisitism (women), centripetal obseity, abdominal striae, proximal muscle weakness, impotence, amenorrhea (women),**

Note: Adrenal gland is a major source of androgens in women but not men. Hypercortisolism and androgen excess occurs in women with adrenal cancer or ACTH-stimulated hyperandrogenism.

Note: Hypercortisolemia and the supression of gonadotropin releasing hormone (GnRH), by negative feedback on the hypothalamus. GnRH is relased by the hypothalamus to cause the secreation of FSH and LH from the pituitary, which would lead to amenorrhea.

Note: Proximal muscle wasting is from the catabolic effects glucocorticoids on muscle.

O/E] HTN
General]
moon facies, facial plethora, hyperpigmentation (high ACTH), hirsutism (women), central obseity
Abdos]
Striae
MSK]
proximal muscle weakness

INVESTIGATIO]
L(O)/Org(Adrenos)]
24 hour urine cortisol collection. Corticotropin (ACTH) and cortisol are secreted in discrete bursts, not only in normal subjects but also in most patients with Cushing’s disease. Twenty-four hour urinary cortisol excretion is an integrated measure of the serum free cortisol concentration (ie, cortisol that is not bound to CBG [transcortin] or other serum proteins). The two most important factors in obtaining a valid result are collection of a complete 24-hour specimen and a reliable reference laboratory.

L(F)/Org(Adrenos)]

• *Dexamethasone Supression Test (DST).** The low-dose DSTs are standard screening tests to differentiate patients with CS of any cause from patients who do not have CS.
• *A low dose of dexamethasone suppresses cortisol in individuals with no pathology in endogenous cortisol production. In a low-dose DST, healthy people will have cortisol production suppressed. People suspected of pathology will continue to produce cortisol that is detected.**

The high-dose DSTs are not used to make the diagnosis of CS. They are used after the diagnosis of CS is made to distinguish patients with Cushing’s disease (CS caused by pituitary hypersecretion of ACTH) from patients with ectopic ACTH syndrome (CS caused by nonpituitary ACTH-secreting tumors. Results indicative of Cushing’s disease (Pituitary) involve no change in cortisol on low-dose dexamethasone, but inhibition of cortisol on high-dose dexamethasone. If the cortisol levels are unchanged by low and high-dose dexamethasone, and ACTH is low then primary hypercortisolism (Cushings syndrome). If the cortisol levels are unchanged by low- and high-dose dexamethasone, and ACTH is elecated in the hundreds, then ectopic ACTH is likely.

Question 4

Glucocorticoids

Answer 4

Immunologic
GCs have anti-inflammatory and immunosupression properties through by regulating differential gene expression. For instance, increased synthesis of Annexin A1 (lipocortin) and inhibiting sythesis of various cytokines having a variety of affects.

1. Anti-inflammatory:
Eicosanides –Increased synthesis ofAnnexin A1inphagocytic cells. Annexin A1 inhibits phospholipase A2, and thereby COX and LOX.Inhibition of inducable COX2 at sites of inflammationby supression of NF-kB.GCs do not seem to affect constitutive COX1.

Bradykinin – Upregulating the synthesis of angiotensin-converting enzyme and neutral-endopeptidase enzymes that degrade bradykinin, which is a vasodilatory peptide central to the generation of some forms of angioedema

• *2. Innate immunity:**
• *Neutrophils – GCs** inhibit IL1 and TNF leading to decreased synthesis of L-Selectins and neutrophil adherence to endothelium. Extravasation is reduced and there are reduced numbers of neutrophils to sites of inflammation and infection. GSs inhibit neutrophil apoptosis.

Eosinophils – GCs reduced synthesis of IL5, which promotes eosinophil apoptosis.

Monocytes and Marcophages – reduced production of inflammatory cytokines, eicosanides, IL1, TNF, and inhibits phagocytic function. Clearance of opsonized bacteria from reticuloendothelial system is reduced.

Mast cell and basophils – inhibition of mast cell degranulation in a time dependent manner by upregulation of inhibitory regulators.

• *3. Acquired Immunity:**
• *Marcophages and dendritic cells –** GCs suppress antigen presentation and number of circulating dentritic cells.

Cell-mediated immunity – GCs reduce the number of circulating T cells by the inhibition of IL2, a T cell growth factor. Immature T cells undergo apoptosis in the thymus (Bcl-2), in glucocorticoid induced apoptosis.
Note: T cells by interacting with antigens presented on MHCII need to differentiate self from non-self. The process of how T cells do this occurs beforehand in T cell selection in the thymus.

Humoral immunity – B cells are less affected and antibody production is largely preserved, although a mild decrement in immunoglobulin G (IgG) and immunoglobulin A (IgA) levels may develop in some patients with chronic use. Immunoglobulin E (IgE) levels may increase.

Metabolic
GCs have metabolic effects by stimulating gluconeogenes in the liver, from non-hexose substrates, amino acids and glycerol.

1. Skeletal muscle breaks down muscle to produce amino acids.

2. Adipose tissue undergoes lipolysis to produce glycerol, through increased lipoprotein lipase expression. Glycerol is used in gluconeogenesis.

3. Increase in caloric intake. Along with the increase in calories, there is anincreasein GC mediatedlipoprotein lipaseexpression. Lipoprotein lipase is found on thesurface of endothelial cells, and an increase in activity leads to higher levels of fatty acids in circulation.Fatty acids are then available for ectopic fat distribution to liver, muscles and central adipocytes.

Note: There is a balance of GC induced lipoprotein lipase activity that causes the production of fatty acids and glycerol. Glycerol is used in gluconeogenesis. Fatty acids are deposited in ectopic tissue.