Synthesis and metabolism of vitamin D in the regulation of calcium, phosphorus, and bone metabolism.

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During exposure to solar UVB radiation, 7-dehydrocholesterol in the skin is converted to previtamin D3, which is immediately converted to vitamin D3 in a heat-dependent process. Excessive exposure to sunlight degrades previtamin D3 and vitamin D3 into inactive photoproducts. Vitamin D2 and vitamin D3 from dietary sources are incorporated into chylomicrons and transported by the lymphatic system into the venous circulation. Vitamin D (hereafter, “D” represents D2 or D3) made in the skin or ingested in the diet can be stored in and then released from fat cells.
Vitamin D in the circulation is bound to the vitamin D–binding protein, which transports it to the liver, where vitamin D is converted by vitamin D-25-hydroxylase to 25(OH)D. This is the major circulating form of vitamin D that is used by clinicians to determine vitamin D status. (Although most laboratories report the normal range to be 20 to 100 ng/mL [50 to 250 nmol/L], the preferred range is 30 to 60 ng/mL [75 to 150 nmol/L].) This form of vitamin D is biologically inactive and must be converted in the kidneys by 25-hydroxyvitamin D-1α-hydroxylase (1-OHase) to the biologically active form 1,25(OH)2D.
 Serum phosphorus, calcium, fibroblast growth factor 23 (FGF-23), and other factors can either increase (+) or decrease (−) the renal production of 1,25(OH)2D. 1,25(OH)2D decreases its own synthesis through negative feedback and decreases the synthesis and secretion of PTH by the parathyroid glands. 1,25(OH)2D increases the expression of 25-hydroxyvitamin D-24-hydroxylase (24-OHase) to catabolize 1,25(OH)2D to the water-solubl biologically inactive calcitroic acid, which is excreted in the bile.

1,25(OH)2D enhances intestinal calcium absorption in the small intestine by interacting with the vitamin D receptor–retinoic acid x-receptor complex (VDR-RXR) to enhance the expression of the epithelial calcium channel (transient receptor potential cation channel, subfamily V, member 6 [TRPV6]) and calbindin 9K, a calcium-binding protein (CaBP). 1,25(OH)2D is recognized by its receptor in osteoblasts, causing an increase in the expression of the receptor activator of RANKL.
RANK, the receptor for RANKL on preosteoclasts, binds RANKL, which induces preosteoclasts to become mature osteoclasts. Mature osteoclasts remove calcium and phosphorus from the bone, maintaining calcium and phosphorus levels in the blood. Adequate Ca2+ and phosphorus (HPO42−) levels promote the mineralization of the skeleton.

Skin manifestations of Pellagra

Pellagra is a a vitamin deficiency disease caused by chronic lack of nicotinic acid (niacin, vitamin B3) or its precursor, tryptophan.Niacin is required for most cellular processes.

CAUSE of Pellagra:

Inadequate niacin and/or tryptophan in the diet mainly seen in developing countries or poverty stricken areas "called Primary pellagra".But usually there is something prevents Niacin absorption and processing and causes secondary pellagra such as:
• Alcoholism, malabsorption, anorexia nervosa, Prolonged diarrhoea, Liver cirrhosis, Drugs e.g. isoniazid, azathioprine

• Carcinoid tumors (excessive use of tryptophan, which produces serotonin)

Symptoms and signs of Pellagra is classically described by "the four D's": diarrhea, dermatitis, dementia and If left untreated, death.

Skin manifestations and clinical finding of Pellagra:

-At first there is reddened skin with superficial scaling in areas exposed to sunlight, heat & friction. This may resemble severe sunburn then gradually subsides leaving a dusky brown-red colouration .
-The rash is usually symmetrical with a clear edge between affected and unaffected skin and sometimes may be itching or burning sensation
-Other features sometimes present include cheilosis, glossitis, angular stomatitis, and oral or perianal sores.

Legs and feet of a patient with niacin deficiency. A, Before therapy. B, After therapy.

(From Swartz MH: Textbook of Physical Diagnosis, 5th ed. Philadelphia, WB Saunders, 2006.)

TREATMENT of Pellagra:

• Nutritional supplementation with niacin will improve the appearance of skin lesions

Algorithm of the cause of Hypokalaemia

A history of vomiting, diarrhoea, or use of medications such as diuretics can be helpful in determining the cause of hypokalaemia. However, in some cases, the cause of hypokalaemia is not readily apparent. In these cases, measurements of BP and urinary potassium excretion, and assessment of acid-base balance are often helpful.

Serum potassium concentrations:
There is no strict correlation between the serum potassium concentration and total body potassium stores. In chronic hypokalaemia, a potassium deficit of 200 to 400 mmol (200 to 400 mEq) is required to lower the serum potassium concentration by 1 mmol/L (1 mEq/L). These estimates are good provided there is no concurrent acid-base abnormality (e.g., for diabetic ketoacidosis or severe non-ketotic hyperglycaemia).

In diabetic ketoacidosis patients may have a normal or even elevated serum potassium concentration at presentation, despite having a marked potassium deficit due to urinary and GI losses.

Spurious hypokalaemia can occur when blood with a high WBC count is left at room temperature due to extraction of potassium by the WBCs. It is therefore important to consider repeating the test for confirmation.

Synthesis of eicosanoid autacoids

The eicosanoids are an important group of endogenous fatty acid derivatives that are produced from arachidonic acid, a 20-carbon fatty acid lipid in cell membranes. Major families of eicosanoids include the straight-chain derivatives (leukotrienes) and cyclic derivatives (prostacyclin, prostaglandins, and thromboxane). Inhibitors of the eicosanoids are shown in Figure below.

ABCD causes of BUN:creatinine elevation

BUN stands for blood urea nitrogen which measures the amount of urea nitrogen, a waste product of protein metabolism, in the blood. Urea is formed by the liver and carried by the blood to the kidneys for excretion. Because urea is cleared from the bloodstream by the kidneys, a test measuring how much urea nitrogen remains in the blood can be used as a test of renal function. However, there are many factors besides renal disease that can cause BUN alterations, including protein breakdown, hydration status, and liver failure.


values for BUN:
* Adult: 7-20 mg/100 ml; men may have slightly higher values than women
* Pregnancy: values decrease about 25%
* Newborn: values slightly lower than adult ranges
* Elderly: values may be slightly increased due to lack of renal concentration

##BUN:creatinine elevation: causes ABCD:

• Azotremia (pre-renal)


• Bleeding (GI)


• Catabolic status


• Diet (high protein parenteral nutrition)

Scheme for Metabolic acidosis

Metabolic acidosis is a commonly presenting feature and is often caused by diabetes, renal failure or poisoning. However, it can cause diagnostic difficulties, particularly in the acute situation when patients can be seriously ill and where the aetiology is not obvious. It is vital that its diagnosis is considered in the clinical context with attention given to history (especially of drugs) and physical signs.

Metabolic acidosis is characterised by a raised [H+] and a low / normal PCO2 (in contrast with respiratory acidosis where the PCO2 is high). A low derived bicarbonate or low plasma total CO2 accompanies the raised [H+].

The raised [H+] stimulates the respiratory centre and hyperventilation occurs with a consequent rise in PO2. Hyperventilation reduces PCO2 and hence some of the potential acid burden on the body and acts to compensate for the metabolic acidosis. Complete compensation does not occur (ie the [H+] remains elevated) and the extent of the compensation will be limited in patients with an underlying diminution in respiratory function.

Some confusion may occur in patients admitted with 'collapse' and in extremis. Cardio respiratory collapse will result in a mixed acidosis due to a peripheral metabolic acidosis due to poor perfusion and a respiratory acidosis due to poor ventilation resulting in a raised [H+] and raised PCO2.

Iron Deficiency Anemia: Causes and Treatment

Mechanisms Linked to Sodium intake in Hypertension

Mechanisms Linked to Increases in Blood Pressure and the Therapeutic Effects of Healthful Dietary Patterns, Sodium Reduction, and Weight Loss.

Sodium intake initiates an autoregulatory sequence that leads to increased intravascular fluid volume and cardiac output, peripheral resistance, and blood pressure. The elevation in blood pressure results in a phenomenon called pressure natriuresis, in which increased renal perfusion pressure leads to increased excretion of fluid and sodium. In essential hypertension, however, sodium excretion is impaired. It is hypothesized that in most cases essential hypertension is a genetic disorder involving many individual genes, each of which influences the body's handling of sodium to varying degrees and becomes expressed in the context of an unhealthful dietary environment, particularly one characterized by excessive intake of salt.

Hyperlipidemia: Cholesterol Guidelines

Dr. Melissa Stiles interviews Dr. Patrick McBride about the NCEP Adult Treatment Panel III Cholesterol Guidelines.
Part 1


Part 2

Clinical Approach to Metabolic Alkalosis

History

Obtain historical data to pinpoint the nature of the disease causing metabolic alkalosis.

* Ask the patient about history of vomiting, other gastric fluid loss, and diuretic use. Loss of gastric fluid and HCl due to vomiting is the most common cause of metabolic alkalosis.

• Vomiting may be caused by pyloric stenosis or ulcers. Occasionally, it may be self-induced.
• Significant gastric fluid loss can occur via long-term nasogastric (NG) tube drainage.
• Diuretic use may lead to increased chloride losses.

* Obtain information about specific disease states such as primary hyperaldosteronism, reninism, hyperglucocorticoidism, Bartter syndrome, and deoxycorticosterone (DOC) excess syndromes.
* Because hypokalemia may lead to metabolic alkalosis, ask about the use of diuretics because these lead to potassium loss.

An algorithm for metabolic alkalosis

Physical

Increased neuromuscular excitability sometimes causes tetany or seizures. Generalized weakness may be noted if the patient also has hypokalemia. Signs and symptoms observed with metabolic alkalosis usually relate to the specific disease process that caused the acid-base disorder.

* Patients who develop metabolic alkalosis from vomiting can have symptoms related to severe volume contraction, with signs of dehydration that include tachycardia, dry mucous membranes, decreased skin turgor, postural hypotension, poor peripheral perfusion, and weight loss.
* Although diarrhea typically produces a hyperchloremic metabolic acidosis, diarrheal stools may rarely contain significant amounts of chloride, as in the case of congenital chloride diarrhea. Children with this condition present at birth with watery diarrhea, metabolic alkalosis, and hypovolemia.
* Weight gain and hypertension may accompany metabolic alkalosis that results from a hypermineralocorticoid state.

Treatment of Hyperkalemia

continuous cardiac monitoring is mandatory if the patient has severe hyperkalemia (serum potassium > 6.5 MEq/L) or cardiac arrhythmias.
a patient with mild-moderate hyperkalemia (serum potassium < qid =""> the patient can be discharged and followed-up in 48 - 72 hours.
a patient with moderate hyperkalemia (serum potassium 6.0 - 6.5 mEq/L) should probably be admitted to hospital for supervised lowering of the serum potassium with a potassium-binding resin.
treat hyperkalemia more emergently if the serum potassium is > 6.5 meq/L or if there are any ECG changes suggestive of hyperkalemia => use sodium polystyrene sulfonate as first line therapy +/- insulin/glucose +/- calcium gluconate.

The following drug order sequence is recommended for life-threatening hyperkalemia (absent P waves + widened QRS complex, and/or serum potassium > 8 meq/L, and/or significant cardiovascular symptoms or arrhythmias, and/or severe neuromuscular symptoms)

1) Calcium gluconate
(there is no "correct" dose)
- 10 ml of 10% calcium gluconate solution over 10 minutes IV (rule of "tens") is a common approach.
(* calcium should preferably be administered in large veins because it is sclerosing)
- works in 1 - 3 minutes and lasts 30 - 60 minutes
- repeat dose in 5 - 10 minutes if no ECG change/improvement
(* calcium only antagonises potassium's deleterious electrical effect on the myocardium and it does not decrease the serum level of potassium - it is used temporarily until the serum potasium can be decreased by insulin + glucose administration)
- special warnings:-

* calcium should be given slowly over 20 - 30 minutes in a digitalised patient by diluting the calcium in 100 ml of normal saline and giving the calcium by an infusion pump - high risk of increased myocardial toxicity in the digitalised patient
* calcium is contra-indicated in digoxin-toxic patients and hypercalcemic states
* don’t give calcium in solutions containing bicarbonate

2) Insulin + Glucose
used to drive potassium into the cells
- 10 units insulin by rapid IV bolus + 50ml of 50% dextrose IV over 20 - 30 minutes; or the insulin can be mixed with 100 ml of 20% dextrose solution and administered IV over 20 - 30 minutes

- glucose should not be given to diabetics without first giving insulin - because insulin is needed to move potassium into the cells; also avoid giving 50% glucose by rapid IV bolus injection.
- onset occurs within 15 - 60 minutes and effect lasts 4 - 6 hours.

3) Albuterol by nebuliser
- 10 - 20mg in 4 ml saline over 10 - 20 minutes (large doses required)
- decreases serum potassium by about 0.5 - 1.0 meq/L

4) Bicarbonate
- only indicated when the patient is significantly acidotic (serum bicarb < depleted =""> use 3 amps of bicarb in 1L of 5DW at desired rehydration rate


5) Kayexalate - sodium polystyrene sulfonate
- defer if the patient is going to be dialysed within 2 hours to avoid a "colonic laundry"
- po route preferred if possible (greater degree of cation exchange)
- 15 - 50g in 100cc of 70% sorbitol po (or use commercial preperation)
- onset within 1 - 2 hours and lasts 4 - 6 hours
- use a retention enema if po administration is not preferable/possible

6) Lasix
- 40 - 80 mg of lasix IV to all patients who can produce urine

7) Dialysis
- primary therapy when renal function is absent
- prompt dialysis may also be required in patients with ARF + associated rhabdomyolysis (large potasssium load)
- also used for intractable hyperkalemia unresponsive to conservative pharmacological measures

8) Treat any underlying cause of the hyperkalemia

Blood Calcium Regulation

Algorithm for determining the cause of the Hypernatremia

Hypernatremia is defined as a serum sodium > 145 mEq/L

- hypernatremia can be due to:-

* net loss of water and sodium from the body with inadequate water replacement (commonest cause)
* inadequate water intake
* increased water loss from the body
* increased sodium load

- hypernatremia most commonly results from a net loss of water and sodium from the body coupled with inadequate water intake

- the hypotonic fluid loss can be due to renal (osmotic diuresis or diuretics) or extra-renal (skin or GIT) causes

Inadequate water intake is a universal prerequisite for the evolution of hypernatremia

(* hypernatremia due to indequate water intake is rarely seen in alert patients with a normal thirst mechanism + access to water + an ability to obtain and drink water)

Algorithm for the diagnosis of Hyperkalemia

Causes of hyperkalemia:
Pseudohyperkalemia

* tight tourniquets and/or fist clenching
* small needle and/or venous sampling in a high vacuum tube
* over-vigorous centrifugation of the blood specimen and/or laboratory error
* red cell hemolysis
* thrombocytosis
* marked leucocytosis
* abnormal red cell membrane and potassium leakage

Excess potassium intake

* transfusion of old blood
* IV potassium administration
* KCl-containing salt substitutes
* Drugs containing potassium - IV penicillin, potassium citrate
* Unusual po sources - geophagia (clay soil), cautopyreiphagia (burnt match heads), black molasses

Redistributional or transcellular shifts

* cellular damage - burns, crush injury
* IV hemolysis
* tumor lysis
* rhabdomyolysis
* acidemia
* hypertonicity - mannitol, hyperglycemia
* medications - digoxin, somatostatin, succinylcholine, beta blockers
* severe physical exertion
* prematurity (first 72 hours of life)
* fasting in a dialysis patient
* toxins - palytoxin, tetrodotoxin, hydrofluouric acid, cocaine
* familial hyperkalemic periodic paralysis

Adrenal-renal

* lack of renin substrate - very advanced liver failure
* hyporeninemia - diabetic nephropathy, interstitial nephritis, type IV RTA, drugs (NSIAD's, beta-blockers, heparin, cyclosporine)
* decreased aldosterone synthesis - congenital adrenal disease (21 hydroxylase enzyme deficiency and other specific synthetic defects) or acquired adrenal disease (Addison's disease, TB of the adrenals)
* absence or blockade of the aldosterone receptors - pseudohypoaldosteronemia type I, drugs (spironolactone,amiloride, triamterine, cyclosporine, trimethoprim, pentamidine)

Acute renal failure

Chronic renal failure

Urinary tract obstruction

Tubular defects in potassium secretion
* interstitial nephritis
* SLE
* sickle cell disease
* diabetic nephropathy
* amyloidosis
* renal allograft
* drugs - sulfas, penicillin, rifampin, NSIAD's

ECG changes in Hyperkalemia

There is no definite correlation between any ECG changes and the serum potassium - the relationship depends on individual patient sensitivity and the rapidity of development of the hyperkalemia

(* ECG signs may be absent if the onset of hyperkalemia is slow - as seen in chronic renal failure - even though the serum potassium is in the range of 7 - 7.5meq/L; by contrast, acute hyperkalemia can produce ECG signs at much lower serum potassium levels)

ECG showing tall T waves - "Tenting"
Note the tall symmetrical T waves in the antero-septal leads

ECG showing "thorn-like" T waves


ECG showing a "sine" wave pattern
Note the wide slurred QRS complex which blends sinuously with the tall T wave into a "sine" wave pattern

ECG changes "mimicing" an AMI
Note the elevated ST segments in two of the inferior leads (S3 and AVF) suggestive of an inferior wall AMI, and the reciprocal ST depression in leads S1, AVL and V 2 - 5 Clues that suggest hyperkalemia = absence of P waves and the tall tented T waves in the chest leads


ECG showing a "dumping" pattern
Note the depression of the ST segments in leads V 2 - 6 - as if something "heavy" had been "dumped" onto the ST segment causing it to sink down

ECG showing "Z-fold pattern"

Note the widening/slurring of the QRS complex and how the ST segment slopes straight up to the tall T wave producing a "Z" pattern

Vitamin D: Interactions of Vitamin D and Calcium

s vitamin D the wonder vitamin? Can it prevent certain cancers and chronic diseases? Find these answers and more in this series brought to you by UCSD School of Medicine and GrassrootsHealth where experts discuss the latest research on vitamin D. In this program, Robert Heaney, MD, talks about vitamin D and calcium metabolism safety. Series: Vitamin D Deficiency - Treatment and Diagnosis

18% tax on pizza and soda can decrease U.S adult`s weight by 5 bounds(2 kg)/year

From Reuters:

With two-thirds of Americans either overweight or obese, policymakers are increasingly looking at taxing as a way to address obesity on a population level.

"Sadly, we are currently subsidizing the wrong things including the product of corn, which makes the corn syrup in sweetened beverages so inexpensive."

Instead, the agricultural subsidies should be used to make healthful foods such as locally grown vegetables, fruits and whole grains less expensive.

Central & Nephrogenic Diabetes Insipidus

Causes of central diabetes insipidus:
1-Head trauma

2-Post-surgical (hypophysectomy)

3-Tumors

* craniopharyngioma
* pinealoma
* meningioma
* germinoma
* leukemia/lymphoma
* metastatic tumors

4-Infections

* tuberculosis
* syphilis
* mycosis
* toxoplasmosis
* encepahlitis
* basilar meningitis

5-Granulomatous disesases

* sarcoidosis
* histiocytosis
* Wegeners' granulomatosis

6-Cerebrovascular diseases

* aneurysms
* cavernous sinus thrombosis
* Sheehan's syndrome (pospartum pituatry infarction)
* CVA

7-Idiopathic

Causes of nephrogenic diabetes insipidus:
1-Congenital

2-Medications

* lithium
* demecyclocine
* amphotericin B
* methoxyflurane
* colchicine
* vinblastine
* aminoglycosides
* cisplatin

3-Obstructive uropathy - during relief of obstruction

4-Chronic tubulo-interstitial kidney diseases

* analgesic nephropathy
* sickle cell nephropathy
* multiple myeloma
* amyloidosis
* sarcoidosis
* Sjogrens disease
* autoimmune/lupus
* polycystic kidney disease
* medullary cystic disease

5-Electrolyte disorders

* hypercalcemia
* potassium depletion