Vitamin D-What, Where, When, How, Why?

Vitamins are not generally considered to be endocrine substance, but it is a organic dietary factors essential for healthy life. The term ‘ vitamin D ’ refers to two steroid like chemicals, namely ergocalciferol and cholecalciferol . Vitamin D is important for good health, growth and strong bones and may also help to prevent other diseases such as cancer, diabetes and heart disease. A lack of vitamin D is very common. Vitamin D is mostly made in the skin by exposure to sunlight.  A mild lack of vitamin D may not cause symptoms but can cause generalised aches and pains and tiredness. A more severe lack can cause serious problems such as rickets (in children) and osteomalacia (in adults), described below. Treatment is with vitamin D supplements. Some people are more at risk of vitamin D deficiency, and so are recommended to take vitamin D supplements routinely. These include all pregnant women, breast-fed babies, children under 5, and people aged 65 and over. Also, people who do not get much exposure to the sun, people with black or Asian skin types, people who do not go out in the sun and people with certain gut, liver or kidney diseases.  We have checked our own patients and found that 9/10 adults of South Asian origin are vitamin D deficient and something like 60% of our white patients are vitamin D deficient.  Most people present with aches and pains and tiredness.

What is vitamin D?

Vitamins are a group of chemicals that are needed by the body for good health. Foods that contain vitamin D include the following though many foods do not contain much vitamin D and exposure to the sun is a better source of vitamin D than foods. Vitamin D is a fat-soluble vitamin. Most foods contain very little vitamin D naturally , though some are fortified (enriched) with added vitamin D.  Foods that contain vitamin D include:

                -Oily fish (such as sardines, pilchards, herring, trout, tuna, salmon and mackerel).

                -Egg yolk.

                -Fortified foods (this means they have vitamin D added to them) such as margarine, some cereals, infant formula milk.

Action of Vitamin D

The 1,25 - (OH)2 -D 3 receptor belongs to a superfamily of nuclear hormone receptors, which bind to their ligand and alter transcription. The hormone travels in the bloodstream in equilibrium between bound and free forms. The latter form is freely able to enter cells, due to its lipophilic nature. The plasma 1,25 - (OH) 2 - D 3 - binding protein (DBP) recognizes the hormone specifi cally. 1,25 - (OH) 2 - D 3 binds to the nuclear receptor; the complex binds to specifi c hormone response elements on the target gene upstream of transcriptional activation sites, and new mRNA and protein synthesis result.

New proteins synthesized include osteocalcin, an important bone protein whose synthesis is suppressed by glucocorticoids. In the GIT, a calcium - binding transport protein (CaBP) is synthesized in response to the hormone – receptor activation of the genome.

Physiological actions of vitamin D

Bone-Vitamin D stimulates resorption of calcium from bone as part of its function to maintain adequate circulating concentrations of the ion. It also stimulates osteocalcin synthesis.

Gastrointestinal tract-1,25 - (OH) 2 - D 3 stimulates calcium and phosphate absorption from the gut through an active transport process. The hormone promotes the synthesis of calcium transport by enhancing synthesis of the cytosolic calcium – binding protein CaBP, which transports calcium from the mucosal to the serosal cells of the gut.

Kidney- 1,25 - (OH) 2 - D 3 may stimulate reabsorption of calcium into the tubule cells while promoting the excretion of phosphate. The tubule cells do possess receptors for vitamin D and CaBP.

Muscle-Muscle cells have vitamin D receptors, and the hormone may mediate muscle contraction through effects on the calcium fl uxes, and on consequent adenosine triphosphate (ATP) synthesis.

Pregnancy-During pregnancy, there is increased calcium absorption from the GIT, and elevated circulating concentrations of 1,25 - (OH) 2 - D 3 , DBP, calcitonin and PTH. During the last 6 months prior to birth, calcium and phosphorus accumulate in the fetus. The placenta synthesizes 1,25 - (OH) 2 - D 3 , as does the fetal kidney and bone. Nevertheless, the fetus still requires maternal vitamin D.

Other roles- Vitamin D may be involved in the maturation and proliferation of cells of the immune system, for example of the haematopoietic stem cells, and in the function of mature B and T cells.

Our main source of vitamin D is that made by our own bodies. 90% of our vitamin D is made in the skin with the help of sunlight.

Ultraviolet B (UVB) sunlight rays convert cholesterol in the skin into vitamin D. Darker skins need more sun to get the same amount of vitamin D as a fair-skinned person. The sunlight needed has to fall directly on to bare skin (through a window is not enough). 2-3 exposures of sunlight per week in the summer months (April to September) are enough to achieve healthy vitamin D levels that last through the year. Each episode should be 20-30 minutes to bare arms and face. This is not the same as suntanning; the skin simply needs to be exposed to sunlight.

So, vitamin D is really important for strong bones. In addition, vitamin D seems to be important for muscles and general health. Scientists have also found that vitamin D may also help to prevent other diseases such as cancer, diabetes and heart disease.

Who gets vitamin D deficiency?

Vitamin D deficiency means that there is not enough vitamin D in the body. Broadly speaking, this can occur in three situations:

1. Increased need for vitamin D

Growing children, pregnant women, and breast-feeding women.

2. Situations where the body is unable to make enough vitamin D

People who get very little sunlight on their skin are also at risk of vitamin D deficiency. This is more of a problem in the most northern parts of the world where there is less sun. In particular:

                 People who stay inside a lot or cover up when outside or use strict sunscreen

                 People with pigmented (dark coloured) skins and elderly people  

                 Some medical conditions can affect the way the body handles vitamin D.

                     People with Crohn's disease, coeliac disease, and some types of liver                                                     and kidney disease, are all at risk of vitamin D deficiency.

                 Vitamin D deficiency can also occur in people taking certain medicines -                                                  examples include: Carbamazepine, Phenytoin, prim done, barbiturates and some anti-HIV                    medicines

3. Not enough dietary vitamin D

Vitamin D deficiency is more likely to occur in people who follow a strict vegetarian or vegan diet, or a non-fish-eating diet.

How common is vitamin D deficiency?

It is very common. This is why we recommend a regular supplement to our patients.  A recent survey in the UK showed that more than half of the adult population in the UK had low vitamin D. This level is found to be greater in people who have dark skin.  In the winter and spring about 1 in 6 people has a severe deficiency. It is estimated that about 9 in 10 adults of South Asian origin may be vitamin D-deficient. Most affected people either don't have any symptoms, or have vague aches and pains, and are unaware of the problem.  80% of our Asian patients have been found to be deficient and 60% of our white patients have found to be deficient.

What are the symptoms of vitamin D deficiency?

Symptoms of vitamin D deficiency are tiredness or general aches.  Because symptoms of vitamin D deficiency are often very vague, the problem is often missed.

How is vitamin D deficiency diagnosed?

Vitamin D deficiency can be diagnosed by a blood test.  However, on balance if you have dark skin and live in the UK you should take supplements. It may be suspected from your medical history, symptoms, or lifestyle. A simple blood test for vitamin D level can make the diagnosis.

RECOMMENDATIONS – Your doctor will advise you if you have deficiency or insufficient vitamin D.  If you have a minor level of vitamin D deficiency we recommend patients buy vitamin D tablets equivalent to 10ug or 12.5ug.  Most are made from vegetables.   If you have been found to be deficient we would recommend you stay on this dose for life as treatment is often needed long-term because the cause of the deficiency, such as dark skin or not enough sunlight, is unlikely to be corrected in the future.  We have observed that it takes at least 6 months taking regular vitamin D for symptoms to resolve and the level of vitamin D to return to normal.  It should be noted that if you have severe deficiency the doctor may recommend that you take a higher dose of vitamin D for a limited time, often equivalent to 25ug for the first 3 months.  Please discuss this with your own doctor.  We recommend that patients buy vitamin D tablets as we are unable to prescribe vitamin D without calcium on the NHS and calcium prescriptions have been associated with increased kidney stones and it is for this reason that we recommend that our patients buy vitamin D.

Maintenance therapy after deficiency has been treated

The dose needed for maintenance maybe lower than that stated.  We advise patients to buy 10ug and take 2 a day.   When the body's stores of vitamin D have been replenished. maintenance treatment is often needed long-term, to prevent further deficiency in the future. This is because it is unlikely that any risk factor for vitamin D deficiency in the first place, will have completely resolved. The dose needed for maintenance may be lower than that needed to treat the deficiency.

Cautions when taking vitamin D supplements

Care is needed with vitamin D supplements in certain situations:

 1. If you are taking certain other medicines that can interact such as  Digoxin (for an irregular         heartbeat – atrial fibrillation),  Thiazide or diuretics (water tablets).                                                   

2. If you have medical conditions such as kidney stones, some types of                                                     kidney disease, liver disease or hormonal disease.

3. Vitamin D should not be taken by people who have high calcium levels.

4. You may need more than the usual dose if taking certain medicines such as Carbamezapine, Phenytoin. HRT or barbiturates. Multivitamins are not suitable for long-term high-dose treatment because the vitamin A which can be harmful in large amounts.

Are there any side-effects from vitamin D supplements?

It is very unusual to get side effects from vitamin D if taken in the prescribed dose. However, very high doses can raise calcium levels in the blood. This would cause symptoms such as thirst, passing a lot of urine, nausea or vomiting.

Prognosis (outlook) in vitamin D deficiency?

The outlook for vitamin D deficiency is usually excellent. Both the vitamin levels and the symptoms generally respond well to treatment. However, it can take time (months) for symptoms to resolve and for bones to recover.  Generally after 6 months of using Vitamin D tablets the patient feels a lot better and symptoms have improved.  This does not mean you need to stop taking the medication.  Vitamin D supplementation is for life.

MCQ on Urinary System Physiology

1) The nephron is:
     a. the site of urine storage
     b. the functional unit of the kidney
     c. the site where ADH is produced
     d. also called the "Bowman's capsule"

2. Which of the following is NOT a stage of urine formation:
     a. glomerular filtration
     b. glomerular secretion
     c. tubular secretion
     d. tubular reabsorption

3. Which of the following is NOT a means of regulating glomerular filtration:
     a. muscular regulation
     b. renal autoregulation
     c. hormonal regulation
     d. neuronal regulation

4. Increased sympathetic nervous system stimulation of afferent arterioles results in:
     a. decreased filtrate production
     b. increased filtrate production
     c. no change in filtration rate
     d. increased kidney function

5. Renin is produced by:
     a. the glomerulus
     b. macula densa
     c. proximal convuluted tubule
     d. juxtaglomerular cells

6. The function of the macula densa cells is to:
     a. prevent water reabsorption in the ascending loop of Henle
     b. add bicarbonate ions to the tubular filtrate
     c. secrete renin in response to decreased afferent arteriole pressure
     d. monitor NaCl concentration in the filtrate
     e. reabsorb Na+ ions into blood from the filtrate

7. Atrial naturiuretic peptide works to:
     a. increase afferent arteriole pressure
     b. increase blood flow to the kidney
     c. enhance the effects of ADH
     d. inhibit the effects of aldosterone
     e. increase blood volume

8. If the level of aldosterone in the blood increases, then:
     a. less sodium is excreted in the urine
     b. less potassium is excreted in the urine
     c. systemic blood pressure will decrease
     d. glomerular filtration will decrease
     e. both c and d

9. The most important function of the juxtaglomerular apparatus (JGA) is to:
     a. secrete water and sodium into the filtrate
     b. reabsorb sodium
     c. generate bicarbonate ions in response to decreased blood pH
     d. secrete renin in response to decreased renal blood pressure or blood flow
     e. constrict the afferent arterioles and decrease sodium reabsorption

10. If the diameter of the afferent arteriole is smaller than the diameter of the efferent arteriole, then:
     a. the net filtration pressure will decrease
     b. blood pressure in the glomerulus will decrease
     c. GFR will increase
     d. a and b only
     e. a, b and c

11. From the distal convoluted tubule, filtrate will then be carried to the:
     a. renal corpuscle
     b. collecting duct
     c. nephron loop
     d. proximal convoluted tubule
     e. glomerular (Bowman's) capsule

12. In a patient who is dehydrated from vomiting and diarrhea, which is likely to be higher than normal in blood:
     a. ADH only
     b. aldosterone only
     c. ANP only
     d. both ADH and aldosterone
     e. both ADH and ANP

13. All of the following are normally found in urine except:
     a. glucose
     b. sodium ions
     c. uric acid
     d. urea
     e. creatinine

14. In some autoimmune diseases, capillaries may become damaged resulting in and high levels of albumin proteins and blood cells appearing in the urine. Which region of the nephron contains capillaries that, when damaged, could cause this appearance in urine:
     a. renal glomerulus
     b. proximal convoluted tubule
     c. nephron loop
     d. distal tubule

15. Regarding the renal circulation:

a) The kidneys receive about 10% of the resting cardiac output

b) As cardiac output increases during exercise renal blood flow rises.

c) Renal blood flow is maintained within narrow limits despite changes in arterial blood pressure.

d) Increased activity in the renal sympathetic nerves results in increased blood flow to the kidneys.

16. Regarding the glomerular filtration rate (GFR):

a) The GFR depends on the pressure in the afferent arterioles.

b) A substance that has a clearance less than the GFR must have been secreted by the renal tubules.

c) The glomerular filtration rate can be determined by measuring the clearance of insulin.

d) The glomerular filtrate has the same composition as plasma.

17. Regarding the transport of glucose by the renal tubules:

a) In a healthy person, the distal tubules reabsorb all of the filtered glucose.

b) Glucose is secreted into the urine in small quantities.

c) The transport maximum for glucose is about 36 mg min^-1.

d) Glucose transport by the renal tubules is linked to sodium transport.

18. Concerning the excretion of acid by the kidneys:

a) The filtered bicarbonate is absorbed by anion transport.

b) The intercalated cells of the distal tubule secrete hydrogen ions to reabsorb bicarbonate from the tubular fluid.

c) All of the filtered bicarbonate is normally reabsorbed in the first half of the distal tubule.

d) Urine pH is normally greater than that of plasma.

19. Regarding the control of water balance by the kidneys:

a) The renal medulla has an osmotic gradient that decreases from the border with the cortex to the renal papilla.

b) ADH is secreted by the anterior pituitary in response to a decrease in the osmolality of the blood.

c) A normal person cannot produce urine with an osmolality greater than 300 mOsmol.kg^-1.

d) ADH acts on the P cells of the collecting ducts to increase their permeability to water.

20. The term "renal autoregulation" refers in part to the fact that

A. the kidney does not require blood flow to sustain its active transport
B. the kidney contains baroreceptors (pressure receptors) that contribute to the regulation of cardiac output
C. renal blood flow is relatively constant over a wide range of systemic arterial pressures
D. renal blood flow is not affected by activation of the sympathetic nerves that innervate the kidney
E. a combination of both C and D above

21. The nerves that innervate the kidney are essential for regulating which of the following?

A. Na-K-ATPase active transport pump rate
B. renal autoregulation of blood flow
C. urine volume and tonicity (osmolality)
D. all of the above
E. none of the above

22. Which of the following would be expected to cause renal inulin (or creatinine) clearance to increase?

A. dilation of the afferent arteriole
B. dilation of the efferent arteriole
C. constriction of the afferent arteriole
D. constriction of the efferent arteriole
E. both A and D above

23. Kidney inflammation may result in the appearance of albumin (a plasma protein) in the urine because

A. more albumin enters the proximal tubule in the glomerular filtrate
B. reabsorption of albumin from the proximal tubule is inhibited
C. secretion of albumin into the distal tubule and collecting ducts is increased
D. increased peritubular blood flow makes more albumin available for diffusion into the tubule
E. reduced active transport of sodium ion reduces cotransport of other substances, including albumin

24. As blood passes along the glomerular capillaries from the afferent to efferent arteriole, the net filtration pressure (DP - Dp)

A. increases
B. decreases
C. first decreases, reaches a minimum about half way along the capillary, then increases
D. first increases, reaches a maximum about half way along the capillary, then decreases
E. remains constant

25. Sodium is actively reabsorbed from the renal tubule in which of the following nephron segments?

A. proximal tubule
B. distal tubule
C. thick ascending limb of the loop of Henle
D. all of the above
E. none of the above

26. The rate of water reabsorption from the proximal tubule is determined primarily by the

A. rate of dissolved particle (solute) reabsorption from the proximal tubule
B. concentration of ADH (antidiuretic hormone) in the blood
C. osmotic pressure developed by plasma proteins in the proximal tubule
D. active transport of water molecules by the proximal tubule cells
E. passive filtration due to the high hydrostatic pressure in the proximal tubule

27. Urea has a higher concentration in the fluid that leaves the proximal tubule (and enters the loop of Henle) than in blood plasma because

A. urea is synthesized by proximal tubule cells
B. urea is secreted into the proximal tubule
C. urea is reabsorbed from the proximal tubule but at a lesser rate that water is reabsorbed
D. urea diffuses back into the proximal tubule because of the high urea concentration in the renal medulla
E. urea is actively transported into Bowman's capsule from the glomerular capillaries

28. In the proximal tubule, penicillin is

A. actively secreted into the tubule
B. actively reabsorbed from the tubule
C. passively reabsorbed from the tubule
D. metabolized by the tubule cells
E. neither secreted nor reabsorbed nor metabolized

29. At which sites would the concentration of creatinine be expected to be highest? (Note: assume the person is normally hydrated.)

A. glomerular filtrate
B. end of the proximal tubule
C. end of the loop of Henle
D. urine
E. the concentration would be the same in all of the above, since creatinine is neither secreted or reabsorbed

30. Suppose a person loses the function of half his nephrons because of renal degenerative disease. Assuming the person survives and reaches a new steady state and that body urea production remains normal, which of the following would be expected to decrease below normal?

A. plasma urea concentration
B. renal urea excretion
C. renal urea clearance
D. urine urea concentration
E. all of the above

31. The following values are measured for potassium ion in a human subject.

Plasma K+                            5 meq/liter
Urine K+                               50 meq/liter
Renal creatinine clearance  80 ml/min
Urine formation rate             1.5 ml/minute

This patient's potassium clearance is closest to which of the following?

A.   5 ml/minute
B. 7.5 ml/minute
C. 15 ml/minute
D. 50 ml/minute
E. 75 ml/minute

32. Assuming the subject in the preceding question is a normal adult, we can conclude that most likely potassium is

A. filtered but not secreted or reabsorbed
B. secreted but not filtered or reabsorbed
C. reabsorbed but not secreted or filtered
D. filtered and secreted
E. filtered and reabsorbed

33. Stimulation of the osmoreceptors in the hypothalamus would be expected to cause all of the following to increase except

A. ADH release from the pituitary
B. water reabsorption from the renal collecting duct
C. rate of urine formation
D. osmolality of urine
E. none of the above; that is, none are exceptions since all would be expected to increase

33. As fluid passes along a juxtamedullary nephron, where is its osmolality (total concentration of dissolved particles) lowest? (Note: assume a normal concentration of circulating ADH.)

A. Bowman's capsule (glomerular filtrate)
B. fluid leaving the proximal tubule and entering the loop of Henle
C. fluid leaving the descending thin limb and entering the ascending thin limb of the loop of Henle
D. fluid leaving the thick ascending segment of the loop of Henle and entering the distal tubule
E. fluid leaving the collecting ducts (urine)

34 Drinking vodka (a beverage with a high ethanol content, for those of you unfamiliar with this substance) would be expected to cause excretion of a

A. large volume of concentrated urine
B. small volume of concentrated urine
C. large volume of dilute urine
D. small volume of dilute urine
E. normal volume of urine of normal osmolality

35. Drinking which of the following would lead to the highest rate of ADH secretion and release?

A. two liters of distilled water
B. two liters of sea water (mainly hyperosmotic saline)
C. two liters of iso-osmotic (isotonic) saline
D. two liters of human blood plasma
E. none of the above, since drinking two liters of any liquid leads to inhibition of ADH release

36. In a patient with severe renal artery stenosis (narrowing), all of the following would be expected to be increased above normal except

A. plasma renin concentration
B. plasma angiotensin II concentration
C. blood pressure (hydrostatic pressure) in the glomerular capillaries
D. resistance to blood flow in the efferent arteriole
E. systemic arterial blood pressure

37. Administration of an Angiotensin Converting Enzyme inhibitor (ACE inhibitor) to the above patient might lead to acute renal failure by

A. inhibiting renal tubule potassium reabsorption
B. increasing renal resistance to blood flow
C. causing plasma proteins to be excreted in the urine
D. causing systemic arterial hypertension
E. reducing glomerular filtration rate

38. Which of the following is the stimulus for increased secretion of atrial natriuretic peptide (ANP)?

A. increase blood plasma osmolality above normal
B. decrease blood plasma osmolality below normal
C. increase systemic arterial pressure
D. increase venous blood volume and atrial pressure
E. increase cardiac contractility (force of contraction)

39. An increase secretion of renin would be expected to have what effect on sodium excretion and potassium excretion in urine?

A. increase in Na+ excretion and increase K+ excretion
B. increase in Na+ excretion and decrease K+ excretion
C. decrease in Na+ excretion and increase K+ excretion
D. decrease in Na+ excretion and decrease K+ excretion
E. decrease in Na+ excretion but no effect on K+ excretion

40. In which of the following fluids is the pH highest (most alkaline)? (Assume the person is normal.)

A. systemic arterial blood plasma
B. systemic venous blood plasma
C. urine
D. all of the above, since pH is normally of the same for all
E. A and B above, since blood plasma pH is relatively uniform

41. The ammonium (NH4⁺) ion that may be present in urine is produced by

A. breakdown of urea in the liver
B. metabolism of amino acids in the renal tubule and collecting duct
C. aerobic carbohydrate metabolism
D. gylcolytic pathways during anaerobic metabolism
E. gluconeogensis during starvation

42. The reason that respiratory compensation for metabolic alkalosis can never be complete (return plasma pH to normal) is that (Note: PaCO₂ = systemic arterial carbon dioxide partial pressure.)

A. high PaCO₂ inhibits respiratory ventilation
B. high PaCO₂ stimulates respiratory ventilation
C. low PaCO₂ inhibits respiratory ventilation
D. low PaCO₂ stimulates respiratory ventilation
E. none of the above, since respiratory compensation for metabolic alkalosis can be complete

43. The appearance of large amounts of ammonium ion (NH4⁺) in the urine is characteristic of the renal response to

A. respiratory acidosis
B. respiratory alkalosis
C. acidosis resulting from pancreatic diabetes
D. alkalosis resulting from gastric vomiting
E. both A and C above

44. An individual hoping for an LSD "acid high" mistakenly gives himself an intravenous injection of hydrochloric acid. The responses of his body which attempt to compensate for this ignorance of physiology include all of the following except

A. hyperventilation
B. increase in the acid form of the blood fixed buffers
C. decrease in blood bicarbonate ion concentration
D. increase in urine bicarbonate ion excretion
E. increase in urine ammonium ion excretion

45. A systemic arterial blood sample taken from the above individual an hour after his HCl "adventure" might show which of the following?

A. base excess = +10 meq/liter; PaCO₂ = 50 mmHg
B. base excess = +10 meq/liter; PaCO₂ = 30 mmHg
C. base excess = -10 meq/liter; PaCO₂ = 50 mmHg
D. base excess = -10 meq/liter; PaCO₂ = 30 mmHg
E. base excess = 0 meq/liter; PaCO₂ = 40 mmHg

46.  A young woman is found comatose, having taken an unknown number of sleeping pills an unknown time before. An arterial blood sample yields the following values:

pH      7.02
HCO₃^-   14 meq/liter
PaCO₂   68 mmHg

This patient's acid-base status is most accurately described as

A. uncompensated metabolic acidosis
B. uncompensated respiratory acidosis
C. simultaneous respiratory and metabolic acidosis
D. respiratory acidosis with partial renal compensation
E. respiratory acidosis with complete renal compensation

Question

Regarding the regulation of plasma sodium:

a) The granular cells of the afferent arterioles cells secrete renin when plasma sodium is low.

b) Angiotensin II is formed from renin by the action of an enzyme found on the endothelium of the pulmonary blood vessels.

c) The uptake of sodium ions is regulated by the proximal tubule.

d) Sodium transport by the thick ascending limb of the loop of Henle occurs by the same mechanism as that of the proximal tubule.

Pigmentation and Discoloration of Oral and Facial Tissues

Pigmentation and Discoloration of Oral and Facial Tissues

Pigmentation is a discoloration of the oral mucosa or gingiva due to the wide variety of lesions and conditions. Oral pigmentation has been associated with a variety of endogenous and exogenous etiologic factors. Also it can be explained as Oral mucosal discolouration, which ranges from brown to black may be due to superficial (extrinsic) or deep (intrinsic in or beneath mucosa) causes.

Types of Oro-maxillofacial Pigmentation

Extrinsic discoloration

Extrinsic discoloration is usually caused by extrinsic pigments. It is rarely of consequence and is usually caused by colored foods, drinks or drugs. Extrinsic discoloration usually affects both mucosae and teeth are discolored. Causes include the following:

• Foods and beverages, such as beetroot, red wine, coffee and tea.

• Confectionery, such as liquorice.

• Drugs, such as chlorhexidine, iron salts, griseofulvin, crack cocaine, minocycline, bismuth subsalicylate, lansoprazole and HRT.

• Tobacco: this may cause extrinsic discolouration, but can also cause intrinsic pigmentary incontinence, with pigment cells increasing and appearing in the lamina propria. This is especially likely in persons who smoke with the lighted end of the cigarette within the mouth (reverse smoking), as practiced mainly in some Asian communities. Tobacco is a risk factor for cancer.

• Betel: this may cause a brownish-red discolouration, mainly on the teeth and in the buccal mucosa, with an irregular epithelial surface that has a tendency to desquamate. It is seen mainly in women from South and Southeast Asia. Betel chewer’s mucosa epithelium is often hyperplastic, and brownish amorphous material from the betel quid may be seen on the epithelial surface and intra- and intercellularly, with ballooning of epithelial cells. Betel chewer’s mucosa is not known to be precancerous, but betel use predisposes to submucous fibrosis and to cancer.

Intrinsic staining

Causes for intrinsic hyperpigmentation are Increased melanin or number of melanocytes, or other materials. Intrinsic discolouration may have more significance than the extrinsic type. Normal intrinsic pigmentation is due to melanin, produced by melanocytes dendritic cells prominent in the basal epithelium.

Localized areas of pigmentation are usually caused by benign conditions:

• Embedded amalgam (amalgam tattoo)

• Embedded graphite (graphite tattoo)

• Other foreign bodies

• Local irritation/inflammation

• Melanotic macule

• Naevi

• Melanoacanthoma.

However, neoplasms, such as Kaposi sarcoma or malignant melanoma, are occasionally responsible. The anterior pituitary gland releases melanocyte stimulating hormone (MSH), which increases melanin production. Melanin pigmentation thus increases under hormonal stimulation, either by MSH, or in pregnancy, or rarely due to the action of adrenocorticotrophic hormone (ACTH), the molecule of which is similar to MSH, or under the influence of other factors (e.g. smoking). Thus in all patients systemic causes should be excluded, such as:

• Drugs; including smoking and the contraceptive pill

• Hypoadrenalism; there is increased ACTH production

• Peutz–Jeghers syndrome

• HIV infection

• Von Recklinghausen’s disease

• Albright syndrome

• Rarely, palatal pigmentation from bronchogenic carcinoma.

Amalgam Tattoo

Betel Stains

Peutz Jeghers Syndrome

List Causes of hyperpigmentation

Localized

• Amalgam, graphite, carbon, dyes, inks or other tattoos

• Ephelis (freckle)

• Epithelioid angiomatosis

• Kaposi’s sarcoma

• Malignant melanoma

• Melanoacanthoma

• Melanotic macule

• Naevus

• Pigmented neuroectodermal tumour

• Verruciform xanthoma

Multiple or generalized

Genetic:

• Racial

• Carney syndrome

• Complex of myxomas, spotty pigmentation and endocrine overactivity

• Laugier–Hunziker syndrome

• Lentiginosis profusa

• Leopard syndrome

• Peutz–Jeghers syndrome

Drugs:

• ACTH

• amiodarone

• antimalarials

• betel

• busulphan

• chlorpromazine

• clofazamine

• contraceptive pill

• ketoconazole

• menthol

• metals (bismuth, mercury, silver, gold, arsenic, copper, chromium, cobalt, manganese)

• methyldopa

• minocycline

• phenothiazines

• smoking

• zidovudine

Endocrine:

• Addison’s disease

• Albright’s syndrome

• Nelson’s syndrome

• pregnancy

Post-inflammatory

Others:

• Gaucher’s disease

• generalized neurofibromatosis

• haemochromatosis

• HIV disease

• incontinentia pigmenti

• thalassaemia

• Whipple’s disease

 

List the Causes of Pigmentation 

Melanin

Melanin, a nonhemoglobin derived brown pigment, is the most common of the endogenous pigments and is produced by melanocytes present in the basal layer of the epithelium. Melancocytes have a round nucleus with a double nucleus membrane and clear cytoplasm lacking desmosomes or attachment plates. Melanin accumulates in the cytoplasm, and the melanosome is transformed into a structureless particle no longer capable of melanogenesis. The number of melanocytes in the mucosa corresponds numerically to that of skin; however,in the mucosa their activity is reduced. Various stimuli can result in an increased production of melanin at the level of mucosa including trauma, hormones, radiation, and medications.Thyrosinase activity is present in premelanosome and melanosomes but absent in melanin granules.

Melanoid

Granules of melanoid pigment are scattered in the stratum lucidum and stratum corneum of the skin. Initially it was assumed melanoid was a degradation product of melanin, but more recently it has been shown that such a relationship is highly improbable. Melanoid imparts a clear yellow shade to the skin.3

Oxyhemoglobin and Reduced Hemoglobin

Oxyhemoglobin and reduced hemoglobin are pigments resulting from hemosiderin deposits.

The skin color is affected by the capillary and venom plexuses shining through the skin.

Carotene

Carotene is distributed in the lipids of the stratum corneum and stratum lucidum and gives a deep yellow color to the skin. It is found in higher concentrations in more women than in men. Pigmented lesions of the oral cavity are of multiple origin. Different classifications are used at this time. Some researchers divide the lesions into two main groups as either endogenous or exogenous lesions. Brocheriou et al.

subdivides pigmented lesions as follows:

• Non tumoral pigmentations

• Non melanin pigmented tumors or tumor like lesions

• Benign melanin pigmented tumors

• Malignant melanomas

In several articles on oral pigmentation, Dummett and others implicate many systemic and local factors as causes of changes in oral pigmentation.

Epidemiology

Oral pigmentation occurs in all races of man.There were no significant differences in oral pigmentation between males and females. The intensity and distribution of racial pigmentation of the oral mucosa is variable, not only between races, but also between different individuals of the same race and within different areas of the same mouth. Physiologic pigmentation is probably genetically determined, but as Dummett suggested , the degree of pigmentation is partially related to mechanical, chemical, and physical stimulation. In darker skinned people oral pigmentation increases, but there is no difference in the number of melanocytes between fair-skinned and dark-skinned individuals. The variation is related to differences in the activity of melanocytes.There is some controversy about the relationship between age and oral pigmentation. Steigmann and Amir et al. stated all kinds of oral pigmentation appear in young children. Prinz, on the other hand, claimed physiologic pigmentation did not appear in children and was clinically visible only after puberty.

Clinical Characteristics

The gingivae are the most frequently pigmented intraoral tissues. Microscopically, melanoblasts are normally present in the basal layers of the lamina propria.The most common location was the attached gingiva (27.5%) followed in decreasing order by the papillary gingiva, the marginal gingiva, and the alveolar mucosa.The total number of melanophores in the attached gingival was approximately 16 times greater than in the free gingival. The prevalence of gingival pigmentation was higher on the labial part of the gingiva than on the buccal and palatal/lingual parts of the arches.The shade of pigment was

classified as very dark brown to black, brown, light brown-yellow.3 Melanin pigmentation of the

oral tissues usually does not present a medical problem, but patients complain of black gums.

Classification and Differential Diagnosis

Oral pigmentation has been associated with a variety of lesions and conditions. Differential diagnosis of oral mucous membrane pigmentations are made according to the following situations:

A. Localized Pigmentations: Amalgam tatoo, graphite or other tattoos, nevus, melanotic macules, melanoacanthoma, malignant melanoma, Kaposi’s sarcoma, epithelioid oligomatosis, verruciform xanthoma

B. Multiple or Generalized Pigmentations

1. Genetics: Idiopathic melanin pigmentation (racial or physiologic pigmentation), Peutz-Jegher’s syndrome, Laugier-Hunziker syndrome, complex of myxozomas, spotty pigmentation, endocrine overactivity, Carney syndrome, Leopard syndrome, and lentiginosis profuse

2. Drugs: Smoking, betel, anti-malarials, antimicrobials, minocycline, amiodarone, clorpromazine, ACTH, zidovudine, ketoconazole, methyldopa, busulphan, menthol, contraceptive pills, and heavy metals exposure (gold, bismuth, mercury, silver, lead, copper)

3. Endocrine: Addison’s disease, Albright’s syndrome, Acanthosis nigricans, pregnancy, hyperthyroidism

4. Postinflammatory: Periodontal disease, postsurgical gingival repigmentation

5. Others: Haemochromatosis, generalized neurofibromatosis, incontinenti pigmenti, Whipple’s disease, Wilson’s disease, Gaucher’s disease, HIV disease, thalassemia, pigmented gingival cyst, and nutritional deficiencies

Systemic and Local Causes of Pigmentation

Many systemic and local factors are caused by changes in oral pigmentation. Some of the important factors are discussed below.

Amalgam Tattoo

The pigmentation of the oral mucous membrane by tooth restoration material (amalgam) is a

common finding in dental practice. Amalgam pigmentation is generally called amalgam tattoo.The lesion represents embedded amalgam particles and usually manifests itself as an isolated bluish or black macule in various areas of the mucosa. The color is usually described as black, blue, grey, or a combination of these. Almost half were located on the gingiva and alveolar mucosa, the mandibular region being affected more than the maxillary region. Almost half of the lesions were asymtomatic and were discovered during routine dental examination. The amalgam granules and fragments were found mainly in the lamina propria but were sometimes seen in the submucosa.

Pigmented Nevi

Pigmented nevi of the oral cavity are uncommon. The pigmented nevi are classified as intramucosal, junctional, compound, or blue according to their histological features. Nevi are seen particularly on the vermillion border of the lips and the gingivae. They are usually grey, brown, or bluish macules and are typically asymptomatic. Melanocytes are pigment producing cells characterized by the ability to syntesize via the enzyme dihydroxyphenylalanine (DOPA). A group of melanocytes (generally four or more) are in contact with the basal layer of the epithelium.

Oral Melanotic Macules

Oral melanotic macules are relatively rare oral mucosal lesions, analogous to skin freckles, due to the focal increase of melanin production.These melanotic macules have been variously termed ephelis, melonosis, lentigo, solitary labial lentigo, labial melanotic macule, and oral melanotic macule.The vermillion border of the lower lip is most commonly involved.The buccal mucosa, palate, and gingiva are less commonly affected. The color is usually described as grey, brown, blue, black, or a combination of these.Histologically, ephelis shows increased melanin pigmentation in the basal cell layer without an increase in the number of melanocytes; otherwise, the epidermis is normal.

Melanoma

Melanoma is a cancerous condition of the melanocyte. Special corpusles in this cell, known as melanosomes, contain the necessary enzyme (tyrosine) to transform amino acids into melanin. Melanocytes are found among the basal cells of the epidermis. Histopathogically, the mucosal epithelium is abnormal with large atypical melanocytes and excessive melanin. Malignant melanoma of the oral mucosa affects both sexes equally usually after 40 years of age. The great majority of the lesions (about 70-80%) occur on the palate, upper gingival, and alveolar mucosa.Initially there usually is a solitary small asymtomatic brown or black macule.

Physiologic Pigmentation

Physiologic pigmentation of the oral mucosa is clinically manifested as multifocal or diffuse melanin pigmentation with variable prevalence in different ethnic groups.2 Melanin is normally found in the skin of all people. In dark skinned persons the gingiva may contain melanin pigment to a greater extent than the adjacent alveolar mucosa. The melanin pigment is synthesized in specialized cells, the melanocytes, located in the basal layer of the epithelium. The melanin is produced as granules. The melanosomes are stored within the cytoplasm of the melanocytes, as well as in the cytoplasm of adjacent keratinocytes. Melanocytes are embryologically derived from neural crest cells that eventually migrate into the epithelium. If pigmented gingiva is surgically resected, it will often heal with little or no pigmentation; therefore, surgical procedures should be designed so as to preserve the pigmented tissues.

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome (intestinal polyposis) is a genetic disorder characterized by mucocutaneous pigmentation and hamartomas of the intestine.It manifests itself as frecklelike macules about the hands, perioral skin, and intraorally to include the gingiva, buccal, and labial mucosa. Pigmented spots are 1 to l0 mm in diameter. Pigmented spots are particularly found on the lower lip and buccal mucosa but rarely on the upper lip, tongue, palate, and gingiva.

Smoker’s Melanosis

Smoker’s melanosis is a benign focal pigmentation of the oral mucosa. It tends to increase significantly with tobacco consumption. Tobacco smokers have significantly more oral surfaces pigmented than non-tobacco users.Clinically, the lesion usually presents as multiple brown pigmented macules less than 1 cm in diameter, localized mainly at the attached labial anterior gingival and the interdental papillae of the mandible. Smoker’s melonosis is more common in females usually after the third decade of life.

Antimalaria Drug Use

Several antimalarial drugs are known to be capable of inducing intraoral melanin pigmentation. These drugs include: quinacrine, chloroquine, and hydroxychloroquine Longterm use may cause pigmentation of the oral mucosa. The pigmentation of the oral mucosa is described as slate-grey in color, bearing some resemblance to pigmentation caused by silver arsplenamine.

Minocycline Use

Minocycline is a synthetic tetracycline that is commonly used in the treatment of acne vulgaris.Although tetracycline causes pigmentation of bones and teeth, minocycline alone is also responsible for soft tissue pigmentation.It is usually seen as brown melanin deposits on the hard palate, gingiva, mucous membranes, and the tongue.

Heavy Metals

Heavy metals absorbed systemically from therapeutic use or occupational environments may discolor the gingiva and other areas of the oral mucosa. Bismuth, arsenic, and mercury produce a black line in the gingiva which follows the contour of the margin. Lead results in a bluish red or deep blue linear pigmentation of the gingival margin (Burtonian line). Exposure to silver causes a violet marginal line, often accompanied by a diffuse bluish-grey discoloration throughout the oral mucosa.

Addison’s Disease

Addison’s disease or primary adrenocortical hypofunction is due to adrenocortical damage

and hypofunction.Bronzing of the skin and increased pigmentation of the lips, gingivae, buccal mucosa, and tongue may be seen. Oral pigmentation may be the first sign of the disease.A biopsy of the oral lesions shows acanthosis with silver-positive granules in the cells of the stratum germinativum. Melanin is seen in the basal layer.

Periodontal Diseases

Periodontal diseases often produce discolorations of the oral mucosa. The pigmentation is worsened by gingivitis, which increases vascular permeability and allows the heavy metals access to the soft tissues.51 Melanin re-pigmentation is related to after surgical inury.

Hemachromatosis

Hemachromatosis (bronze diabetes) is a chronic disease characterized by the deposition of excess iron (ferritin and hemosiderin) in the body tissues, resulting in fibrosis and functional insufficiency of the involved organs. Hyperpig mentation may appear both in skin and mucous membranes (oral and conjunctiva). Gingival or mucosal pigmentation is reported to occur in 15 to 25% of patients with hemachromatosis. The oral mucosa shows diffuse homogeneous pigmentation of gray-brown or deep brown in about 20% of the cases. The buccal mucosa and the attached gingiva are the most frequently involved sites.

HIV Infection

In patients infected with human immunodeficiency virus (HIV), progessive hyperpigmentation of the skin, oral mucosa, fingernails, and toenails have been reported being related to primary adrenocortical deficiency and to zidovudine (azidothymidine) therapy in some cases.Clinically, oral pigmentation appears as irregular macules with brown or dark brown color. The tongue, buccal mucosa, and palate are the most commonly affected sites.