Pathophysiology of Celiac Disease

Pathophysiology of Coeliac Disease with correlation with its histologic presentation
Ji Keon LOOI
Monash University Sunway Campus

Introduction
•A.k.a. Gluten-sensitive enteropathy
•an autoimmune inflammatory disease of the small intestine
•Precipitated by the ingestion of gluten
•genetically susceptible persons
Oral tolerance
•Ingested protein does not normally provoke an immune response - "oral tolerance"

Oral intolerance / true allergy to an ingested protein (milk or soy protein)
•a typical IgE-mediated response
–urticaria,
–angioedema, and
–bronchoreactivity

Pathophysiology (1)
•involves plasma cells - IgA and IgG
•little or no IgE involvement

Current theory
•Ingested alpha-gliadin and related peptides bind with tissue transglutaminase in enterocytes
•The alpha-gliadin is rich in glutamine; transglutaminase deamidates glutamine residues, forming glutamic acid.
•Deamidation enhances the immunogenicity of alpha-gliadin by creating epitopes that are recognized as foreign by host cell­mediated immunity

Pathophysiology (2)
•IgA and IgG (by plasma cells) direct against a variety of antigens
–transglutaminase, endomysium, gliadin, and reticulin.
•Locally elaborated lymphokines attract inflammatory cells à villous flattening appearance
•Followed by malabsorption of micronutrients and macronutrients
•Small-bowel involvement is most prominent proximally and may be "patchy," especially in patients with "silent" celiac disease (i.e., minimal or no symptoms) and those with dermatitis herpetiformis.

My Task
•To explain the histologic charateristics of Coeliac Disease

Note: These slides were provided by Dr Rakesh Naidu on Monday's PCL.

Histologic Findings of Coeliac Disease
Histology
•In untreated coeliac disease
•inflammed lining of the intestine becomes inflamed
•villous atrophy
–flat appearance
•reduced surface area à nutritional deficiencies

Histological Description of CD
•Disease causality was established when the characteristic features of
–villous flattening,
–crypt hyperplasia, and
–increased intraepithelial lymphocytes

Before - After
A At time of diagnosis. There is severe villous abnormality associated with marked enterocyte damage (black arrows), in keeping with untreated coeliac disease.
B After 6 months of gluten-free diet. There is partial improvement of the previous villous abnormality, but a moderate villous abnormality with associated crypt hyperplasia remains

Remember……
•Exclusion of dietary gluten results in healing of the mucosa, resolution of the malabsorptive state, and reversal of most, if not all, effects of celiac disease.

Thank you!
•http://www.aafp.org/afp/20021215/2259.html
•http://content.answers.com/main/content/wp/en/6/60/CoeliacDisease.png

Investigations of Cushing Syndrome

1. Lab Studies

Biochemical evaluation of Cushing syndrome

The diagnosis of Cushing syndrome due to endogenous overproduction of cortisol requires the demonstration of inappropriately high serum or urine cortisol levels.

Currently, 4 methods are accepted for the diagnosis of Cushing syndrome: urinary free cortisol level, low-dose dexamethasone suppression test, evening serum and salivary cortisol level, and dexamethasone–corticotropin-releasing hormone test.

- Urinary free cortisol (UFC) determination provides measurement of cortisol over a 24-hour period. Urine free cortisol values higher than 3-4 times the upper limit of normal are highly suggestive of Cushing syndrome.

- Dexamethasone suppression tests mimic the physiology of the pituitary, which in the presence of steroids decreases the release of ACTH causing a fall in plasma and urine cortisol. In Cushing syndrome, a loss of sensitivity to glucocorticoids occurs and ACTH is therefore not suppressed and adrenal production of cortisol is not affected. The overnight 1-mg dexamethasone suppression test requires administration of 1 mg of dexamethasone at 11 pm with subsequent measurement of cortisol level at 8 am. In healthy individuals, the serum cortisol level should be less than 2-3 mcg/dL. A cutoff value of less than 1.8 mcg/dL (50 nmol/L) excludes Cushing syndrome. Its ease of administration makes the 1-mg dexamethasone suppression test a widely used screening tool.
- Late night serum and salivary cortisol levels take advantage of the alterations in circadian rhythm of cortisol secretion in patients with Cushing syndrome. Normally, nighttime cortisol values are at their lowest level; in patients with Cushing syndrome, elevated nighttime cortisol can be an early but not definitive finding. This test requires hospitalization with blood samples obtained within 5-10 minutes of waking a patient and is not a practical test.

- Measuring salivary cortisol level is a simple and convenient way of obtaining a nighttime sample. This measurement allows patients to collect their own samples at home. With repeated measurements, levels less than 1.3 ng/mL (radioimmunoassay) or 1.5 ng/mL (competitive protein-binding assay) exclude Cushing syndrome. Less experience has been gathered for this assay, and it is expensive. Readings are obtained over several evenings to increase accuracy.

- The dexamethasone-CRH test is intended to distinguish patients with Cushing syndrome from those with pseudo-Cushing states. It combines a 48-hour low-dose dexamethasone suppression test with CRH stimulation. Dexamethasone (0.5 mg every 6 hours) is given 8 times, CRH is then administered intravenously and plasma cortisol and ACTH levels are obtained at 15-minute intervals for 1 hour. A cortisol value greater than 50 nmol/L (1.4 mcg/dL) identifies Cushing syndrome. This test is reserved for patients with high clinical suspicion for Cushing syndrome but equivocal results on other diagnostic tests.

Unfortunately, mild Cushing syndrome is often difficult to distinguish from normal cortisol secretion or pseudo-Cushing states. The aforementioned tests can produce both false-positive and false-negative results. False-positive results are associated with obesity, alcoholism, chronic renal failure, affective disorders, strenuous exercise, or eating disorders. Other potential confounders in the interpretation of tests include the following:

Medications that increase corticosteroid-binding globulin, such as estrogen and tamoxifen, may cause appropriate increases in serum cortisol levels.
Medications that facilitate the metabolism of dexamethasone, such as phenobarbital, phenytoin, and rifampin, may cause false-positive results with the dexamethasone suppression test.

Acute illness activates the Hypothalamic- Pituitary- Adrenal (HPA) axis, resulting in increases in ACTH and cortisol, the laboratory workup for Cushing syndrome should not be performed when subjects are acutely ill.

Other laboratory abnormalities seen in Cushing syndrome include the following:
Elevated white blood cell count greater than 11,000/mm3
Hypokalemic metabolic alkalosis may occur in patients with urinary free cortisol levels higher than 1500 mcg/24 h.

Once the diagnosis is established, the next step requires determining the etiology of Cushing syndrome. This first involves identifying if the hypercortisolism is an ACTH-dependent or ACTH-independent disorder.

· A plasma ACTH level that is undetectable is diagnostic of ACTH-independent Cushing syndrome. There are patients with cortisol-producing adrenal adenomas, where the ACTH may be undetectable; therefore, several collections should be obtained.
· A plasma ACTH (measured by an immunoradiometric assay) of less than 5 pg/mL is suggestive of a primary adrenal tumor.
· An ACTH level greater than 10-20 pg/mL is consistent with ACTH-dependent Cushing syndrome.
· For ACTH-dependent disease, the high dose (8-mg) overnight dexamethasone suppression test and the 48-hour high-dose dexamethasone test determine whether a patient who has pituitary-dependent or ectopic ACTH disease.

8-mg overnight dexamethasone suppression test: Individuals ingest 8 mg dexamethasone orally at 11 pm, with measurement of an 8 am cortisol level the next day. Suppression of serum cortisol level to less than 50% of baseline is suggestive of a pituitary source of ACTH rather than ectopic ACTH.

48-hour high-dose dexamethasone suppression test: Patients ingest 2 mg dexamethasone every 6 hours for 8 doses. A decrease in urinary free cortisol of greater than 50% is suggestive of an anterior pituitary adenoma rather than ectopic ACTH.

· Testing with CRH is also used in the differential diagnosis of ACTH-dependent Cushing syndrome. In most patients with pituitary ACTH secretion, the intravenous administration of CRH causes a rise in plasma ACTH and cortisol levels. In patients with ectopic secretion of ACTH, CRH does not affect ACTH or cortisol levels. ACTH and cortisol samples are obtained before administration of ovine CRH (oCRH), and subsequently at 15, 30, 45, 60, 90, and 120 minutes after administration of 1 mcg/kg of CRH.

· If concern for adrenal carcinoma exists, measurement of 17-ketosteroid or other cortisol precursors (eg, serum dehydroepiandrosterone sulfate [DHEAS]) is useful.

2. Imaging Studies:

Imaging studies for Cushing syndrome should be performed after the biochemical evaluation has been performed. The rationale for this is that unguided imaging of the pituitary or adrenal glands may yield a 10% incidence of incidental nonfunctioning pituitary or adrenal adenomas, which may mislead one from proper therapy and surgery. Ideally, the biochemical abnormalities should reconcile with the anatomic abnormalities before definitive therapy is offered.

- An abdominal CT scan is recommended if a primary adrenal problem is suspected. The presence of an adrenal mass larger than 4-6 cm raises the possibility that the mass is an adrenal carcinoma.
- If a pituitary source of excess ACTH is suspected, patients should undergo a contrast-enhanced magnetic resonance imaging (MRI) study of the pituitary.
- Chest and abdominal CT scans should be performed in patients with suspected ectopic ACTH production.

Contributed by John Lee

Source: http://www.emedicine.com/emerg/topic117.htm

Psychosocial Issues

Issues relating to Cushing's:

• Loss of energy, a decreased level of activity and fitness
• Loss of libido, infertility, low sex drive, impotence
• Lack of self-esteem/confidence (body image issues) due to altered body image/physical changes/imbalance of hormones
  
• Feelings of loss of control
• Depression**/mood swings
• restlessness, agitation
• memory affected
• sleep patterns affected
  
• "Something is wrong with me"
  
• History of being treated for other stress/mood related disorders. Doctors tend to imply to patients that they suffer from psychological disorders rather than physical disorders.

Because of the above factors:

• strain on relationships
• unmarried? divorced? - could this be an underlying reason?
  
• family/relatives - unable to cope with the change in personality/mood swings etc.
  
• snide or unkind comments from family/relatives/co-workers/friends regarding inability to lose weight/other physical changes or mood changes
• strain on employment
• unable to carry out normal duties due to depressive personality
• unable to cope with stresses

Treatment/Management issues:

• "Uncertainty is worse than reality" - therefore important for patient to learn all about the condition to reduce uncertainty and perhaps aid in alleviating depression
  
• Cortisol replacement:
  
• worries regarding the ups and downs of cortisol replacement
• financial issues: able to pay for drugs? insurance?
  
• forgetting to take medication daily?
• stress!
• Surgery:
  
• distress regarding the procedures/risks
• Managing depression*:
• moderate alcohol/caffeine intake
• have hormone levels checked
• anti-depressants?
• talk with others (cognitive behaviour therapy/mindful meditation/support group)
• adequate sleep (reduced alcohol and caffeine intake helps)
• proper diet and exercise routine - even after surgery, may take a while for body to go back to 'normal'
  
• stressful life? change it! Or change reaction to stresses

Sources:
http://www.pituitary.org.uk/content/view/69/80/
http://www.pituitary.org.uk/content/view/278/157/

Definition and Causes of Cushing's Syndrome

Cushing’s Syndrome

Definition: Cushing’s Syndrome (also known as hypercorticolism) is a hormonal disorder caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol, either produced excessively by the body or through excessive intake of cortisol or other steroid hormones.

What Causes Cushing’s Syndrome?

1. Pituitary Adenomas

- most common cause (also known as Cushing’s Disease)

- benign tumors or hyperplasia of the pituitary gland, secreting increase amounts of ACTH

- affects women five times more frequently than men, and usually as a single adenoma

2. Ectopic ACTH Syndrome

- benign or malignant tumors that arise outside the pituitary gland producing ACTH

- most common is lung tumors ( >50% of ectopic cases), usually by small cell lung cancer

- thyromas, pancreatic islet cell tumors, medullary carcinomas of the thyroid (C cells)

3. Adrenal Tumors

- more commonly Adrenal Adenomas which releases excess cortisol

- Adrenocortical carcinomas, least common cause, secrete excess levels of several adrenal cortical hormones including cortisol and adrenal androgens. Cause very high hormone levels and rapid development of symptoms

4. Intake Of Glucocorticoid Hormones

- also known as Exogenous Cushing’s Syndrome

- due to intake of glucocorticoids such as prednisone or dexamethasone for treatment purposes

- for asthma, rheumatoid arthritis, lupus, inflammatory diseases, immunosuppression after transplantation

5. Familial Cushing’s Syndrome

- very rare; due to inherited tendency to develop tumors of one or more endocrine glands

- Primary Pigmented Micronodular Adrenal Disease: children or young adults develop small cortisol-producing tumors of the adrenal glands

- Multiple Endocrine Neoplasia Type I (MEN I): due to pituitary, ectopic or adrenal tumors

References

http://endocrine.niddk.nih.gov/pubs/cushings/cushings.htm

http://www.nlm.nih.gov/medlineplus/ency/article/000410.htm

Cortisol

Cortisol / Glucocortisol
Ji Keon LOOI

Outline of presentation
This presentation will cover:
•Site of production
•Site of release
•Target organ
•Means of transport
•Action
•Feedback Loop
Of cortisol

To clear things up before we start
•Two major types of adenocorticol hormones – mineralocorticoids and glucocorticoids
•Mineralocorticoids affect the electrolytes (minerals) of the ECF Na+ and K+ in particular
•Glucocorticoids increase blood glucose concentration, effects on CHO, protein and fat metabolism

The glucocorticoids
•Cortisol
•Corticosterones
•Cortisone
•Prednisone
•Methylprednisone
•Dexamethasone

Introduction to CORTISOL
•Principal glucocorticoid, 95% of all GC activity
•Secretion stimulated by ACTH, which in turn is controlled by CRF.
–What are sites of production?
•Produced by adrenal cortex
–Which layers?
•A.k.a stress hormone
•Hydrocortisone (synthetic)

Secretion of adrenocortical hormones by the different zones of the adrenal cortex and secretion of catecholamines by the adrenal medulla. (Diagram from Guyton)

Means of transport & Action
•Cortisol (hydrophobic) travels through the body in the blood via serum globulin.
•It diffuses through the cell membrane.

•Inside the cell, cortisol binds with its protein receptor in the cytoplasm, and the hormone-receptor complex (HRC) then interacts with specific regulatory DNA sequences, called glucocorticoid response elements, to induce or repress gene transcription. (Interaction facilitated by Transcription factors)
•It increases or decreases transcription of many genes to alter synthesis of mRNA for the proteins that mediate their multiple physiologic effects.
•Thus, most of the metabolic effects of cortisol are not immediate but require 45 to 60 minutes for proteins to be synthesized, and up to several hours or days to fully develop.
•N.B.: steroid hormones, exerts its effects by first interacting with intracellular receptors in target cells.

More about the stress hormone…
•Secretion in accordance with circadian rhythm. High in the early morning, low in late evening. Changes in sleeping habits alter the cycles.
–Clinical application: - measurement of blood cortisol only meaningful when expressed in terms of the time in the cycle at which the measurements are made
•Physical/Mental stress enhances secretion of ACTH and consequently cortisol.
•Negative feedback mechanism to decrease CRF and ACTH formation

Effects of Cortisol (1)
CHO metabolism
•Stimulates gluconeogenesis
•Decreases glusoce utilisation by cells
•Elevates blood glucose concentration and “adrenal diabetes”

Protein metabolism
•Reduces cellular protein
•Increases liver and plasma protein
•Increases blood aa, diminishes transport of aa into extrahepatic cells and enhances transport into hepatic cells

Fat Metabolism
•Mobilisation of FACs
•Excess results in obesity

Effects of Cortisol (2)
•Resists stress and inflammation ( )
•Blocks inflammatory response to allergic reactions
Mechanism for regulation of glucocorticoid secretion. ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor.


THE DISORDERS OF CORTISOL SECRETION
Plasma Cortisol Plasma ACTH

Primary Hypercortisolism ↑ ↓
(Cushing Syndrome)

Secondary Hypercortisolism ↑ ↑
(pituitary, Cushing's disease)

Primary Hypocortisolism ↓ ↑
(Addison's disease)

Secondary Hypocortisolism ↓ ↓
(pituitary)

Thank you!!!
Sources
•Guyton, Textbook of Medical Physiology 11th Edn
•Prof. Khalid’s lecture *Components of the Endocrine System*
•http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Adrenals.html

List of symptoms of Cushing's syndrome

The list of signs and symptoms mentioned in various sources for Cushing's syndrome includes the 81 symptoms listed below:


Specific childhood or adolescent Cushing's symptoms:

Extreme weight gain
Growth retardation
Missed periods - in teenage girls
Excess hair growth
Body hair growth
Facial hair growth
Acne
Reddish-blue streaks on the skin
High blood pressure
Tiredness
Muscle weakness
Very early puberty
Very late puberty





Adult Cushing's symptoms

Extreme weight gain
Upper body obesity
Rounded face
Increased neck fat
Excess hair growth
High blood pressure
Sleep disturbances
High blood sugar
Diabetes-like symptoms
Hyperadrenocorticism
Bruising easily
Skin problems
Thin skin
Fragile skin
Poor healing
Stretch marks
Abdominal stretch marks
Mood changes
Irritability
Anxiety
Depression
Moodiness
Fatigue
Mental disturbances
Weak muscles
Backaches
Thinning arms
Thinning legs
Weak bones
Rib fractures
Spinal column fractures
Sexual and fertility problems
Irregular menstrual periods
Absent menstrual periods
Reduced libido
Reduced male fertility
Virilisation
Deepening voice
Balding
Loss of scalp hair
Hirsutism
Increased facial hair
Increased body hair
Increased weight
Rounded face
Obesity around trunk
Slender limbs
Red face
Thin skin
Fragile skin
Slow-healing skin
Weakened connective tissue
Reddish-blue stretch marks
Excessive hair thickness in women
Menstrual disorders
Impaired male fertility
Reduced male sex drive
Absent male sex drive
Hypertension
Brittle bones
Fractures
Osteoporosis
Hyperglycemia
Severe weakness
Fatigue
Psychiatric disturbances

Note that Cushing's syndrome symptoms usually refers to various symptoms known to a patient, but the phrase Cushing's syndrome signs may refer to those signs only noticable by a doctor.

By Chris
source: http://www.wrongdiagnosis.com/c/cushings_syndrome/symptoms.htm

Labelling our posts

To avoid confusion to differentiate between pcl materials from MED2031 and MED2042 since we start with Week 1 again this semester, I would suggest that we label our work according to the title of the week.

I have entered all the pcl titles under this post and they should appear when you type in the first letter into the label slot. Alternatively, click on Show all to display all the pcl title.

Thanks.

Ji Keon