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endo1 Flashcards

1
Q

What is the significance of the thyroid C-Cell?

A
  1. Produces calcitonin which inhibits Ca2+ absorption, inhibits osteoclasts, and inhibits renal reabsorption Ca+
  2. Main cell in thyroid medullary Ca

**Calcitonin is like an ‘anti-PTH’ EXCEPT, that like PTH, it also inhibits renal tubular reabsorption.

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2
Q

Describe the steps involved in thyroid hormone synthesis.

A
  1. Albumin-bound iodide gets taken up and extracted by the NIS (Na+/Iodide symporter) on the basal surface of the follicle cell and stored at the apical surface of the cell.
  2. TSHr is activated by TSH resulting in follicular release of Thyroglobulin (Tg) into the colloid, along with Iodine (Io) (via Pendrin transporter).
  3. Thyroid peroxidase (TPO) catalyses a reaction resulting in the binding of Tg and Io.
  4. The Tg-Io complex is taken back up into the follicular cell where it is processed by the lysosome into T3 and T4
  5. T3 and T4 are released out the basal membrane into the bloodstream where it feeds back on TSH and TRH respectively.
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3
Q
  1. What is the mechanism of Amiodarone hypothyroidism?
  2. Where and in who is it a problem?
  3. How do you manage it?
  4. How do you monitor it?
A
  1. Loss of escape from the Wolff-Chaikoff effect in autoimmune thyroiditis resulting in iodine-driven hypothyroidism
  2. Iodine-replete countries, women, and when anti-TPO positive.
  3. Levothyroxine, continue amiodarone
  4. Monitor TSH - T4 will be elvated regardless due to suppression of deiodinase.
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4
Q

What is the difference between Amiodarone-Induced Thyrotoxicosis (AIT) Types 1 and 2?

A

Type 1: Activation and increased production (Graves, MNG)

Type 2: Destruction and excess release (acute thyroiditis due to thyroid gland destruction and stored hormone release)

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5
Q
  1. What is the mechanism of Amiodarone-Induced Thyrotoxicosis Type 1?
  2. What imaging would you do? What would it show?
  3. How do you treat it? How does it work?
A
  1. Increased iodine leads to hyperthyroidism from excessive hormone synthesis (Jod-Basedow effect)
  2. Colour flow Doppler U/S: Increased vascularity. Thyroid scintiscan is not useful due to high levels of endogenous iodine which inhibits tracer uptake. Decreased or normal uptake however may favour type 1 AIT.
  3. Carbimazole: prevents TPO from iodinating thyroglobulin à decreased T3 and T4 production . Cease amiodarone (unless it’s really needed, it has a long T1/2)
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6
Q
  1. What is the mechanism of Amiodarone-Induced Thyrotoxicosis Type 2?
  2. What characterises AIT Type 2?
  3. How do you image it and what does it show?
  4. How do you treat it?
A
  1. Drug-induced lysosomal activation → destructive thyroiditis with histiocyte (tissue macrophage) accumulation in the thyroid → release of pre-formed T3 and T4
  2. No intrinsic thyroid abnormality, incidence increases with amiodarone dose.
  3. Colour flow Doppler: Decreased vascularity
  4. Prednisone 40-50mg daily, and cease amiodarone (unless you really need it!)
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7
Q

What is the Wolff-Chaikoff effect?

A

Hypothyroidism due to high iodine load.

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8
Q

What is the Jod-Basedown effect?

A

Excess iodine causes hyperthyroidism in pre-existing thyroid disease

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9
Q

What is the difference between thyrotoxicosis and hyperthyroidism?

A

Thyrotoxicosis is defined as the state of thyroid hormone excess and is not synonymous with hyperthyroidism, which is the result of excessive thyroid function.

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10
Q

How do you tell if a patient likely has Type 1 or Type 2 AIT when presenting with a mixed-picture Amiodarine-induced thyrotoxicosis?

A

A rapid response (reduction in thyroid hormone levels) to combined treatment (pred AND carbimazole) suggests Type 2 AIT. Steroids work faster and pre-existing hormone will be depleted while carbimazole has rapid-antithyroid effect but takes longer on levels due to stored pre-existing hormone which is still being replenished.

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11
Q

What is the management of Graves Disease?

A
  1. Beta-blockers - control adrenergic effects
    - propranolol 0.25mg-0.5mg/kg 3-4 times per day
    - start as soon as dx made - don’t wait for uptake scan
  2. Thionamides (‘imazoles and PTU)
    - Methimazole / Carbimazole (prodrug of Methimazole) is preferred
    - longer acting
    - once daily dosing
    - more rapid efficacy
    - Less side effects (agranulocytosis, deranged LFTs)
    - Teratogenic in first trimester
    - PTU
    - 1st trimester

Goal: rapid euthyroidism in 3-8 weeks
Need baseline bloods: FBC and LFTs - C/I if neutropaenic, deranged LFTs
Titrate dose to size of goitre and severity of hyperthyroidism
Not curative for most

  1. Radioactive iodine ablation
    - only once euthyroid
    - C/I if pregnant/severe opthalmopathy (can use concurrent steroids if mild)
    - Hormone stores must be depleted prior - otherwise destructive release –> thyrotoxicosis
    - main SE: hypothyroidism
    - Curative
  2. Surgery
    - big or obstructive goitre
    - opthalmopathy
    - pregnancy (preferably be six months prior to avoid use of thionamides
    - suspicion of malignancy or hyperparathyroidism
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12
Q

Outline the how the renin-angiotensin system works.
<br></br>

What are the effects of angiotensin 2?

A

RAAS - it’s job is to restore normovolaemia.

<br></br>

Macula densa (JGA) detects<u> low chloride concentration</u> in the tubule, <u>baroreceptors</u> in the afferent arteriole detects decreased perfusion pressure.

<br></br>

Renin is then secreted from the glomerulus and JGA, resulting in the production of AT1 (renin is the substrate), followed by conversion to ATII, catalysed by ACE (mainly present in the lung).

<br></br>

AT2 effects (all except vasoconstriction via AT1 receptors):

•<span> </span><u>Systemic vasoconstriction</u> of vascular smooth muscle (via AT2 receptors)

•<span> </span><u>Na+ reabsorption</u> (early proximal tubule)

•<span> </span><u>Aldosterone secretion</u> from the adrenal cortex resulting in Na+ reabsorption in the cortical collecting tubule

* <u>Catecholamine release</u>

•<span> </span><u>Maintenance of GFR</u> via afferent + efferent arterioles with the help of thromboxane A2 (a vasoconstrictor) and local prostaglandins (vasodilators). This happens in response to a drop in systemic pressure, by constricting the efferent arteriole and opening up the afferent, the net result is maintenance of renal perfusion.

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13
Q

What is the medical management of BPH? How do the drugs work?

A

Management options

watchful waiting

medication: alpha-1 antagonists, 5 alpha-reductase inhibitors. The use of combination therapy was supported by the Medical Therapy Of Prostatic Symptoms (MTOPS) trial
surgery: transurethral resection of prostate (TURP)

Alpha-1 antagonists e.g. tamsulosin, alfuzosin

decrease smooth muscle tone (prostate and bladder)

considered first-line, improve symptoms in around 70% of men

adverse effects: dizziness, postural hypotension, dry mouth, depression

5 alpha-reductase inhibitors e.g. finasteride

block the conversion of testosterone to dihydrotestosterone (DHT), which is known to induce BPH

unlike alpha-1 antagonists causes a reduction in prostate volume and hence may slow disease progression. This however takes time and symptoms may not improve for 6 months. They may also decrease PSA concentrations by up to 50%

adverse effects: erectile dysfunction, reduced libido, ejaculation problems, gynaecomastia

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14
Q

What are the electrolyte abnormalities in Addison’s disease and how do you establish the diagnosis?

A

In a patient with suspected Addison’s disease the definite investigation is a ACTH stimulation test (short Synacthen test). Plasma cortisol is measured before and 30 minutes after giving Synacthen 250ug IM. Adrenal autoantibodies such as anti-21-hydroxylase may also be demonstrated

Associated electrolyte abnormalities

hyperkalaemia

hypercalcemia

hyponatraemia

hypoglycaemia

metabolic acidosis

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15
Q

How do you test for coeliac disease?

A

NICE issued guidelines on the investigation of coeliac disease in 2009. If patients are already taking a gluten-free diet they should be asked, if possible, to reintroduce gluten for at least 6 weeks prior to testing.

Immunology

tissue transglutaminase (TTG) antibodies (IgA) are first-choice according to NICE

endomyseal antibody (IgA)

anti-gliadin antibody (IgA or IgG) tests are not recommended by NICE

anti-casein antibodies are also found in some patients

Jejunal biopsy

villous atrophy

crypt hyperplasia

increase in intraepithelial lymphocytes

lamina propria infiltration with lymphocytes

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16
Q

What does the adrenal medulla secrete?

A

The adrenal medulla secretes virtually all the adrenaline in the body as well as secreting small amounts of noradrenaline. It essentially represents an enlarged and specialised sympathetic ganglion

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17
Q

What does the B3 receptor do?

A

Enhancement of lipolysis in adipose tissue.

Thermogenesis in skeletal muscle

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18
Q

What does the insulin receptor do?

A
  1. TKI
  2. Increases glut-4 transporter molecules on outer membrane of tissues ie muscle and fat
  3. Influx of glucose, glycogen synthesis, glycolysis, FFA synthesis
  4. Mutations are rare.
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19
Q

Name three points about leptin

A
  1. Appetite suppressant
  2. Precursor is alpha-melanocyte stimulating hormone which acts in the hypothalamus
  3. Increased in obese people.
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20
Q

What is C-peptide and why is it important?

A
  1. Fragment of proinsulin that is removed to create insulin.
  2. Distinguishes between established Type 1 & MODY diabetes (C-Peptide will be low as not producing), and type 2 diabetes/obesity (high due to insulin resistance)
  3. Measured instead of insulin because it can be measured while someone is receiving insulin injections, and due to the liver metabolising insulin quite variably in the portal circulation.
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21
Q

Which one of the following is the most common biochemical association of obesity?

A. Mutation of the insulin receptor. 


B. Reduced serum leptin.

C. Mutation of the β3-adrenergic receptor. 


D. Raised serum C-peptide. 


E. Raised blood glucose. 


A

D

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22
Q

Which diseases cause hypokalemia with hypertension?

A

Cushing’s syndrome

Conn’s syndrome (primary hyperaldosteronism)

Liddle’s syndrome

11-beta hydroxylase deficiency*

Renovascular hypertension

*21-hydroxylase deficiency, which accounts for 90% of congenital adrenal hyperplasia cases, is not associated with hypertension

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23
Q

Which diseases cause hypokalaemia without hypertension?

A

diuretics

GI loss (e.g. Diarrhoea, vomiting)

renal tubular acidosis (type 1 and 2**)

Bartter’s syndrome

Gitelman syndrome

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24
Q

Describe Polymorphic eruption of pregnancy

A
  • pruritic non-blistering condition associated with last trimester
  • lesions often first appear in abdominal striae
  • management depends on severity: emollients, mild potency topical steroids and oral steroids may be used
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25
Q

Describe Pemphigoid gestationis

A
  • pruritic blistering lesions
  • often develop in peri-umbilical region, later spreading to the trunk, back, buttocks and arms
  • usually presents 2nd or 3rd trimester and is rarely seen in the first pregnancy

oral corticosteroids are usually required

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26
Q

Which lipid profiles are associated with an increased risk of coronary artery disease?

A

High levels of LDL

High triglycerides with low HDL

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27
Q

Which one of the following best describes the association between hyperinsulinaemia (insulin resistance) and coronary heart disease?

The relationship is:

A. independent of total cholesterol. 


B. confined to subjects with low HDL (high density lipoprotein) cholesterol. 


C. confined to obese individuals. 


D. confined to hypertensive subjects only. 


E. confined to diabetic subjects only. 


A

A. The dyslipidaemia associated is usually hypertriglyceridaemia and low HDL. This is more important than total cholesterol.

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28
Q

What is the basic pathogenesis of type 1 and 2 diabetes?

A

Type 1
- deficiency of insulin secretion

  • elevated plasma glucagon
  • due to autoimmune pancreatic B-islet cell destruction
  • prone to ketoacidosis

Type 2

  • combination of insulin resistance and inadequate secretion to compensate
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29
Q

What is the major cause of Type 1 DM?

When does it occur?

A
  • Immune mediated Type 1A in over 95% of cases
  • Idiopathic in <5% (type 1b)
  • peak incidence before school age and again around puberty
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30
Q

What is the influence of genetics on type 1 diabetes?

A
  • 1/3 due to genes, 2/3 to environmental factors
  • 95% are either HLA-DR3 or DR4 positive
  • HLA-DQ genes more specific - HLADQB1*0302 is found in Type 1 patients, while HLADQB*0602 is found in controls.
  • 10% of genetic risk found at 5’ polymorphic region of the insulin gene - affects the expression of the insulin gene in the thymus resulting in depletion of specific T-lymphocytes.
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31
Q

What circulating antibodies are present in type 1 diabetes?

What happens to their levels as time goes on?

A
  • islet cells (ICA)
  • insulin (IAA)
  • glutamic acid decarboxylase 65 (GAD 65)
  • tyrosine phosphatase IA2 (ICA-512)
  • Zinc transporter 8 (ZNT8)
  • levels decline with increasing duration of disease

Almost all insulin-treated patients will develop anti-insulin antibodies.

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32
Q

What are the features of Autoimmune polyendocrine syndrome type 1?

A
  • Autosomal recessive mutation of AIRE (autoimmune regulator) gene which usually confers immune tolerance.
  • mild immune deficiency and hyposplenism –> mucosal candidal infections
  • Hypoparathyroidism and Addisons disease
  • Hypothyroidism, gonadism, vitiligo, diabetes, pernicious anaemia, autoimmune hepatitis.
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33
Q

What are the features of Autoimmune polyendocrine syndrome type 2?

A
  • polygenic, affects HLA DQ2, DQ8, and DRB1*0404
  • most common polyglandular syndrome, women more than men
  • Addison’s, primary hypothyroidism, Graves, Pernicious anaemia, DM1, Vitiligo, coeliac disease, MG
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34
Q

What is latent autoimmune diabetes of adulthood?

A

Milder form of type 1 diabetes that presents later in life as pancreatic b-cell function is maintained for longer.

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35
Q

What is the strongest evidence for environmental factors playing a role in type 1 diabetes?

A
  • more common in Scandinavian countries
  • becomes progressively less frequent as you get closer to the equator
  • risk increases when individuals who have low risk emigrate to the Northern hemisphere.
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36
Q

What is idiopathic type 1 DM (type 1b)?

A
  • no evidence of pancreatic b-cell autoimmunity
  • Asians and Africans
  • 5% of Type 1 DM (pts can get ketoacidotic)
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37
Q

Why is ketoacidosis not present in Type 2 DM?

A
  • circulating endogenous insulin sufficient to prevent ketoacidosis but inadequate to prevent hyperglycaemia in the face of increased needs due to tissue insensitivity (insulin resistance)
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38
Q

What happens early in the disease process of Type 2 DM? Later?

A
  • hyperplasia of pancreatic B-Cells
  • hyperinsulinaemia, exaggerated insulin and proinsulin responses.
  • chronic deposition of amyloid in the islets occurs later and may combine with inherited genetic defects to progressively impair b-cell function.
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39
Q

What kind of fat is associated with Type 2 DM?

What prevents it?

A
  • Increased visceral fat
  • May not be overtly obese but if present, they are ‘metabolically obese’.
  • Daily exercise prevents it.
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40
Q

What are the adipokines implicated in Type 2 DM and what are their actions?

A

Leptin and adiponectin - increase tissue sensitivity to insulin

TNF-alpha: inactivates insulin receptors

Resistin - interferes with insulin action on glucose metabolism

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41
Q

How does hyperglycaemia impair insulin action?

A
  • causes accumulation of hexosamines in muscle and fat tissue
  • inhibits glucose transport (acquired glucose toxicity)
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42
Q

What are the features of Maturity-Onset Diabetes of the Young (MODY)?

A
  • rare monogenic autosomal dominant disorder
  • age at onset of 25 years or younger
  • impaired glucose-induced secretion of insulin
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43
Q

What is the underlying mutation involved in MODY diabetes?

Where does MODY-2 differ?

A
  • Mutation of transcription factor
  • EXCEPT MODY-2 which is a defect in the glucokinase gene.
  • glucokinase is rate-limiting step in glycolysis and determines rate of ATP production from glucose and insulin secretory response in the beta-cell.
  • MODY-2 usually mild and can be diet controlled or managed with lose dose OHAs.
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44
Q

What is the most common form and features of MODY diabetes?

A
  • MODY 3 is most common
  • mutation in hepatic nuclear factor 1-alpha
  • progressive beta cell failure and need for insulin therapy.
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45
Q

What mutation causes type 1 diabetes at a later age than MODY diabetes (around 35 years)?

A
  • mutation in one allele of pancreatic duodenal homeobox 1 (PDX1)
  • two alleles = pancreatic agenesis
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46
Q

What are the features of DM caused by a mitochondrial DNA mutation?

A
  • only mother transmits (sperm do not contain mitochondria)
  • happens even if only a small percentage of mitochondria carry the mutation due to heteroplasmy (mitochondria carries more than one type or organellar genome)
  • onset in late 30s, also have hearing loss (maternally inheritied diabetes and deafness (MIDD))
  • not overweight, resembles Type 1 DM but without autoimmunity
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47
Q

What is Wolfram syndrome?

A
  • Autosomal recessive neurodegenerative disorder that starts in childhoohd
  • DI, DM, optic atrophy and deafness (DIDMOAD)
  • mutation in WFS1 gene that protects beta-cells from endoplasmic reticulum stress and apoptosis in times of high insuilin demand
  • Cranial DI and sensorineural deafness develop in teens
  • May also develop ureterohydronephrosis, neurogenic bladder, cerebellar ataxia, peripheral neuropathy, and psychiatric illness.
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48
Q

What are the secondary causes of hyperglycaemia due to tissue insensivity to insulin?

A

Hormonal tumors: acromegaly, Cushings, glucagonoma, phaeo

Drugs: Steroids, sympathomimemtics, niacin

Liver disease: Cirrhosis, haemochromatosis

Muscle disorders: Myotonic dystrophy

Fat disorders: Lipodystrophy, truncal obesity

Insulin receptor disorders (rare): acanthosis nigricans syndromes, leprechaunism

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49
Q

What are the secondary causes of hyperglycaemia due to reduced insulin secretion?

A

Hormonal tumors: Somatostatinoma, phaeo

Pancreatic disorders: Pancreatitis, haemosiderosis, hemochromatosis

Drugs: Thiazides, phenytoin, pentamidine (PCP and leishmaniasis)

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50
Q

What effect does growth hormone, glucocorticoids, catecholamines and glucagon have on insulin?

A

They reduce peripheral responsiveness to insulin.

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51
Q

Aside from reducing peripheral responsiveness to insulin, what else do catecholamines do to insulin?

A

They decrease insulin secretion

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52
Q

What does somatostatin do to insulin?

A

Decreases it’s secretion

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53
Q

What do cyclosporine, tacrolimus and sirolimus do to insulin?

A

Cyclo and tac impair insulin secretion

Sirolimus increases insulin resistance.

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54
Q

How can you ameliorate the hyperglycaemia that thiazides cause?

A

Treat the associated hypokalaemia, in may reverse the hyperglycaemia.

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55
Q

What does chronic pancreatitis or subtotal pancreatectomy do to a person’s glycaemic status?

A
  • reduces number of functioning B-cells
  • metabolic derangement similar to type 1 DM
  • concomitant reduction in glucagon secretion means that lower doses of insulin replacement are needed.
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56
Q

What does glucagon do?

A
  • stimulates liver to convert stored glycogen into glucose via glycogenolysis, lipolysis and gluconeogenesis
  • increases circulating glucose
  • secreted from pancreatic alpha cells
  • stimulated by hypoglycaemia, adrenaline via a1, a2, and b2 receptors, and by cholecystokinin
  • inhibited by somatostatin, insulin, PPARy, increased FFAs, ketoacids, and urea
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57
Q

What is the worldwide definition of the metabolic syndrome?

A

Central obesity (defined as waist circumference - ethnicity specific, can be assumed if BMI over 30 and don’t need waist circumference) and any two of the following

  • Raised triglycerides >1.7 mmol/L or on treatment for hypertriglyceridaemia
  • Reduced HDL cholesterol <1.03 mmol/L or on treatment for same
  • Hypertension: systolic BP >130 or diastolic >85 or on treatment for same
  • Raised fasting plasma glucose >5.6mmol/L or previously diagnosed type 2 diabetes (OGTT if above this helpful but not necessary)
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58
Q

Aside from the defined criteria and hyperinsulinaemia, what are the other physiological changes associated with metabolic syndrome that increase the risk of atherosclerosis?

A
  • small dense LDL
  • hyperuricaemia (more gout in this population)
  • prothrombotic state with increased plasminogen activator inhibitor type 1 (PA-1)
  • pro inflammatory state
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59
Q

What is the result of an absolute insulin deficiency as seen in Type 1 DM?

A

accumulation of circulating glucose and fatty acids with consequent hyperosmolality and hyperketonaemia

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60
Q

What is the mechanism of ketoacidosis in type 1 diabetes? Symptoms?

A

Muscle mass is diverted to form glucose and ketone bodies from amino acids

Exacerbates dehydration and hyperosmolality by producing anorexia,nausea and vomiting and interferes with oral fluid replacement.

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61
Q

What is the mechanism of dehydration in type 1 diabetes?

A

Hyperglycaemia –> osmotic diuresis –> loss of free water, glucose, and electrolytes –> postural hypotension, potassium loss

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62
Q

What is the mechanism of blurred vision in type 1 diabetes?

A

Lenses are exposed to hyperosmolar fluids

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63
Q

What is a serious prognostic sign in type 1 diabetes?

A

Hypotension in the recumbent position

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64
Q

What are the features of type 2 DM that are specific to women?

A

Generalised pruritus and vaginitis

Chronic candidal vulvovaginitis

Large babies

Polyhydramnios

Preeclampsia

Unexplained fetal loss

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65
Q

What are the physical features of a type 2 dm patient?

A
  • fat deposits on upper segment of body (abdomen, chest, neck and face) with skinny limbs
  • acanthosis nigricans (significant insulin resistance) - pigmented and hyperkeratotic
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66
Q

What is the definition of a high waist circumference in men and women?

A

>102 cm in men

>88cm in women

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67
Q

What are the skin features of a patient with concurrent uncontrolled T2 DM who also have familial hypertriglyceridemia?

A

Xanothomas on flexor surfaces of limbs and on the buttocks with lipemia retinalis

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68
Q

What is the main difference in coma states between type 1 and 2 dm?

A

Type 1 has Kussmaul breathing, Type 2 doesn’t

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69
Q

What is nondiabetic glycosuria?

A
  • also known as renal glycosuria
  • benign asymptomatic condition where glucose appears in urine in spite of normal blood glucose
  • mutation in SGLT2 gene or general dysfunction of proximal renal tubule (Fanconi syndrome or CKD), or elevated GFR (i.e pregnancy)
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70
Q

What is the plasma glucose level diagnostic of diabetes and risk of diabetes?

When should you do an OGTT?

A

All are fasting:

Impaired: 5.6 - 6.9 mmol/L
Diagnostic: 7mmol/L or higher on more than one occasion after at least 8 hours of fasting

When the result is less than 7mmol/L but you still suspect diabetes

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71
Q

What are the values diagnostic of diabetes on an OGTT?

Why should this test be performed in the morning?

What causes false positives?

A

Normal: <7.8

Impaired: 7.8-11.0

Diabetes: >11

  • diurnal vriation in OGTT, also should not smoke or be active during the test
  • false positives: malnourished, bedridden, infection or severe emotional stress.
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72
Q

What are the HBA1c values diagnostic of diabetes mellitus?

A

Normal: <5.7 %

Impaired: 5.7-6.4

DM: >6.5

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73
Q

What time period does the HBA1c effectively measure?

A
  • previous month to past 3 months
  • any condition that shortens erythrocyte age or survival will give a falsely low number.
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74
Q

What is the reason for the HBA1c cutoff value of 6.5 in the diagnosis of DM?

When is the HBA1c an inappropriate test?

A
  • risk of retinopathy substantially increases above this value.
  • inappropriate if high red cell turnover (i.e. haemolysis) or in populations with high prevalence of haemoglobinopathies
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75
Q

What is the value of the serum fructosamine test? What does it reflect?

A
  • useful if abnormal Hb or haemolytic state or when a narrower time frame of glycaemic control is needed i.e. when a diabetic woman has recently become pregnant
  • reflects state of glycaemic control for preceding 1-2 weeks
  • bound to albumin (glycosylated albumin) - reduced if hypoalbuminaemia i.e. nephrotic state or hepatic disease
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76
Q

What are the limitations of self-monitoring glucose systems?

A
  • increases or decreases in haematocrit can decrease or increase measured values
  • accuracy not as good for higher and lower glucose levels
  • amperometric systems underestimate glucose levels in the presence of high oxygen tension - important in the critically ill who are receiving supplemental oxygen.
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77
Q

Why isn’t blood glucose measured on the forearm? Why the fingertip?

A

5-20 minute lag in glucose response on the arm with respect to the fingertip - could delay the detecion of rapidly developing hypoglycaemia.

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78
Q

What is diabetic dyslipidaemia?

A
  • characteristic of insulin resistance syndrome
  • low HDL <0.8 (major feature predisposing the macrovascular disease)
  • high TGL > 3.4-4.5
  • qualitative change in LDL particles - smaller dense particle whose membrane carries suparnormal amounts of free cholesterol. More susceptible to oxidation –> more atherogenic
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79
Q

What did the Diabetes Prevential Trial-1 show?

A
  • immune intervention (regular insulin) failed to affect the onset of type 1 DM in patients who were first degree relatives of type 1 dm patients with detectable islet cell antibodies and reduced early insulin release.
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80
Q

What did the Diabetes Control and Complications Trial (DCCT) show?

A
  • Near normalisation of blood glucose in Type 1 diabetics delayed onset and slowed progression of established microvascular and neuropathic complications during a followup of ten years.
  • Reduction in diabetic retinopathy, nephropathy, and neuropathy.
  • risk of cardiovascular disease decreased by nearly half.
  • benefits of good glucose control persisted even if that control worsened later.
  • formed the basis of current glucose control standards.

Exceptions: Elderly, advanced CKD as risk of hypoglycaemia outweighed the benefits of good glycaemic control.

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81
Q

What is the major signal transducing element of the t-cell receptor and what is it’s role in type 1 diabetes?

A

CD3 complex.

Trials of anti-CD3 antibodies underway.

Anti-CD3 antibodies modulate autoimmune response by selectively inhibiting the pathogenic t-cell or by inducing regulatory t-cells.

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82
Q

What did the Diabetes Prevention Program study show?

A

Diet + exercise or Metformin to prevent onset of Type 2 DM with impaired glucose tolerance

  • Diet and exerise reduced risk of progression to T2DM better than Metformin (although it stillw orked)

Metformin was relatively ineffective in the less obese or older.

‘Impaired glucose tolerance’ was changed to ‘prediabetes’ as a result.

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83
Q

What is the ‘honeymoon period’ of Type 1 DM?

A

Soon after dx pt’s go into a partial remission requiring little to no insulin, but eventually relapse. Due to initial remaining significant B-cell function.

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84
Q

What did the United Kingdom Prospective Diabetes Study show?

A

Whether macrovascular or microvascular complications could be reduced by intensive BSL control with OHAs or insulin.

Whether tight BP control with stepwise therapy could also prevent above (added later)

  • risk of retinopahy and nephropathy was decreased with tight glycaemic control.
  • weight gain occurred except when meformin was used as monotherapy.
  • no therapeutic agent conferred cardiovascular benefit or adverse CV outcome.
  • tight BP control substantially reduced risk of microvascular disease and stroke but not MI
  • reducing BP had greated impact on microvascular outcomes than lowering HBa1c by 1%
  • every 10mmHg decrease was assoc with 11% reduction in risk for MI.
  • no sustained benefit of BP control
  • sustained benefit of glucose control even if that control deteriorated later.

In obese subgroup

  • intensive tx with insulin or sulfonylurea alone did NOT reduce microvascular complications
  • metformin therapy was beneficial with fewer MIs, stroke, diabetes related deaths - but no significant reduction re microvascular complications.
  • if added to sulfonylurea, metformin showed an INCREASE in deaths
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85
Q

What did the Steno-2 study show?

A
  • aimed to target multiple concomitant risk factors for both micro and macrovascular disorders in Type 2 DM
  • aimed for BP <130, total chol <4.5 and TGL <1.7
  • stopped smoking, mod exercise, reduced dietary fat, and vitamin C, E and chromium supplements.

Found a reduction in CV events, nephropathy, retinopathy, and autonomic neuropathy.

Sustained benefit after study: lower risk of retinal photocoagulation, renal failure, CV endpoints and CV mortality.

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86
Q

What did the ACCORD, ADVANCE, and VADT studies demonstrate?

A
  • near normal glucose control in Type 2 DM did not reduce CV events before 10 years in people with well established type 2 DM.
  • shows that benefits better in early stages of DM rather than later.
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87
Q

What effect do monounsaturated fats have on serum lipids?

A
  • lower TGLs
  • increase HDL
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88
Q

What dietary modification needs to be made in patients with diabetic nephropathy?

A
  • reduce protein as may cause progression of kidney disease
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89
Q

What is the difference between soluble and insoluble fiber?

A

Soluble (gums & pectins ie beans, oatmeal, apple skin) slow nutrient absorption rates, slowing glucose absorption and reducing hyperglycaemia

Insoluble (cellulose/hemicellulose i.e. bran) - increase intestinal transit, may have beneficial benefits on colonic function

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90
Q

How is the glycaemic index determined?

A

BSL AUC (test food) / BSL AUC (reference food)

Low = <55

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91
Q

What effect dose fructose have on BSL and lipids?

A
  • only slight increase in plasma glucose levels, does not require insulin for metabolism
  • large amounts raise serum chol, triglycerides and LDL
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92
Q

Name the categories of hypoglycaemic drugs by mechanism

A
  1. Stimulates secretion by binding the sulfonylurea receptor - sulfonylureas
  2. Reduce glucose levels at liver, muscle, adipose tissue (Metformin: liver, thiazolidinediones - SKM and adipose tissue
  3. Reduced absorption of glucose - alpha glucosidase inhibitors (acarbose and miglitol)
  4. Incretin mimic’ers or incredtin prolongers: GLP1 receptor agonists and DPP IV inhibitors
  5. Renal glucose absorption inhibitors (SGLT2) - (the glifozins)
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93
Q

What are the important features of sulfonylureas?

A
  • stimulate insulin release from pancreatic B-cells via sulfonylurea surface receptors on pancreas
  • potassium channels close resulting in permanent depolarisation –> calcium influx –> insulin release
  • improves early phase of insulin release that has become refractory to acute glucose stimulation
  • metabolised by the liver - one active metabolite, the rest inactive
  • renally excreted
  • avoid in severe liver or kidney impairment
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94
Q

Name the different sulfonylureas and their features

A

All cause weight gain.

Glibenclamide/Glyburide - short acting, unique amongst sulfonylureas as also becomes sequestered in beta cell –> prolonged biologic effect despite relatively short circulating half life.

Glipizide - short duration of action, lower potency, preferred in elderly patient if sulfonylurea must be used.

Gliclazide - intermediate action (12 hours)

Glimepiride - long duration (once or twice daily dosing. Most potent - highest BSL lowering with lowest dose of any of the sulfonylureas

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95
Q

How does Metformin work? What are it’s indications?

A
  • lowers glucose level by acting on liver
  • increases hepatic AMPK activity –> reduces hepatic gluconeogenesis and lipogenesis
  • substrate for organic cation transporter 1 (found abundantly in hepatocytes and gut)
  • short half life, not bound to plasma proteins, excreted unchanged (i.e. not metabolised) by kidneys

- first line therapy for type 2 DM.

- improves fasting and postprandial hyperglycaemia and hypertriglyceridaemia in obese diabetics without weight gain.

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96
Q

Why should Metformin be avoided in acute illness, CKD, liver disease, and ETOH abuse?

A

Too much = overstimulation of lactic acid production

  • entirely renally excreted so failure to excrete Metformin AND lactate –> high blood and tissue levels of metformin that could provoke lactic acid buildup without necessarily increasing production
  • defective hepatocytes (i.e. liver and ETOH disease) –> cannot remove lactate / alcohol induced reduction of nucleotides –> deficient lactate clearance
  • tissue hypoxia –> compromised lactate removal –> lactic acid overproduction and buildup

Risk factors are same as contraindications –> kidney, liver, cardioresp insufficiency, alcoholism, advanced age.

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97
Q

Why is Metformin withheld on the day of IV contrast administration?

A
  • acute renal failure can occur with contrast –> metformin is renally excreted –> buildup can cause lactic acidosis
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98
Q

What are the main side effects of Metformin?

A

GI sx most frequent (N&V, anoxrexia, abdo pain, diarrhoea) - dose related, occurs at onset of therapy, often transient

  • less with extended release metformin
  • NO hypoglycaemia
  • reduced B12 absorption but serum B12 remains the same, worth screening occasionally or if there is peripheral neuroapthy or macrocytic anaemia
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99
Q

Why is the risk of lactic acidosis higher in a patient on metformin who is suffering tissue hypoxia?

A

Normally, therapeutic doses of Metformin reduce lactate uptake by the liver but serum lactate rises only minimally as the kidneys can remove the excess.

Tissue hypoxia essentially compromises lactate removal by the kidneys.

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100
Q

How do thiazolidinediones work?

A
  • sensitise peripheral tissues to insulin
  • bind peroxisome-activated receptor gamma (PPAR-gamma)
  • increased glucose transporter expression (GLUT1 & GLUT4)

Results in:

  • decrease FFA levels
  • decrease hepatic glucose output
  • increase adiponectin
  • decreased release of resistin from adipocytes
  • increase differentiation of preadipocytes into adipocytes
  • do not cause hypoglycaemia
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101
Q

How are thiazolidinediones used?

A
  • monotherapy or combination
  • lower HBA1c by 1-2%
  • with insulin: reduce dose by 30-50%
  • in combination with metformin wont cause hypoglycaemia.
  • Rosiglitazone: increases total chol, LDL and HDL, reduces FFAs
  • Pio: lowers TGLs, increases HDL
  • may improve NAFL
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102
Q

What are the SEs of the thiazolidinediones?

A

As a class:

Oedema - especially if concomitant insulin therapy –> may result in CHF

  • contraindicated in NYHA III and IV
  • new onset or worsening macular oedema (goes away with cessation)
  • anaemia (may be dilutional)
  • weight gain - esp with sulfonylurea or insulin (fluid and fat mass)
  • avoid in liver disease or if pretreatment ALT is >2.5 x upper limit of normal

Specifically

  • pio: increased risk of bladder cancer after 24 months
  • rosi: increases risk of angina or MI. Contraindicated in heart disease, especially is on nitrates.
    - not indicated for T1 DM, concomitant insulin, triple therapy
  • decreased bone density and increased fracture risk in women
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103
Q

What are the features of alpha-glucosidase inhibitors?

A
  • affects absorption of glucose
  • competitively inhibit alpha-glucosidase enzymes in the gut that digest dietary starch and sucrose
  • lower absorption of carbohydrate and lower postprandial glycaemic excursion
  • lowers HBa1c by 0.5-1%
  • main SE is flatulance due to undigested carbs in lower bowel - discourages carbohydrate consumption and promotes improved dietary compliance in type 2 DM
  • no risk of hypoglycaemia as monotherapy, might increase in combo.
  • efficacy reduced by SEs and noncompliance
  • contraindicated in renal impairment and bowel disease.
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104
Q

Why dose oral glucose stimulate more insulin release than IV glucose?

What is the name of this effect?

A
  • gut hormones GLP-1 and GIP-1 are released in presence of gut glucose whilch amplify glucose-induced insulin release
  • incretin effect.
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105
Q

What are incretins and what do they do?

Which one is more active and what does it do?

A
  • stimulate insulin release in presence of gut glucose (GLP-1 and GIP-1)
  • impaired in type 2 DM

GLP-1

  • suppress glucagon secretion (diabetics are hyperglucagonaemic)
  • improves post prandial hyperglycaemia
  • preserves islet cell integrity (in culture)
  • reduces islet apoptosis (in culture)
  • acts on the stomach to delay gastric emptying (greatly augmenting glucose lowering effect)
  • may suppress appetite
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106
Q

What are the features of the GLP-1 receptor agonists?

A

Exenatide and liraglutide

  • must be given subcut
  • short half life, glucose lowering lasts about 6 hours
  • same effects as GLP-1 on glucagon suppression and gastric emptying
  • assoc with weight loss
  • lowers HBa1C by 0.4-06.% (Exe), 0.5-1.5% (lira)
  • main SE is nausea - dose dependent, decreases with time
  • hypoglycaemia with concomitant sulfonylurea
  • rare acute pancreatititis or renal impairment if risk factors present.
  • delayed gastric emptying may impair absorption of other meds so take them 1 hour before exenatide.
  • contraindicated if GFR <30
  • contraindicated in medullary thyroid cancer or MEN-2 as stimulates c-cell tumors in rats.
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107
Q

What are the features of the DPP-4 inhibitors?

A
  • ‘gliptins’
  • inhibits the DPP-4 enzyme which breaks down GLP-1 and GIP, prolonging their action
  • effective alone and in combo with metformin and pio
  • Hba1c improves 0.5-1.4%
  • dose reduction required for renal failure
  • no weight loss/gain
  • main SE: nasopharyngitis or URTI
  • sitagliptin: serious allergy inc anaphylaxis, angioodema, SJS, pancreatitis
  • may be due to prolonging actions of neuropeptide Y and substance p
  • Saxa: CYP3A4
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108
Q

What are the features of the renal glucose absorption inhibitors?

A
  • the ‘glifozins
  • type 2 DM
  • block subtype 2 of sodium-glucose transport proteins (SGLT2) which are responsible for at least 90% of glucose reabsorption in the kidney
  • lowers Hba1c by 0.9% when added to metformin
  • SEs: heavy glycosuria –> rapid weight loss and tiredness, dehydration due to osmotic diuresis, worsening of UTIs and thush, hypotension
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109
Q

What is the mechanism of action of insulin glargine (Lantus)? Other features?

A

Forms microprecipitates in neutral pH environment of subcut tissue that slowly releases insulin into the circulation

  • lasts 24 hours without any pronounced peaks so can be given once a day as basal coverage
  • cannot be mixed with other insulins as acidic
  • fasting hyperglycemia superior to bedtime NPH (protaphane) insulin, may also be less nocturnal hypoglycaemia.
  • greater affinity for IGF-1 receptor
  • may increase cancer risk.
  • not recommended in pregnancy
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110
Q

Which should be given first? Rapid/short acting insulin or intermediate?

A

Give short acting first then and then intermediate immediately.

Combine formulation if vision/dexterity impaired.

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111
Q

How are the rapid-acting analog insulins turned into intermediate acting? What is the benefit for doing so?

A
  • a protamine complex is added
  • can give BD combined with rapid acting

Benefits

  • can be given within 15 minutes of starting a meal
  • superior in controlling postprandial glucose rise after a carb-rich meal
  • not superior to human protaphane/actrapid combo in controlling HBa1C
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112
Q

Can the longer acting insulin analogs be mixed with shorter insulins?

A

No.

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113
Q

What are the general principles of injecting insulin?

A
  • variability of absorption rates from different sites may contribute to glycaemic instability in Type 1 diabetics, esp in exercise or if injection sites are rotated too frequently around different areas of the body.
  • Limit sites to single region and rotate within that region
  • Abdomen recommended as regular insulin absorbs more rapidly from there from other subcut sites
  • effect of anatomic regions less pronounced with analog insulins.
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114
Q

When is insulin pump therapy recommended?

Complications?

A

Motivated

Mechanically inclined

Well educated about dieabetes

Willing to check BSL 4-6x / day

Ketoacidosis (when insulin delivery interrupted)

Skin infections

Expensive

Time consuming staff-wise to initiate therapy.

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115
Q

When should pancreatic transplant be considered in diabetes?

A
  • in absence of renal transplant, consider if they have failed all other insulin therapeutic approaches and who have frequent severe hypoglycaemia or life threatening complications related to their lack of metabolic control.
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116
Q

What are the lab investigations in diabetes and why do you perform them?

A

Can differentiate type 1 from type 2 based on clinical features and on whether or not there are ketones with the glycosuria.

In occasional circumstances measure:

ICA, GAD65, IAA and ICA512 antibodies to distinguish between.

C-peptide does not reliable distinguish between type 1 and 2 as those with newly diagnosed type 1 diabetes still have significant endogenous insulin production so c-peptide will still be present.

Lab dx should document fasting BSL >7mmol/L or postprandial above 11.1

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117
Q

What effect does strenuous exercise have on insulin-dependent diabetes?

A
  • can precipitate hypoglycaemia
  • need to reduce insulin dose prior to exercise or take supplemental carb
  • inject insulin farther away from muscles will help as will be less rapidly mobilised
  • exercise training increases effectiveness of insulin.
  • infection can cause insulin resistance.
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118
Q

What are the features of therapy for type 1 diabetes?

A
  • 4x BSL measurements daily (at least)
  • 3-4 insulin injections necessary
  • rapidly acting analogs safer and more convenient for preprandial use, better postprandial control, reduced hypoglycaemic episodes
  • need to be combinde with longer acting for basal coverage and avoid hyperglycaemia prior to next meal.
  • fat ingestion has an impact on rapidly acting drugs
  • with low carb high fate meals, there is increased risk of hypo’s from insulin lispro within 2 hours after the meal.
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119
Q

What is the Somogyi effect in type 1 diabetes?

A

Nocturnal hypoglycaemia leads to a surge of counterregulatory hormones to produce high morning BSLs

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120
Q

What is the dawn phenomenon of type 1 DM?

A

decreased tissue sensitivity to insulin between 0300 to 0800 requiring more overnight insulin

  • present in as many as 75% of type 1 patients and may aggravate Somogyi and waning insulin effects
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121
Q

How do you treat the waning insulin and the Somogyi effects of type 1 DM?

A

Waning insulin over nighttime: increase evening dose or shift it from dinnertime to bedtime

Somogyi: eliminate intermediate insulin dose at dinnertime and give it at a lower dosage at bedtime, or supply more food at bedtime.

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122
Q

What is the role of weight reduction in Type 2 DM?

A
  • can achieve normalisation of hyperglycaemia
  • improves tissue senstivity to insulin
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123
Q

What are the features of Orlistat?

A
  • reversible inhibitor of gastric and pancreatic lipase, preventing hydrolysis and absorption of dietary TGLs
  • in obese type 2 diabetics: more weight loss, lower HBa1C and improves lipid profiles

SEs: GI: oily stools, flatus, fecal urgency and frquency, malabsorption of fat-soluble vitamins - need to be on MV taken 2 hours either side of orlistat.

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124
Q

What is the role of gastric banding in type 2 DM?

A
  • can resolve manifestations of diabetes and keep patients diabetes free
  • most marked with procedure that causes the greatest weight loss (biliopancreatic diversion/duodenal switch)
  • 20-25% of weight regained over 10 years
  • clinically significant deficiencies in Ca++, folic acid, iron, Vit D, B12, A and K
  • need lifelong supplementation and monitroing
  • early and late dumping
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125
Q

What is the important lifestyle measure for non-obese patients with type 2 DM?

A
  • increased visceral adipostiy ‘metabolically obsee
  • EXERCISE more important than weight loss.
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126
Q

What is the general drug mx of Type 2 DM?

A

Metformin at diagnosis - don’t wait for patient to try lifestyle measures

  • lowers serum TGLs and promotes some weight loss
  • less CV events
  • GI SEs and can’t use in kidney disease

THEN

add sulfonylureas –> hypoglycaemia and weight gain

127
Q

When should pioglitazone be considered?

A

Severe insulin resistance

Pio improves peripheral resistance

Lowers glucose w/o hypoglycaemia

BUT weight gain, fluid retention, fractures in women, possible bladder ca

Contraindicated in active liver disease and in LFTs >2.5x normal

128
Q

When should a sulfonylurea be considered in type 2 DM?

A

Not well controlled with initial tx (metformin) and have hyperglycaemia after carb-heavy meals. Secretagogue will get the BSL back into target range.

129
Q

When should a GLP-1 receptor agonist or DPP-IV inhibitor considered?

A

In patients who are concerned about weight gain - usually third line

GLP-1 - subcut only, lower risk of hypglycaemia and promote weight loss, but nausea, pancreatitis and contraindicated in patients w/ gastroparesis

DPP-IV inihbitors - low risk of hypo, no N&V, contra in kidney impairment, possible severe allergy/SJS risk, pancreatitis.

130
Q

When should insulin be considered in type 2 dm?

A

When combo of oral agents and injectable GLP1 receptor agonsits fail to achieve euglycaemia or if the HBa1c is too elevated for lowering effects of OHA.

Commence bedtime long active to reduce nocturnal hepatic glucose output and contine OHAs initially, then initiate daytime insulin if that doesn work

Can continue Metformin as it reduces hepatic glucose output

Pio - more weight gain with insulin and oedema

Continue weight loss even after starting insulin as makes dosing simpler later.

131
Q

What are the acceptable levels of glycaemic control in diabetics?

A

Pre meals: 5-7.2

Post meals: no higher than 10 at 1 hour, and 8.3 at 2 hours.

Hba1c <7% in nonpregnant adults

Less stringent in children, hx of severe hypos, limited life expectancy, advanced micro and macro complications, elderly (Hba1C 8% is ok)

Value of BP control great or greater than glycemic control with regards to micro and macrovascular complications.

132
Q

At what BSL levels do the symptoms of hypoglycaemia appear?

A

3-4 mmol: Glucagon mediated (earliest) –> hunger, borgborygmi, headache

3mmol: sympathetic (tachy, palpitations, sweating, tremor) and parasympahetic (nausea and hunger)
2. 8 mmol: neuroglycopaenic: irritability, confusion, blurred vision, tiredness, headache

<2.8 - LOC, seizure

133
Q

What are the features of hypoglycaemic unawareness?

A
  • happens with repeated episodes of hypoglycaemia - due to adaptation
  • autonomic symptoms don’t occur until BSL much lower - first symptoms are often due to neuroglycopaenia
  • can be reversed by keeping glucose levels high for several weeks
  • Avoid b-blockers as will blunt sympathetic symptoms except sweating.
  • Use B1 selective blockers if you have to
134
Q

What are the behaviouraly causes of hypoglycaemia in insulin-treated patients with diabetes?

A
  1. Behavioural
    - too much insulin for carbs ingested.
    - ETOH excess on empty stomach
    - exercise - during or several hours later
    - insulin ‘stacking’ (people who give second dose before first has had it’s full action
    - aggressive BSL control
135
Q

What are the counterregulatory causes of hypoglycaemia in insulin-dependent diabetes?

A
  1. Counterregulatory
    - impaired glucagon response
    - impaired sympatho-adrenal response due to aging, autonomic neuropathy and hypoglycaemic unawareness
    - cortisol deficiency
    - in diabetes >5 years duration - lose of glucagon response in relation to hypoglycaemia
    - Addison’s disease (sometimes develops) –> insulin requirement drops –> hypoglycaemia
136
Q

What are the complications that cause hypoglycaemia in insulin-dependent diabetes?

A
  • autonomic neuropathy
  • gastroparesis - if insulin is given before a meal, insulin may work before food is absorbed causing hypoglycaemia
  • end-stage CKD - decreased insulin clearnce by kidneys (so more running around), loss of renal contribution to gluconeogenosis post-absorption.
137
Q

How does glucagon work in an acute hypoglycaemic state? How much is given?

A
  • mobilises glycogen from the liver, raising the BSL by about 2mmol/L in about 15 minutes.
  • need to give extra PO carbs
  • 1mg IM or SC is given.
138
Q

What is the mechanism of insulin allergy?

A

Rare - tissue mast cells sensitised by adhernece of anti-insulin IgE antibodies.

  • Very very rare if only human insulin has ever been used.
139
Q

What is immune insulin resistance?

A
  • lower titre of circulating IgG that neutralises the action of insulin to a small extent develops in most insulin-treated patients.
  • was far stronger in old animal insulins (now using highly purified human or pork insulins)
  • severe response not reported with the analogs.
140
Q

What is lipodystrophy in the context of diabetes?

What is lipohypertrophy?

A
  • atrophy of subcut fat leading to disfigurement at site of injection
  • immune reaction now rare with pure and human insulin

Lipohypertrophy - consequence of pharamcologic effect of insulin being ijected in same spot repeatedly - rotation will prevent.

141
Q

What are the major causes of death in Type 1 and Type 2 diabetics respectively?

A

Type 1 - complications of end stage CKD which is far more common than in type 2

Type 2 - macrovascular disease - MI and stroke are the main causes.

142
Q

What are the ocular complications of diabetes?

A
  • premature cataracts - correlates with duration and severity of chronic hyperglycaemia. Assoc w/ nonenzymatic glycosylation of lens protein.
  • diabetic retinopathy (separate slide)
  • glaucoma - 6% of diabetics, responds to usual therapy for open-angle disease.
143
Q

What is the prevalence of diabetic retinopathy in type 1 and type 2 patients?

A

Type 1 - prevalnce 75-95% after 15 years

Type 2 - prevalence 60% after 16 years

144
Q

What is non proliferative diabetic retinopathy?

A

Nonproliferative ‘background’ retinopathy

  • ealiest stage
  • microaneurysms, dot haemorrhages, exudes and retinal oedema
  • retinal capillaries leak proteins, lipids, or red cells into the retina
  • when it occurs in the macular causing clinically significant macular oedema, visual acuity is impaired
  • most common cause of visual impairment in type 2 DM.
145
Q

What is the most common cause of visual impairment in type 2 diabetes?

A

Nonproliferative retinopathy

146
Q

What is proliferative retinopathy?

A
  • growth of new capillaries and fibrous tissue within the retina and vitreous chamber
  • consequence of small vessel occlusion and hypoxia –> new growth on disc or elsewhere on retina
  • more common in type 1 but occurs in type 2
  • preproliferative phase of arteriolar ischaemia ‘cotton wool spots (small infarcts on retina) - normal vision until vitreous haemorrhage or retinal detachment.
147
Q

How is proliferative retinopathy treated?

A
  • treated with APC or focal treatment to reduce severe visual loss or when associated with recent vitreous haemorrhage or where extensive new vessels are on or near the optic disc
  • anti VEGF (Avastin, bevacizumab) into the eye stops growth of new BVs
  • avoid tobacco and correct HTN.
  • no contraindication to aspirin
148
Q

What is the indication for referral to an opthalmologist in diabetes?

A
  • proliferative retinopathy leading cause of blindness and increases risk of retinal detachment
  • doesn’t appear in type 1s for first 3-5 years/before puberty
  • up to 20% of type 2s have retinopathy at dx.
  • in Type 1: annual consultation after 3-5 years
  • in Type 2: All type 2’s because they were probably diabetic prior to diagnosis
  • any macular oedema, severe nonproliferative retinopathy or proliferative require referral.

Macular oedema occurs in both kinds of retinopathy

149
Q

What is the initial manifestation of diabetic nephropathy?

A

Hyperfiltration then proteinuria

150
Q

What is the best way to confirm or test for microalbuminuria? Why?

A

Early morning spot A/C/R on waking (<30 is normal, 30-300 is abnormal)

Superior to 24 hour urine due to conveneince and wide variability in excretion due to being upright, dietary protein, and exercise.

Need at least 2 over 3-6 month period.

ESCKD can be predicted by persistent urinary albumin excretion rates exceeding 30mcg/m

Short term hyperglycemia, exercise, UTI, CHF, and acute febrile illness can cause transient albuminuria - avoid testing during this time.

151
Q

How is microalbuminuria controlled in diabetes?

A

Glycemic control with low protein diet may reduce both hyperfiltration and elevated microalbuminuria in early stage diabetes and diabetic nephropathy

ACEIs reduce intraglomerular pressure as well as lowering systemic hypertension and impede progression to proteinuria, prevents increase in albumin excretion rate.

152
Q

Why might a ‘normotensive’ diabetic patient have microalbuminuria?

A

Microalbuminuria is ocorrelated with elevated nocturnal systolic BP - they have BP elevations during sleep.

Possible reason why ACEI’s reduce microalbuminuria.

153
Q

What is the natural history of diabetic nephropathy?

A

microalbuminuria –> proteinuria –> nephrotic syndrome with hypoalbuminaemia –> oedema, increase in LDL cholesterol, progressive azotemia –> glycosuria and ESCKD

In contrast to all other kidney disorders - proteinuria persists with ESCKD

154
Q

What is the role of dialysis in ESCKD of diabetes?

A

Improved cumulative survival.

155
Q

What are the features of diabetic peripheral neuropathy?

A
  • distal symmetric polyneuropathy most common
  • axonal process - motor and sensory nerve conduction delay with loss of ankle jerks
  • loss of vibration, pain and temp
  • denervation –> clawing of toes and displacement of submetatarsal fat pads anteriorly –> increased plantar pressures –> foot ulcers
156
Q

What are the features of Charcot arthropathy?

A
  • peripheral neuropathy, autonomic neuropathy and trauma predisposes
  • acutely: pain and swelling
  • untreated: rocker bottom deformity and ulceration
  • xr: joint subluxation and periarticular fracture - deranged and unstable midfoot joint
157
Q

What is the management of diabetic foot ulcers?

A
  • mechanical unloading
  • debride and antibiotics - takes 8-10 weeks to heal
158
Q

What are the features of isolated peripheral neuropathy of diabetes?

A
  • One nerve (mononeuropathy) or several (multiplex) - sudden onset with subsequent recovery
  • cranial and femoral nerves, mainly motor
  • cranial: d iplopia with single third, fourth or sixth nerve weakness with pupillary sparing
  • femoral: diabetic amyotrophy - severe pain in front of thigh with quad wasting.
  • improve diabetic control, symptpms improve over 6-18 months
159
Q

What are the features of painful diabetic neuropathy?

A
  • hypersensitivity to light tough and burning pain at might
  • amitryptiline at night time helps with good relief in 48-72 hours (as opposed to anti-depressant effect in two weeks)
  • may get drwosy, change if no improvement after 5 days
  • switch to nortriptyline if too much anticholinergic effect

Can also use duloxetine, gabapentin, pregabalin or topical capsaicin. Slowly increase all inc amitryptiline.

160
Q

What is diabetic neuropathic cachexia?

A
  • syndrome of symmetric peripheral neuropathy associated with profound weight loss (up to 60% ot TBW) and painful dysesthesias of prox lower limbs, hands or lower trunk
  • treat with insulin and analgesia
  • good prognosis wrt weight and resolution of pain within 1 year
161
Q

What are the features of diabetic autonomic neuropathy?

A
  • affects diabetics of long duration
  • gastroparesis esp when unexpected fluctuations of BSL after meals - metoclopramide helps due to central antiemetic effects and cholinergic action on gastric emptying
  • erythromycin binds motilin receptors in the stomach and improves emptying but loses effectiveness over time
  • botox into pylorus can relax it
  • diarrhoea - often undergoes spontaenous remission, can give loperamide, codeine etc
  • orthostatic hypotension; treat with fludrocort (watch for supine hypertension and hypokalemia) or midodrine (alpha agonist)
  • erectile dysfunction
  • incomplete bladder emptying
162
Q

What are the features of erectile dysfunction in diabetic autonomic neuropathy?

A
  • combination of neurologic (autonomic), psych or vascular causes
  • erection requires relaxation of arterial SM of corpus cavernosum, mediated by NO induced cGMP formation
  • cGMP-specific phosphodiesterase type 5 (PDE5) inhibitors improve erection (Sildenafil, tadalafil, vardenafil) in diabetics.
  • PDE5 inhibitors potentiate hypotensive effects of nitrates so contraindicated if patient is on nitrate
  • caution if prev MI, stroke, arrhythmia within last 6 months, resting hypo/hypertension, hx cardiac failure or unstable MI
  • rarely: vision loss
163
Q

What are the features of diabetic heart disease?

A
  • heart disease due to atherosclerosis
  • MI leading cause of death and 3-5x more likely
  • microangiopathy may explain CCF in diabetics w/o CAD
  • premenopausal women who generally have lower risk, lose this protection when diabetes develop.
164
Q

What are the guidelines for cholesterol and BP management in diabetes?

A
  • lowering LDL cholesterol reduces first events in patients without known CAD and secondary evens with.
  • LDL should be less than 2.6, lowering to 1.8 may have additional benefit and reasonable target for most patients with type 2 DM and multiple risk factors for CAD.
  • Aim BP 130/80 or less - Ramipril reduced risk of MI, stroke or death from CARD by 25% - consider if established CV disease or microalbuminuria.
165
Q

What is the role of aspirin in type 2 DM?

A
  • give to diabetics with >10% 10 year risk of CV events
  • usually diabetic man over 50, women over 60 plus one additional risk factor (smoking, hypertension, dyslipidemia, FHx of prem CV disease or albuminuria)
  • aspirin inhibits platelet thromboxane synthesis and is effective in reducing CV mobidity and mortality in hx of MI or stroke (secondary prevention)
  • avoid if allergy, bleeding, active hepatic disease
  • does not influence course of proliferative retinopathy so safe to use if vitreous haemorrage etc.
166
Q

What are the features of peripheral vascular disease in diabetes?

A
  • athersclerosis accelerated at large arteries esp in areas of turbulent blood flow, ie bifurcation of the aorta.
  • foot gangrene 30x that of controls
  • small vessel disease with neurogenic inflammation and secondary infection common
  • avoid smoking and propanolol as they reduce peripheral blood flow
  • cholesterol lowering drugs useful as adjuncts in early ischemia with dyslipidemia.
  • endarterectomy and bypass possible in some.
167
Q

What are the skin and mucous membrane complications of diabetes?

A
  • chronic pyogenic infections in poorly controlled
  • intertriginous candidal infections esp with glycosuria - will go away if reduced
  • severe hypertriglyceridaemia in poorly controlled –> eruptive cutaneous xanthomas on extensor surfaces and pancreatitis, disappears with control
  • necrobiosis lipoidica diabeticorum - ant surface of legs or dorsal ankles; oval shaped well demarcated borders and yellow surface, granulomatous inflam of tissue and BVs, more in women. Assoc with type 1 diabetes - treat with topical and subcut steroids.
  • shin spots - brown round painless and atrophic.
168
Q

What are the bone and joint complications of diabetes mellitus?

A
  • progressive stiffness of the hand secondary to contracture and tightening of skin over the joints (diabetic cheiroarthopathy), frozen shoulder (adhesive capsulitis), carpal tunnel syndrome and Dupuytrens contractures
  • due to glycosylation of collagen
  • increased risk for nonvertebral fractures in type 2
  • women with type 1 have increased risk of fracture.
  • DISH - diffuse idiopathic skeletal hyperostosis (ossification of ant longitudinal spinal ligaments)
  • Gout due to hyperuricaemia
  • recurrent bursitis
169
Q

What is the perioperative management of diabetes?

A
  • surgery = stress = insulin antagonisms (catecholamines, GH, steroids)
  • w/h oral agents on day of and give small doses of short acting insulin
  • post-op creatinine before recommencing metformin
  • minor surgery = 2 hours and able to eat, major > 2 hours, invasion of a body cavity and fasting afterwards
  • Type 1s must receive some insulin - an infusion resulting in 1-1.8 units of insulin per hour will keep in range.
  • Type 2s on insulin can last for a few hours w/o post-op
  • Aim for surgery in early morning.
  • Restart insulin and stop infusion 30 minutes after first subcutaenous dose
170
Q

What is the target BSL of ICU patients?

A

7.8-10

Reduces morbidity - AKI and increases early weaning from ventilator but not mortality.

171
Q

What are the risks of poor glycaemic control in pregnancy to the foetus?

A

Spontaneous abortion

Congenital malformation

Polyhydramnios

Preterm labor

Stillbirth

Fetal macrosomia

172
Q

What are the risks of poor glycaemic control to the mother?

How is it managed?

A
  • diabetic retinopathy or worsening if it’s present
  • worsening albuminuria –> risk of pre-eclampsia
  • pre-existing renal failure (GFR <80) means high risk for further irrerversible renal failure
  • exacerbation of N&V if pre-existing gastroparesis
  • control with insulin, not OHAs and maintain near normal BSLs while avoiding hypos.
  • NPH is preferred intermediate for basal coverage
  • carry to term unless increasing fetal weight.
173
Q

What is the prognosis of type 2 DM?

A
  • with glycaemic control –> reduction in microvascular disease (except in obese
  • with BP control –> improved cardiovascular outcomes and microvascular disease amongst hypertensive patients
  • if viscerally obese - major challenge to control bsl, dyslipidemia, and hypertension
174
Q

When should a T2DM patient be referred to an endocrinologist?

A
  • if treatment goals not met or if increasingly complex regimen required to maintain glycaemic control
175
Q

When should a diabetes patient be referred to an opthalmologist?

A

Type 1 - 5 years post dx

Type 2 - immediately

176
Q

When should a diabetic be referred to a podiatrist?

A
  • presence of peripheral neuropathy with loss of protective threshold (unable to detect filament) or structural foot problems
177
Q

What does PTH do?

A
  • increases bone osteoclasts
  • increases renal Ca++ reabsorption
  • stimulates synthesis of 1,25 Vit D
  • inhibits absorption of phosphate and bicarb by renal tubule

Net effect is increase in serum calcium

178
Q

What are the general features of hypoPTHism and pseudohypoPTH?

A
  • low serum Ca++
  • high serum phosphate
  • normal ALP
  • reduced urine Ca++
  • low or low-normal PTH in setting of hypocalcium
  • +/- low serum Mg++
  • positive Chvostek/Trousseau signs
  • tetany carpopedal spasms, tingling of lips and hands, muscle/abdo cramps, psych changes
179
Q

What is acquired hypoparathyroidism?

A
  • usually post thyroidectomy/multiple parathyroidectomies
  • may also occur after a PTHadenoma due to suppression of remaining normal parathyroids and accelerated remineralization of the skeleton ‘hungry bone syndrome’
180
Q

What is autoimmune hypoparathyroidism?

A
  • isolated or in polyglandular autoimmunity, SLE or by antiparathyroid antibodies.
  • Wilson or iron disease, granuloma, tumor, infection
181
Q

What is the typical presentation of polyglandular autoimmunity (PGA) type 1?

A

Also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

  • presents in childhood
  • at least two of: candidiasis, hypoPTH or Addison disease
  • may also get cataracts, uvieitis, alopecia, vitiligo
  • fat malabsorption in 20% resulting in low Vit-D
182
Q

What is the likely mechanism of fat malabsorption in polyglandular autoimmunty?

A
  • deficiency in jejunal enteroendocrine cells that produce cholecystokinin –> reduction in bile acid secretion.
183
Q

What are the causes of functional hypoparathyroidism?

A
  • Mg deficiency (malabsorption, chronic alcoholism) which prevents secretion of PTHl
  • Mg excess can also cause (renal disease, Mg supplements, laxatives or antacids)
184
Q

What is the feedback loop on the parathyroid gland?

A

CaSr - calcium sensing receptors sense serum calcium concentration and suppress PTH secretion via G-protein coupled mechanisms.

185
Q

What is congenital hypoparathyroidism?

A
  • gain-of-function mutation (constitutive activation) of the CaSr gene –> constant PTH gland suppression –> hypocalcaemia w/o concomitant PTH rise.

Outcome: Autosomal dominant hypocalcaemia with hypercalciura from deficient secretion of PTH

186
Q

Which drug can precipitate acute hypoparathyroidism and hypocalcaemia in someone with indolent hypoparathyroidism?

A

A PPI

187
Q

What are the symptoms of chronic hypoparathyroidism?

A
  • lethargy
  • personality change
  • anxiety
  • blurred vision due to premature cataracts
  • Parkinsonism
  • Mental retardation
  • thin and brittle nails
  • dry and scaly skin
  • loss of eyebrows
  • hyperactive deep tendon reflexes
188
Q

What are the lab findings in hypoparathyroidism?

A

Low serum Ca (corrected)

High serum phosphate

Low urinary calcium

Norlmal ALP

Low PTH

Hypomagnesiumema may exacerbate sx and decrease PTH function

189
Q

What are the imaging findings in hypoparathyroidism?

A
  • basal ganglia calcification
  • denser bones than normal
  • cutaenous calcification
190
Q

What does slit lamp examination show in hypoparathyroidism?

A
  • early posterior lenticular cataract formation
191
Q

What does the ECG show in hypoparathyroidism?

A

prolonged QT and T wave abnormalities

192
Q

What are the complications of hypoparathyroidism?

A
  • Acute tetany with stridor if assoc w/ vocal cord palsy –> airway obstruction –> trache
  • associated autoimmunity –> sprue syndrome, pernicious anaemia, Addison disease
  • ossification of paravertebral ligaments and nerve root compression
  • seizures
  • overtx with vit-D and calcium may produce nephrocalcinosis and impairment of kidney function
  • heart failure of chronic hypocalcemia
193
Q

What is the DDx of hypoparathyroidism?

A
  • Resp alkalosis can cause muscle cramps and tetany, hyperventilation can accentuate already-present hypocalcaemic symptoms
  • Rapid volume expansion from citrate blood
  • acute pancreatitis
  • osteoblastic metastatic Ca (esp breast) - but usually hyperCa++
  • azotemia
194
Q

Which drugs can cause a blood picture that mimics hypoparathyroidism?

A
  • Drugs that cause hypocalcaemia - loop diuretics, phenytoin, alendronate, foscarnet, phosphate, CTx
195
Q

What is the genetic cause of hypocalcemia with hypercalciuria? How do you differentiate it from hypoparathyroidism?

A

familial syndrome involving mutation of CaSr (activating mutation)

Normal PTH levels distinguish it from hypoparathyroidism.

Treatment with calcium and vitamin D may cause nephrocalcinosis

196
Q

What is congenital pseudohypoparathyroidism?

A
  • group of disorders characterised by tissue insensitivty to PTH
  • renal tubular resistance causes hypercalciuria with hypocalcaemia. PTH levels are high and PTH receptors in bone are not involved resulting in bony changes
197
Q

What is pseudohypoparathyroidism type 1a?

What is pseudopseudohypoparathyroidism?

A
  1. Hypocalcaemia and hyperphosphataemia plus Albright hereditary osteodystrophy; mental retardation, short stature, obesity, round face, short fourth metacarpals, ectopic bone formation, hypothyroidism and hypogonadism.
  2. Patients without hypocalcaemia but have the same phenotype as above.
198
Q

What is the treatment for an acute attack of hypoparathyroid tetany?

A
  • usually occurs post-op and is an emergency
    1. IV Ca gluconate 10ml of 10& - slowly
    2. Oral Ca++ as soona s possible
    3. Vitamin-D therapy as soon as PO calcium starts
    4. Mg++ if hypoMg
    5. Transplant of cryopreserved PTH tissue removed during prior surgery - restores PTH function in about 23% of cases.
199
Q

What is the maintenance therapy of hypoparathyroidism?

A
  • maintain serum Ca in slightly low but asymptomatic range
  • will minimise the hypercalciura and provides margin of safety against overdosage and hypercalcaemia.
  • no tx if mild asymptomatic hypocalcaemia
  • regular Vitamin D with mandatory 3 monthly Ca++ monitoring
200
Q

What are the features of ergocalciferol?

A

Plant based high dose Vitamin D

Slow acting and stored in fat –> long duration of action

Toxicity is hypercalcaemia and treated with hydration and prednisone - may persist for weeks after it is discontinued

201
Q

What is the role of teriparatide in hypoparathyroidism?

A
  • recombinant human PTH
  • for severe hypoparathyroidism that fails to respond to vitamin D
  • extremely expensive, injected.
202
Q

Which drugs should be administered with caution in hypocalcaemic patients?

A

Phenothiazines - they may precipitate EPS

Frusemide - will worsen hypocalcaemia

203
Q

What is the prognosis of hypoparathyroidism?

A
  • good if prompt treatment
  • cataracts, dental changes, brain calcifications are permanent
  • hypercalcaemia that suddently develops in stable hypoparathyroidism may be a sign of Addison disease
  • high risk of mood and psych disorders
204
Q

What are the general features of hyperparathyroidism?

A
  • frequently incidental
  • renal calculi (stones), polyuria, hypertension, fatigue, mental changes, constipation
  • bone pain; rarely cystic lesions and path fractures
  • high urine and serum calcium
  • high urine phosphate with low-normal serum phosphate
  • normal to elevated ALP
  • elevated PTH
205
Q

What is the most common cause of hypercalcaemia?

Who does it it affect?

What causes it?

A

Primary hyperparathyroidism

Women in their 70s

Hypersecretion of PTH usually due to a single parathyroid adenoma

206
Q

What are the less common causes of primary hyperparathyroidism?

A
  1. Before age 30, multiglandular disease
  2. Parathyroid carcinoma (size correlates with serum PTH)
  3. Familial - MEN-1 (initial manifestation, eventually affects 90%) and MEN 2a and 2b less frequently
207
Q

What is the biochemical effect of hyperparathyroidism?

A
  • excessive renal Ca and phosphate excretion resulting in hypercalciura due to overhwhelmed tubular reabsorptive capacity
  • renal tubular reabsorption of calcium and hypercalcaemia
208
Q

What is the effect of hyperparathyroidism on bone?

A
  • cortical demineralisation particular at the wrist (and hip)
  • -* severe; diffuse demineralisation, path fractures and cystic bone lesions –> osteitis fibrosa cystica
209
Q

What is secondary hyperparathyroidism?

What is the name of the bone disease associated with this?

A

CKD –> hyperphosphataemia and decreased renal production of 1,25 OH-D –> decrease in ionized calcium –> stimulation of parathyroids.

Renal osteodystrophy

210
Q

What is tertiary hyperparathyroidism?

A

Autonomous PTH secretion following prolonged secondary hyperparathyroidism

211
Q

What are the important features of ionized calcium?

A
  • binds to negatively charged proteins i.e. albumin, competing with hydrogen ions for same sites
  • pH dependent and alters blood level
  • alkalosis promotes increased protein binding
  • acidosis decreases protein binding resulting in increased free calcium levels

Less than 0.5mmol/L can be life threatening

Multiple blood transfusions may req Ca+ admin

>7 may cause coma

212
Q

What effect does uremia have on the parathyroids?

A

May cause extremely high serum PTH –> vascular calcification

Hypercalcemia often then occurs after a kidney transplant

213
Q

What are the clinical findings of hyper parathyroidism?

A
  • incidental
    1. Bones. Loss of cortical bone and gain of trabecular. Wrist involvement and asymptomatic vertebral fractures. Osteitis fibrosa cystica –> path fractures or ‘brown tumors’ / jaw cysts. Bone pain and arthralgia.
    2. Stones. Renal stones.
    3. Abdominal groans - constipation
    4. Psychic moans with fatigue overtones. (Hypercalcaemia)
214
Q

What are the neurological manifestations of hypercalcaemia?

A

Neuromuscular: parasthesias, muscle weakness, diminished deep tendon reflexes = neuromuscular.

CNS: malaise, sleepiness, psychosis, stupor

215
Q

What are the cardiovascular manifestations of hypercalcaemia?

A

Hypertension,

prolonged P-R

shortened Q-t,

sensitivity to antiarrhythmic effects of digitalis,

bradyarrhythmias,

heart block and asystole

216
Q

What are the clinical renal manifestations of hypercalcaemia?

A

polyuria and polydipsia caused by hypercalcemia induced nephrogenic diabetes insipidus.

Calcium containing kidney stones.

217
Q

What are the GIT features of hypercalcaemia?

A

anorexia, nausea, vomiting, abdo pain, weight loss and constipation

218
Q

What are the skin manifestations of hypercalcaemia?

A

Pruritus.

Precipitation of Ca in skin and small arteries causing small vessel thrombosis and skin necrosis (calciphylaxis)

219
Q

What is the opthalmological complication of hypercalcaemia?

A

Corneal precipitation of calcium (band keratopathy

220
Q

What are the complications of primary hyperparathyroidism in pregnancy?

A
  • kidney stones
  • hyperemesis
  • pancreatitis
  • muscle weakness
  • cog changes
  • hypercalcaemic crisis

Fetus

  • fetal demise
  • preterm delivery
  • low birth weight
  • postpartum neonatal tetany
  • permanent hypoparathyroidism
221
Q

What are the lab findings of primary hyperparathyroidism?

A
  • hypercalcaemia
  • ionised calcaem not that helpful unless hyperproteinaemic i.e. hyperalbuminaemia, Waldenstronm, myeloma, or thrombocytosis and usually >1.5mmol
  • high or normal urine calcium but low for degree of hypercalcaemia
  • low serum phosphate
  • excessive urinary phosphate in setting of hypophosphataemia (primary hyperPTH only)
222
Q

How do you differentiate primary from secondary hyperparathyroidism?

A

In secondary - high serum phosphate (low in primary)

  • elevated ALP if bone disease is present.
  • higher serum calcium in primary
  • really really high intact PTH level with somewhat normal calcium level in secondary
223
Q

How is the diagnosis of hyperparathyroidism confirmed?

A

Intact PTH

224
Q

What disease should a patient with low bone density, normal serum calcium, and an elevated PTH be screened for?

A

Secondary hyperparathyroidism

225
Q

Why should you screen for vitamin-D deficiency in hyperparathyroidism?

A
  • low 25 OHD <20 can aggravate hyper PTHism and bone manifestations, replacement is helpful for treatment.
226
Q

In hyperparathyroidism, what disease should be screened for?

How?

What drug should be stopped?

What does it mean if the urine calcium is low?

A

Familial benign hypocalciuric hypercalciuria.

24 hour urine test for calcium and creatinine

Stop Thiazides prior

Low urine calcium is not typical for primary hyperPTH and suggests FBHH

227
Q

What is the mechanism of familial hypercalcemic hypocalciuria?

What is the treatment?

A

loss of function mutations in the CASR gene, which encodes a calcium-sensing receptor, expressed in parathyroid and kidney tissue.

The perceived lack of calcium levels by the parathyroid leads to constitutively high levels of parathyroid hormone, and therefore hypercalcemia

No treatment, it’s generally mild

228
Q

Aside from renal failure, what are the other secondary causes of hyperparathyroidism?

A

Vitamin D or calcium deficiency

Hyperphosphataemia

229
Q

In patients with a low bone density, elevated serum PTH and normal serum calcium who don’t have secondary parathyroidism - what is the management?

A

This is normocalcaemic hyperparathyroidism - need monitoring as they may develop hypercalcaemia.

230
Q

What is the imaging for hyperparathyroidism?

A
  • preop nuclear (sestamibi-iodine) scan and neck u/s can locate parathyroid adenoma preoperatively
  • crucial if they’ve had prior neck surgery
  • does not improve outcome of initial bilateral neck exploration
  • improves outcome for limited necksploration with only modest success.
  • NOT useful for dx of hyperparahytoidism which is made on serum Ca++ and PTH.
  • 50% will have benign incidentalomas of thyroid on imaging.
231
Q

Which is the preferred imaging modality for preoperative localisation of parathyroid adeoma?

A

MRI superior to CT as better soft tissue contrast and less adversely affected by postop changes in the neck.

232
Q

What additional imaging should be considered in patients with hyperparathyroidism?

A
  • CTKUB for Ca++ stones - can help decide if parathyroidectomy required in asymptomatic patients
  • DXA scanning can help determine bone loss - need to do 3 areas - lumbar spine, hip, and distal radius.
  • XR not req for dx but demineralisation, subperiosteral resorption of bone (esp dist radius/fingers), loss of teeth lamina, cystic skeletal changes, mottling of the skull ‘salt and pepper’ appearance, or path fractures. Articular cartilage calfication (chondrocalcinosus)
233
Q

What are the complications of hyperparathyroidism?

A
  • rapid rise of Ca++ –> delirium, precipitation of Ca through soft tissues, AKI
  • intractactable peptic ulcer and pancreatitis
  • assoc insulinoma or gastrinoma (MEN-1)
  • pseudogout before and after tumor reomval
  • neonatal hypocalcaemia if hypercalcemic during pregnancy
  • tertiary hyperparathyroidism due to CKD –> high serum Ca and phosphate –> calciphylaxis (levels only semi-correlate)
234
Q

What is calciphylaxis?

A
  • disseminated calcification in the skin, soft tissues and arteries resulting in painful ischemic necrosis of the skin and gangrene, cardiac arrhythmias and respiratory failure.
  • seen in tertiary hyperparathyroidism due to CKD.
235
Q

What is the DDx of hypercalcaemia and hyperparathyroidism?

A
  1. Artifact - lab error or tourniquet time, high serum protiein, dehydration, hypertriglyceridemia –> all cause hyper ca++
  2. Malignancy - breast esp due to bony mets, or tumors that secrete PTHrP (differentiated by low PTH)
  3. Multiple Myeloma causes renal dysfunction resulting in increased levels of carboxyl temrinal hyperPTH
  4. Granulomatous disease esp sarcoidosis –> macrophages synthesize 1,25OHD so chech level. Sarcoid can also secrete PTHrP.
  5. Ca++ or Vit-D ingestion will cause hypercalcaemia. Esp w/ concomitant thiazide use.
  6. Familial benign hypocalciuric hypercalcaemia.
  7. Vit-D deficiency (secondary hyperPTHism)
  8. Adrenal insufficiency - untreated Addisons’s disease –> increased Ca+ uptake by calcium and gut –> hypercalcemia.
  9. Immobilisation hypercalcaemia - esp in adolescents, critically ill due to AKI and extensive Pagets. Normal/mild elevation of PTH.
236
Q

What is the treatment of asymptomatic primary hyperparathyroidism?

A
  • no treatment
  • keep active
  • avoid immobilisation
  • drink adequate fluids
  • oestrogen replacement tx reduces serum Ca and improves BMD in postmenopausal women with hyperPTHism
  • avoid thiazides, large doses of vitamin A and ca++ containing antacids or supplements
  • twice yearly Ca+ and alb, renal function and urine calcium once yearly, and three site BMD every 2 years.
237
Q

What is the indication for surgical parathyroidectomy?

A
  • symptomatic hyperparathyroidism, kidney stones, bone disease and pregnancy (done in second trimester).

Additionally:

elevated serum calcium with hypercalciura

osteoporosis of cortical bone (wrist or hip) or previous fragility fracture

  • age under 50
  • difficulty following up patient
  • operating on ‘asymptomatic’ patients may benefit emotional function
238
Q

What is the surgical management of hyperparathyroidism in MEN1 patients? What is the complication?

A

subtotal parathyroidectomy

recurreny hyperparathyroidism or postop hypo

239
Q

What is an alternative to surgery in secondary or tertiary hyperparathyroidism associated with uremia?

What surgery is performed when it is done?

A

Cinacalcet

Subtotal - three and one half glands are usually removed and a metal clip left to mark the location of the remaining one

240
Q

What are the features of parathyroid carcinoma?

A

Severe hypercalcemia with very high serum PTH

Large invasive tumor

Therapy - en bloc resection and ipsilateral thyoid lobe. High risk of local and distal mets with reoperation usually necessary

Adjuvant Rtx requiwed

Cinalcalcet and IV bisphosphonates used as needed.

241
Q

What are the complications of parathyroidectomy?

A
  • hypocalcemic paresthesias or tetany due to serum PTH dropping below normal within hours of succesful surgery
  • hypocalcemia evening after or next day - need to frequently monitor Ca++ beginning the eveing after surgery
  • once hypercalcemia resolved –> PO calcium
  • magnesium salts sometimes needed postop since MG is needed for recovery of remaining suppressed PTH glands.
  • secondary hyperparathyroidism around 1 week postop due to ‘hungry bones’ and is treated with calcium and vitamin D
  • hyperthyroidism due to release of stored thyroid hormone from a pranged thyroid - may need propanolol
242
Q

What is hungry bone syndrome?

A

Hypocalcaemia, hypophosphataemia and hypomagnesiumaemia and resultant hyperparathyroidism occurring approximately 1 week post-op for parathyroidectomy.

Due to bones sucking in serum calcium following cessation of hyperparathyroidism and longstanding bone resorption.

Treated with high dose Ca++ and Vitamin D with adequate correction of Mg++

243
Q

What is the initial management of hypercalcaemia?

A

Aggressive rehydration

IV bisphophosonates (temporary measure until underlying cause fixed i.e. hyperparathyroidism)

244
Q

What is the role of vitamin-D in primary hyperparathyroidism?

A

Careful replacement beneficial if deficient - doesn’t usually aggravate hypercalcemia

245
Q

What is the role of vitamin-D in secondary and tertiary hyperparathyroidism associated with azotemia?

A

Calcitriol after dialysis suppresses hyperparathyroidism of kidney disease - often causes hypercalcemia so must monitor serum Ca++ and phosphate

  • if these rise, have to switch to cinacalcet (only if on dialysis), may cause transient N&V

Other

Phosphate binders and low phosphate diet prevents or delays renal osteodystrophy

HRT given to postmenopausal women reduces hypercalcemia slightly

Raloxifene reduces serum calcium by 0.4

Propranolol for adverse cardiac effects

246
Q

What are the three forms of Vitamin D?

A

Cholecalciferol - unhydroxylated inactive form of D3, synthesised in the skin by exposure to UV-B - this is activated in the liver to Calcidiol (Calcifidiol)

Calcidiol - 25OHD, one of the blood forms used to check status. This is hydroxylated by 1-alpha hydroxylase in the kidney to form calcitriol

Calcitriol - activated form of D3

247
Q

What is the prognosis hyperparathyroidism?

A

If symptomatic –> worsening disease unless untreated

If asymptomatic w/ mild hypercalcemia –> usually remains stable with careful monitoring, hydration and mobilisation

Surgical removal of isolated adenoma is highly successfuly

In MEN1, subtotal parathyroidectomy will generate long remission but frequently recurs.

Bones with severe cysts, deformity and fracture will heal if PTH tumour is removed.

Pancreatitis increases mortality rate but resolves with correction of hypercalcemia

248
Q

What are the ongoing risk associations with hyperparathyroidism?

A

Despite treatment:

  • all cause mortality
  • cardiovascular disease
  • kidney stones
  • renal failure

Likely due to residual pre-treatment hypertension and nephrolithiasis.

249
Q

What are the definitions of osteoporosis and osteomalacia?

A

Osteoporosis - bone matrix and mineral decreased

Osteomalacia - bone matrix intact, mineral decreased

250
Q

What are the general features of osteoporosis?

A
  • spine, hip, pelvis and wrist fractures from demineralisation
  • Normal serum PTH, Ca+, pshophate and ALP
  • often comorbid Vit-D
251
Q

What is bone osteoid? In what condition is this lost?

A
  • unmineralized, organic portion of the bone matrix that forms prior to the maturation of bone tissue.
  • Osteoblasts secreting the osteoid as several specific proteins.
  • Once mineralised, it and adjacent bone cells become new bone.

Osteoporosis

252
Q

What is the general state of bone formation and resorption in osteoporosis?

A

Rate of formation normal but rate of resorption is increased

253
Q

What are the most common causes of osteoporosis?

A

Age

High dose corticosteroids

Alcoholism

Sex hormone deficiency - particularly menopause

254
Q

What are the features of osteogenesis imperfecta?

A
  • major mutation in gene encoding type 1 collagen
  • spontaneous fractures in utero or chilhood
  • blue sclerae
  • collagen disarray, hypogonadal or idiopathic osteoporosis
255
Q

What are clinical features of osteoporosis?

A

Asymptomatic until fractures

Backache

Loss of height

256
Q

What are the lab findings in osteoporosis?

What additional tests should you consider?

A

Normal serum ca, phos, PTH

ALP normal but may be elevated post fracture

Vitamin-D deficiency

Additional

Thyrotoxicosis

Coeliac (serum IgA, endomysial Ab, TTGab)

257
Q

Who should get a dexa scan? What are it’s limitations?

A
  • all patients at risk for osteoporosis or osteomalacia
  • anyone with pathological fractures or radiographic evidence of diminised bone density
  • cannot distinguish osteoporosis from osteomalacia - both are often present
  • may be misleadingly high in compressed vertebrae and extensive arthritis
  • overestimates tall people and underestimates short people
258
Q

What is the criteria for diagnosis osteoporosis in postmenopausal white women?

What does it mean for fracture risk?

A

T score >1 = normal

T score <1 - -2.5 = osteopaenia

T score -2.5 = osteoporosis

T score -2.5 plus fracture = severe osteoporosis

Fracture risk increaes about 2x for each standard deviation drop in BMD

259
Q

How often should surveillance BMD be performed?

A

Postmenopausal women with specific t-scores

Every 5 years with osteopaenia (-1.0 to -1.5

Every 3-5 years with slightly worse osteopaenia (-1.5 to -2)

Every 1-2 years for osteoporosis (scores under -2)

260
Q

What is the BMD Z-score?

A
  • expresses bone denisty in premenopausal women, younger men, and children as standard deviation from age, race, and sex matched means.
261
Q

What sort of exercise can improve bone density?

A

High impact activity i.e. jogging

Stair climbing in women

262
Q

When is treatment for osteoporosis indicated?

A

T-score < -2.5

All patients with fragility fractures

Prophylaxis if advanced osteopaenia (T-score -2.0 - -2.5)

263
Q

What is the role of Vitamin D osteoporosis?

A

Supplementation reduces incidence of vertebral fracture more than nonverterbal.

Vitamin D prevents osteomalacia but not osteoporosis.

Esp required in winter and hospitalised, if level <20 and in intestinal malabsorption.

264
Q

What is the role of calcium supplementation in osteoporosis?

A
  • does not reduce fracture risk in otherwise healthy menopausal women and may increase risk of MI.
  • may increase risk of Ca+ contianing kidney stones unless taken with meals
  • should only be given if diet is low in calcium
265
Q

How do bisphosphonates work?

How should they be taken?

A
  • inhibit osteoclast induced bone resorption and bind hydroxyapatite.
  • increase bone density and reduce incidence of both vertebral and nonvertebral fractures
  • effective in preventing corticosteroid induced osteoporosis.

Take with lots of water at least 40 minutes before consumption of anything else as undergoes cation binding.

Remain upright after taking to reduce risk of oesophagitis.

266
Q

What modificaitons need to be made to bisphosphonates in renal disease?

A

Excreted in urine

No dose adjustment required unless CrCl <35ml/min

267
Q

What is the difference between alendronate and risedronate?

A
  • alendronate more potent and equally well tolerated
268
Q

When are IV bisphosphonates indicated?

A

If they cant tolerate or if oral is contraindicated

269
Q

What are the general and common side effects of bisphosphonates?

A

Nausea, chest pain and hoarseness (oral bisphosphonates)

Erosive oeseophagitis esp if hiatus hernia and reflux.

Acute-phase response with first IV infusion of zoledronic acid - fever, chills, flushing, MSK pain, N&V&D, eye inflam - diminishes with time. Can sub in pamidronate for subseuqnet treatment if severe

270
Q

What are the features of osteonecrosis of the jaw in the context of bisphosphonate therapy?

A
  • rare.
  • particularly after tooth extraction.
  • 95% of cases after high dose IV zoledeonric acid or pamidronate in patients with myeloma or solid tumor osteolytic mets.
  • incredibly rare in osteoporosis, more common in cancer.
  • treated with antibiotics and chlorhex MW.
271
Q

What is the major complication of bisphosphonate therapy aside from osteonecrosis of the jaw?

A

Atypical chalkstick fractures of the femur

Happen after 5 years on bisphosphonates

Low absolute risk (0.1% yearly)

  • subtrochanteric or diaphyseal, little trauma, and usually transverse as opposed to more common comminuted or spiral fem shaft fractures
  • can get bilateral femoral fracturse
  • most have prodromal thigh pain prior to fracture
  • risk is increased if concomitant high dose steroids
272
Q

What cancer are you at increased risk of getting with PO bisphosphonate therapy?

A

Oseophageal cancer - NEVER use in Barrett’s!

273
Q

What is a frequent calcium-related complication of bisphosphonate therapy?

A

Hypocalcemia resulting in secondary hyperparathyroidism

274
Q

What is the half life of alendronate in bone? What should you do about it?

A

10 years.

Discontinute after 5 years

Repeat BMD at 3 years - density falls in first year in some, but 80% have improved BMD with continued treatment

275
Q

What is the role of eostrogen replacement therapy in osteoporosis?

A
  • low dose ERT prevents postmenopausal OP but is not an effective treatment once established.
  • male hypogonadism may be treated with testosterone.
276
Q

What are the features of Raloxifene?

A
  • replaces oestrogen for prevention of osteoporosis
  • increases BMD by 1% over 2 years in postmenopausal women (2% with ERT
  • reduces risk of vertebral #’s by 40% but non nonvertebral
  • reduces LDL but doesn’t rise HDL (oestrogen does both)
  • worsens hot flushes, no effect on vaginal dryness
  • does not cause endometrial hyperplasia, uterine bleeding or ca
  • reduces breast cancer risk by 76%
  • increased vte risk
  • contraindicated in pregnancy
277
Q

What are the indications for use of Raloxifene?

A
  1. Prevention and treatment of OP in postmenopausal women
  2. Reduction in risk of invasive breast ca in postmenopausal women with osteoporosis
  3. Reduction in risk of invasive breast ca in postmenopausal women at high risk of invasive breast ca (on bx - LCIS, atypical hyperplasia or first degree FHx, or high 5 year predicted risk)
278
Q

What is teriparatide?

What is it’s role in osteoporosis?

A

PTH analog - stimulates production of new collagenous bone matrix that must be mineralised.

Must be on vit-d and calcium

Improves bone density in most bones except the distal radius

Promotes healing of bisphosphonate related atypical chalkstick fractures.

Risk of osteosarcoma (in rats) at high doses

Avoid in Pagets, prev sarcoma, open epiphyses and hypercalcaemia

SEs: dizziness and leg cramps

Steroids and thiazides + oral Ca++ plus teripraratide may result in hypercalcemia.

279
Q

Why does teriparatide - a PTH analog, improve bone formation instead of resorb it?

A

Intermittent exposure to PTH activates osteoblasts more than osteoclasts resulting in new bone formation.

Chronically elevated PTH increases serium calcium via bone resorption.

280
Q

What is calcitonin?

What does it do?

A

PTH opposer that reduces serum calcium secreted from thyroid c-cells. Protects the skeleton during calcium mobilisation i.e. pregnancy and esp lactation.

Stimulated by increase in serum Ca++, and gastrin.

Lowers blood Ca by:

Inhibits intestinal Ca++ absorption

Inhibits bone osteoclasts

Stimulates osteoblasts

Inhibits renal tubular reabsorption resulting in urinary excretion

Mimics PTH in that it

inhibits phosphate reabsorption by the tubules

281
Q

What is the role of calcitonin in osteoporosis?

A

Not approved for osteoporosis in Australia.

Reduces new vertebral (but not non-vertebral) and increases bone 2-3%)

282
Q

What are the features of Denosumab?

A
  • mAb that inhibits proliferation and maturation of preosteoclasts into mature osteoclast bone-resorbing cells
  • binds the osteoclast receptor activator of nuclear factor kappa B ligand (RANK-L)
  • increases BMD more than oral alendronate
  • decreases serum Ca++ (avoid in hypocalcaemia
  • SEs: flu like symptoms, eczema, dermatitis, infection, malignancy and pancreatitis
  • indicated for severe osteoporosis that hasn’t responded or unable to tolerate bisphosphonates. Expensive.
283
Q

What are the indications for denosumab?

A
  • osteoporosis in postmenopausal women - significantly reduces vertebral, nonvertebral and hip fractures
  • increase bone mass in men with osteopaenia receiving androgen deprivation therapy for nonmetastatic prostate ca
  • increase bone mass in men at increased risk of fracture
284
Q

What do osteocytes do?

A
  • mechanosensor cells that control the activity of osteoblasts and osteoclasts within a basic multicellular unit (BMU), a temporary anatomic structure where bone remodeling occurs.
  • generate an inhibitory signal that is passed through their cell processes to osteoblasts for recruitment to enable bone formation.
285
Q

Describe how a mature osteoclast is produced

A

Myeloid progenitor produces an osteoclast precursor which expresses the RANK receptor.

Osteoblast/stromal cells increase expression RANK-ligand in the presence of PTH, and certain interleukins.

When the RANK receptor and ligand bind, the pre-osteoclast becomes a mature osteoclast and resorbs bone and cartilage.

286
Q

What is osteoprotogerin and what does it do?

A

Acts a decoy for the osteoclastic RANK receptor, binding it instead of RANK-L.

Prevents NF-KB activation which in turn stops production of inflammatory cytokines, and reduces production of osteoclasts by inhibiting their differentiation, tipping the balance in favour of osteoblasts.

Stimulated by oestrogen and strontium.

287
Q

What are the indications and actions of strontium ranelate?

A
  • last line for osteoporosis due to side effects/intolerance
  • indicated for severe OP at high # risk and unable to reduce that risk
  • reduces both kinds of fractures, increases bone mass and BMD in postmenopausal women
  • increases femoral neck and hip BMD in older men with osteoporosis

Dual action

  • increases osteoblast precursor replication
  • alters osteoclast structure and decreases resorbing activity.
288
Q

What is the black box warning for strontium ranelate?

SEs?

A

Strongly contraindicated in IHD, PVD, CVD, HTN, VTE, PE, renal failure

Strongly contraindicated if immobilised.

Use with caution if cardiac risk factors.

Risk of CVS events and VTE.

SEs: Hypersensitivity reactions and angioedema - need to discontinue permanently. Bone pain/arthralgia.

289
Q

What is the prognosis of osteoporosis?

A

Hypogonadal women not on HRT should get enough Vit-D

Bisphosphonates and raloxifene can reverse progressive osteoporosis and decrease fracture risk

Hypogonadal men can have testosterone to prvent osteoporosis

Men with prostate ca cannot receive testosterone and should be monitored with BMD

Bisphosphonates can reverse progressive osteopaenia and osteoporosis in men

290
Q

What are the general features of osteomalacia?

A
  • painful proximal muscle weakness (esp pelvic girdle), bone pain and tenderness
  • decreased bone density from defective mineralisation
  • increased ALP, decreased 25 OHD, hypocalcaemia, hypocalciuria, hypophosphataemia and secondary hyperparathyroidism
291
Q

What is osteomalacia?

A

Defective skeletal mineralisation caused by any condition that results in inadequate ca++ or phosphate mineralisation of bone osteoid

292
Q

What is osteoid?

A

Osteoid is the unmineralized, organic portion of the bone matrix that forms prior to the maturation of bone tissue. Osteoblasts begin the process of forming bone tissue by secreting the osteoid as several specific proteins. When the osteoid becomes mineralized, it and the adjacent bone cells have developed into new bone tissue.

293
Q

What is the aetiology of osteomalacia?

A
  • mainly vitamin D deficiency (dietary and UVB sunlight)
294
Q

What is the most common cause of osteomalacia? Why?

A

Vitamin D deficiency

  • result of urbanised world and less exposure to sunlight
  • institutionalised elderly
  • malnutrition
  • malabsorption (pancreatic insufficiency, cholestatic liver disease, sprue, IBD, jejunoileal bypass, Billroth type 2 gastrectomy, orlistat, nephrotic syndrome)
  • drugs - anticonvulsants inhibit hepatic production of 25OHD, phenytoin directly inhibits bone mineralisation with normal serum vit-d.
295
Q

What are the genetic causes of osteomalacia?

A

Vitamin D-dependet rickets type 1

  • AD
  • defect in renal 1-alpha-hydroxylase resulting in defetive synthesis of 1,25 OHD.
  • needs oral calcitriol

Type 2 (hereditary 1,25 OHD resistant rickets)

  • defective 1,25 OHD receptor
  • variable response to oral calcitriol
296
Q

What are the non-vitamin D causes of osteomalacia?

A

Deficient calcium intake (malnutrition, age related reduced absorption, excessive wheat bran!)

Phosphate deficiency

Aluminium toxicity

Hypophosphatasia

297
Q

What are the features of FGF-23?

A

Plasma phosphate regulator

Secreted by osteocytes in response to elevated calcitriol

Acts on kidneys (NPT2 transporter) –> decreases reabsorption and increases urinary excretion of phosphate.

298
Q

What is autosomal dominant hypophosphataemic rickets?

A

Families with autosomal dominant hypophosphatemic rickets have a gain-of-function mutation in the gene encoding FGF23 that makes it resistant to prote-olytic cleavage, thereby increasing serum FGF23 levels.

One of the nine hypophosphataemic rickets variants.

299
Q

What is tumor induced osteomalacia?

A
  • benign mesenchymal tumours secrete FGF-23 –> hypophosphataemia due to renal phosphate wasting
  • hypophosphataemia, excessive phosphaturia, reduced or normal serum 1,25OHD
  • difficult to find tumours
  • in-ocreotide or FDG-PET imaging may help find tumours.
300
Q

What is an ocreotide scan?

A

An octreotide scan or octreoscan is a type of scintigraphy used to find carcinoid and other types of tumors and to localize sarcoidosis. Octreotide, a drug similar to somatostatin, is radiolabeled with indium-111,[1] and is injected into a vein and travels through the bloodstream. The radioactive octreotide attaches to tumor cells that have receptors for somatostatin. A radiation-measuring device detects the radioactive octreotide, and makes pictures showing where the tumor cells are in the body.

301
Q

What are the general causes of hypophosphataemia?

A

Poor nutrition

Refeeding

Alcoholism

Chelation of phosphate by aluminium antacids, calcium acetate and sevelamer (renagel)

Excessive losses ie proximal renal tubular acidosis and fanconi syndrome

302
Q

What is the role of aluminium toxicity in osteomalacia?

A

Bone mineralisation inhibited by aluminium

May occur in long term haemodialysis patients using tap water dialysate or aluminium containing antacids used to reduce phosphate levels

Or long-term parenteral nutrition if casein hydolysate used for amino acids contains high aluminium levels.

303
Q

What is hypophosphatasia?

A
  • deficiency of bone alkaline phosphatase effect
  • rare genetic cause of osteomalacia, frequently misdiagnosed as OP.
  • premature loss of teeth, foot pain (MT stress fractures), thigh pain (femoral pseudofractures), arthritis due to chondrocalcinosis
  • low serum alkaline phosphatase for age
  • dx confirmed with 24hr urine phosphoethanolamine (substrate for ALP) which is always elevated in this disease
  • tx - supportive care.
304
Q

What is alkaline phosphatase?

A

hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation. As the name suggests, alkaline phosphatases are most effective in an alkaline environment.

305
Q

What is fibrogenesis imperfect ossium?

A

progressive bone pain and pathologic fractures. Bones have a dense “fishnet” appearance on radio- graphs. Serum alkaline phosphatase levels are elevated. Some patients have a monoclonal gammopathy, indicating a pos- sible plasma cell dyscrasia causing an impairment in osteo- blast function and collagen disarray.

306
Q

What are the clinical symptoms of phosphate deficiency?

A

Muscle weakness and bone pain

307
Q

What are the clinical findings of osteomalacia?

A

bone pain

Muscle weakness due to calcium deficiency

Pathological fractures

Vit-D deficiency assoc w/ increased risk of MS, RA, DM

308
Q

How is osteomalacia diagnosed?

A

Serum

Ca - low

Alb

Phosph - low

ALP - elevated

PTH

Low urine ca

1, 25 OHD low (even if 25 OH D2 levels are normal)

Xr

  • pseudofracture - confirms diagnosis
309
Q

What is a pseudofracture?

A

Diagnostic form of osteomalacia

A band of bone material of decreased density may form alongside the surface of the bone. Thickening of the periosteum occurs. The formation of callouses in the affected area is also common. This gives the appearance of a false fracture. T

310
Q

How do you distinguish osteomalacia from osteoporosis?

A
  • Hx low sunlight exp
  • proximal muscle weakness
  • low 25 OH Vitamin D
  • low serum ca/phos
  • high ALP in severe OM but not in OP
  • phosphate deficiency must be distinguished from hyperparathyroidism
311
Q

How is osteomalacia prevented and treated?

A

Increase sunlight exposure

Eat fish esp salmon, mackerel, cod liver oil, sardines or tuna canned in oil

Plant derived not very bioavailable

Supplementation in sunlight deprived and if on phenytoin

Vitamin D3 more effective in raising levels of 25 OHD

Monitor serum Ca++

Vitamin D supplementation assoc with improved muscle strength and reduced fall risk.

312
Q

How is hypophosphataemic osteomalacia treated?

A

Correct nutritional deficiency

Stop aluminium containing antacids

Give bicarb for those with renal tubular acidosis

If genetic - oral phosphate given long term, and calcitriol

Hypophosphatasia - possibly teriparatide.

313
Q

What are the general features of Paget’s disease of bone (osteitis deformans)?

A
  • often asymptomatic with bone pain as first symptom
  • Kyphosis, bowed tibias, large head, deafness and frequent fractures
  • normal serum Ca and phos, elevated ALP, urinary hydroxyproline elevated
  • dense expanded bones on radiographs

► Med Misc 27 (12 decks)

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