F O R W A R D Mount Nittany Health L I F E F O R W A R D...–BPH(International Prostate Symptom Score >19) –Hematocrit >50% –Untreated severe obstructive sleep apnea Mount Nittany

10/18/2012

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Mount Nittany Health L I F E F O R W A R D

Common Challenges in the Management of Endocrine Problems in Primary Care

Jan Ulbrecht [email protected]


Low T(estosterone):

• In classic disease– Either high LH/FSH = primary, e.g. mumps– Or normal LH/FSH = secondary, i.e. pituitary disease

• Metabolic Syndrome / obesity are associated with low T. Normal? Pathology?

• Very little data in this group, therefore no authoritative guidelines

• In one study older men with baseline T 100-350 ng/dl had more strength but more CV events after 6 months of T treatment …


Low T:

• Endocrine Society advises against T therapy if

– Prostate cancer

– PSA >3-4 ng/ml

– BPH(International Prostate Symptom Score >19)

– Hematocrit >50%

– Untreated severe obstructive sleep apnea


Low T – an approach:

• Must have some sexual symptoms (morning erections, drive,

function); studies are inconsistent in linking other symptoms to low T

• Low T must be documented on early morning specimen (within 2-3 hours of waking up)– Low Total T <8 nmol/L (<230 ng/dl)– Possibly Low Total T 8-12 nmol/L (230-350 ng/dl)

• Also want to see (by dialysis if in question)– Low Free T <170 pmol/L (<49 pg/ml)– Possibly Low Free T 170-220 pmol/L (49-64 pg/ml)

• The lower the T the more inclined I am to treat• If in doubt do a well informed (prostate, CV events)

therapeutic trial


Low T:

• 1. Bremner WJ. Testosterone deficiency and replacement in older men. N Engl J Med. 2010;363(2):189-91.

• 2. Yeap BB. Testosterone and ill-health in aging men. Nat ClinPractEndocrinolMetab. 2009;5(2):113-21.

• 3. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-22.

• 4. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363(2):123-35.

• 5. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J ClinEndocrinolMetab. 2010;95(6):2536-59.


TSH

T4 & T3

Diagnosing Thyroid Dysfunction:

mailto:[email protected]

mailto:[email protected]

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Low TSH

HIGH or high nl T4 or T3

Primary Hyperthyroidism


Slightly high TSH

HIGH or high nlT4 & T3

Secondary HyperthyroidismYOU WILL NEVER SEE A CASE


High TSH

Low or low nl T4; T3 maybe nl

Primary Hypothyroidism


Low or nlTSH

Low or low nl T4; T3 maybe nl

Secondary Hypothyroidism


Thyroid Function Tests• TSH rules EXCEPT

– May take 2-3 months to fully equilibrate• After LT4 dose change

• In destructive thyroiditis

– In secondary hypothyroidism

• In SYMPTOMATIC hyperthyroidism the TSH will always be below the detection limit EXCEPT– Very early, typically in destructive thyroiditis

• Acute illness (ER, ICU), steroids and HCG (early pregnancy) will suppress TSH– Eg. 8 may become 2 mIU/L; 1 may become 0.1 mIU/L


Destructive thyroiditis

0

1

2

3

4

5

6

7

0

1

2

3

-4 1 6 11 16

TSH

mIU

/L

FT4

ng/

dl

Weeks

FT4

TSH

• Painful is viral, usually resolves (very high ESR)• Painless is autoimmune, often post-

partum, often does not resolve DO NOT TEST THIS OFTEN

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When and how to test for thyroid dysfunction:

• 1 in 5 women over the age of 60 years have thyroid dysfunction; the problem is not as frequent among men

• TSH is sufficient most of the time

• Get free T4 and possibly free T3 only if TSH normal and symptoms are very persuasive


SubclinicalHypothyroidism:

Normal ranges are usually defined as mean ±2SD of a healthy sample …

4321TSH

0

Nu

mb

er o

f p

eop

le


Subclinical Hypothyroidism:

TSH uU/L

1.0 4.03.02.0 6.05.0 7.00.0 8.0

Normal Lab Range 0.3 – 4.3

% with Symptoms

0%

80%


Hypothyroidism –how much T4?

100%

0%

Thyr

oid

Ho

rmo

ne

Req

uir

emen

t

Endogenous

Exogenous 1.6 ug/kg/day


T3 vs. T4, “natural” and other FAQs …

• There are no studies showing that T4 + T3 is better than just T4, but there are some patients where it seems to make a difference

• BUT first be sure to treat to TSH 0.2-0.6 mIU/L

• T4 is natural (ok, man-made but identical)

• Though I do have to agree that pig thyroid extract is natural; as is cyanide, arsenic …


This patients thyroid dose keeps changing …

• You may be testing TSH too often

• You may be changing dose too often

• The patient may be taking thyroid hormone with other medications, tea, coffee, juice, etc

• The patient may be forgetting her thyroid hormone

– Use pill box, ok to make up 7 pills per week

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Thyroid Cartilage

Cricoid Cartilage The

Nightmare Will Not End – aka Thyroid

Nodules


The nightmare of thyroid nodules:

• Reported prevalence of thyroid nodules by ultrasound is 5.2 – 67%

• Reported prevalence of (mostly occult < 1-1.5 cm) thyroid carcinoma at autopsy is 5.7 – 13%

• Mortality of thyroid carcinoma has been almost stable over years while incidence has skyrocketed (mostly of <2 cm tumors)

• Number of biopsies and of thyroidectomies have both increased dramatically


Thyroid Cancer over Time:

#12 among all cancers Top 15 all > 5


Size Matters:

• When to order a thyroid US:– When you feel a thyroid nodule– When you feel an irregular thyroid– For an incidental finding, maybe (for profit companies

“screening”; carotid US, MRI, CT)– In other words only if you have a clear question to

which you are willing to accept an unclear answer

• Because size matters– You want to be diagnosing thyroid malignancy at

around 1.5 – 2 cm diameter– In a multinodular goiter any one nodule has the same

risk of malignancy as any other

American Thyroid Association 2009 Guidelines


Ultrasound Nodule Present– What Next (size matters):

• Check TSH – Rarely LO, toxic nodule– HI increases chances of malignancy

• FNA if– Solid and >1-1.5 cm– Mixed solid/cystic >1.5-2 cm

• Higher risk if microcalcifications, hypoechoic, increased vascularity, infiltrative margins, taller than wide. You don’t have to remember but your radiologist has to tell you.

– If more then one nodule, biopsy all that need it.

• No FNA if simple cyst

American Thyroid Association 2009 GuidelinesMount Nittany Health L I F E F O R W A R D

FNA Negative or not Indicated – What Next:

• If FNA not initially indicated– Repeat US 6-18 months later

– FNA if size / risk characteristics reached

– If not repeat US in 3-5 years (or never)

• If initial FNA negative – Repeat US 6-18 months later

– Repeat FNA if > 20% increase in 2 dimensions• And recall high risk characteristics

– If no change repeat US in 3-5 years (or never)

American Thyroid Association 2009 Guidelines

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Osteoporosis: Screening DEXA

• The USPSTF (2011)

– screening for osteoporosis in women >65 years, younger if other risk factors (NOF same)

– current evidence is insufficient for men (NOF screen men >70 years)

• Rescreening?

– Osteoporosis develops in <10% postmenopausal women

• After 15 years with normal BMD or mild osteopenia (T >-1.5)

• After 5 years with moderate osteopenia (T = -1.5 to -2.0)

• After 1 year with advanced osteopenia (T = -2.0 to -2.5)

Gourlay ML et al, NEJM, 2012, 366(3):225.


Osteoporosis & OsteopeniaIndications for Treatment

• A hip or vertebral fracture

• T score ≤−2.5 at the femoral neck or spine (exclude secondary causes)

• Low bone mass (T score −1.0 to −2.5 at the femoral neck or spine) AND a 10-year FRAX hip fracture risk ≥3% or a 10-year FRAX major osteoporosis fracture ≥20%

• http://www.shef.ac.uk/FRAX/ (or an app; note that past fracture = low impact or osteoporotic fracture)


Osteoporosis & OsteopeniaTreatment Options

• Bisphosphonates have most data

• Among them alendronate (Fosomax) has most data

• Make sure adequate vit D and calcium

• Repeat DXA at 2 years, stability is adequate

• Treat for 5 years (atypical femur fractures)

• At 5 years repeat DXA, if worried refer

• Repeat DXA 2 years later, if worried refer or resume bisphosphonate


Diagnosing Primary Hyperparathyroidism(p

g/m

l)

NEVER use a scan for diagnosis

3 per 1,000 people


Indications for Parathyroidectomy

• All symptomatic patients– But how can you tell? Maybe a trial of cinacalcet

(Sensipar)

– Kidney stones …

• Also– Calcium >1 mg/dl above upper limit

– Creatinine clearance <60 mL/min

– T score <-2.5 or fragility fractures

– Age <50 years

Eastell R et al (Third International Workshop), JCEM, 2009, 94:340.


DCCT Correlation HbA1c vs. MBG

Hb

A1

c

MBG (mmol/l)

x x

x

x

x

xxx

xx

Variability in HbA1c testing

http://www.shef.ac.uk/FRAX/

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HGI = actual HbA1c – predicted HbA1c202 children, 1612 visits over 6 years

N=176.2%

N=165.8%

Soros AA et al, Pediatric Diabetes, 2010 Nov;11(7):455-61.


Possible Causes of Variable Hemoglobin Glycosylation

• Erythrocyte turnover rates

• Variability in intracellular glucose concentrations

• Intracellular or extracellular pH

• Activity of deglycating enzymes

• Inorganic phosphates

• Hemoglobin oxygenation status

• Cellular redox status

• Rate of conversion from unstable to stable glycation products

Mostly genetically

determined

Soros AA et al, Pediatric Diabetes, 2010 Nov;11(7):455-61.


Racial Disparity in HbA1c

• Female 51.1%

• Caucasian 71.7%

• Age 12.5±3.6 years

• DM Duration 4.9±3.4 years

Kamps JL et al, Diabetes Care, 2010, 33(5):1025.

Caucasians African Americans

Mean HbA1c 8.3±0.1% 9.1±0.1%

Controlling for MBG, age and DM duration


Conclusions:

• HbA1c is NOT blood sugar and is NOT THE GOAL of therapy• Biological variability in HbA1c exists

– ~6% of patients have HbA1c >1% HIGHER than expected– ~6% of patients have HbA1c >1% LOWER than expected

• These differences are likely to be genetic and African Americans may run higher HbA1c

• Analytical differences in HbA1c results exist, lab-to-lab, test-to-test and day-to-day– Rule of thumb about 0.5 %HbA1c units is norm

• Look at MBG and BG patterns; BG is GOAL!!!!!!! (download meters)• Don’t force HbA1c among FAST glycosylators too low (result will be

hypoglycemia) • Don’t accept HbA1c among SLOW glycosylators too high (result will

be hyperglycemia)


Diabetes Screening:

• Screen every 3 years after age 45 and before that for BMI > 25 + another risk factor

• Diabetes– FBS > 126 mg/dl– 2h GTT BS > 200– HbA1c > 6.5%1

• High Risk (prediabetes)– FBS 100 – 125 mg/dl2

– 2h GTT 140 – 199 mg/dl– HbA1c 5.7 – 6.4%

1 Misses 30% of undiagnosed cases c/w FBS

2 By the time FBS is in the 90-100 mg/dl range, ~50% of insulin function is lost

ADA Practice Guidelines, 2012.


What to do?

• 57 year old male who just moved to the area.

• Obesity (BMI 38), treated hypertension.

• Fasting Labs –

– glucose 97 mg/dl; TG 185 mg/dl; HDL 32mg/dl.

• You get an HbA1c = 5.6%; useful?

• Now what?

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What to do?

• 39 year old female last seen in primary care 7 years ago (sees GYN annually).

• H/o GDM but since has lost down to BMI 24; gym 3 days a week, pedometer daily >6,000 steps.

• FH - DM, CAD, colon cancer.

• Screening HbA1c at MNMC health fair 6.7%.

• Now what?


A Case of Hypoglycemia

• 52 year old male presenting with classical symptoms of hypoglycemia usually 1-3 hours after eating; never at night or fasting. Happens 2-3 times per week.

• Got worse since he stopped exercising because of a leg injury.

• Otherwise no complaints. No meds, but does not see doctors very much. Last “physical” 3 years ago.

• FH – obesity, hypertension, CAD.• Labs 3 years ago – fasting glucose 96 mg/dl; TG 212 mg/dl;

HDL 35 mg/dl.• Obese (6ft, 238lb; BMI 32), BP 152/92.• Diagnosis? Treatment?


A Case of …

• 32 year old woman coming in for annual GYN exam.

• In addition to doing that and discussing seatbelts, alcohol, immunizations, safety at home …

• You also note– Ht 65in, wt 165lb, BMI 27.5,

BP 132/84.

• What next?

Fasting•Glucose 92 mg/dl• Insulin 12 mIU/l•TG 189 mg/dl•HDL 45 mg/dl


A Case of Diabetes:

• I am now seeing that same woman at 46 yo

• Because she was recently diagnosed with diabetes

• The chart reveals

– Recent HbA1c 7.2%, abnl HbA1c going back 3 years

– FBS in the 95-115 mg/dl range going back 8 years

• She first recalls being told of a BS problem a year ago … *yes, I know, it takes 2 to communicate+


Dementia

Acanthosis Nigricans

Gene set modulates all

relationships!

Malignancies

Liver

Problems

Gout

InflammationClotting

Abnormalities

Metabolic Syndrome (IR Syndrome, Syndrome X):

Coronary AD & Stroke

Elevated

Triglycerides

& Low HDL

High LDL

Smoking

High BPDiabetes

Genetics / Islet Cell Exhaustion / Aging

Pre-Diabetes &Gestational DM

PCOD

Thrifty Gene

Hypothesis

Insulin Resistance

High BloodInsulin Levels

Low Activity Level

"Modern" Diet

Central Obesity

Psychological Factors,

ETOH, Poor Sleep

IntrauterineFactors

Inflammation (periodontal disease;

adipocytes; hepatitis)

Maternal LineNutrition


Metabolic Syndrome Prevalence, NHANES 2003-06

0

10

20

30

40

50

60

70

80

20-29 30-39 40-49 50-59 60-69 >70

%

Age Group (years)

WC1

WC2

WC3

Ford ES et al, J of Diabetes, 2010;2:180-193.

Based on 2009 joint taskforce definition with different WCs.

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Don’t own her problem,

guide her to own it.


Create a LEADER in her community:

• We the health care system cannot go home with every patient and “take care of” this for them

– Focus on the ones who decide to get better and try to turn them into leaders

– Get involved in your community as a leader yourself; join the Mount Nittany Diabetes Network!


Suggestions …

• Plate method• Pedometer – cannot be normal weight much below 5,000

steps per day• Work on this with a friend• Start a health oriented group at church• Change the snack culture at work• Join Weight Watchers®• Join the YMCA• “Mrs. Jones, I know it must be upsetting to learn about this

significant health problem, and I would be glad to talk with you about this more in the future. When would you like to come back to talk about this some more?”


The Plate Method

Vegetable green + color

9 in plateFoods should not touch

PotatoesShelled peas & cornBreadPasta, rice

No calorie-containing beverages

• What would a pasta dinner look like?

• How would you make a sandwich?


Suggestions …

• Plate method• Pedometer – cannot be normal weight much below 5,000

steps per day• Work on this with a friend• Start a health oriented group at church• Change the snack culture at work• Join Weight Watchers®• Join the YMCA• “Mrs. Jones, I know it must be upsetting to learn about this

significant health problem, and I would be glad to talk with you about this more in the future. When would you like to come back to talk about this some more?”


The relationship between control and complications in EARLY DIABETES is log-linear:

Complications Risk

HbA1c 5% 6% 8%7% 9% 10% 11%

(UKPDS) Stratton IM, BMJ,

2000, 321(7258):405.

Setting Individual

HbA1c Goals

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Action to Control CardiovascularORisk in (LATE) Diabetes

The glucose control part of the study was discontinued because there were more

deaths in the intensive group

257 vs 203

HR 1.22

P=0.04

ACCORD, NEJM, 2008, 358(7):2545.


ACCORD, NEJM, 2008, 358(7):2545.

Action to Control Cardiovascular Risk in Diabetes Results

MI, CVA or vascular death:

Previous vascular event:NOYES

Baseline HbA1c:< 8%> 8%


Further Analysis of ACCORD

• Mortality was clustered in patients in the intensive group who were ‘pushed’ by the study protocol to lower HbA1c, but their HbA1c remained high

• In this group there was also increased frequency of unrecognized hypoglycemia

• Fast glycosylators?


Conclusions:

• Aggressive control early prevents complications AND cost is low.

• Because of the log-linear relationship between control and complications, absolute benefits are greatest at high HbA1c values.

• Metformin is king (reduces progression of diabetes and reduces incidence of atherosclerotic events i.e. MIs)!

• Pushing patients with advanced disease (particularly macrovascular complications) to ‘tight’ control that they cannot achieve probably increases mortality [attention to hypoglycemia and particularly nocturnal hypoglycemia may be a useful metric to follow].


Ulbrecht HbA1c Default Goals:

Patient Type Default Goal

Typical type 1 7.2%

‘Early’ type 2 5.8%

Typical type 2 6.8%

‘Late’ type 2 7.5%

HypoG Unawareness 8.0%

Adjust for Glycosylation Rate based on SMBG!!


Complications and HbA1c after the DCCT

(the “METABOLIC MEMORY” effect)

EDIC Study, JAMA, 2003, 290(16):2159.

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Progression of Retinopathy

EDIC Study, NEJM, 2000, 342(6):381.


Prevalence and Cumulative Incidence of Microalbuminuria

after the DCCT

EDIC Study, JAMA, 2003, 290(16):2159.


Cu

mu

lati

ve In

cid

ence

of

GFR

<6

0 (%

)

Years since Randomization

DCCT Average HbA1c EDIC

9.1% Conventional 8.0%

7.3% Intensive 7.9%

DCCT / EDIC

DCCT/EDIC, NEJM, 2011, 365(25):2366.Mount Nittany Health L I F E F O R W A R D

Metabolic Memory:

• Same metabolic memory effects have been shown for both type 1 & 2 diabetes and retinopathy, neuropathy and nephropathy Try to help patients with this image!!

Documents

F O R W A R D Mount Nittany Health L I F E F O R W A R D...–BPH(International Prostate Symptom Score >19) –Hematocrit >50% –Untreated severe obstructive sleep apnea Mount Nittany