Laboratory analysis of the obese child – recommendations and discussion

Laboratory analysis of the obese child – recommendations and discussion

MacKenzi

Hillard

May 4, 2011

aka: What to do with “Fasting Labs”

The Obesity EpidemicThe prevalence of obesity in adolescents has tripled since 1980

31% of children are overweight and 17% are obese

The ConcernObesity is associated with numerous medical comorbidities:

Elevated blood pressure

Dyslipidemia

Impaired glucose tolerance / Type 2 DM

Non-alcoholic fatty liver disease

From: Singhal V, Schwenk WF, and Kumar S. Evaluation and management of childhood and adolescent obesity. Mayo Clin Proc 2007; 82(10): 1258-1264.

Objectives

Discuss the role of the primary care physician to identify obese children with three common comorbidities - altered glucose tolerance, NAFLD and dyslipidemia.

Discuss the appropriate utilization and interpretation of laboratory screening tests and subsequent management.

Question #1You are seeing an obese 14 year old female patient. Her mother asks you to test her for diabetes because it runs in the family. You order a fasting blood glucose and it is 120. You tell her mother:

Answers #1

Your daughter’s labs are normal.

Your daughter has impaired glucose tolerance.

Your daughter has diabetes.

Your daughter has prediabetes.

Altered glucose toleranceInsulin resistance and altered glucose metabolism is a component of the metabolic syndrome

Altered glucose tolerance

Prediabetes

Impaired fasting glucose

(IFG)

fasting glucose 100-125 mg/

dL

Impaired glucose tolerance (IGT)

plasma glucose after 2 hr oral glucose tolerance test (OGTT) is 140-199 mg/

dL

Type 2 DM

Fasting glucose >126 mg/

dL

plasma glucose after OGTT > 200 mg/

dL

Two random plasma glucose values >200

Altered glucose tolerance

10-30% of obese children have

prediabetes

45% convert to normal glucose tolerance over 2 years

20% convert to type 2 DM

Goal of screening is to detect these at-risk patients and intervene before disease progresses

Who should be screened?

The American Diabetes Association recommends obtaining a

fasting plasma glucose

in any obese individual who has 2 additional risk factors ….

Family history

Ethnicity: African-American, American Indian, Hispanic, Pacific-Islander

Signs of insulin resistance or of conditions associated with insulin resistance:

acanthosis

, PCOS, SGA, HTN,

dyslipidemia

Mother with GDM in pregnancy

… beginning at age 10 or at the onset of puberty and repeating every 3 years

Fasting plasma glucoseEasy to obtain, easily reproducible, relatively inexpensive

Problem: only identifies a portion of patients who are prediabetic.

Impaired fasting glucose vs. impaired glucose tolerance

FG alone only has a 21% sensitivity to detect IGT

Tsai

J

et al

, Horm Res Paediatr

2010

Who should get an oral glucose tolerance test?

OGTT is not recommended for a first line screen

Inconvenient

Not readily reproducible

No specific recommendations exist for when to order an OGTT in an obese child

Consider when fasting glucose is normal and you have a high suspicion for a pre-diabetic state (PCOS, strong family history)

Hemoglobin A1creflects average blood sugar over the previous 3 months

What about using HbA1c as a screening test?

HbA1C has been looked at as a predictor of impaired glucose tolerance

Cut-off of 5.5% has the best combined sensitivity (85.7%) and specificity (56.9%) for IGT

However, low specificity means that other tests will still be indicated to make a diagnosis so not currently recommended as a screen

Screening for hyperinsulinemia

Fasting insulin levels have been historically used as a marker of insulin resistance

Screening for hyperinsulinemia

A few problems ….

Insulin levels normally rise in puberty while insulin sensitivity decreases to facilitate rapid growth

Fasting insulin levels

do not

correlate well with the euglycemic hyperinsulinemic clamp measure of insulin sensitivity (gold standard)

Correlation of 0.42 at age 13 and 0.29 at age 15

Screening for hyperinsulinemia

Fasting insulin levels should not be routinely obtained and applied to clinical decision making

Management of altered glucose tolerance by the PCP

Prediabetes

: goal of treatment is to slow the progression to diabetes

1.

lifestyle modification:

Weight loss + physical activity

Management of altered glucose tolerance by the PCP

2.

metformin

has been shown to slow the progression from

prediabetes

-> diabetes in adults

may initiate treatment at diagnosis of altered glucose tolerance or wait 3-6 months to see effects of lifestyle changes

Risk of Diabetes

Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study.

The Lancet

2009.

374

(9702): 1677-1686

Management

T2 DM

lifestyle modification

metformin

Consider referral to endocrinology

(especially if HbA1c is >8)

insulin if needed

Summary

The ADA recommends obtaining a fasting blood glucose as an initial screen.

This test will miss some patients who might have IGT on an OGTT –> obtain an OGTT if you have additional concerns.

Fasting insulin levels and HbA1C are not recommended as screening tests.

Advise lifestyle changes and consider starting

metformin

in obese children with

prediabetes

.

Question #2You obtain a hepatic panel on a 15 year old obese male patient. His ALT measures 110 u/L and his AST is 100 u/L. He has no previous labs on record and is asymptomatic. There is no family history of liver disease. You advise which of the following?

Answer #2

Counsel on lifestyle changes and repeat a hepatic panel with other labs in 2 years.

Counsel on lifestyle changes and repeat labs in 3 months.

Obtain a liver ultrasound.

Refer immediately to GI.

Non-alcoholic fatty liver disease

The most common liver disease among adolescents in North America

Autopsies suggest a prevalence of 9.8% in American children, 38% of obese children

Male predominance (2:1)

More prevalent in Hispanics and Asians, less prevalent in African-Americans

Non-alcoholic fatty liver diseaseStrongly associated with other components of the metabolic syndrome, particularly insulin resistance and increased visceral fat

Non-alcoholic fatty liver disease

A

Steatosis

- triglyceride deposition in

hepatocytes

(reversible)

B

Steatohepatitis

(NASH)

- inflammation and fibrosis (may be irreversible)

Increased fibrosis, cirrhosis

Characterized by accumulation of triglycerides in hepatocytes

From : Takahashi Y, Fuckusato T. Pediatric non-alcoholic fatty liver disease: emphasis on histology.

World Journal of Histology

2010. 16(42). 5280-5285

NAFLD – what’s the risk

Children with NAFL have a 13.8 times greater risk of dying or requiring liver transplant in 20 years after diagnosis

Children diagnosed with NAFLD

From: Fieldstein AE et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years.

Gut

2009 58: 1538-1544

NAFLD – clinical signs

Initial presentation:

Asymptomatic with ALT

NAFLD – screening

Recommendation is to measure

transaminases

on all obese children, especially those with other components of metabolic syndrome

No consistent recommendations for timing of initiation or frequency of screening

ALT > 2x normal that persists for > 3 months suggests the diagnosis

NAFLD – a diagnosis of exclusion

Need to rule-out

hepatitis B and C

autoimmune hepatitisWilson’s disease

alpha-1 antitrypsin deficiency

drug-induced liver injury

NAFLD – interpreting results

Consider checking a

ceruloplasmin

in any patient with elevated

transaminases

and screen for

autoimmune hepatitis in females with a family history

before waiting for repeat labs.

Obtain a full CMP with PT/INR to evaluate liver function when labs are repeated

NAFLD – interpreting results

Transaminase

measurement is the only acceptable screening test, but realize …

not extremely sensitive - 23% of patients with evidence of NAFLD on biopsy have normal ALT

Liver biopsy is gold standard of diagnosis to assess the degree of

steatosis

, inflammation and/or fibrosis

Expensive, invasive – not recommended for routine screening

NAFLD – further evaluation

Ultrasound may reveal an enlarged,

echogenic

liver but is not always needed

Patients with suspected NAFLD should be referred to and followed by GI

NAFLD - management

Address the metabolic

comorbidities

OBESITY : Diet/Lifestyle modification

Moderate weight loss can decrease the

transaminitis

and inflammation but does not consistently reverse fibrosis

INSULIN RESISTANCE:

Metformin

may help to reduce

transaminitis

?

ANTIOXIDANT THERAPY – Vitamin E

SummaryNAFLD is common and often asymptomatic.All obese patients should have transaminases measured as a screening test.

If initial screen is abnormal, r/o Wilson’s and autoimmune hepatitis in at risk patients, then repeat a CMP with INR in 3 months.

Recommend lifestyle changes, consider GI referral.

Question #3 Which is the most common lipid abnormality in obese children …

Answer #3

Elevated total cholesterol

Elevated LDL

Low HDL

Elevated triglycerides

Dyslipidemia

Elevated LDL and triglycerides and a low HDL increase risk for CVD

Atherosclerosis begins

in childhood

42% of obese youth

24% elevated triglycerides

20% have low HDL

14.2 % have high LDL

Dyslipidemia

Metabolic syndrome

HDL < 50 (women)

or <40 (men)

Triglycerides > 150

Dyslipidemia – AAP screening recommendations

Screen pediatric patients with a fasting lipid profile who have any of the following risk factors:

family history of

dyslipidemia

overweight or obesity

hypertension

diabetes

mellitus

cigarette smoking

Begin screening between ages 2 and 10, repeat every 3-5 years

Dyspidemia - management

Low HDL or elevated triglycerides

-> weight management and increased physical activity

Consider pharmacologic treatment for

LDL >190 (or >160 if multiple risk factors)

with initial goal <160

Statins

Fish Oil

Plant Sterols

Conclusions

The initial laboratory evaluation of the obese child who is developmentally normal and growing (too) well should include a fasting glucose, a hepatic panel, and a lipid panel.

There is a room for a great deal of inter-provider variability in the interpretation of these results and selection of subsequent tests.

Lifestyle changes are the answer to just about everything.

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The Lancet

2009.

374

(9702). 1677-1686.

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Kuma

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Fuckusato

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