diabetes%20mellitus%20(pediatric)
DIABETES MELLITUS (PEDIATRIC)
Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
It can occur at any age and the earlier the onset, the more serious is the long-term damage, dysfunction and failure of various organs due to the chronic hyperglycemia with diabetes mellitus patients having <10 year in life span compared to non-DM patients.
Type 1 DM patients have complete insulin deficiency due to beta-cell destruction. It may be immune-mediated or idiopathic. More commonly occurs in children 7-15 year of age, but may occur at any age.
Type 2 DM patients have insulin resistance and relative insulin deficiency.
Neonatal DM is hyperglycemia that occurs in the first 6 months of life.

Diagnosis

Type 1  Diabetes Mellitus (DM)

  • Occurs in children usually between 7-15 years old, but may present at any age

Immune-mediated

  • Caused by absolute deficiency of insulin secretion due to autoimmune destruction of pancreatic islet beta cells
  • Both genetic susceptibility & environmental factors contribute to the pathogenesis of this type
  • Associated w/ other autoimmune diseases (eg Graves’ disease, thyroiditis, celiac disease, multiple sclerosis & Addison’s disease)

Idiopathic

  • Manifests as alternating episodic ketoacidosis & insulin deficiency
  • No β-cell autoimmunity & human leukocyte antigen (HLA) association present
  • Treatment w/ Insulin replacement is flexible

Diagnosis

  • Clinical presentation can vary from polyuria, polydipsia, polyphagia, weight loss to severe dehydration, shock & diabetic ketoacidosis (DKA)
  • Most important clue is an inappropriate polyuria in any child w/ dehydration, poor weight, or “the flu”
  • Hyperglycemia, glycosuria, ketonemia & ketonuria occurs w/ the classic symptoms
  • Can be diagnosed if polyuria, polydipsia, polyphagia, weight loss are present & fasting plasma glucose (FPG) concentration is ≥126 mg/dL (7.0 mmol/L) &/or random plasma glucose is ≥200 mg/dL (11.1 mmol/L)
  • Once hyperglycemia is confirmed, evaluate for presence of DKA & manage accordingly

Type 2  Diabetes Mellitus (DM)

  • Patients who have insulin resistance & relative insulin deficiency
  • Many causes including genetic defects
  • Aggravated by environmental factors (eg low physical activity or hypercaloric lipid-rich diet)
  • Insulin treatment is not usually needed until disease progresses
  • Usually seen in obese children, not insulin dependent & infrequently develop ketosis
  • History of polyuria & polydipsia is relatively uncommon
  • When DKA occurs, it is associated w/ the stress of another illness eg severe infection & may resolve when the stressful illness resolves
  • Most patients remain asymptomatic for month to year as symptoms of hyperglycemia are not as dramatic as the polyuria & weight loss accompanying Type 1 DM
  • Often seek medical care because of excessive weight gain & fatigue as a result of insulin resistance &/or incidental finding of glycosuria during routine physical exam
  • Prolonged hyperglycemia may be accompanied, in time, by microvascular & macrovascular complications

Screening guidelines adapted from the American Diabetes Association 2016

  • Age of 10 years or at onset of puberty if puberty occurs at a younger age
  • Overweight, defined by body mass index (BMI) >85th percentile for age & gender, weight for age >85th percentile, or weight >120% of ideal for height plus any 2 of the following risk factors:
    • Family history of Type 2 DM in 1st- or 2nd-degree relative
    • Race/ethnicity (Native American, Asian American, Black, Hispanic, or Asian/Pacific Islander)
    • Signs of insulin resistance or conditions associated w/ insulin resistance [eg acanthosis nigricans, hypertension, dyslipidemia, polycystic ovarian syndrome (PCOS), or small-for-gestational-age birth weight]
    • Maternal DM/gestational DM
  • Frequency of testing: every 3 years
  • FPG is recommended as the primary screening test for Type 2 DM because of decreased cost & greater convenience
  • 2-hour oral glucose tolerance test (OGTT) is recommended as a secondary test
  • Clinical judgment should be used to test for Type 2 DM in high-risk patients who do not meet these guidelines

Diagnosis

  • Can be diagnosed if polyuria, polydipsia, polyphagia, wt loss are present & FPG concentration is ≥126 mg/dL (7.0 mmol/L) &/or casual plasma glucose is ≥200 mg/dL (11.1 mmol/L)
  • Clinical manifestations of Type 2 DM:
    • Obese (BMI >95th percentile for age & gender) or overweight (BMI ≥85th-94th percentile for age & gender)
    • Normal - elevated C-peptide & insulin levels
    • Absence of autoantibodies to insulin, islet cell, &/or glutamic acid decarboxylase
    • Signs of insulin resistance
      • Acanthosis nigricans
      • Dyslipidemia
      • Hypertension
      • PCOS

Other Specific Types of Diabetes Mellitus (DM)

Diabetes secondary to genetic defects of beta-cell function

  • Neonatal DM
    • Hyperglycemia that occurs in the first 6 months of life
    • Insulin is required for initial treatment
    • May be transient w/o recurrence, transient w/ recurrence after 7-20 years or permanent

Transient Neonatal DM

  • Onset in the 1st week of life & persists for several weeks to months before spontaneous resolution
  • Occurs most often in infants who are small for gestational age
  • Characterized by hyperglycemia & pronounced glycosuria, resulting in severe dehydration & sometimes, metabolic acidosis but w/ minimal or no ketonemia or ketonuria
  • Insulin responses to glucose or Tolbutamide are low to absent; basal plasma insulin concentrations are normal
    • After spontaneous recovery, the insulin responses to these same stimuli are brisk & normal, implying a functional delay in beta-cell maturation w/ spontaneous resolution
  • Occurrence of the syndrome in consecutive siblings has been reported
  • Abnormalities of chromosome 6 are common in transient neonatal DM
  • Administration of insulin is mandatory during the active phase of neonatal DM
    • 1-2 U/kg/day of an intermediate-acting insulin in 2 divided doses results in dramatic improvement, accelerated growth & weight gain
    • May attempt reducing the dose as soon as recurrent hypoglycemia manifests

Permanent Neonatal DM

  • DM in the newborn period may be permanent if associated w/ pancreatic agenesis
  • Studies revealed that almost one-half of neonatal DM patients had permanent diabetes, one third had transient diabetes & about one fourth had transient diabetes that recurred when they were 7-20 years old
  • Affected twin & families w/ >1 affected infant have been reported
  • May initially present as euglycemic & w/in the 1st month of life
  • Maturity-onset diabetes of the young (MODY)
    • A primary defect in insulin secretion characterized by early onset between 9 & 25 years of age, absence of ketosis & autosomal dominant inheritance
    • Should be considered if:
      • Diagnosed w/ diabetes in the first 6 months of life
      • Family members w/ type 2 DM but w/ uncommon presentation
      • Mild fasting hyperglycemia (100-150 mg/dL or 5.5-8.5 mmol/L) but young & nonobese
      • Absent diabetes-associated autoantibodies & w/ atypical presentation of type 2 DM
      • Some patients respond to diet therapy, exercise &/or oral antidiabetic agents; others may require insulin therapy
  • Mitochondrial DNA mutation

Genetic defects in insulin action

  • Type A insulin resistance
  • Leprechaunism
  • Rabson-Mendenhall syndrome
  • Lipoatrophic diabetes

Exocrine pancreatic diseases

  • Pancreatitis
  • Pancreatic trauma that may require pancreatectomy
  • Neoplasia
  • Cystic fibrosis
  • Hemochromatosis
  • Fibrocalculous pancreatopathy
  • Pancreatic resection

Endocrinopathies

  • Acromegaly
  • Cushing’s syndrome
  • Glucagonoma
  • Pheochromocytoma
  • Hyperthyroidism
  • Somatostatinoma
  • Aldosteronoma

Uncommon forms of immune-mediated diabetes mellitus (DM)

  • “Stiff-man” syndrome
  • Anti-insulin receptor antibodies
  • Autoimmune polyendocrine syndrome deficiencies I & II

Drug- or chemical-induced

  • Glucocorticoids
  • Thyroid hormones
  • Diazoxide
  • Beta-adrenergic agonists
  • Nicotinic acid
  • Thiazides
  • Dilantin
  • Alpha-interferon
  • Pentamidine
  • Rodenticide (eg Vacor)

Genetic syndromes

  • Down syndrome
  • Klinefelter’s syndrome
  • Turner syndrome
  • Wolfram syndrome
  • Friedreich’s ataxia
  • Huntington’s chorea
  • Laurence-Moon-Biedl syndrome
  • Myotonic dystrophy
  • Porphyria
  • Prader-Willi syndrome

Infections

  • Congenital rubella
  • Cytomegalovirus

Classification

Type 1 Diabetes Mellitus (DM) 

  • Beta-cell destruction which leads to complete insulin deficiency
  • May be immune-mediated or idiopathic
  • Most common endocrine metabolic disorder of childhood & adolescence
  • Occurs more commonly in children 7-15 years, but may occur at any age

Type 2 Diabetes Mellitus (DM)

  • Patients who have insulin resistance & relative insulin deficiency
  • Insulin treatment is not usually needed until disease progresses
  • Many causes including genetic defects

Other specific types of Diabetes Mellitus (DM)

  • Uncommon causes; underlying cause or disease is identified
  • Eg genetic defects, drug use, pancreatic disease, chemical exposure, other diseases, etc

Neonatal Dibaetes Mellitus (DM)

  • Hyperglycemia that occurs in the first 6 months of life
  • Insulin is required for initial treatment
  • May be transient w/o recurrence, transient w/ recurrence after 7-20 years or permanent

Evaluation

Should include but is not limited to the following: 

  • Exclusion of secondary causes

Growth impairment

  • Evaluate height & weight based on growth chart every clinic visit.
    • See Growth Charts in MIMS Pediatrics
  • Monitor thyroid-stimualting hormone (TSH) levels at diagnosis, every 1-2 years & w/ occurrence of abnormal growth rate
  • Evaluate for celiac disease w/ unsatisfactory weight gain

Diabetic ketoacidosis (DKA)

  • Hyperglycemia, accumulation of ketone bodies & metabolic disease due to insulin deficiency
  • Type 1 DM patients may initially present w/ DKA at diagnosis
    • Obtain capillary glucose in children w/ excessive thirst, polyuria, abrupt unexplained weight loss, excessive tiredness, reduced level of consciousness, N/V, abdominal pain, hyperventilation, & appears dehydrated
  • May also be caused by missed Insulin doses
  • Monitor venous pH, central venous & intra-arterial pressure
    • Mild DKA: Venous pH 7.2-7.3 & <15-18 mmoL/L bicarbonate
    • Moderate DKA: Venous pH 7.1-7.2 & <10-15 mmoL/L bicarbonate
    • Severe DKA: Venous pH <7.1 & <10 mmoL/L bicarbonate
  • Monitor heart rate (HR), respiratory rate (RR), blood pressure (BP), neurologic status, fluid input & output, evidence of hyper- or hypokalemia
  • Monitor capillary glucose hourly
  • Perform laboratory tests on electrolytes, blood glucose & blood gases every 2-4 hours

Hypoglycemia

  • Blood glucose <3.9 mmol/L (70 mg/dL) causing cognitive impairment
    • Cognitive impairment may be more pronounced in patients <5 years
  • May occur more frequently in those w/ lower HbA1C levels, history of hypoglycemia, use of high Insulin doses, younger children, male gender
  • May be mild, moderate or severe
    • Mild hypoglycemia: Sweating, pallor, palpitations, tremors, mild symptoms of neutropenia
    • Moderate hypoglycemia: Aggressiveness, drowsiness, confusion associated w/ neuroglycopenia; autonomic symptoms
    • Severe hypoglycemia: Altered states of consciousness, coma, seizures
  • Determine frequency of hypoglycemia every clinic visit
    • Assess for unawareness of hypoglycemia & assess blood glucose

Nephropathy

  • Microalbuminuria is the primary manifestation of diabetic nephropathy
    • At the development of microalbuminuria, nephropathy may still be reversible
  • Poor glycemic control, smoking, family history of essential hypertension & cardiovascular disease (CVD) are associated w/ the development of nephropathy
  • Screen for microalbuminuria annually once the patient starts puberty or is ≥10 years & had DM for 5 years
    • More frequent testing is indicated w/ increased values
  • Confirmed elevated albumin-to-creatinine ratio (ACR) (>30 mg/g) consists of 2 out of 3 specimens obtained from separate days over a 6-months interval after treatment initiation for hypo/hyperglycemia & BP for age
    • Timed overnight or a 24-hours analysis w/ elevated albumin excretion rate (AER) of 20-199 mcg/minute may also be used
    • Exercise, smoking & menstruation may affect results, confirm on another day
  • Obtain baseline estimated glomerular filtration rate (eGFR) measurement & repeat based on patient’s age, clinical status, duration of disease & treatment history
  • Exclude non-DM related causes upon confirmation of diagnosis
  • Monitor microalbumin excretion every 3-6 months

Hypertension

  • Common comorbidity of DM
  • Determine BP every clinic visit & evaluate for parental hypertension which is a major risk
    • ≥95th percentile of systolic or diastolic BP for age, gender & height percentile measured on at least 3 separate days is definitive of hypertension
    • “High-normal” BP is >90th but <95th percentile of systolic or diastolic BP for age, gender & height percentile measured on at least 3 separate days
  • Exclude non-DM related causes upon confirmation of diagnosis
  • Evaluate renal functional status by urinalysis, serum creatinine (Cr) & blood urea nitrogen (BUN)
  • Obtain urinary albumin excretion if not obtained w/in previous 6 months

Dyslipidemia

  • Elevated plasma lipid concentration, smoking, hypertension, obesity, family history of heart disease & DM contribute to the development of atherosclerosis
  • Perform fasting lipid profile on >2 years prepubertal patients w/ Type 1 DM if w/ family history of hypercholesterolemia, CVD before 55 years
  • Screen at puberty (≥10 years) if w/o mentioned family history
  • Obtain fasting lipid profile in patients ≥10 years of age after glucose control has been achieved
  • Repeat screening if low-density lipoprotein cholesterol (LDL-C) is borderline (100-129 mg/dL) or abnormal (≥130 mg/dL)

Retinopathy

  • Has been reported w/ DM of 1-2 years duration
  • Identify early & treat appropriately
  • Hypertension, poor metabolic control, presence of albuminuria, dyslipidemia, smoking, longer duration of DM & pregnancy are associated w/ increased risk for retinopathy
  • Refer patient to ophthalmologist w/ expertise in diabetic retinopathy & its risks in the pediatric patient
    • Schedule regular ophthalmological screening w/ initial exam when the patient is ≥10 years or post-puberty onset & had DM for 3-5 years & annually from then on
    • Patient planning pregnancy should have an ophthalmological exam prior to conception during the 1st trimester & at the recommendation of the ophthalmologist

Neuropathy

  • Initial foot examination at the beginning of puberty & at least annually for protective sensation, pulses, skin integrity & treatable nail problems (eg ingrown toenails)
  • Comprehensive foot exam should include inspection, dorsalis pedis & posterior tibial pulse palpation, patellar/ Achilles tendon reflex testing, & proprioception/vibration/monofilament sensation assessment

Thyroid disease

  • Most common autoimmune disorder in Type 1 DM patients
  • May be euthyroid, hypothyroid or hyperthyroid
  • Screen for autoimmune thyroid disease at diagnosis & recheck TSH levels every 1-2 years for patients w/ normal TSH or if growth rate is abnormal
    • See Growth Charts in MIMS Pediatrics
  • Monitor for thyroid control after establishing metabolic control
  • Measure thyroid autoantibodies & TSH
    • Identify patients at increased risk of autoimmune thyroid disease w/ the presence of thyroid autoantibodies [antithyroid peroxidase (APO), & antithyroglobulin (TG)]
    • Treat patients w/ elevated TSH levels
    • Measure free T4 if TSH is abnormal
    • Perform thyroid function test whenever thyroid dysfunction is suspected & if patient has thyromegaly
  • Evaluate for hypothyroidism thoroughly & treat appropriately

Celiac disease

  • Type 1 DM patients have high risk for celiac disease
    • Immune-mediated damage to the mucosa of the small intestine due to ingestion of food w/ gluten (eg wheat, rye, barley & oats)
  • Symptoms include diarrhea, weight loss or poor wt gain, growth failure, abdominal pain, chronic fatigue, irritability, inability to concentrate, malnutrition due to malabsorption & other GI problems
  • Symptoms of DM patient w/ celiac disease include unpredictable blood glucose levels, unexplained hypoglycemia & deterioration in glycemic control
  • Screen for celiac disease by testing for the presence of IgA autoantibodies to tissue transglutaminase (tTG) or deaminated gliadin antibodies, or endomysial autoantibody (EMA) assay
    • Perform test upon diagnosis of type I DM & in children w/ 1st-degree relatives w/ celiac disease, growth failure, failure to gain weaight & gastroenterologic symptoms (diarrhea, flatulence, abdominal pain, signs of malabsorption), & those w/ frequent unexplained hypoglycemia or deteriorating glycemic control
    • Confirm elevated tTG antibodies
    • Interpret low to moderate tTG antibodies along w/ symptoms & repeat screening after 6-12 months
  • Confirm positive Ab levels
    • Recommend small bowel biopsy if patient has elevated tTG antibodies
  • Refer patient to gastroenterologist once celiac disease is confirmed
    • Recommend consultation w/ registered dietitian experienced w/ DM & celiac disease in pediatric patients
  • Screen periodically in patients negative for celiac disease

Psychiatric disorders

  • DM is a risk factor for psychiatric disorders (eg depression, generalized anxiety disorders) in adolescent patients
  • An increasing number of adolescents newly diagnosed w/ DM considers suicide
  • Screen patients ≥10 years annually for depression
  • Screen for psychiatric disorders in patients w/ difficulties in achieving treatment goals & w/ recurrent DKA
    • Patients w/ DKA are more likely to develop psychiatric disorders

Eating disorders

  • Associated w/ DM in adolescent patients
  • Patients w/ eating disorders are at risk for poor metabolic control & recurrent hospitalization
  • Mental health professional should screen for eating disorders w/ failure in treatment goals especially if patient is underweight

History

Early in the evaluation of a new patient w/ diabetes mellitus (DM), it is important to distinguish between Type 1 & Type 2 DM to optimize therapy

  • Past &/or current DM characteristics including age of onset, diagnosis, management & treatment
  • Previous or ongoing infection(s)
  • Growth records
  • Family history of DM & cardiovascular disease (CVD)
  • History of DM-related complications
  • Medications, nutritional status, eating patterns & exercise history
  • Tobacco, alcohol use & drug history
  • Sexual activity & contraceptive use
  • Risk factors for atherosclerosis
  • Glycosylated hemoglobin (HbA1c) history
  • History of hypoglycemia
  • History of diabetic ketoacidosis (DKA)
  • History of gestational diabetes or macrosomia
  • History of other disorders (eg endocrine, eating & mood disorders)

Physical Examination

  • Height & weight, calculate body mass index (BMI), measure waist circumference
  • Blood pressure (BP) measurement
  • Hand & foot examination, & evaluation of pulses by palpation w/ auscultation
  • Funduscopic, oral, abdominal examination
  • Cardiac & thyroid examination
  • Skin examination for acanthosis nigricans
  • Neurological examination
  • Evaluate signs of puberty/physical development

Laboratory Tests

  • If there is suspicion or any evidence of diabetes ketoacidosis (DKA), include:
    • Serum glucose
    • Electrolytes
    • Arterial or venous pH
    • Serum or urine ketones
  • HbA1c
  •  Fasting lipid profile [total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) & triglycerides (TG)]
  • Test for microalbuminuria
  • Thyroid antibodies
  • Liver function test
  • Genetic testing - if presentation is atypical & w/ family history of monogenic diabetes

Screening

Diagnostic criteria for diabetes mellitus (DM) adapted from the American Diabetes Association 2016

Any of the following:

  • HbA1c >6.5% (48 mmol/mol)
  • Done in a National Glycohemoglobin Standardization Program (NGSP)-certified method traceable to the Diabetes Control & Complications Trial (DCCT) reference assay
  • Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L)
    • Fasting is defined as no caloric intake for at least 8 hours
  • 2-hours plasma glucose of ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT)
    • Perform test as described by the World Health Organization (WHO), using a glucose load of 75 g anhydrous glucose dissolved in water or 1.75 g /kg body weight if weight is <40 lbs (18 kg)
    • OGTT is not recommended for routine clinical use, but may be required in the evaluation of patients when diabetes is still suspected despite a normal FPG
  • Symptoms of polyuria, polydipsia & unexplained wt loss w/ random plasma glucose ≥200 mg/dL (11.1 mmol/L)
    • Random is defined as any time of day w/o regard to time since last meal

If typical hyperglycemic symptoms are not present, a repeat test should be done on a different day to confirm diagnosis

  • Confirm diagnosis if FPG ≥126 mg/dL or 2-hours plasma glucose of ≥200 mg/dL or random glucose of ≥200 mg/ dL in high-risk patient screened for DM
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