Diabetes%20mellitus%20(pediatric) Diagnosis

Type 1 Diabetes Mellitus 

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

Type 2 Diabetes Mellitus 

• Patients have insulin resistance and relative insulin deficiency
• Causes include genetic, metabolic and environmental factors
• Initial treatment could be Metformin alone, insulin alone or a combination of Metformin and insulin

Other Specific Types of Diabetes Mellitus 

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

Type 1 Diabetes Mellitus

Immune-mediated

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

Idiopathic

• No beta-cell autoimmunity and without human leukocyte antigen (HLA) association

Diagnosis

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

Type 2 Diabetes Mellitus

• Usually seen in obese children, not insulin dependent and infrequently develop ketosis
• Aggravated by environmental factors (eg low physical activity or hypercaloric lipid-rich diet)
• History of polyuria and polydipsia is relatively uncommon
• When DKA occurs, it is associated with the stress of another illness eg severe infection and may resolve when the stressful illness is resolved
• Most patients remain asymptomatic for months to years as symptoms of hyperglycemia are not as dramatic as the polyuria and weight loss accompanying type 1 DM
• Often seek medical care because of excessive weight gain and fatigue as a result of insulin resistance and/or incidental finding of glycosuria during routine physical exam
• Prolonged hyperglycemia may be accompanied, in time, by microvascular and macrovascular complications
• Pediatric patients with type 2 DM tend to have faster deterioration of beta-cell function and onset of diabetes-related complications
• Additional risk factors in pediatric patients with type 2 DM: Adiposity, family history of DM, low socioeconomic status, female

Screening Guidelines Adapted from the American Diabetes Association 2022

• 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 and gender, weight for age >85th percentile, or weight >120% of ideal for height or obese (BMI >95th percentile) plus one or more 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 with 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 if normal: Every 3 years
  • May reduce interval if BMI is increasing
• Recommended tests:
  • FPG is recommended as the primary screening test for type 2 DM because of decreased cost and greater convenience
  • 2-hour oral glucose tolerance test (OGTT) is recommended as a secondary test
  • HbA1c may also be used to test for diabetes in the youth
• Clinical judgment should be used to test for type 2 DM in high-risk patients who do not meet these guidelines

Diagnosis

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

Other Specific Types of Diabetes Mellitus

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
  • Genetic testing will identify patients with K_ATP channel mutation [Kir6.2 subunit (KCNJ11) and SUR1 subunit (ABCC8)] who can be transitioned from insulin to sulfonylurea therapy
  • May be transient without recurrence, transient with recurrence after 7-20 years or permanent

Transient Neonatal DM

• Onset in the 1st week of life and persists for several weeks to months before spontaneous resolution
• Occurs most often in infants who are small for gestational age
• Characterized by hyperglycemia and pronounced glycosuria, resulting in severe dehydration and sometimes, metabolic acidosis but with 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 and normal, implying a functional delay in beta-cell maturation with 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
  • 0.5-1 U/kg/day of an intermediate-acting insulin in 2 divided doses results in dramatic improvement, accelerated growth and 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 with pancreatic agenesis
• Most commonly secondary to autosomal dominant mutations in the genes encoding the Kir6.2 and SUR1 subunits of the beta-cell K_ATP channel
• Studies revealed that almost one-half of neonatal DM patients had permanent diabetes, one third had transient diabetes and about one fourth had transient diabetes that recurred when they were 7-20 years old
• Affected twin and families with >1 affected infant have been reported
• May initially present as euglycemic and within the 1st month of life

• Maturity-onset diabetes of the young (MODY)
  • A primary defect in insulin secretion characterized by early onset between 9 and 25 years of age, absence of ketosis and autosomal dominant inheritance
  • Should be considered if:
    • Diagnosed with diabetes in the first 6 months of life
    • Family members with type 2 DM but with uncommon presentation
    • Mild fasting hyperglycemia (100-150 mg/dL or 5.5-8.5 mmol/L), stable A1c between 5.6% and 7.6% (38 mmol/mol and 60 mmol/mol) but young and nonobese
    • Absent diabetes-associated autoantibodies and with atypical presentation of type 2 DM
    • Some patients respond to diet therapy, exercise and/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

Drug- or Chemical-induced

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

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

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

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

Early in the evaluation of a new patient with DM, it is important to distinguish between type 1 and type 2 DM to optimize therapy

• Past and/or current DM characteristics including age of onset, diagnosis, management and treatment
• Previous or ongoing infection(s)
• Growth records (eg weight, length or height, BMI)
• Family history of DM and CVD
• History of DM-related complications
• Medications, nutritional status, eating patterns and exercise history
• Tobacco, alcohol use and drug history
• Contraceptive use
• Risk factors for atherosclerosis
• Glycosylated hemoglobin (HbA1c) history
• History of DKA
• History of gestational diabetes or macrosomia
• History of other disorders (eg endocrine, eating and mood disorders)

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

• If there is suspicion or any evidence of DKA, include:
  • Fasting or random plasma 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) and triglycerides (TG)]
• Plasma blood glucose test [fasting blood glucose, fasting plasma glucose (FPG)]
  • Should be used if increased red blood cell turnover (ie hemodialysis, blood transfusion, recent blood loss,etc) is present
• Test for microalbuminuria
• Thyroid antibodies
• Liver function test (LFT)
• Genetic testing - if presentation is atypical and with family history of monogenic diabetes

Diagnostic Criteria for DM Adapted From the American Diabetes Association 2022

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 and Complications Trial (DCCT) reference assay
  • If there is a discrepancy between HbA1c and plasma glucose measurements, the presence of hemoglobin variants (ie hemoglobinopathies) causing HbA1c assay interference can be considered, hence, plasma blood glucose may be used instead in order to diagnose DM
• 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 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 lb (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
• Patients presenting with characteristic symptoms of increased blood glucose level or hyperglycemic crisis with a random plasma glucose of ≥200 mg/dL (11.1 mmol/L)

Confirmation of Results

• If the results for hyperglycemia are not well-defined, a repeat test is done for confirmation
• The same test should be repeated or another type of laboratory test is done immediately using a new blood specimen
  • If 2 different tests are used and both results are in the diabetic range, DM is then confirmed
  • If 2 different tests are used and showed conflicting results, then the test that is above the normal range should be repeated, taking into consideration the presence of HbA1c assay interference, if HbA1c is one of the tests used
    • The confirmatory test would be the basis of the diagnosis

With the exclusion of secondary causes, evaluation should include but is not limited to the following:  

Growth Impairment

• Evaluate height and weight based on growth chart every clinic visit.
  • Please see Growth Charts clinical reference table for further information
• Monitor thyroid-stimualting hormone (TSH) levels at diagnosis, every 1-2 years and with occurrence of abnormal growth rate
• Evaluate for celiac disease with unsatisfactory weight gain

Diabetic Ketoacidosis (DKA)

• Hyperglycemia, accumulation of ketone bodies and metabolic disease due to insulin deficiency
• Clinical signs of DKA include dehydration, tachycardia, tachypnea, deep sighing respiration, acetone breath, nausea, vomiting, abdominal pain, blurry vision, confusion, drowsiness, progressive decline in the level of consciousness
• Type 1 DM patients may initially present with DKA at diagnosis
  • Obtain capillary glucose in children with excessive thirst, polyuria, abrupt unexplained weight loss, excessive tiredness, reduced level of consciousness, N/V, abdominal pain, hyperventilation, and appears dehydrated
• May also be caused by missed insulin doses
• Monitor venous pH, central venous and intra-arterial pressure
  • Mild DKA: Venous pH 7.2-7.3 or <15 mmoL/L plasma bicarbonate
  • Moderate DKA: Venous pH 7.1-7.2 or <10 mmoL/L plasma bicarbonate
  • Severe DKA: Venous pH <7.1 or <5 mmoL/L plasma bicarbonate
• Monitor heart rate (HR), respiratory rate (RR), blood pressure (BP), neurologic status, fluid input and output, evidence of hyper- or hypokalemia
• Monitor capillary glucose hourly
• Perform laboratory tests on electrolytes, blood glucose and blood gases every 2-4 hours

Hypoglycemia

• Blood glucose <70 mg/dL (<3.9 mmol/L) causing cognitive impairment
  • Cognitive impairment may be more pronounced in patients <5 years
• Evaluate for hypoglycemia in patients with DM receiving pharmacologic therapy
• May occur more frequently in those with 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 with neuroglycopenia; autonomic symptoms
  • Severe hypoglycemia: Altered states of consciousness, coma, seizures
• Determine frequency of hypoglycemia every clinic visit
• Assess for unawareness of hypoglycemia and assess blood glucose

Nephropathy/Diabetic Kidney Disease

• 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 and cardiovascular disease (CVD) are associated with the development of nephropathy
• In type 1 DM patients, it is recommended to screen for albuminuria annually by testing a random (morning) spot urine specimen for albumin-to-creatinine ratio (ACR) once the patient is at puberty or is >10 years old and has DM for 2-5 years
  • More frequent testing is indicated with increased values
• In patients with type 2 DM, ACR must be obtained at the time of diagnosis and annually thereafter
• Confirmed elevated ACR (>30 mg/g) consists of 2 out of 3 specimens obtained from separate days over a 6-month interval
  • Timed overnight or a 24-hour analysis with elevated albumin excretion rate (AER) of 20-199 mcg/minute may also be used
  • Exercise, smoking and menstruation may affect results, confirm on another day
• For type 1 DM patients baseline estimated glomerular filtration rate (eGFR) measurement must be obtained and repeated based on patient’s age, clinical status, duration of disease and treatment history
• For type 2 DM patients eGFR must be obtained at the time of diagnosis and repeated annually thereafter
• 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 and evaluate for parental hypertension which is a major risk
  • Ambulatory BP monitoring is recommended in adolescents with type 2 DM and with BP ≥90th percentile for age, sex, and height or type 2 DM patients ≥13 years old with BP ≥120/80 mmHg on 3 separate occasions
  • ≥95th percentile of systolic or diastolic BP for age, gender and height percentile measured on at least 3 separate days is definitive of hypertension
  • “High-normal” BP is ≥90th percentile of systolic or diastolic BP for age, gender and height percentile
• Exclude non-DM related causes upon confirmation of diagnosis
• Evaluate renal functional status by urinalysis, serum creatinine (Cr) and blood urea nitrogen (BUN)
• Obtain urinary albumin excretion if not obtained within previous 6 months

Dyslipidemia

• Elevated plasma lipid concentration, smoking, hypertension, obesity, family history of heart disease and DM contribute to the development of atherosclerosis
• Lipid profile should be determined as soon as diagnosis of type 1 DM is confirmed and preferably after glycemia has improved and patient is ≥2 years old
  • Nonfasting non-HDL-C level determination may be used as initial test but confirmatory testing should be done with fasting lipid panel
  • Repeat screening may be done at 9-11 years of age if initial screen is normal, then every 3 years if LDL-C level is within the accepted value (<100 mg/dL or <2.6 mmol/L)  
• Initial lipid screening for patients with type 2 DM is recommended soon after its diagnosis and preferably after glucose control has been achieved then annually thereafter
• Screen at puberty (≥10 years) if without mentioned family history
• Obtain fasting lipid profile in patients ≥10 years of age after glucose control has been achieved
  • If with abnormal result, repeat the test after fasting
  • If with abnormal lipids, monitor level after 6 months; optimize glycemic control, medical nutrition therapy and exercise
  • Repeat screening if LDL-C is borderline (100-129 mg/dL) or abnormal (≥130 mg/dL)

Retinopathy

• Commonly encountered after puberty and after 5-10 years of having DM
• Has been reported with DM of 1-2 years duration
• Identify early and treat appropriately
• Hypertension, poor metabolic control, presence of albuminuria, dyslipidemia, smoking, longer duration of DM and pregnancy are associated with increased risk for retinopathy
• Refer patient to ophthalmologist with expertise in diabetic retinopathy and its risks in the pediatric patient
  • Schedule regular ophthalmological screening with initial examination when the patient is ≥11 years of age or at onset of puberty and has type 1 DM for 2-5 years and every 2 years from then on if normal
    • Less frequent examinations (every 4 years) is advisable, depending upon the recommendation of an eye care professional and the presence of risk factors
  • Patients with type 2 DM should undergo screening for retinopathy thru dilated fundoscopy at the time of diagnosis then annually thereafter
    • Less frequent examinations (every 2 years) may be done if glycemic targets are achieved and eye exam is normal
  • Patient planning pregnancy should have an ophthalmological exam prior to conception during the 1st trimester and at the recommendation of the ophthalmologist

Neuropathy

• Annual foot exam is recommended for type 2 DM patients and at the beginning of puberty or at ≥10 years of age when patient has had type 1 DM for 2-5 years
• Inspection of the foot may be done in each clinic visit
• Comprehensive foot exam should include inspection, dorsalis pedis and posterior tibial pulse palpation, patellar/Achilles tendon reflex testing, and 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 by checking TSH level when clinically and metabolically stable and recheck every 1-2 years for patients with normal TSH or earlier if growth rate is abnormal, if with signs and symptoms of thyroid abnormalities or if there is a discrepancy in blood glucose levels, for reasons that cannot be identified
  • Please see Growth Charts clinical reference table for further information
• Monitor for thyroid control after establishing metabolic control
• Measure thyroid autoantibodies and TSH
  • After diagnosis of type 1 DM, identify patients at increased risk of autoimmune thyroid disease with the presence of thyroid autoantibodies [antithyroid peroxidase (APO) and antithyroglobulin]
  • Treat patients with elevated TSH levels
  • Measure free T4 if TSH is abnormal
  • Perform thyroid function test whenever thyroid dysfunction is suspected and if patient has thyromegaly
• Evaluate for hypothyroidism and hyperthyroidism thoroughly and 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 with gluten (eg wheat, rye, barley and oats)
• Prevalence is low in Southeast Asia
• Symptoms include diarrhea, weight loss or poor weight gain, growth failure, abdominal pain, chronic fatigue, irritability, inability to concentrate, malnutrition due to malabsorption and other GI problems
• Symptoms of DM patient with celiac disease include unpredictable blood glucose levels, unexplained hypoglycemia and deterioration in glycemic control
• Screen patients with type 1 diabetes for celiac disease by testing for the presence of IgA autoantibodies to tissue transglutaminase (tTG) if with normal total serum IgA or IgG tissue transglutamine and deaminated gliadin antibodies if with deficient IgA
  • Perform test upon diagnosis of type I DM and in children with 1st-degree relatives with celiac disease, growth failure, failure to gain weight and gastroenterologic symptoms (diarrhea, flatulence, abdominal pain, signs of malabsorption), and those with frequent unexplained hypoglycemia or deteriorating glycemic control
  • Repeat within 2 years after DM diagnosis, and after 5 years
  • Frequent screening is performed in symptomatic patients or to those with a 1st-degree relative with celiac disease
  • Confirm elevated tTG antibodies
  • Interpret low to moderate tTG antibodies along with symptoms and repeat screening after 6-12 months
  • In patients with signs and symptoms referable to celiac disease, screening for tTG antibodies is recommended at other times
• Confirm positive antibody levels
  • Recommend small bowel biopsy if patient has elevated tTG antibodies, as well as in asymptomatic children who are at risk for celiac disease
  • Biopsy may be excluded in those with >10x the upper limit of normal if other tests were done (eg endomysial antibody test), performed on a different blood specimen
  • Check for HLA types in patients without a history of an intestinal biopsy
• Refer patient to gastroenterologist once celiac disease is confirmed
  • Recommend consultation with registered dietitian experienced with DM and celiac disease in pediatric patients for a diet that is gluten-free
• 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 with DM considers suicide
• Screen patients ≥10 years old annually for depression
• Screen for psychiatric disorders in patients with difficulties in achieving treatment goals and with recurrent DKA
  • Patients with DKA are more likely to develop psychiatric disorders

Eating Disorders

• Associated with DM in adolescent patients
• Patients with eating disorders are at risk for poor metabolic control and recurrent hospitalization
• A mental health professional should screen for eating disorders with failure in treatment goals especially if patient is underweight
• Type 1 DM patients should be screened for eating disorders at age 10-12 years

Smoking

• Inquire for personal history of smoking including e-cigarettes and exposure to secondhand smoke
  • Discourage smoking in both smokers and non-smokers

Psychosocial Issues

• Addressed at diagnosis and during follow-up, including family conflicts and refer to a mental health professional, with experience in pediatric diabetes
  • Support and participation of the patient’s family is important for compliance to the treatment plan
• Health care providers should inquire regarding the child’s school performance and social issues
• At 7-8 years of age, evaluate the patient for psychosocial issues and the burden of diabetes
• At 12 years of age or at a stage that it is reasonably possible, allow the pediatric patient to talk alone with their health care provider(s)
  • “Mature minor rule”: Children 12-13 years, who seem mature enough, have the right to secure consent to or decline a treatment, except when it would place their health at risk
• Preconception counselling should be part of the routine care of all adolescent girls of childbearing potential

Other Conditions

• Evaluate patient for other autoimmune diseases (eg Addison disease, autoimmune hepatitis, autoimmune gastritis, dermatomyositis, myasthenia gravis)
• Non-alcoholic fatty liver disease should be evaluated by measuring AST and ALT in type 2 DM patients at the time of diagnosis and annually thereafter
• Other comorbidities that are also needed to be evaluated:
  • PCOS
  • Other comorbidities with pediatric obesity (eg sleep apnea, hepatic steatosis and musculoskeletal complications)