Clinical Pathology

Carbohydrates
IJA, MD

I. CARBOHYDRATES o A rare condition caused by mutations in the ProInsulin

• Carbohydrates are the major constituents of physiologic Gene
systems • Concentration of C-Peptide in blood is higher than that of
• They are organic compounds composed of Carbon, Insulin, primarily because of the Hepatic Clearance of
Hydrogen, and Oxygen [Cx(H2O)y], which, along with LIPIDS Insulin
and PROTEINS, provide energy and contribute to the o The half-life of both C-Peptide and ProInsulin is
structure of organisms. approximately 30 minutes, whereas it is only 4 to 9
• There are different DIETARY HEXOSES (6-Carbon- minutes for Insulin.
Containing Carbohydrates): • Cirrhosis
a. D-Glucose o HyperInsulinemia is due to decreased Hepatic Insulin
b. D-Galactose Clearance
c. D-Fructose • Conditions with High Insulin Levels:
• Important Disaccharides: 1. With Low Glucose → suggests inappropriate secretion
a. Lactose → Glucose + Galactose or administration of Insulin
b. Sucrose → Glucose + Fructose 2. Insulin-Resistant individuals who need to secrete extra
• Principal circulating sugar is GLUCOSE → primarily used as Insulin to keep blood Glucose levels normal.
energy sources or are stored as GLYCOGEN Hypoglycemia
• Contribute to the structure of organisms and are needed for • Unregulated Excess Insulin Secretion → HYPOGLYCEMIA
specific cellular functions and can modify proteins and their o Seen in Insulinoma and Congenital Hyperinsulinism
function by GLYCOSYLATION • Insulinoma:
• Complex Carbohydrates are digested into Simple Sugars 1. Low Serum Glucose Level
• Carbohydrates are measured in WHOLE BLOOD, SERUM, or 2. Elevated Insulin and ProInsulin Levels
PLASMA 3. Hypoglycemic Symptoms
• In addition, measurements of Glucose in URINE, • Congenital Hyperinsulinism
CEREBROSPINAL FLUID, INTERSTITIAL FLUID, and other body 1. Cause dysregulation in Insulin secretion and
fluids are important clinically. Hypoglycemia
• The concentration of Glucose in blood is normally controlled • C-Peptide Levels are measured in hypoglycemic states to
within narrow limits by many hormones, the most significant help identify the cause of the Hypoglycemia
of which, INSULIN, is produced by the ENDOCRINE • High Insulin and C-Peptide Levels:
PANCREAS A. Insulinoma
• DIABETES MELLITUS is the most common disease of B. Congenital Hyperinsulinism
carbohydrate metabolism • High Insulin and LOW C-Peptide Levels:
Function of the Endocrine Pancreas A. Hypoglycemia from INJECTED or EXOGENOUS INSULIN
• The Endocrine Pancreas secretes several hormones from Diabetes Mellitus
different cells residing in the ISLETS OF LANGERHANS. • C-Peptide and Glucose can be measured
1. Beta Cells: Insulin and Amylin (Islet Amyloid o Overnight 8-hour fast
Polypeptide [IAPP]) o After stimulation by an oral mixed meal or after Glucagon
2. Alpha Cells: Glucagon, can also produce Glucagon-like stimulation
Peptide 1 (GLP-1) after there has been injury to Beta o Evaluates the Beta Cell Secretory capacity
Cells • C-Peptide
3. Delta Cells: Somatostatin o Urine C-Peptide:Creatinine has also been used to assess
4. Epsilon Cells: Ghrelin Beta Cell function
5. PP (Gamma or F) Cells: Pancreatic Polypeptide (PP) o Low C-Peptide levels are characteristic of the absolute
A. Insulin Insulin Deficiency of Type 1 Diabetes
• Anabolic Hormone, with a o Evaluation after Pancreatectomy and Post-Pancreatic
mass of approximately Transplantation
5800 daltons (Da), with a • RENAL FAILURE can cause elevation of both C-Peptide and
21 Amino Acid A chain and ProInsulin since both are primarily degraded in the kidneys
a 30 amino acid B chain B. Amylin
that are linked by two • 37 amino acid protein secreted by Pancreatic Beta Cells
disulfide bonds • Amylin is colocalized and co-secreted with Insulin in
• Synthesized initially as response to STIMULATION BY NUTRIENTS
PREPROINSULIN • Amylin slows gastric emptying and inhibits Postprandial
• Immediate precursor of Glucagon secretion → overall result is a lowering of
Insulin is PROINSULIN Postprandial Hyperglycemia
o ProInsulin will be • Can also reduce food intake and can be associated with
converted to INSULIN weight loss
by C-PEPTIDE → • High Levels of AMYLIN have been observed in
removal of the 31 HyperInsulinemic, Insulin-Resistant States, such as:
amino acid peptide A. Impaired Glucose Tolerance
segment that connects B. Early Type 2 Diabetes → Amyloid Deposits, fibroid
the A and B chains material derived from IAPP, are observed in islets in
• ProInsulin and its metabolites may cross-react with Insulin Type 2 Diabetes
in some Insulin Immunoassays. C. Pancreatic Cancer
o This can be significant, especially because the half-life • Amylin Analogs may be helpful in Diabetes management by
of ProInsulin is at least 3x as long as that of Insulin limiting Postprandial Glucose Excursions and Promoting
• Insulin-Sensitive Tissues: Skeletal Muscle, Fat, and Liver Satiety
• Functions: C. Glucagon
1. Stimulates Glucose uptake and the formation of • Proglucagon is synthesized in the Pancreatic Alpha Cells
Glycogen and the L Cells of the Distal Small Bowel.
2. Inhibits Glucose Production o Alpha Cells will produce Glucagon and Incretin
3. Increases Protein and Triglyceride Synthesis Glucagon-Like Peptide 1 (GLP-1) in the L Cells of the
• ELEVATED PROINSULIN:INSULIN are found in the following: Intestines
1. Type 2 Diabetes • In Diabetes, the processing of Proglucagon in Alpha Cells can
2. Recent-Onset Type 1 Diabetes be altered, producing GLP-1.
3. Partial Pancreatectomy • Functions:
o These conditions are either due to reduced conversion of A. Stimulates Glucose Production
ProInsulin to Insulin or if there is a decrease in the B. Important regulator of Hepatic Glycogenolysis,
secretion of Insulin by Beta Cells Gluconeogenesis, Ketogenesis, and Hepatic Amino Acid
• Familial HyperproInsulinemia Turnover
o Associated with:
a. Impaired Glucose Tolerance
b. Type 2 Diabetes

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 Clinical Pathology
Carbohydrates
IJA, MD
• In Type 1 Diabetes, over time, PROGRESSIVE GLUCAGON
DEFICIENCY develops → results in increased glycemic
fluctuations and difficulty recovering from Hypoglycemia.
• In Type 2 Diabetes → inappropriately elevated postprandial
levels of glucagon are observed
• Ratio of Insulin to Glucagon is important in the regulation of
Carbohydrate Metabolism
A. Anabolism → favored when there is a relative increase
in the Insulin-to-glucagon ratio (postprandial state)
B. Catabolism → favored with a relative decrease in this
ratio (Fasting State)
o The Ratio of Insulin to Glucagon is influenced by
Somatostatin, Neural Input, Intestinal Peptides, and the
concentrations of Glucose and other metabolites
o Ratio of Insulin to Glucagon is tightly regulated to keep
blood Glucose concentrations within the normal range
Glucagonomas
• Rare islet cell tumors that produce excessive Glucagon
• Clinically, Glucagonomas present with:
A. Characteristic Necrotizing Migratory Erythematous
Rash
B. Stomatitis
C. Glossitis
D. Weight Loss
E. Anemia
F. Mild Diabetes Mellitus
• Usually associated with Fasting Glucagon Levels >120 pg/mL,
but levels can range from 900 to 7800 pg/mL
• The processing of Proglucagon is impaired, and large
molecular weight forms can be seen.
Familial Hyperglucagonemia
• Autosomal-Dominant disorder
• Glucagon levels are high in the absence of tumor.
• Family history is helpful in making this diagnosis.
Other Conditions with Milder Elevations of Glucagon
• Includes:
a. Multifunctional Neuroendocrine Tumors
b. Cirrhosis
c. Nonalcoholic Fatty Liver Disease
d. Renal Insufficiency
e. Cushing Syndrome
f. Pancreatitis
g. Acromegaly
h. After Gastric Bypass Surgery
D. Somatostatin
• Tetradecapeptide with a disulfide bond
• Was originally discovered as a HYPOTHALAMIC HORMONE
that inhibited Growth Hormone secretion, but the discovery
of Somatostatin in the Islets of Langerhans prompted
further investigation of its function in the endocrine
pancreas.
o Subsequently, Somatostatin was found in the
Gastrointestinal Tract and Nervous System.
• Produced in the Delta Cells of the Islet and in Extra-Islet
Neuroendocrine Cells
• It inhibits the secretion of:
1. Pituitary Hormones (Growth Hormone and Thyrotropin)
2. Pancreatic Hormones (Insulin, glucagon, PP)
3. Gastric Inhibitory Polypeptide (GIP)
• Somatostatin-28:
o Contains an N-terminal extension
o A more potent inhibitor of Insulin secretion
• Inhibits:
o Gastrin, Secretin, Vasoactive Intestinal Peptide,
Cholecystokinin, Motilin, Arginine Vasopressin,
Acetylcholine, Epidermal Growth Hormone, Neurotensin,
and Serotonin
• Nonendocrine Functions Include Inhibition of:
a. Gastric Acid Secretion
b. Gastrointestinal Motility, including Gastric Emptying
Time
c. Gallbladder Contractions
d. Pancreatic Enzyme Release
• High Levels of Somatostatin:
1. Somatostatinomas
2. Small Cell Lung Cancer, Medullary Thyroid Cancer, and
Pheochromocytoma
• Octreotide and Lanreotide
o Long-acting Somatostatin analogs
o Used to treat Pituitary Tumors (Acromegaly,
Adrenocorticotropic Hormone [ACTH]– and Thyroid-
Stimulating Hormone [TSH]–Producing Tumors), as well
as other tumors and syndrome
o Octreotide Scintigraphy has also been used for the
diagnosis, localization, and detection of metastatic
disease, and for prediction for success of treatment with
Somatostatin Analogs for Gastroenteropancreatic
Neuroendocrine Tumors.
E. Ghrelin and Pancreatic Polypeptide
• A 28 amino acid peptide that is primarily synthesized in the
STOMACH but also is made in Islets, the Heart, Lungs,
Kidney, Immune System, and Hypothalamus and Pituitary
Glands
• It STIMULATES APPETITE primarily by actions in the
Hypothalamus and is associated with weight gain and
adiposity
• Pancreas:
o Ghrelin inhibits Glucose-Stimulated Insulin Secretion
and stimulates Glucagon Secretion.
• Ghrelin also increases Growth Hormone secretion, Gastric
Emptying, and Acid Secretion
Pancreatic Polypeptide
• A 36 amino acid peptide
• Secretion is increased by NUTRIENT INGESTION, through
vagal-cholinergic stimulation
• PEPTIDE YY and NEUROPEPTIDE Y
o Part of the PP Family
o Found in the Gastrointestinal Tract and Nervous System
o Affect gastrointestinal function, food intake, and satiety
• PP increases satiety, delays gastric emptying, and inhibits
gall bladder motility and exocrine pancreas secretion
• Excessive PPE:
1. Tumors of PP Cells and some Insulinomas
2. Gastrinomas
3. Glucagonomas
4. VIP-Secreting Tumor
F. Incretins
• Oral nutrients stimulate the release of Incretins from the
intestines
• The Incretin effect refers to the greater and earlier Insulin
response to the oral administration of Glucose compared
with intravenous Glucose
• The most important Incretins in the regulation of Insulin
secretion are:
1. GLP-1
2. Glucose-Dependent Insulinotropic Peptide (Gastric
Inhibitory Polypeptide [GIP])
• GLP-1
o Rapidly stimulates Insulin and Somatostatin secretion,
suppresses Glucagon secretion, and slows gastric
emptying in response to a meal
II. GLUCOSE MEASUREMENTS
Glucose Measurement Methods
• Measurements of Glucose are critical for the diagnosis and
management of diseases affecting Carbohydrate
Metabolism.
• Glucose is measured in Whole Blood, Plasma, Serum,
Cerebrospinal Fluid, Pleural Fluid, and Urine for a variety of
diagnostic and management purposes.
• The standard clinical laboratory analysis of Glucose is
performed on PLASMA OR SERUM derived from a
phlebotomy specimen
• Most measurements of Glucose employ enzymatic method:
1. Glucose Oxidase
2. Hexokinase
Specimen Considerations
• Glycolysis causes plasma Glucose to decline over time while
the plasma is in contact with cells.
o A specimen is appropriate for Glucose analysis if serum
or plasma is separated from the cells within 30 minutes
o Until separation has been performed, it is recommended
that specimens be kept on ice.
• Sodium Fluoride, long used to prevent in vitro Glycolysis, is
now recognized to be INEFFECTIVE
Whole Blood Glucose
• Whole Blood Glucose Specimens, analyzed with point-of-
care monitoring devices, are used in the home, in the
physician’s office, or at the bedside in the hospital to
monitor for Hypoglycemia and Hyperglycemia
• Most of these devices have been calibrated to give results
similar to plasma levels and can report plasma or whole
blood readings.
• Capillary Blood is the source for most of these whole blood
Glucose measuring devices
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 Clinical Pathology
Carbohydrates
IJA, MD

• Capillary Blood Glucose is similar to Arterial Glucose but can • Can cause nerve damage → DIABETIC NEUROPATHY
vary markedly from venous samples depending on timing • Most Diabetes-Related Deaths, however, are related to the
relative to food ingestion. increased risk of developing ATHEROSCLEROTIC DISEASE.
• Capillary Glucose Tests performed with point-of-care o People with Diabetes are at least 2-4x more likely to have
devices should NOT be used to diagnose Diabetes or Heart Disease and Cerebrovascular Disease than those
Hypoglycemic Disorders. without Diabetes
Monitoring Devices are DM Diagnosis
Causes of Error
Influenced By:
• Insufficient Volume of • High Levels of:
Blood 1. Salicylate
• Milking the Finger to 2. Acetaminophen
Acquire Sufficient Blood 3. Levodopa
• Outdated Test Strips 4. Vitamin C
• Alternative Sites 5. Uric Acid
• Environmental Factors 6. Bilirubin
(Humidity, Heat, Altitude) 7. Lipids
• Malfunctioning Meter • Low Oxygen Levels
• Dirty Meter • Others are altered by
• Hypertriglyceridemia touching the reaction area
• Hypotension
• Measurements Outside of
the Hematocrit or
Temperature Range
• Other Factors • To diagnose Diabetes, 2 abnormal results from one or more
Interstitial Glucose of the following tests are required:
• Interstitial Glucose Monitoring with Continuous Glucose 1. Fasting Plasma Glucose level of 126 mg/dL (7.0 mmol/L)
monitoring (CGM) helps individuals with Diabetes better or higher (the Glucose level should be obtained after an
self-manage their disease, reducing Hypoglycemia, Glucose 8-hour fast)
variability, and HbA1c levels 2. Plasma Glucose Level ≥200 mg/dL (11.1 mmol/L) 2 hours
• Most CGM devices measure Glucose levels using after a Glucose Load (75-g Oral Glucose Tolerance Test
Electrochemical Methods or Fluorescence-Based Sensor. [OGTT])
• These devices measure Glucose levels in the INTERSTITIAL 3. Random Glucose ≥200 mg/dL (11.1 mmol/L) with
FLUID using a Subcutaneous Tissue Sensor symptoms of Hyperglycemia
o A transmitter is placed on the skin directly over the 4. Hemoglobin A1c (HbA1c) of ≥6.5%
sensor • Tests can be performed on two different days or 2 different
tests can be performed on the same day.
• “Real-Time” CGM Devices
o Glucose readings are automatically transmitted to a • If the patient has discordant results from two different tests,
smartphone, Insulin Pump, smartwatch, or device- then the test for which the result is above the diagnostic cut
specific receiver every 5 minutes point should be repeated.
o Contains alerts/alarm that can be set for current or Classification of Diabetes Mellitus
approaching Hypo-/Hyperglycemic Episodes • The most common forms of Diabetes are Type 1 and Type 2
• “Flash” CGM Devices • Characterized by ABSOLUTE INSULIN
o “Flash” (intermittently scanned) CGM devices measure DEFICIENCY and BETA CELL
Glucose every minute, record readings every 15 minutes DESTRUCTION
o Require the user to intermittently scan a reader over the • Used to be called Juvenile-Onset Diabetes
Type 1 DM
transmitter to view results. or Insulin-Dependent Diabetes.
• Trend Analysis • Although this disease is most commonly
o The person with Diabetes views Glucose readings along diagnosed in young people, its onset can
with trend arrows that indicate the direction and rate of occur at any age
change of Glucose. • Characterized by INSULIN RESISTANCE
o Tracings display Glucose readings over time, providing and INSULIN SECRETORY DEFECTS
information about Glucose patterns over hours or days • Used to be called Adult-Onset or Non-
o Glucose “Trend Analysis” can reveal unsuspected Insulin Dependent Diabetes
NOCTURNAL HYPOGLYCEMIA or POSTPRANDIAL Type 2 DM • Although the onset of Type 2 Diabetes is
HYPERGLYCEMIA and is used for modifying treatment most common in older adults, it can occur
• Integrated CGM (iCGM) Devices at any age, including childhood.
o Integrated CGM (iCGM) devices can transmit Glucose • Many patients with Type 2 Diabetes use
readings to different digitally connected devices such as Insulin Therapy
Insulin Pumps or can be used alone. Other Considerations
o CGM devices can help direct Insulin Delivery. • PreDiabetes
o In some systems, the Insulin Pump will stop delivering o PreDiabetes designates conditions in which Glucose
Insulin if a Hypoglycemic Threshold has been reached or homeostasis is abnormal, but serum Glucose levels are
is predicted to occur not high enough to be classified as Diabetes
o In the “Hybrid” Artificial Pancreas Systems, Basal Insulin o Patients have impaired Fasting Glucose and impaired
is delivered automatically based on CGM readings Glucose Tolerance
o There are studies of a BIONIC PANCREAS → an o At increased risk for Cardiovascular and Cerebrovascular
automated wearable Insulin and Glucagon subcutaneous Diseases
infusion system that communicates with a continuous
• Formal OGTTs
Glucose monitor o Formal OGTTs are not generally recommended for
• The Mean Absolute Relative Difference (MARD) is frequently routine clinical use in the diagnosis of Diabetes
used to assess CGM accuracy o 2 Exceptions:
• Capillary Glucose Measurements need to be used if 1. Diagnosis of Cystic Fibrosis-related Diabetes
Hypoglycemia is suspected but not observed by CGM 2. Diabetes during pregnancy
III. DIABETES MELLITUS • Cystic Fibrosis
• Diabetes Mellitus is a group of diseases in which BLOOD o Annual screening with a 2-hour 75-g (1.75 g/kg) OGTT is
GLUCOSE LEVELS ARE ELEVATED. recommended beginning at least by age 10 years.
• Diabetes is the most common set of disorders of o HbA1c testing for screening for Cystic Fibrosis-Related
Carbohydrate Metabolism Diabetes is not recommended
• Diabetes is the leading cause of treated End-Stage Renal • Pregnant Woman
Disease, the most common cause of Nontraumatic o Pregnant women with risk factors for Type 2 Diabetes
Amputations, and the foremost cause of New Blindness in should be screened using an OGTT test at their INITIAL
adults ages 20 to 74 years. PRENATAL VISIT

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 Clinical Pathology
Carbohydrates
IJA, MD

o If testing results are abnormal during the 1st Trimester • It is not unusual to diagnose Type 2 Diabetes after the onset
using standard criteria, the woman is considered to have of complications.
had UNDIAGNOSED DIABETES PRIOR TO PREGNANCY o Therefore, ROUTINE SCREENING for high-risk individuals
o All other women who do not have the risk factor should is recommended.
be screened between 24 and 28 weeks’ gestation. • The American Diabetes Association (ADA) recommends
screening for Type 2 Diabetes in any overweight or obese
adult if one or more risk factors are present
o In general, it is recommended that adults ages ≥45 years
be screened for Diabetes every 3 years, but screening
should be performed earlier and more frequently if the
individual is at high risk.
• The preferred test is a FASTING PLASMA GLUCOSE or HbA1c
LEVEL.
o If a Random Plasma Glucose Level is 160 mg/dL (8.9
mmol/L) or higher, a Fasting Plasma Glucose, HbA1c, or 2-
hour 75-g OGTT should be performed
• Before an OGTT is performed, individuals should ingest at • Home Blood Glucose Monitoring Devices SHOULD NOT be
least 150 g/day of Carbohydrates for the 3 days preceding used to diagnose Diabetes
the test without limitation in physical activity, and the test • In recent years, Type 2 Diabetes has been diagnosed in
should be performed after an overnight 8- to 14-hour fast. younger individuals, including children
Type 1 Diabetes Mellitus • ADA recommends screening children and adolescents,
• Caused by an AUTOIMMUNE DESTRUCTION of Insulin- beginning at age 10 years or at onset of puberty, on the
Producing Beta Cells in the Islets of the Pancreas, causing an following conditions:
ABSOLUTE DEFICIENCY IN INSULIN PRODUCTION. 1. Overweight (BMI ≥85th percentile) or Obese (≥ 95th
• The genetic susceptibility to develop Type 1 Diabetes is percentile
related, at least in part, to the inheritance of specific immune 2. One or more risk factors
response genes associated with HLA-DR/DQ on Risk Factors
Chromosome 6, as well as other genes and genetic markers. 1. Overweight or Obesity (BMI ≥25 kg/m2 or ≥23 kg/m2 in Asian
• It is hypothesized that a precipitating event occurs, such as Americans)
a Viral Infection, Toxin Exposure, or other environmental 2. Sedentary Lifestyle
influence, which TRIGGERS the autoimmune destruction of 3. First-Degree Relative with Diabetes
the Beta Cells. 4. Advanced Age (≥45 years)
• Most or all of the Beta Cells are DESTROYED, resulting in 5. High-Risk Ethnicity (African Americans, Latinos, Native
inadequate or absent Insulin secretion and Hyperglycemia Americans, Asian Americans, and Pacific Islanders)
o Therefore, C-Peptide levels and Endogenous Insulin 6. Polycystic Ovary Disease
7. History of Gestational Diabetes or Delivery Before Diabetes
levels are VERY LOW or UNDETECTABLE.
of a Baby Weighing >9 Pounds
• People with Untreated Type 1 Diabetes develop DIABETIC
8. Hypertension
KETOACIDOSIS (DKA).
9. Vascular Disease
• Insulin Therapy is required for all people with Type 1
10. Dyslipidemia (HDL Cholesterol ≤35 mg/dL [0.90 mmol/L]
Diabetes. and/or Triglyceride level ≥250 mg/dL [2.82 mmol/L])
• Antibody markers of Beta Cell destruction are commonly 11. HbA1c ≥5.7%
present before and at the time of onset of Type 1 Diabetes 12. Impaired Fasting Glucose
• Measurements of Pancreatic Autoantibodies can be useful 13. Impaired Glucose Tolerance
for prediction and diagnosis 14. Other conditions associated with Insulin Resistance (i.e.,
• Autoantibody Assays are available for the 65 kDa isoform of: acanthosis nigricans)
a. Glutamic Acid Decarboxylase (GAD65) Characteristics of Type 1 and Type 2 DM
b. Insulin (IAA) Type 1 DM Type 2 DM
c. Insulinoma-Associated Protein 2 (IA-2, a tyrosine Frequency 5-10% 90-95%
phosphatase–related protein) More common with
Any, but most common in
d. Zinc Transporter 8 (ZnT8A) Age of Onset children and young
advancing age, but can
• Although the presence of antibodies may help in the occur in children and
adults
adolescents
differentiation of Type 1 Diabetes from other types of
Genetic, obesity, sedentary
Diabetes early in the course of the disease, the absence of
lifestyle, race/ethnicity,
antibodies does not exclude this diagnosis Genetic, autoimmune,
Risk Factors hypertension,
• Those individuals at greatest risk of developing Type 1 environmental
dyslipidemia, polycystic
Diabetes have high titers of multiple autoantibodies ovarian syndrome
o In family as well as in population studies, the detection No Autoimmunity
Destruction of
of at least 2 Autoantibodies is associated with increased Insulin Resistance and
Pathogenesis Pancreatic Beta Cells,
progressive Insulin
risk of developing Type 1 Diabetes. usually autoimmune
deficiency
• IAAs are more common in young children who develop Type C-Peptide
1 Diabetes, whereas GAD65 is more common in adults Very low or undetectable Detectable
Levels
• Prediction for the development of Type 1 Diabetes is Pancreatic
enhanced by use of the Diabetes Prevention Trial-Type 1 Prediabetes
autoantibodies (GAD65, Pancreatic Autoantibodies
Risk Score that includes parameters related to: IA-2, IAA, ZnT8) may be absent
present
1. Glycemia
Insulin absolutely Oral agents and/or non-
2. Age Medication necessary; multiple daily Insulin injectable
3. Body Mass Index (BMI) Therapy injections or Insulin hypoglycemic drugs
4. C-Peptide Level pump Insulin commonly needed
Type 2 Diabetes Mellitus Lifestyle (weight loss if
• Type 2 Diabetes is the most common type of Diabetes Therapy to overweight or obese and
Prevent or None known increased physical activity)
• This disease is familial, but the underlying genetic defects
Delay Onset Clinical Trials in progress Oral Medications
for most of those affected have yet to be determined. of Diabetes (Metformin, Acarbose) may
• Unlike Type 1 Diabetes, this is not an autoimmune disease; be helpful
thus, PANCREATIC AUTOANTIBODIES ARE ABSENT Measures of Glycemic Control
• C-Peptide levels are measurable in Type 2 Diabetes, but • Good Glycemic Control is associated with preventing or
there is usually a reduction in beta cell mass over time. delaying the progression of microvascular complications in
• Most patients are: Diabetes.
1. Insulin Resistant • Lowering Glucose levels in patients with Type 1 Diabetes
2. Overweight or Obese slows or prevents the development of Retinopathy,
3. Have deficiency in Insulin Secretion Neuropathy, and Nephropathy
• People with new-onset Type 2 Diabetes can be • The standard of care is to measure HbA1c levels every 3 to
ASYMPTOMATIC 6 months to monitor glycemic control

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 Clinical Pathology
Carbohydrates
IJA, MD
• Defined as Hemoglobin A that is
IRREVERSIBLY GLYCOSYLATED at one or
both N-terminal Valines of the β-chains of
the tetrameric hemoglobin molecule,
including Hemoglobin that may also (but
not solely) be glycosylated on Lysine
Residues
• HbA1c Testing provides an index of average
blood Glucose levels over the past 2 to 4
months.
• HbA1c levels represent a “weighted”
average of Glucose levels, with the
youngest erythrocytes contributing to a
greater extent than older ones.
• Approximately 50% of the HbA1c level is
determined by plasma Glucose levels over
the previous month.
• Certified methods are available for
measuring HbA1c:
1. Immunoassay
Glycosylated 2. Ion-Exchange HPLC
Hemoglobin 3. Eletrophoresis
(HbA1c) 4. Boronate Affinity HPLC
5. Enzyme Methods
• All HbA1c assays are affected by:
a. Blood Loss
b. Blood Transfusions
c. Conditions that affect the Age or
Survival of Red Blood Cells, such as
Hemolysis, Pregnancy, and the use of
drugs that stimulate Erythropoiesis
• Shortened Red Blood Cell Survival or lower
mean age will lower HbA1c levels as a result
of reduced exposure to plasma Glucose.
• HbA1c assay without interference are used
for patients with abnormal hemoglobin but
normal red cell turnover
• Fructosamine and Glycated Albumin
assays may be useful in patients for whom
HbA1c assays are inaccurate, such as those
with Hemoglobinopathies, Advanced
Chronic Kidney Disease, and Hemolytic
Anemias.
• Measures Glycosylated Albumin and other
Glycosylated Protein such as Globulins and
Lipoproteins
• These measurements can be affected by
alterations in serum protein levels that are
present during:
1. Acute Illnesses
2. Nephrotic Syndrome
3. Thyroid Disease
Fructosamine
4. Liver Disease
Assay
• Use serum samples and automated
equipment → thus, they are simple to
perform and low cost.
• However, they are not well standardized
and are sensitive to variations in
temperature
• The assay should not be performed if the
Serum Albumin Level is ≤3.0 g/dL (0.45
mmol/L)
• Better standardized, more precise, and
inexpensive
• Have better Specificity and Sensitivity over
Fructosamine Assay
• Several methods are available for
Glycated measuring Glycated Albumin, including:
1. Boronate Affinity Chromatography
Albumin
2. Ion-Exchange Chromatography
Assays
3. HPLC
4. Immunoassays
5. Enzymatic Methods
• Glycated Albumin results can be reported
as a percent of Total Albumin and are not
affected by elevated serum bilirubin levels
Ketone Testing
• The Ketone Bodies β-Hydroxybutyric Acid, Acetoacetic
Acid, and Acetone are products of FATTY ACID
DEGRADATION.
• Using urine or blood is particularly important for individuals
with Type 1 DM to detect KETOSIS
o DKA is a serious and potentially fatal hyperglycemic
condition requiring urgent treatment.
o Clinically presents with nausea, vomiting, abdominal
pain, electrolyte disturbances, and severe dehydration.
o β-Hydroxybutyric Acid and Acetoacetic Acid are normally
present in a 1:1 ratio at concentrations of 0.5 to 1.0
mmol/L each → greatly increased in DKA as a result of the
altered redox state and elevated levels of NADH in the
hepatic mitochondria
• The most commonly used strips and tablets use SODIUM
NITROPRUSSIDE (Sodium Nitroferricyanide) and turn
PURPLE in the presence of ELEVATED levels of Acetoacetic
Acid.
o Acetone is detected in the presence of GLYCINE
o False Negative Results:
1. Old Strips
2. Strips with Excessive Contact with Air
3. Large Amounts of Vitamin C (very acidic urine)
o False Positive Results:
1. Use of Sulfhydryl-Containing Medications (e.g.,
Captopril)
2. Presence of Highly Colored Urine
• During DKA, the β-Hydroxybutyric Acid levels fall and
Acetoacetic Acid and Acetone levels rise making β-
Hydroxybutyric Acid not detected by the old Nitroprusside-
Based Testing
o Direct measurement of β-Hydroxybutyrate is preferred
over older Nitroprusside-Based Tests.
o β-Hydroxybutyric Acid can be measured in serum by
Enzymatic, Electrochemical, Chromatographic,
Electrophoretic, and Colorimetric Methods.
• For the monitoring of recovery from DKA in the hospital
setting:
1. Serial measurements of serum electrolytes, including
Bicarbonate with calculation of the Anion Gap, are often
used
2. Serial measurement of β-Hydroxybutyric Acid provides
an additional tool to monitor resolution of DKA.
IV. HYPOGLYCEMIA
• Hypoglycemia results from an IMBALANCE between
GLUCOSE UTILIZATION (by brain, erythrocytes, muscle, and
kidneys) and PRODUCTION (endogenous Glucose production
by liver and kidneys and from ingestion of carbohydrates)
• Rate of Glucose Utilization exceeds the rate at which
Glucose is being produced
• Categories of Symptoms in Hypoglycemia:
1. Neurogenic Symptoms → triggered by the Autonomic
Nervous System
o Tremulousness, palpitations, and anxiety are
Catecholamine Mediated
o Diaphoresis, hunger, and paresthesia are related
to Acetylcholine release
2. Neuroglycopenic Symptoms → due to diminished
Glucose supply to the CNS
o Dizziness, tingling, difficulty concentrating,
blurred vision, confusion, behavioral changes,
seizure, and com
• Major Cause of Hypoglycemia:
o Treatment of Diabetes Mellitus with Insulin or agents that
increase Insulin secretion (Insulin secretagogue drugs),
such as Sulfonylureas
• Pancreatic HyperInsulinemic Hypoglycemia
o Can be diagnosed by demonstrating that Insulin
secretion is not suppressed normally when the individual
develops Hypoglycemia
• Measurements to Determine the Correct Diagnosis of
Hypoglycemia:
1. Insulin
2. C-Peptide
3. Pro-Insulin
4. Insulin and Insulin Receptor Autoantibodies
5. β-Hydroxybutyrate
6. Drugs (i.e., Sulfonylurea and Meglitinide levels)
• An important tool in assessing patients
with episodes suggestive of low plasma
Glucose levels
• Composed of:
1. Symptoms consistent with
Whipple’s Triad
Hypoglycemia
2. Documented Low Plasma Glucose
Level
3. Relief of Symptoms with Correction
of Hypoglycemia
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Drug-Induced Hypoglycemia • A deficiency in the secretion of these counterregulatory

• Most cases of Drug-Induced Hypoglycemia have been hormones can contribute to low blood Glucose levels.
described in patients with Diabetes Mellitus who are on • Hypoglycemia in adults is rarely attributable to deficiencies
Glucose-Lowering Medications such as Insulin and Insulin of Glucagon or Catecholamines, but POOR GLUCAGON and
Secretagogue Drugs (Sulfonylureas, Repaglinide, and EPINEPHRINE RESPONSES TO HYPOGLYCEMIA are
Nateglinide). common in patients with Long-Standing Diabetes Mellitus
• Exogenous Insulin: and are associated with Prolonged Hypoglycemic Episodes
1. Elevated Insulin • Infants and children with a deficiency of Cortisol and
2. Low C-Peptide Growth Hormone are prone to develop Hypoglycemia,
• Oral Agents (Insulin Secretagogue Drugs) especially during Fasting and Acute Illness
1. High Insulin • Adults with Glucocorticoid or Growth Hormone Deficiency
2. High C-Peptide can also develop Hypoglycemia, usually after a Prolonged
3. Positive for Drug Screening Fast
• Blood tests should be drawn during the Hypoglycemic Non-Beta Cell Tumors
Episode • Non-Islet Cell Tumor Hypoglycemia (NICTH) originates
• Pentamidine directly damages Pancreatic Beta Cells. from Non-Beta Cell Tumors, which cause Hypoglycemia
o Hypoglycemia can occur within a few hours to days of without producing Insulin.
administration of pentamidine • Tumors Associated with NICTH:
• Sulfonamide-Induced Hypoglycemia 1. Mesenchymal Origin:
o Associated with increased Insulin and C-Peptide levels in a. Mesothelioma
susceptible individuals b. Hemangiopericytoma
• Salicylate-Induced Hypoglycemia c. Solitary Fibrous Tumors
o May be due to: 2. Epithelial Origin:
1. Increased peripheral Glucose utilization secondary a. Hepatocellular
to uncoupling of oxidative phosphorylation b. Gastrointestinal Stromal Tumor (GIST)
2. Decreased Hepatic Glyconeogenesis • These tumors are associated with increased paraneoplastic
3. Increased Insulin release production of Insulin-like growth factor-II (IGF-II)
• Beta Blockers (e.g., Propranolol) • Elevated levels of IGF-II increase Glucose Utilization and
o Can cause Hypoglycemia by antagonizing suppress Endogenous Glucose Production → causing
Catecholamine-Mediated Glycogenolysis Hypoglycemia
• Fluoroquinolone, Gatifloxacin, Levofloxacin, and • The tumor is usually detected on physical examination and
Temafloxacin is confirmed by radiologic diagnostic studies
o Blocks Kir6.2 Subunit of the Pancreatic Beta Cell • The diagnosis of NICTH is made by the presence of:
• Alcohol Consumption 1. Fasting Hypoglycemia
o Inhibit Hepatic Gluconeogenesis 2. Low Insulin
o Increase Glycogen Phosphorylase activity, depleting 3. Low Proinsulin
Hepatic Glycogen Stores and resulting in Hypoglycemia 4. Low C-Peptide Levels
o Plasma β-Hydroxybutyrate levels are elevated, and 5. Elevated IGF-II-to-IGF-I Ratio
plasma Insulin and C-Peptide Levels are low during the 6. Low Growth Hormone
hypoglycemic episode 7. Low β-Hydroxybutyrate Levels
Severe Medical Illness • Hypokalemia is frequently associated with Hypoglycemia
• Hypoglycemia in Hepatic Disease and Severe Cardiac due to Insulin-like activity of big IGF-II
Failure can be due to: Endogenous Hyperinsulinism
1. Impaired Gluconeogenesis • Hypoglycemia from endogenous Insulin secretion can be
2. Hepatic Congestion with Decreased Oxygen Delivery to due to:
Hepatocytes 1. Insulin-secreting Beta Cell Tumors (Insulinoma)
3. Impaired Insulin Degradation 2. Congenital Hyperinsulinism
4. Shunting of Portal Blood into the Systemic Circulation 3. Autoantibodies to Insulin in patients who have never
• Hypoglycemia in Severe Sepsis is due to: been treated with Insulin
1. Decrease in Glycogen Reserves • A supervised 72-hour fast is recommended for the diagnosis
2. Failure of Gluconeogenesis of Insulinoma with frequent clinical and biochemical
3. Enhanced Glucose Utilization monitoring for signs of Hypoglycemia.
• Patients with very low muscle mass, such as those with • Blood or urine screening tests for Sulfonylurea/Meglitinide
SPINAL MUSCULAR ATROPHY and CONGENITAL drugs are also performed.
MYOPATHY, are at risk for Hypoglycemia during
• Insulinomas are the most common tumors
PROLONGED FASTING (23 hours), presumably related to
of Islet Cells.
poor availability of the Gluconeogenic Substrate ALANINE
• The diagnostic criteria for an Insulinoma
• Hypoglycemia in End-Stage Renal Disease (ESRD) are:
o Hypoglycemia in End-Stage Renal Disease (ESRD) can be
1. Signs and symptoms of Hypoglycemia,
related to:
with a plasma Glucose level of ≤55
1. Defective Gluconeogenesis
mg/dL (3.1 mmol/L)
2. Impaired Hepatic Glycogenolysis due to Poor
2. Insulin Level ≥3 μU/mL (18 pmol/L) by
Nutritional Status
Immunochemiluminometric Assay
o Alcohol Ingestion, use of Insulin or Sulfonylurea Drugs, Diagnostic 3. C-Peptide Concentration of ≥0.6
Sepsis, Malnutrition, Liver Disease, and Cardiac Failure Criteria for ng/mL (0.2 nmol/L)
can increase the likelihood of hypoglycemic events in a Insulinoma 4. Proinsulin Concentration of ≥5.0
patient with Renal Failure
pmol/L
Hormone Deficiencies
5. β-Hydroxybutyrate of ≤2.7 mmol/L
Hormones that 6. Increase in the Plasma Glucose
Mechanism
Increase Glucose Concentration of ≥25 mg/dL (1.4
Initially stimulates Glycogenolysis and mmol/L) in response to a 1-mg
Glucagon
later Gluconeogenesis Glucagon Injection given
Increase Glycogenolysis, Gluconeogenesis, intravenously
and Lipolysis 7. Negative Sulfonylurea/Meglitinide
Catecholamines
Decrease Insulin-Mediated Glucose Uptake Blood/Urine Screen
Inhibit Insulin Release Alimentary Hypoglycemia
Decrease Insulin-Mediated Tissue Glucose • Alimentary (“Reactive”) Hypoglycemia occurs usually
Uptake within 4 hours after eating a meal.
Growth Hormone Increase release of Glucose into the
• Hypoglycemia has been described in patients who have
and Cortisol circulation
undergone Bariatric Surgery for Obesity, particularly after
Mediate Glycogenolysis and
Roux-en-Y Gastric Bypass
Gluconeogenesis
o Hypoglycemia in this condition is not associated or a
characteristic of an early Dumping Syndrome

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→ Dumping Syndrome → characterized by vasomotor
symptoms, such as sweating, dizziness, and
weakness, which usually occur less than an hour
after ingestion of a meal.
o The onset is usually >1 year after surgery.
o There is rapid gastric emptying associated with an early,
rapid, exaggerated transient peak in blood Glucose
concentrations.
o Increased Insulin and GLP-1 levels, as well as alterations
in Glucagon secretion
o The pattern is Postprandial Hypoglycemia in the
absence of Fasting Hypoglycemia
o OGTTs are poorly tolerated and not recommended.
• Idiopathic Reactive Hypoglycemia (Hypoglycemia without
GI Pathology)
o Individuals without Gastrointestinal Pathology report
spontaneous symptoms suggestive of Hypoglycemia 1-4
hours after intake of Carbohydrate-rich meals but have a
normal laboratory evaluation
o Caused by increased Insulin Sensitivity, delayed release
of Insulin in response to a meal, or concomitant alcohol
ingestion
Autoimmune-Related Hypoglycemia
• Hypoglycemia can be due to antibodies directed against
endogenous Insulin or the Insulin receptor
• Individuals with Autoimmune Diseases or recent ingestion of
Sulfhydryl-Containing Medications (i.e., Methimazole,
Penicillamine, Captopril, Imipenem, Hydralazine,
Procainamide, Isoniazid, Penicillin G) are at increased risk
for Autoimmune Insulin Syndrome (AIS)
• In some patients, Fasting Hypoglycemia, as well as
Hypoglycemia precipitated by increased physical activity
have been reported → due to excessive amounts of Insulin
secreted after a meal are bound to antibodies
Hypoglycemia in Infancy and Childhood
• Hypoglycemia in neonates, infants, and children is usually a
problem of FASTING ADAPTATION
• Normal infants and children develop HYPERKETONEMIA and
HYPOGLYCEMIA after 24 to 36 hours of fasting compared
with 48 to 72 hours in normal adults.
o This results in normal infants and children being more
susceptible to Fasting Hypoglycemia during illnesses
that impair feeding.
• Hypoglycemia during the first 2 years of life may cause
significant and permanent neurologic damage since this is a
crucial period for brain growth and development.
• Can occur in normal-term infants and
is associated with IMMATURE
HEPATIC GLUCONEOGENESIS and
KETOGENESIS.
Transient Neonatal • Neonatal Hyperinsulinism due to
Hypoglycemia maternal factors can also cause
Transient Neonatal Hypoglycemia.
o This is seen in infants of women
with poorly controlled Diabetes
Mellitus
• Neonates exposed to perinatal
stress—such as Birth Asphyxia,
Maternal Toxemia, Prematurity,
Prolonged Neonatal Intrauterine Growth Restriction, or
Hyperinsulinism other Perinatal Stress—are at high
risk for PROLONGED
HYPOGLYCEMIA due to PROLONGED
NEONATAL HYPERINSULINISM
• Persistent Hypoglycemia in Infants and Children
o Due to:
1. Deficiencies of Counterregulatory Hormones
(Growth Hormone Deficiency and Glucocorticoid
Deficiency)
2. Congenital Hyperinsulinism
3. Ketotic Hypoglycemia
4. Inborn Errors of Metabolism
• Older infants and children with Hypoglycemia due to
HYPOPITUITARISM present with KETOTIC HYPOGLYCEMIA
Congenital Hyperinsulinism
• In Congenital Hyperinsulinism (CHI) there is inappropriate
secretion of Insulin by Pancreatic Beta Cells that leads to
HYPERINSULINEMIC HYPOGLYCEMIA (HH)
• Infants have large-for-gestational-age birth weight and
severe, persistent Hypoglycemia requiring high Glucose
infusion rates (>10 mg/kg/min) to treat the Hypoglycemia
• Compensatory Ketogenesis is prevented by elevated Insulin
levels, causing a lack of alternate sources of fuel to protect
the brain from Hypoglycemia
• Common in patients with Turner Syndrome
• Diagnosis in children relies heavily on markers of excessive
Insulin action at the time of Hypoglycemia
• Biochemical criteria that support the diagnosis of
Hyperinsulinism at the time of plasma Glucose:
1. Detectable Insulin
2. Hypoketonemia (β-Hydroxybutyrate <2.0 mmol/L)
3. Inhibition of Lipolysis (Free Fatty Acids <1.5 mmol/L)
4. Inappropriate Glycemic Response to Glucagon 1 mg
IV/IM (change in Glucose >30 mg/dL [1.7 mmol/L])
Beckwith Wiedemann Syndrome
• Beckwith Wiedemann Syndrome (BWS) is a fetal overgrowth
syndrome caused by genetic defects affecting an imprinted
region on 11p15.4 that is close to the two KATP channel
genes
o Paternally: promoting gene IGF2
o Maternally: Growth Suppressor Genes and Voltage-Gated
Potassium Channel Gene (H19 and CDKN1C; KCNQ1)
• Hyperinsulinism occur sin about half of BWS neonates
o Hyperinsulinism is usually TRANSIENT but may be
persistent and nonresponsive to pharmacologic therapy
(Diazoxide).
o Hyperinsulinism in these patients is associated with a
large area of islet adenomatosis and is usually
accompanied by additional manifestations in other
organs (e.g., Hemihypertrophy, Macroglossia).
Kabuki Syndrome
• Kabuki Syndrome is linked to monoallelic de novo mutations
of Lysine-Specific Methyltransferase 2D (MLL2, encoded by
KMT2D), and Lysine-Specific Demethylase 6A (KDM6A on
Xp11.3)
• Hyperinsulinism presents in a significant proportion of
patients and is usually responsive to pharmacologic therapy
(diazoxide)
Ketogenic Hypoglycemia
• Ketogenic Hypoglycemia is the most common noniatrogenic
cause of Hypoglycemia in children between 18 months and 5
years of age
• Hypoglycemia REMITS SPONTANEOUSLY by 8 or 9 years of
age.
• These patients have RECURRENT MORNING
HYPOGLYCEMIA.
• Usually, an episode of illness or prolonged fasting is
associated with the Hypoglycemia.
V. INBORN ERRORS OF CARBOHYDRATE METABOLISM
• Normal Glucose level are maintained by:
1. Absorption of Glucose from the diet
2. Synthesis of Glucose during Gluconeogenesis
3. Release of Glucose from Glycogen → the principal
storage form of Glucose
• Inborn errors are inherited conditions that affect the
function of enzymes that regulate Glycogen Metabolism
(glycogen storage diseases) and Gluconeogenesis that
result in Hypoglycemia
• Inborn Errors of Carbohydrate Metabolism:
A. Glycogen Storage Diseases
B. Disorders of Gluconeogenesis
C. Defects in Galactose Metabolism
D. Defects in Fructose Metabolism
A. Glycogen Storage Diseases
• Inherited diseases that present in late infancy or childhood
• Caused by defects in the enzymes that regulate Glycogen
Synthesis or Glycogenolysis, resulting in abnormal quality or
quantity of Glycogen.
• Liver and Muscle, the main storage sites for Glycogen, are
most commonly affected by defects in glycogen
metabolism.
o Hepatic Glycogenosis → associated with Hypoglycemia
and Hepatomegaly
o Muscle Glycogenosis → muscle cramps, exercise
intolerance, fatigue, and weakness
• Affected children present with FAILURE TO THRIVE or
HEPATOMEGALY, and display a significant tolerance to
Chronic Hypoglycemia
• Blood Glucose levels of 20 to 50 mg/dL (1.1–2.8 mmol/L) are
not often associated with symptoms, possibly because
Ketones and Lactic Acid serve as ALTERNATE SOURCES OF
ENERGY for the CNS.
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Hepatic Glycogenoses Muscle Glycogenoses • A GALACTOSE-FREE DIET can reverse Cataracts if started in
Ia / von Gierke Disease II / Pompe Disease early infancy
Ib IV (Anderson Disease) GALE Deficiency
IIIa (also called “Cori”’ or V (McArdle Disease) • The benign form of Uridine Diphosphate GALE Deficiency is
“Forbes” Disease) VII (Tarui Disease) associated with enzyme deficiency limited to Erythrocytes
IIIb Phosphoglycerate Kinate and Leukocytes.
VI / Hers Disease Deficiency • These affected individuals are usually ASYMPTOMATIC and
IX GSD IXd (Muscle Phosphorylate DO NOT REQUIRE TREATMENT.
O Kinase Deficiency) • In the severe form, clinical findings are similar to those seen
XI / Fanconi-Bickel Syndrome GSD X (Phosphoglycerate in GALT deficiency, with additional findings of Hypotonia
Mutase Deficiency) and Sensorineural Deafness.
GSD XI (Lactate Dehydrogenase • Treatment consists of dietary restriction of Galactose
Deficiency)
D. Defects in Fructose Metabolism
GSD XII (Fructose-1,6-
bisphosphate Aldolase A • Clinical Conditions:
Deficiency) 1. Essential Fructosuria
GSD XIII, GSD IV, GSD XV 2. Hereditary Fructose Intolerance
3. Fructose-1,6-Diphosphatase Deficiency
B. Disorders of Gluconeogenesis
• Essential Fructosuria
• Major Enzymatic Defects:
o Autosomal-Recessive disorder resulting from
1. Fructose 1-Phosphate Aldolase (Hereditary Fructose
Fructokinase Deficiency.
Intolerance)
o Fructokinase catalyzes the conversion of Fructose to
2. Fructose-1,6-Diphosphatase
Fructose-1-Phosphate
3. Phosphoenol Pyruvate Carboxykinase (PEPCK)
o The condition is asymptomatic and usually is diagnosed
4. Pyruvate Carboxylase
incidentally by the detection of Fructose in urine as a
• Hypoglycemia usually occurs during periods of METABOLIC reducing substance.
DECOMPENSATION, which can be spontaneous or triggered o No treatment is necessary
by illnesses or prolonged fasting Lactic Acidosis
• VOMITING and TACHYPNEA are the most prominent
• Lactic Acid is a product of Pyruvic Acid metabolism
symptoms
o Derived from Glucose via the Glycolytic Pathway and
• Growth Retardation or impaired Neuromuscular
Deamination of Alanine
Development are seen even when severe episodes are
• Eliminated by several mechanisms, including buffering by
infrequent.
extracellular buffers and removal primarily by the liver and
C. Defects in Galactose Metabolism
kidneys.
• Galactose is the monosaccharide, together with Glucose, • Excessive accumulation of L-Lactic Acid is caused by
that constitutes the Disaccharide LACTOSE overproduction and/or underutilization of L-Lactate.
• Milk and milk products are the main sources of GALACTOSE • Classification:
• Main role is the formation of complex glucolipids and 1. Type A → includes etiologies related to the presence of
glycoproteins tissue hypoxia
• 3 Enzymatic Defects: 2. Type B → not associated with tissue hypoxia
1. GALT (Galactose-1-Phosphate Uridyl Transferase) • High levels of Lactic Acid produced during strenuous
2. GALK (Galactokinase) exercise are rapidly cleared by both Renal and Hepatic
3. GALE (Uridine Diphosphate (UDP) Galactose 4′- Mechanisms as well as by Aerobic Metabolism in muscle
Epimerase) (half-life approximately 60 minutes).
GALT Deficiency (Classic Galactosemia) • Generally seen in Diseases of the Liver and Kidneys.
• The most common mutation of the GALT gene is the Q188R • Defects in the removal of Lactic Acid have been associated
mutation for the protein encoded by the gene on with Hepatic Insufficiency, Specific Enzymatic Defects, and
Chromosome 9. Severe Acidosis.
• Symptoms start as soon as the baby starts ingesting milk • Defined as Blood Lactate Concentration
(breast milk or formula) and have been seen as early as the of ≥2 mmol/L.
2nd day of life • Severe Hyperlactatemia (“lactic
• Early changes in the lens have been described as “Oil Drop acidosis”) is diagnosed by:
Changes” and CATARACT FORMATION occurs. 1. High Blood Lactate Levels (>45
• Clinical Findings include feeding intolerance (vomiting, mg/dL or >5.0 mmol/L)
diarrhea, bloating), irritability, and failure to thrive. 2. Elevated Anion Gap
• As Liver Dysfunction develops, these infants have Jaundice, 3. Low Blood pH (<7.35)
Hepatomegaly, and Easy Bruisability due to Coagulopathy • Treatment of Lactic Acidosis consists of
• They can also have Hyperchloremic Metabolic Acidosis, Hyperlactatemia correction of underlying conditions that
Albuminuria and Aciduria (Renal Fanconi Syndrome), initiated the disruption in normal Lactate
Galactosuria, Glycosuria, and Vitreous Hemorrhage Metabolism
• Long-term complications in GALT deficiency include o Tissue oxygenation, improved fluid
Impaired Cognition, Ovarian Failure in Females, Impaired status, amplification of cardiac
Growth, and Ataxic Neurologic Disease status, and treatment of Sepsis play
• Milder form of Galactosemia important roles in the treatment of
Duarte • Characterized by decreased red cell Lactic Acidosis.
Variant enzyme activity, which generally is of NO • Dialysis is sometimes necessary for
CLINICAL SIGNIFICANCE removal of Lactate.
GALK Deficiency
• In GALK deficiency, Galactose cannot be converted into Gal-
1-P.
• Patients accumulate Galactose, which is converted to
Galactiol and Galactonate, leading to CATARACT
FORMATION.
o Cataracts may be the only major clinical manifestation in
older children with GALK deficiency
• Conversion of Galactose to Galactiol is mediated by ALDOSE
REDUCTASE, which is downregulated in the kidney.
o This may explain why these patients do not have Renal
Impairment
• Diagnosis:
1. Elevated Blood Galactose
2. Normal Uridyl Transferase Activity
3. Absence of Galactokinase Activity in Erythrocytes

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