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300
Time (minutes)
Insulinemia (µU/mL)
210
28 Metabolic Syndrome
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Fig. 28.1 Insulin curve after oral glucose tolerance test.
(Copyright EDISES 2021. Reproduced with permission).
275
250
225
200
175
150
125
100
75
50
25
0
0306090
413
Normal insulinemia
Insulin resistance
120 150 180
secretion; subsequently, blood glucose trends are assessed in
response to a continuous infusion of glucose and insulin.
The hyperinsulinemic-euglycemic clamp is based on the
infusion of an insulin quota to bring the hormone’s blood values, for a time of 120 min, to a constant value of 100 μU/
mL.At the same time, glycemia is constantly maintained at a
basal level of about 90mg/dL through a variable infusion of
glucose, punctually adjusted by a feedback mechanism based
on glycemic determinations repeated during the test. In conditions of constant insulinemia, in the last 40min of the test, the
amount of glucose infused in the unit of time to maintain euglycemia corresponds to the amount of glucose used by peripheral tissues, with transport dependent on the action of insulin.
It is, therefore, an index (“M value” in mol/min/kg) of the tissuessensitivity to the insulinaction. Although this test represents the gold standard for assessing insulin resistance, it is not
commonly used in clinical practice because it is difcult to
perform and requires time and expert personnel.
The HOMA index is based on a mathematical model that
relates fasting serum glucose and insulin concentrations. The
QUICKI (less used because it is more complex than the
HOMA) is derived by calculating the inverse of the sum of the
logarithms of fasting blood glucose and fasting insulin.
Therapy
In 2001, the Adult Treatment Panel III (ATP III) recommended two primary treatment goals for patients with metabolic syndrome. These goals have been reinforced by a report
from the American Heart Association (AHA) and the
National Institutes of Health (NIH) and clinical guidelines
from The Endocrine Society:
• Treat the underlying causes (overweight, obesity, and
physical inactivity) by modifying lifestyle and eating
habits
• Treat cardiovascular risk factors if they persist despite
lifestyle modications
All components of the metabolic syndrome benet from
weight loss, maintained over time, achieved through caloric
restriction and physical activity. There is no direct evidence
that attempting to prevent type 2 diabetes and cardiovascular
disease by treating the metabolic syndrome is effective. It is
possible to treat IR with drugs that potentiate the action of
insulin (e.g., thiazolidinediones and metformin).
Recommended Readings
Capurso C, Capurso A (2013) Dall’obesità alla resistenza insulinica: il
ruolo degli FFA.Giornale Italiano dell’Arteriosclerosi 4(1):37–52
DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a
method for quantifying insulin secretion and resistance. Am J Phys
237:E214–E223
Grundy SM, Hansen B, Smith SC Jr etal (2004) Clinical management
of metabolic syndrome: report of the American Heart Association/
National Heart, Lung, and Blood Institute/American Diabetes
Association conference on scientic issues related to management.
Circulation 109:551
Knowler WC, Barrett-Connor E, Fowler SE etal (2002) Reduction in
the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393
Meigs JB (2003) The metabolic syndrome. BMJ 327
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (2001) Executive summary of the third report
of The National Cholesterol Education Program (NCEP) expert
panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 285:2486
Genuth S, Alberti KG, Bennett P etal (2003) Follow-up report on the
diagnosis of diabetes mellitus. Diabetes Care 26:3160
Grundy SM, Cleeman JI, Daniels SR et al (2005) Diagnosis and
management of the metabolic syndrome: an American Heart
Association/National Heart, Lung, and Blood Institute Scientic
Statement. Circulation 112:2735
Rosenzweig JL, Ferrannini E, Grundy SM et al (2008) Primary pre-
vention of cardiovascular disease and type 2 diabetes in patients at
metabolic risk: an endocrine society clinical practice guideline. J
Clin Endocrinol Metab 93:3671
Hypoglycemia
after restoration of normal blood glucose levels
Sy
w plasma glucose concentration
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MarcelloCiaccio andLuisaAgnello
29
Introduction
Hypoglycemia is a metabolic condition characterized by
reduced circulating glucose levels associated with clinical
signs and/or symptoms such as alterations in mental status
and/or stimulation of the sympathetic nervous system.
In healthy, fasting adults, the lower limit of plasma
glucose concentration is 70 mg/dL (3.9 mmol/L).
However,glucose levels may reach lower values away
from meals.Hypoglycemia is clinically manifested when
plasma glucose concentration is <55mg/dL (3mmol/L).
Clinical manifestations of hypoglycemia are nonspecific.
Additionally, low plasma concentration may be an artifact. Thus, hypoglycemia should always be confirmed by
satisfying thecriteria of Whipple’s triad: (1) signs, symptoms, or both, consistent with hypoglycemia; (2) low
plasma glucose concentration; and (3) resolution of signs
and/or symptoms after the restoration of normal plasma
glucose concentration (Fig.29.1).
In the absence of the Whipple’s triadcriteria, hypoglycemia is unlikely.
Epidemiology
Hypoglycemia is a relatively frequent condition in patients
with type 1 diabetes mellitus (DM1), who develop, on average, two episodes of symptomatic hypoglycemia per week
and at least one episode per year of severe hypoglycemia,
temporarily disabling, often associated with epilepsy and
coma. In DM1, hypoglycemia results from treatment with
M. Ciaccio (*) · L. Agnello
Department of Biomedicine, Neurosciences and Advanced
Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular
Medicine and Clinical Laboratory Medicine, and Department of
Laboratory Medicine, University Hospital “P.Giaccone,”,
Palermo, Italy
e-mail: marcello.ciaccio@unipa.it
Lo
HYPOGLYCEMIA
mptoms and/or clinical signs
consistent with hypoglycaemia
Resolution of symptoms and/or clinical signs
Fig. 29.1 Whipple’s triad. (Copyright EDISES 2021. Reproduced
with permission)
insulin or insulin secretagogues. A severe complication of
hypoglycemia is sudden death secondary to cardiac
arrhythmia.
In patients with type 2 diabetes mellitus (DM2), therapy
is initially based on drugs, such as metformin or thiazolidinedione, that do not inuence insulin levels or reduce plasma
glucose concentrations, so they should not cause hypoglycemia. However, over time, patients with DM2 may develop
endogenous insulin deciency and, therefore, require treatment with exogenous insulin or insulin secretagogues. In this
case, the frequency of development of hypoglycemia
becomes superimposable to that of patients with DM1.
Hypoglycemia is a relatively rare condition in individuals
who are not under treatment for diabetes. It is important to
note that the plasma glucose concentration used to document
Whipple’s triad, in the absence of treatment of diabetes with
insulin or insulin secretagogues, must be measured by a reliable laboratory method. Although the nding of a low plasma
glucose concentration, measured by a reliable method, in the
absence of signs or symptoms should not be ignored, this
nding could be due to a condition of “pseudohypoglycemia,” that is, an artifact of continued invitro glucose metabo-
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. Ciaccio (ed.), Clinical and Laboratory Medicine Textbook, https://doi.org/10.1007/978-3-031-24958-7_29
415
416
ation symptoms
Plasma blood glucose (mg/dL)
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M. Ciaccio and L. Agnello
lism by the corpuscular elements of the blood after the
sample has been drawn. This condition can occur when the
blood sample is collected in a tube that does not contain a
glycolysis inhibitor or the separation of plasma (or serum)
from the corpuscular elements is delayed, especially in the
presence of erythrocytosis, leukocytosis, or thrombocytosis.
Documentation of Whipple’s triad conrms the presence
of a hypoglycemic alteration, the etiology of which may be
obvious (e.g., in a patient with diabetes treated with insulin
or insulin secretagogues) or a diagnostic challenge (e.g., in a
healthy individual with an insulinoma). On the other hand, in
an individual without diabetes mellitus, an unequivocally
normal plasma glucose concentration (>70 mg/dL
(3.9mmol/L)) during a symptomatic episode indicates that
those symptoms are not the result of hypoglycemia.
The pathophysiology of hypoglycemia and the diagnostic
approaches and management of patients with diabetes mellitus are different from those without diabetes.
Symptoms
Symptoms associated with hypoglycemia are generally nonspecic and can be subdivided into neuroglycopenic, related
to glucose deprivation in the central nervous system (CNS),
and neurogenic (or autonomic), related to the autonomic nervous system activation (Table 29.1 and Fig.29.2). In a patient
without diabetes, the onset of neuroglycopenic symptomsis
strongly indicative of an underlying hypoglycemic disorder.
Hypoglycemic symptoms are usually the same during each
episode that may occur in the fasting or postprandial state.
Patients often cannot describe their episodes in detail due
toamnesia.
glucagon secretion; (3) and, in the absence of the latter,
increased adrenaline secretion. On the other hand, behavioral defense mainly consists of carbohydrates assumption. This behavior is induced by the perception of
symptoms, mainly neurogenic, mediated by the neural
activation of the sympathetic system. All these defense
mechanisms, not only insulin secretion, are impaired in
DM1 and, in the long run, also in DM2. In overt DM1,
circulating insulin levels does not reduce in response to
decreased plasma glucose levels. In addition to the lack
pancreatic β-cells response, α-cells also fail to produce
glucagon in response to hypoglycemia. In the absence of
the primary defense mechanisms (insulin and glucagon),
DM1 patients are highly dependent on the third defense
mechanism, i.e., the adrenalinesecretion. The adrenaline
response to hypoglycemia is often attenuated due to mechanisms that are not yet fully dened. In the context of a
failure to decrease insulin and increase glucagon, when
there is a fall in blood glucose levels in response to therapyinduced hyperinsulinemia, the attenuated adrenaline
response causes the clinical syndrome of glycemic counterregulation deciency.
Patients with this syndrome have a 25-fold increased risk
of developing hypoglycemia. In addition, the attenuated
sympathetic neural response causes the clinical syndrome of
unconscious hypoglycemia, characterized by the impairment or complete loss of alarm symptoms that trigger
behavioral defense. Unconscious hypoglycemia is associated with a sixfold increased risk of developing severe
hypoglycemia.
The concept of hypoglycemia-associated autonomic
failure in diabetes assumes that recent and antecedent
Hypoglycemia inDiabetes
In patients with diabetes, hypoglycemia is the result
oftherelative or absolute excess of exogenous insulin and
the compromised physiological and behavioral defense
against falling plasma glucose concentrations. The physiological defense against falling plasma glucose concentrations includes (1) reduced insulin secretion; (2) increased
Table 29.1
Neurogenic Neuroglycopenic
Adrenergics
Tachycardia
Tremors
Pallor
Agitation
Hypoglycemia symptoms
Cholinergic
Sweating
Hunger
Paresthesia
Difculty paying
attention
Confusion
Diplopia
Blurred vision
Convulsions
Headache
Coma
90
80
70
60
50
40
30
20
10
0
Fig. 29.2 Signs and symptoms of hypoglycemia. (Copyright EDISES
2021. Reproduced with permission)
Light neurological symptoms
Counter-regulation
Adrenergic activ
Symptoms of neuroglycopenia
Lethargy
Coma
Convulsions
Permanent brain damage
Death
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417
hypoglycemia causes both decits in glycemic counterregulation (by reducing the response to adrenaline without
insulin and glucagon response) and unconscious hypoglycemia (mainly by reducing the sympathetic neural response
and the resulting neurogenic symptoms) and, therefore,
triggers a vicious cycle of recurrent hypoglycemia. In subjects with DM1, unconscious hypoglycemia and adrenaline
deciency are reversible after 2–3 weeks of scrupulous
attention to avoiding therapy-induced hypoglycemia. The
glycemic counter- regulatory deciency syndrome is primarily due to β-cell deciency. Thus, DM2 patients may
also develop it in the long run. In addition, the threshold for
the sympathoadrenal response shifts toward lower plasma
glucose concentrations due to antecedent hypoglycemia,
similar to DM1. Table29.2 shows the main risk factors for
hypoglycemia and hypoglycemia- associated autonomic
failure in patients with diabetes. There are many variables
at stake. Thus,theinsulin treatment must be carried out by
adequately trained people who can recognize and managethe various and changing factors making the necessary
corrections;for example, occasionally changing the insulin
dose according todiet or after intense physical exercise. In
this case, hypoglycemia can appear from 1–2h up to 17h
after the end of the physical effort. Aerobic exercise causes:
1. The increase in the insulin-dependent and -independent
muscular glucoseuptake
2. The 40–60% reduction in the endogenous insulin
secretion
3. Theincrease in insulin sensitivity in the next 2h
Hypoglycemia without Diabetes
In subjects not affected by diabetes mellitus, hypoglycemia
could be due to different causes. The Endocrine Society has
proposed classifying the causes of hypoglycemia according
to the subject’s health status.(Table 29.3).
Drugs
Drugs represent the most common cause of hypoglycemia.
Numerous drugs responsible for hypoglycemia have been
described, with varying degrees of evidence (Table29.4). In
Table 29.3
patients
Causes of hypoglycemia in
patients with concomitant
diseases
Drugs (Table29.4):
– Insulin and insulin
–Alcohol
Chronic and acute diseases:
– Hepatic, renal, and
–Sepsis and malaria
–Inanition
Hormonal deciencies:
–Cortisol
–Glucagon
–Adrenaline
Non-insular tumors
Classication of the hypoglycemic causes in non diabetic
Causes of hypoglycemia in
apparently healthy subjects
Endogenous hyperinsulinism:
–Insulinoma
secretagogues
cardiac insufciency
– Hypoglycemic syndrome of
pancreatic origin not secondary
to insulinoma
– Hypoglycemia after gastric
bypass
–Autoimmune hypoglycemia
Accidental, voluntary, or factitia
hypoglycemia
Therefore, it is always necessary to adjust doses accord-
ing to glucose consumption.
Table 29.2 Risk factors for hypoglycemia and hypoglycemia-associated autonomic failure associated with hypoglycemia in patients with
diabetes mellitus
Risk factors for
Conventional risk factors associatedto
a relative or absoluteinsulin excess
Excessive, inappropriate, or incorrect
measurement of exogenous insulin or
insulin secretagogues
Reduction of exogenous glucose
release (e.g., after skipping a meal or
during an overnight fast)
Increased use of glucose (e.g., during
exercise)
Reduced endogenous production of
glucose (e.g., after alcohol intake)
Increased insulin sensitivity (e.g.,
following weight loss, an increase in
regular exercise or better glycemic
control, and in the middle of the night)
Reduced insulinclearance (e.g.,
kidney failure)
hypoglycemia-associated
autonomic failure
Absolute deciency of
endogenous insulin
History of severe
hypoglycemia, unconscious
hypoglycemia, or both, as
well as previous exercise
Aggressive glycemic
therapy
Table 29.4
hypoglycemic agents)
Moderate evidence
Cibenzolina
Gatioxacin
Pentamidine
Quinine
Indomethacin
Glucagon
Low evidence
Sulfonamides
Artesunate/Artemisinin
IGF-1
Lithium
Propoxyphene/dextropropoxyphene
Very low evidence
Ace inhibitors
Angiotensin receptor antagonists
Beta-blockers
Levooxacin
Mifepristone
Disopyramide
Trimethoprim sulfamethoxazole
Heparin
6-Mercaptopurine
Drugs inducing hypoglycemia (excluding alcohol and oral
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M. Ciaccio and L. Agnello
particular, drug-induced hypoglycemia is more common in
elderly patients with underlying comorbidities. Moreover,
the incidence of hypoglycemia in hospitalized patients is frequent when insulin or secretagogue drugs are administered
to patients in whom parenteral nutrition is suspended or
when insulin sensitivity increases (as when steroid therapy is
interrupted). Another common cause of hypoglycemia is
alcohol intake, as itinhibits gluconeogenesis. Consequently,
alcohol-induced hypoglycemia usually occurs after a few
days of alcohol abuse, especially when the subject does not
adequately eat.
Chronic andAcute Illnesses
Among hospitalized patients, renal and hepatic failure
and sepsis are common causes of hypoglycemia. In liver
failure, hypoglycemia is due to the reducedendogenous
glucose synthesis; in renal failure, it is caused by reduced
insulin clearance and reduced mobilization of gluconeogenesis precursors. During sepsis, the recruitment of
macrophages to the infected tissues leads to the release
of cytokines that induce increased glucose utilization. In
inanition, on the other hand, hypoglycemia may be due
to loss of adipose tissue and subsequent reduction of
gluconeogenesis precursors and increased glucose
utilization.
Hormonal Deciencies
Growth hormone (GH) and cortisol deciency are associated
with reduced availability of substrates for gluconeogenesis
and increased peripheral glucose utilization.
ring mainly in the fasting and only occasionally in the postprandial period.
Hypoglycemic syndrome of pancreatic origin not secondary to insulinoma, is clinically characterized by episodes of postprandial neuroglycopenia secondary to
hyperinsulinism. From a histological point of view, it is
characterized by β-cell hypertrophy and hyperplasia of the
β-cell nuclei.
Autoimmune hypoglycemia is a rare condition characterized by anti-insulin antibodies without pancreatic β-cell
alteration. In rare cases, anti-insulin receptor antibodies may
also be found.
Finally, postprandial hypoglycemia can be observed in
obese patients undergoing bariatric surgery. In these patients,
increased levels of the intestinal incretin GLP-1 and subsequent glucagon suppression increase insulin secretion. In
addition, the increased expression of IGF-1 and IGF-2
growth factor receptors results in increased β-cell activity,
thus contributing to the insulin levelsincrease.
Hypoglycemia Factitia
Hypoglycemia can be caused intentionally, such as during
the performance of a clinical test (insulin-tolerance test);
accidentally, for example, as a result of a pharmacy error; or
as a result of taking insulin as a potent anabolic agent,such
as in athletes. Hypoglycemia factitia should always be suspected if hypoglycemia occurs suddenly in a healthy subject.
In the case of voluntary insulin administration, the decisive
diagnostic criterion is related to the discrepancy between the
nding of elevated plasma insulin concentrations and normal
C-peptide values.
Non-insular Tumors
Fasting hypoglycemia secondary to non-insular tumors is
occasionally observed in patients with large mesenchymal or
epithelial tumors. It is due to hyperproduction of insulin-like
growth factor 2 (IGF-2) or immature precursors resulting in
hypoglycemic episodes similar to those observed in patients
with insulinoma.
Endogenous Hyperinsulinism
There are many causes of endogenous hyperinsulinism.but
the underlying mechanism is the failure to reduce insulin levels during hypoglycemia. Insulinoma, a rare pancreatic
β-cell tumor, benign in 90% of cases, is the leading cause of
endogenous hyperinsulinism. From a clinical point of view,
insulinoma is characterized by periods of neuroglycopenia
due to endogenous hyperinsulinemic hypoglycemia occur-
Diagnosis
Once the suspicion of hypoglycemia has been conrmed by
Whipple’s triad criteria(Fig. 29.1), it is necessary to make a
differential etiological diagnosis to start the most appropriate
therapy.
Patients with diabetes should suspect the possibility of
developing hypoglycemia when the self-monitored glucose
concentration decreases rapidly or is not >70 mg/dL
(3.9mmol/L). This cutoff allows the patient to intervene preemptively to avoid symptomatic hypoglycemia. In addition,
because self-monitoring is usually performed by analytically
inaccurate devices, especially at low glucose levels, the
70mg/dL glucose cutoff provides a margin for their analytical inaccuracy. Hypoglycemiain a diabetic patientmust be
treated by modifying therapy and then the improvement
should be documented. If there is a history of unconscious
hypoglycemia (recurrent hypoglycemia without symptoms),
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419
Fig. 29.3 Algorithm for the
etiological diagnosis of
hypoglycemia. (Copyright
EDISES 2021. Reproduced
with permission)
Hypoglycemia
Diabetes mellitus
Treatment adjustment
Documenting improvement
Subjects with diseases, chronic or acute,
and/or under drugs treatment
Infusion of adequate
glucose, treat
underlying causes
Insulin
Pro-insulin
C-peptide
No diabetes mellitus
• Medical history
• Physical examination
• Laboratory test
Apparently
individual
During an episode of
hypoglycemia (induced or
spontaneous) measure:
insulin, C-peptide,
pro-insulin and
hypoglycemic agents
healthy
Insulin
Pro-insulin
C-peptide
Insulin
Pro-insulin
C-peptide
+ Oral hypoglycemic
drugs
a 2–3-week period of scrupulous attention to avoid hypoglycemia is recommended.
Non-diabetes mellitus subjects with hypoglycemia often
present with signs and symptoms, such as mental confusion,
altered consciousness, epilepsy, or afterthe casual nding of
low plasma glucose concentrations. In a symptomatic subject, the conrmation of hypoglycemia is based on the nding of low plasma glucose levels and the resolution of
symptoms afterglycemiacorrection.
The differential diagnosis is based on: (1) accurate anamnesis, which includes a detailed description of the events, the
relationship with meal intake (hypoglycemia that occurs
2–3h after meals is suggestive of hyperinsulinism, whereas
if it occurs after prolonged fasting, it suggests an altered
mechanism of gluconeogenesis), the presence of comorbidities, and the pharmacological therapy taken by the patient
and family members; (2) physical examination; and (3) laboratory datato assess the role of insulin in hypoglycemia genesis(Fig. 29.3).
First,drugtherapy, especially insulin, and alcohol, should
be considered. The presence of diseases, chronic or acute,
Endogenous
hyperinsulinism
Hypoglycemia factitia
(from exogenous insulin)
Iatrogenic
hypoglycemia
hormonal deciencies, non-β-cell tumors, and previous gastric surgery should also be considered.
If all these conditions are absent, and thus the subject is
healthy, further laboratory investigations should be performed. In particular, during an episode of hypoglycemia,
blood glucose, insulin, C-peptide, and proinsulin should be
measured simultaneously and a toxicological screening for
oral hypoglycemic agents should be performed (Table29.5).
In some cases, patients experience symptoms of hypoglycemia after a short period of fasting; in such cases, continued
observation, especially after an overnight fast, could result in
an episode of symptomatic hypoglycemia. During the observation period, blood glucose should be measured continuously; if symptoms occur and hypoglycemia is documented
(plasma glucose <55 mg/dL), the tests described above
should be performed (Table29.5). If this approach results in
neither symptoms nor hypoglycemia and clinical suspicion
remains high, the patient should undergo a stimulus test such
as a 72-hour fast. The aim of this test is to induce homeostatic responses allowing the maintenance of plasma glucose
concentrationnot associated with symptoms of hypoglyce-
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M. Ciaccio and L. Agnello
Table 29.5
Insulin
(μU/
mL)
>>3 <0.2 <5 No Exogenous
≥3 ≥0.2 ≥5
≥3 ≥0.2 ≥5
a
Insulinoma, hypoglycemic syndrome of pancreatic origin not second-
ary to insulinoma; hypoglycemia after gastric bypass
Differential diagnosis of hypoglycemia
C-peptide
(nmol/L)
Proinsulin
(pmol/L)
Hypoglicemic
drugs Interpretation
No Endogenous
Yes Oral
insulin
a
insulin
hypoglycemic
agents
(drug-induced)
mia under fasting conditions. Increased release of glucagon,
adrenaline, and, to a lesser extent, growth hormone and
cortisol are the most critical components of this response. All
hormonal responses begin long before the onset of symptomatic hypoglycemia. Normal subjects do not experience symptomatic hypoglycemia after prolonged fasting due
to hormone-induced increase in glucose production.
Prolonged fasting results in hypoglycemia only if there is a
defect in normoglycemiamainteinance due, for example, to
an excess of insulin that inhibits endogenous glucose
production.
During the 72-hour fast, patients cannot assume food but
can only consume sugar-free and caffeine-free drinks.
Fasting starts after the last meal. Blood samples should be
collected every 6h until blood glucose is <60mg/dL; at
this point, samples should be collected every 1–2h. Insulin,
C-peptide, and proinsulin should only be assayed in samples with blood glucose <60mg/dL.Fasting ends when the
glucose concentration is <45 mg/dL, the patient exhibits
signs and/or symptoms of hypoglycemia, 72 hour have
elapsed, or blood glucose is <55mg/dL if Whipple’s triad
has been documented previously. The absence of signs and
symptoms of hypoglycemia, as well as a low plasma glucose concentration during a 72-h fast, does not preclude a
hypoglycemic disorder that may cause only postprandial
symptoms. At the end of the test, 1mg of intravenous glucagon is administered, and plasma glucose is measured
after 10, 20, and 30min; then, the patient can eat. Insulin is
an anti- glycogenolytic, and hyperinsulinemia allows
hepatic glycogen storage. Consequently, patients with
hypoglycemia secondary to hyperinsulinism (as in the case
of insulinoma) respond to glucagonadministration (which
is a potent glycogenolytic agent) by releasing glucose; in
particular, aglycemia increase of at least 25mg/dL will be
observed compared to the glycemia at the end of the test.
The healthy subjects, instead, will have released virtually
all the hepatic glucose within the 72hour of fasting and,
therefore, will present a reasonable response to the stimu-
lus of glucagon, with a much smaller increase of
glycemia.
In case of non-insular tumorssuspicion, autoimmune etiology, or hormonal deciency, the measurement of antiinsulin antibodies, anti-insulin receptor, IGF-1/2, plasma
cortisol, glucagon, and growth hormone can be performed.
If symptoms of hypoglycemia occur within 5h of meals,
patients should be assessed in the postprandial state by
mixed-meal testing. Specically, the patient take a nonliquid
meal, resultingin the onset of symptoms, and be kept under
observation for the next 5h. Plasma glucose assay will be
performed before the mixed meal and after intake every
30min for the next 5h. If severe symptoms occur before 5h,
samples should be collected before carbohydrate administration (to assess the correction of symptoms). Insulin,
C-peptide, and proinsulin should be tested only in samples of
blood glucose <60mg/dL (Table29.5).
If an insulinoma is suspected, radiological investigationsshould conrm the diagnosis. Computed axial tomography (CAT) and nuclear magnetic resonance (NMR) are the
most commonly used noninvasive diagnostic procedures to
detect the tumor site. However, more invasive techniques,
such as endoscopic ultrasonography and venous sampling
after arterial stimulation, are more accurate in preoperative
localization of insulinoma and superior to standard noninvasive localization techniques. Finally, positron emission
tomography (18F-DOPA-PET) is a technique successfully
used for the localization of insulinomas, and, in children
with hypoglycemia due to congenital hyperinsulinism, it represents the gold standard for thelesions localization before
surgery.
Autoimmune hypoglycemia is a rare condition characterized by antibodies directed against insulin or the insulin
receptor, resulting in hypoglycemia. Detection of anti- insulin
and anti-insulin receptor antibodies is necessary to conrm
the diagnosis of autoimmune hypoglycemia. Autoimmune
hypoglycemia should be suspected when hypoglycemia is
associated with high insulin levels (>100 μU/mL) and incompletely suppressed C-peptide levels. Finally, although elevated insulin levels may be observed following exogenous
insulin administration, the associated C-peptide levels are
usually extremely low.
Recommended Readings
Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist
ER, Service FJ, Endocrine Society (2009) Evaluation and manage-
ment of adult hypoglycemic disorders: an endocrine society clinical
practice guideline. J Clin Endocrinol Metab 94(3):709–728. https://
doi.org/10.1210/jc.2008- 1410
Desimone ME, Weinstock RS (2000) Non-diabetic hypoglycemia.
[Updated 2017 Sep 23]. In: De Groot LJ, Chrousos G, Dungan K
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etal (eds) Endotext [Internet]. MDText.com, Inc, South Dartmouth
(MA). Available from: https://www.ncbi.nlm.nih.gov/books/
NBK355894/
Dynkevich Y, Rother KI, Whitford I, Qureshi S, Galiveeti S, Szulc AL
etal (2013) Tumors, IGF-2, and hypoglycemia: insights from the
clinic, the laboratory, and the historical archive. Endocrine Rev
34:798–826
Galati SJ, Rayeld EJ (2014) Approach to the patient with postprandial
hypoglycemia. Endocr Pract 20:331–340
Ito T, Igarashi H, Jensen RT (2012) Pancreatic neuroendocrine tumors:
clinical features, diagnosis and medical treatment: advances. Best
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SID-AMD.Standard Italiani per la Cura del Diabete Mellito– 2016
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Whipple AO (1944) Hyperinsulinism in relation to pancreatic tumour.
Surgery 16:289–298
The Role of Laboratory inPregnancy
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MarcelloCiaccio andLuisaAgnello
30
Introduction
The clinical laboratory has a critical role in pregnancy, both
in the phases preceding conception to verify the general
health status, orto identify the presence of pathological conditions before conception, and during pregnancy to monitor
the health statusof the mother and fetus, and, in some cases,
in the postpartum period to evaluate the evolution of pathologies related to the pregnancy (e.g., gestational diabetes).
Preconception Laboratory Test
In the period preceding conception and pregnancy, it is
essential to be aware of any clinical conditions to intervene
preventively and avoid maternal–fetal pathologies, thus
allowing a normal pregnancy and correct fetal development.
Useful laboratory tests in this context are:
• Indirect Coombs test
• Toxoplasmosis, Others, Rubella, Cytomegalovirus, and
Herpes Simplex (TORCH)
• Complete blood count (CBC)
• Hemoglobin levels
• Glycemia
• Cervical cancer screening (PAP test)
M. Ciaccio (*)
Department of Biomedicine, Neurosciences and Advanced
Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular
Medicine and Clinical Laboratory Medicine, University Hospital
“P.Giaccone”, Palermo, Italy
Department of Laboratory Medicine, University Hospital
“P.Giaccone”, Palermo, Italy
e-mail: marcello.ciaccio@unipa.it
L. Agnello
Department of Biomedicine, Neurosciences and Advanced
Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular
Medicine and Clinical Laboratory Medicine, University Hospital
“P.Giaccone”, Palermo, Italy
Indirect Coombs Test
The Coombs test evaluates a possible incompatibility
between maternal and fetal blood through the detection of
maternal immunoglobulin (Ig)G antibodies that, crossing the
placenta, can develop an immunological response against
antigens of fetal erythrocytes, leading to severe consequences
for the fetus, such as intrauterine death and hemolytic disease of the newborn (HDN), characterized by anemia, neonatal jaundice, edema, and hydrops. The antibodies involved
may be different (anti-Kell, anti-C, anti-E, etc.), but in most
cases, they are anti-D.In particular, the Coombs test is used
to evaluate the possible presence of maternal antibodies
directed mainly against the erythrocyte Rh antigen, also
known as the D antigen.
The Rh factor is a protein present on the surface of red
blood cells in about 15% of the population that is, therefore,
dened as Rh+; the remaining 85% of the population does
not present this antigen on red blood cells and is, therefore,
dened as Rh−. Unlike the AB0 system, Rh subjects do not
present anti-Rh antibodies in the serum unless exposed to
Rh+blood cells (e.g., transfusion). The Rh factor is inherited
as an autosomal dominant trait, so if the mother is Rh− and
the father is Rh+, the fetus will likely be Rh+and, therefore,
there may be an incompatibility between maternal and fetal
blood. Under normal conditions, the placenta acts as a barrier between maternal and fetal blood; only small amounts of
fetal blood can reach the maternal circulation. However,
these are generally insufcient to induce an immune response
producing antibodies to Rh+fetal blood cells. However, special conditions, such as previous pregnancies, blood transfusions, or promiscuous use of syringes, can lead to maternal
immunization to D antigen. In addition, invasive diagnostic
procedures, such as chorionic villus sampling or amniocentesis, may result in the passage of fetal blood into the maternal circulation. To prevent an Rh− mother of an Rh+fetus
from developing antibodies to the D antigen, she should
receive prophylaxis with anti-D immunoglobulin before
undergoing invasive testing. At the time of delivery, mainly if
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. Ciaccio (ed.), Clinical and Laboratory Medicine Textbook, https://doi.org/10.1007/978-3-031-24958-7_30
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M. Ciaccio and L. Agnello
traumatic obstetrical maneuvers are performed, or in the case
of abortion, large amounts of fetal blood may come into contact with maternal blood, thus stimulating a process of
immunization leading to the synthesis of anti-D antibodies.
Therefore, subsequent pregnancies will be at high risk of
developing HDN because exposure to the antigen (fetal
Rh+blood cells) triggers a secondary immune response with
the production of IgG antibodies that can cross the placenta
and damage fetal red blood cells. At birth, the Rh group of
the newborn is determined. If the newborn is Rh−, then the
mother does not need to undergo further immunoprophylaxis. On the other hand, if the newborn is Rh+ and the
mother is Rh−, the mother will have to undergo immunoprophylaxis again.
Thus,Rh− women can get immunized:
• After deliverydue toimmunoprophylaxis with inadequate
or absent anti-D Ig
• During pregnancydue to events associated with transplacental hemorrhages, such as miscarriage, amniocentesis,
villocentesis, ectopic pregnancy, intrauterine fetal death,
external version maneuvers, or abdominal trauma.
After sensitizing events, postpartum and prenatal anti-D
prophylaxis reduces maternal immunization risk.
Experimental studies have shown that routine prenatal prophylaxis in Rh− pregnant women results in an absolute
reduction in the risk of immunization. Therefore, all nonsensitized Rh-pregnant women should receive immunoprophylaxis at 28weeks of gestation.
There is certainly no risk to the fetus if both parents are
Rh− or the mother is Rh+.
The Coombs test is performed by drawing maternal blood.
Maternal serum/plasma is mixed with Rh+blood at 37°C for
a sufcient period (45–60min) for IgG class D antibodies,
which may be present in the maternal serum/plasma, to recognize and bind to the D antigen. Coombs serum, an antihuman IgG antiserum, is then added and bridges between the
attached antibodies to cause obvious agglutination of the red
blood cells. In the presence of agglutination, the test is positive and, therefore, the mother will be Rh+; in the absence of
agglutination, the test will be negative and, therefore, the
mother will be Rh−.
TORCH
TORCH stands for Toxoplasmosis, Others (syphilis, hepatitis, HIV, HCV, etc.), Rubella, Cytomegalovirus, and Herpes
Simplex. It refers to infectious agents (bacteria, viruses, and
parasites) that can be dangerous to the fetus if contracted
during pregnancy. The risk varies according to the infectious
agent and the number of weeks of gestation, decreasing as
the gestational period progresses. It is important to perform
serological screening for antibodies against TORCH agents
in the preconception phase to implement preventive measures to minimize the risk of infection during pregnancy (if
the screening is negative), thus allowing proper fetal
development.
Toxoplasmosis
Toxoplasmosis is a zoonosis caused by the intracellular parasitic protozoan Toxoplasma gondii. The cat is the denitive
host of Toxoplasma, and humans, andother mammals and
various birds, are intermediate hosts. The parasite multiplies
in the intestine of felines and produces oocysts that are
excreted with feces; accidentally, other animals (cattle or
sheep) may ingest the oocysts and become infested.
Therefore, the meat and viscera of these intermediate hosts,
which contain Toxoplasma, can be ingested by other animals, where the cycle begins again. The disease can be contracted by coming into contact with oocysts contained in cat
feces, raw or undercooked infected meat, vegetables, and
fruit that have not been well washed. The acute infection is
asymptomatic in 90% of cases, while the remaining 10%
develop only mild lateral and retrocervical adenopathies. In
Italy, 60% of the population is susceptible to infection.
Maternal–fetal transmission occurs when the infection is
contracted during pregnancy, that is, in a previously seronegative woman. The overall risk of transmission to the fetus
and the clinical picture and severity of the congenital infection depend on the gestational age. In contrast, the risk of
fetal infection increases with increasing gestational age
because the placenta progressively thins out. Vice versa, the
earlier the infection, the more serious the damage to the
fetus. The major sequelae are chorioretinitis, blindness,
hydrocephalus, neurological damage, and mental
retardation.
Prenatal screening is based on a serological test aimed at
establishing the immunological status of the woman through
the detection of specic anti-toxoplasma IgG and IgM antibodies. In this way, it will be possible to determine if the
woman is seronegative and, therefore, susceptible to infection, if she had a previous or ongoing infection (Table30.1).
Table 30.1 Serological toxoplasmosis screening
IgG IgM Interpretation Indications in pregnancy
− −
± + Possible acute
+
Ig immunoglobulin
Absent immunity Follow food hygiene rules.
infection
Previous
−
immunity
Repeat the serological test every three
months
Perform diagnostic investigations to
accurately establish the stage of
infection
Do not repeat the serological test
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