HYPOGLICEMIA

HYPERURICEMIA
 HYPOGLYCEMIA

-Definition of hypoglycemia
-Pathophysiology of hypoglycemia
-Classification of hypoglycemia
-Diagnosis of hypoglycemia
-Treatment of hypoglycemia
-Prognosis hypoglycemia
 DEFINITION OF HYPOGLYCEMIA

• Whipple’s triad:
– hypoglycemia, a low plasma glucose concentration
• ≤ 55 mg/dl (3 mmol/l) in persons without diabetes
• ≤ 70 mg/dl (3.9 mmol/l) in person with diabetes, and

– symptoms, signs, or both and

– resolution of those symptoms or signs after the
plasma glucose concentration is raised
 PATHOPHYSIOLOGY OF HYPOGLYCAEMIA
HYPOGLYCEMIA
=
• sum of glucose utilization from the circulation:
– largely by the brain
– obligatory glycolytic tissues (renal medullae, erythrocytes)
– insulin-sensitive tissues (muscle, liver, adipocytes)
– all other tissues
>
• sum of glucose delivery into the circulation:
– ingested carbohydrates
– hepatic and renal glucose production
PATHOPHYSIOLOGY OF HYPOGLYCAEMIA
PATHOPHYSIOLOGY OF HYPOGLYCAEMIA
 PARTICULARITIES OF HORMONAL RESPONSE IN DIABETES

Compromised defense mecanism against falling glycemia in T1DM

and long-standing T2DM:
• Insulin and glucagon responses to falling glucose levels are lost;
• Epinephrine response to hypoglycemia is often attenuated due to
autonomic diabetic neuropathy
ETIOLOGICAL CLASSIFICATION OF HYPOGLYCEMIA
1. Hypoglycemia with hyperinsulinemia

1.1. Exogenous - induced by drugs

•Insulin or insulin secretagogue
•In patients with diabetes
•Accidental, surreptitious, or malicious administration
•Others: Salicylates, Indomethacin, ACEI, Angiotensin receptor antagonists, b-
Adrenergic receptor antagonists, Levofloxacin, etc

1.2. Endogenous, with organic cause (fasting hypoglycemia)

•Insulinoma
•Nesidioblastosis (metaplasia and proliferation of epithelial cell from pancreatic
canaliculi into insulin-secreting cells)
•Insulin autoimmune hypoglycemia
•Antibody to insulin
•Antibody to insulin receptor
 ETIOLOGICAL CLASSIFICATION OF HYPOGLYCEMIA
1. Hypoglycemia with hyperinsulinemia

1.2. Endogenous, functional (postprandial hypoglycemia)

•Post gastric surgery
•Prolonged parenteral nutrition
•Obese subjects with prediabetes
•Spontaneous reactive hypoglycemia (It occurs in emotive individuals and the
secondary hyperinsulinism is due to an increased vagal tone)

2. Hypoglycemia with hypoinsulinemia

• Alcohol (decreases gluconeogenesis and the perception of hypoglycaemia)
• Hormone deficiency: Cortisol, Glucagon, Epinephrine, Growth hormone
• Hepatic failure (decrease glycogenolysis and gluconeogenesis),
• Renal failure (decrease insulin clearance and catabolism, decrease renal
gluconeogenesis)
• Inanition
• Nonislet cell tumor (hypoglycaemia occur through increased consumption of
glucose and secreting insulin-like substances by tumoral cells)
• Inborn errors of metabolism (intolerance to fructose, galactose)
 RISK FACTORS FOR HYPOGLYCEMIA IN DIABETES
• Relative or absolute insulin excess
• Insulin or insulin secretagogue:
•doses are too high
•wrong type of insulin,
•accidental, surreptitious, or malicious insulin/insulin
secretagogue administration
•Insulin or insulin secretagogue clearance is decreased –renal failure
•Exogenous glucose delivery is decreased
• missed or delayed meals
•digestive intolerance (vomiting, diarrhea)
•Glucose utilization is increased – during exercise without additional
supply of CH or without decreasing insulin dose
 RISK FACTORS FOR HYPOGLYCEMIA IN DIABETES
• Relative or absolute insulin excess
•Endogenous glucose production is decreased
•after alcohol ingestion
• liver faillure
•Sensitivity to insulin is increased (rapid drop in insulin requirements)
•after weight loss, birth, or treatment of infections or acute illness
•after decrease of gluco and lipotoxicity in patients with diabetes new
case
•transient remission of diabetes ("honeymoon"): period of 1-12
months after diagnosis of type 1 diabetes, when the pancreas releases
the last insulin reserves.
•History of severe or unawareness hypoglycemia (secondary to autonomic
diabetic neuropathy)
•Aggressive glycemic therapy per se (too low glycemic/HbA1c goals).
Hypoglycemia in this case is the price paid for maintaining optimal metabolic
control.
CLINICAL CLASSIFICATION. SEVERITY OF HYPOGLYCEMIA
• Mild
– Autonomic symptoms present
– Individual is able to self-treat
• Moderate
– Autonomic and neuroglycopenic symptoms
– Individual is able to self-treat
• Severe
– Requires the assistance of another person to
actively administer carbohydrate, glucagon
– Coma or seizure may appear
– Plasma glucose is typically < 50 mg/dl
CLINICAL CLASSIFICATION OF HYPOGLYCEMIA IN PERSONS
WITH DIABETES

• Documented symptomatic hypoglycemia:

– typical symptoms of hypoglycemia
– measured plasma glucose concentration ≤70mg/dl
• Hypoglycemia unawareness :
– presence of cognitive symptoms in the absence of
autonomic symptoms
– measured plasma glucose concentration ≤70mg/dl
– diabetic autonomic neuropathy or previous hypoglycemic
episodes lead to the unawareness hypoglycemia
 CLINICAL CLASSIFICATION OF HYPOGLYCEMIA IN PERSONS
WITH DIABETES
• Probable symptomatic hypoglycemia:
– typical symptoms of hypoglycemia
– not accompanied by a plasma glucose determination
– explanation: many patients choose to treat the hypoglycemic symptoms by
ingestion of carbohydrates without prior checking of glycemia
• Relative hypoglycemia:
– person with diabetes reports typical symptoms of hypoglycemia and
interprets those as indicative of hypoglycemia
– measured plasma glucose concentration > 70 mg/dl
– occur in patients with poor glycemic control in wich the hypoglicemia
symptoms associated with glycemia >70mg/dl may be justified by rapid drop
of glycemia from a high value.
 DIAGNOSIS OF HYPOGLYCEMIA

• Whipple’s triad:
– symptoms, signs, or both and
– hypoglycemia, a low plasma glucose concentration, and
– resolution of those symptoms or signs after the
plasma glucose concentration is raised
• Etiological diagnosis of hypoglycemia
 SYMPTOMS AND SIGNS OF HYPOGLYCEMIA
AUTONOMIC NEUROGLYCOPENIC
(result of the neurohormonal response (result of brain glucose
triggered by hypoglycemia) deprivation per se)
ADRENERGIC CHOLINERGIC
Palpitations Sweating Behavioral changes
Tremor Hunger Fatigue
Anxiety Numbness Headache
Pallor Blurred vision
Tachycardia Dizziness
Increase BP Confusion
Diplopia
Difficulty in thinking or speech
Neurologic deficits
Seizure
Coma
 EVALUATION OF HYPOGLYCEMIA IN PERSONS WITHOUT DIABETES

• When the cause of the hypoglycemic disorder is not evident,

during an episode of spontaneous hypoglycemia measure:
– plasma glucose
– Insulin, C-peptide, proinsulin
– β-hydroxybutyrate (ketone body)
– plasma glucose response to i.v. injection of 1 mg glucagon
– oral hypoglycemic agents
– insulin antibodies
• When a spontaneous hypoglycemic episode cannot be
observed, recreate the context in which symptomatic
hypoglycemia is likely to apper– 72 h fast test.
 EVALUATION OF HYPOGLYCEMIA IN PERSONS WITHOUT DIABETES

Steps of 72 h fast test:

• At the beginning of the fast:
– Collect samples for plasma glucose, insulin, C-peptide, proinsulin, and b-
hydroxybutyrate every 6 h until the plasma glycemia is less than 60 mg/dl; at
that point the frequency of sampling should be increased to every 1 to 2 h.
• End the fast when:
– 72 h have elapsed without symptom
– plasma glycemia <45mg/dl with symptoms and/or signs of hypoglycemia
– plasma glycemia <55mg/dl without symptoms and/or signs if Whipple's triad
was documented unequivocally on a prior occasion.
• At the end of the fast:
– collect samples for plasma glucose, insulin, C-peptide, proinsulin, b-
hydroxybutyrate, oral hypoglycemia agents
– inject 1.0 mg of glucagon iv and measure plasma glucose 10, 20, and 30 min
later.
ETIOLOGICAL DIAGNOSIS OF HYPOGLYCEMIA
 Diagnosis of insulinoma
• In a patient with documented fasting or postprandial
endogenous hyperinsulinemic hypoglycemia,
negative screening for oral hypoglycemic agents, and
no circulating insulin antibodies, it is indicated to
perform procedures for localizing an insulinoma.
• These may include:
– transabdominal ultrasonography
– computed tomography or MRI,
– endoscopic ultrasonography
 MANAGEMENT OF HYPOGLYCEMIA

• The management of hypoglycemia involves three

phases:
– restoring normal levels of glycemia
– relieving symptoms
– correction of the causes of the hypoglycemia
TREATMENT OF HYPOGLYCEMIA WHEN THE PATIEN IS CONSCIOUS
Roule 15:15
HYPOGLYCEMIA TREATMENT WHEN THE PATIEN IS CONSCIOUS

 A! Hypoglycaemia is a situation where SUGAR is not only

allowed, but even mandatory for people with diabetes.

 A! Chocolate should be avoided because of its fat

content which may delay the glucose absorption.

 A! Parenteral administration of glucose should be

avoided if the patient is conscious and can swallow
TREATMENT OF SEVERE HYPOGLYCEMIA
Key messages
HYPOGLYCEMIA AND DRIVING

Safe blood glucose (BG) prior to driving BG ≥ 90 mg/dl (5.0 mmol/L)

• If BG < 90 mg/dl (5.0 mmol/L) prior to driving:

– Take 15 g carbohydrate
– Re-check in 15 minutes
– When BG > 90 mg/dl (5 mmol/L) for at least 45 minutes  safe to
drive
• Need to re-check BG every 4 hours of continuous driving
and carry simple carbohydrate snacks
Iain S. Begg et al . Canadian Journal of Diabetes. 2003;27(2):128-140.
Hypoglycemia: evolution, complications, prognosis

Indian J Endocrinol Metab. 2013 Sep-Oct; 17(5): 819–834.

Hypoglycemia: evolution, complications, prognosis

• The clinical manifestations can be completely reversible if the

treatment of hypoglycemia is applied correctly and timely.
• The irreversible damage to the central nervous system and
cardiovascular system may appear if the carbohydrate intake is
delaied.
• Possible consequences:
– Post-hypoglycemic encephalopathy: progressive personality changes,
memory impairment, psychosis, dementia progression.
– Myocardial infarction, severe cardiac arrhythmias.
– Stroke
– Death
 HYPERURICEMIA AND GOUT
TABLE OF CONTENT

•Definition
•Classification
•Diagnostic
•Medical nutrition therapy
•Pharmacological treatment
 DEFINITION
• Hyperuricemia is defined as an elevated serum uric acid greater
than 7mg/dl
• Asymptomatic hyperuricemia is defined as elevated serum urate
concentration without a urate crystal deposition disease
• Urate crystal deposition disease:
– Gout
• Acute gouty arthritis
• Intercritical gout
• Chronic tophaceous gout
– Uric acid renal disease:
• acute hyperuricemic nephropathy
• chronic hyperuricemic nephropathy
• uric acid nephrolithiasis
 CLASSIFICATION
Hyperuricemia is generally divided into three
pathophysiologic categories:
– increased uric acid production (overproduction)
– decreased uric acid excretion (underexcretion),
– combined causes

Uric acid
Uric acid
production
excretion
 CLASSIFICATION
Underexcretion can result from:
• Decreased glomerular filtration: renal insufficiency
• Decreased tubular secretion occurs in patients with acidosis (the
organic acids that accumulate in these conditions compete with urate for tubular
secretion):
– diabetic ketoacidosis,
– Lactic acidosis
– ethanol intoxication
– salicylate intoxication,
– starvation ketosis
• Enhanced tubular reabsorption
– diuretic therapy, nicotinic acid, ethambutol, pyrazinamide, aspirin (low
doses)
– diabetes insipidus
 CLASSIFICATION
Overproduction
• Exogenous - diet rich in purines or fructose
• Endogenous - increased purine nucleotide breakdown
– rapid cell proliferation and turnover or cell death
(lymphoproliferative disorders, myeloproliferative disorders,
psoriasis, rhabdomyolysis, cytotoxic therapy)
• Enzymatic defects:
– Lesch-Nyhan syndrome - complete deficiency of hypoxanthine
guanine phosphoribosyltransferase (HGPRT)
– Kelley-Seegmiller syndrome - partial deficiency of HGPRT
– Increased activity of 5-phospho-alpha-d-ribosyl pyrophosphate
(PRPP) synthetase
 CLASSIFICATION
Combined mechanisms
• Alcohol consumption which results in:
– high purine content of some drinks, such as beer
– generation of lactic acid that compete with urate for tubular
secretion
– accelerated hepatic breakdown of ATP
• Obesity
• Fructose raises serum uric acid levels by:
– accentuating degradation of purine nucleotides and
increasing purine synthesis
– decreasing renal uric acid excretion
• Enzymatic defects
– glycogenoses type I (von Gierke disease)
– aldolase-B deficiency
 ASYMPTOMATIC HYPERURICEMIA

• An elevated serum uric acid greater than 7mg/dl and

an urinary uric acid excretion greater than 600 – 800
mg/dl, without any clinical symptoms, discovered by
screening tests or occasionally;
• In most cases, is discovered in adolescent men and in
women at menopause age;
• In 5 % cases, asymptomatic hyperuricemia leads to
gout
 ACUTE GOUTY ARTHRITIS
• It is the consequence of deposition of monosodium
urate crystals in joints as a result of persistent
hyperuricemia;
• Acute gouty arthritis typically manifests as
monoarthritis, most commonly in the toe and less
frequently in the tarsal joint, knee, and other joints.
• The joints that are extremely rarely affected are: the
shoulder, the hip, the spine, the sacroiliac joint, the
mandible
• Acute bursitis may occur (prepatella, the elbow joint, the
Achille tendon, Heberdeen lumps)
 ACUTE GOUTY ARTHRITIS

• Acute gouty arthritis can be caused by traumatic injury,

overfeeding, alchool consumption, acute stress,
infection, intensive weight loss, starting allopurinol
treatment
• The pain starts suddenly, often during the night, being
often described as crushing or excruciating and typically
reach maximum intensity within 8-12 hours
• In acute gouty arthritis, the affected joint is typically
warm, erythematous, swollen, and exquisitely painful
 RECURRENT ATTACKS OF ACUTE GOUTY ARTHRITIS

• Next attaks of acute arthritis can reoccur after

months/years of evolution, more suddenly, more often
and involving more than one joint
• The lab exams indicate high serum levels of uric acid,
leucocytosis and inflammation markers
• Identification of monosodium urat (MSU) crystals in a
joint fluid sample is required for a the diagnosis of gout
(MSU crystals are found to be negatively birefringent
under polarized microscopy)
 ACUTE GOUTY ARTHRITIS
DIFFERENTIAL DIAGNOSIS
- Septic arthritis
- Rheumatoid arthritis
- Psoriatic arthritis
- Lupus arthritis
- Arthrosis
 INTERCRITICAL GOUT

• Following recovery from acute gouty arthritis, the

patient reenters an asymptomatic phase of the
disease
 CHRONIC TOPHACEOUS GOUT
• Tophi are chalky deposits of sodium urate
• Patients with chronic gouty arthritis may develop tophi
in the helix or antihelix of the ear, along the ulnar surface
of the forearm, in the olecranon bursa, or in other
tissues (tongue, epiglottis, vocal cords, corpus
cavernosum, aortic and mitral valve, cardiac conduction
system)
• Tophi do not appear in the liver, lungs, central nervous
system.
• Articular tophaceous gout can result in a destructive
arthropathy and chronic secondary osteoarthritis
 CHRONIC TOPHACEOUS GOUT

• The duration of time between the first gouty attack

and tophaceous disease is highly variable and may
range from 3 to 42 years
• Tophaceous disease is more likely to occur in patients
with:
– polyarticular presentation,
– serum urate level higher than 9.0 mg/dL
– younger age at disease onset (i.e., 40 years old or younger);
 CHRONIC TOPHACEOUS GOUT

• Classic radiologic features of gout include:

– tophi,
– overhanging edge of cortex
– “punched-out” erosion of bone with sclerotic borders
• The hallmark sign of late-phase gout is the appearance of
large and numerous interosseous tophi and joint-space
narrowing
• Marked deformities and subluxation may also be noted in
affected areas, as well as calcium deposits in the soft tissues.
 RENAL COMPLICATIONS

• Three forms of kidney disease have been attributed

to hyperuricemia:
– acute uric acid nephropathy;
– chronic urate nephropathy;
– uric acid nephrolithiasis.
 ACUTE URIC ACID NEPHROPATHY

• Acute uric acid nephropathy is the term applied to

the development of acute renal failure caused by
renal tubular obstruction by urate and uric acid
crystals
• Hyperuricemia is caused by rapid cell turnover or
cell lysis observed in patients with acute leukemia
and lymphoma or with chemotherapy or radiation
therapy

Mark T. Fahlen, Vecihi Batuman. Uric Acid Nephropathy, medscape, 2013, accesed on august 2015: http://emedicine.medscape.com/article/244255-overview
 CHRONIC URATE NEPHROPATHY

• Microtophi formation in the renal medullary

interstitium. These deposits were found to contain
monosodium urate monohydrate and to be
surrounded by a giant cell reaction.
• Urate deposition triggers a foreign body reaction and
leads to chronic inflammation and fibrosis.
 URIC ACID NEPHROLITHIASIS

• Uric acid stones represent 5-10% of all renal calculi,

resulting from uric acid precipitation in the
collecting system
• Urine oversaturation with uric acid and subsequent
crystal formation is determined largely by low
urinary pH.
• Uric acid nephrolithiasis should be considered in a
patient with a history of gout who presents with pain
in the flank, abdomen, or inguinal region, dysuria or
hematuria

Mark T. Fahlen, Vecihi Batuman. Uric Acid Nephropathy, medscape, 2013, accesed on august 2015: http://emedicine.medscape.com/article/244255-overview
 MEDICAL NUTRITION THERAPY

• Healthy lifestyle advice should include maintenance

of ideal body weight, avoidance of excess alcohol,
sugar sweetened drinks
• 10% of patients benefit from lowering the uric acid
levels throughout a low purine diet;
• A reduction in body weight close to normal offers a
reduction of 1,8 mg/dL in uric acid levels;
 MEDICAL NUTRITION THERAPY
• Low calorie diet (maximum 1600 kcal/day);
• Low protein diet (0,8-1 g/kgc/day), it should be prefered no more than
100 g of elderly meat (hen, cow) per day, low fat dairy products in no-
meat days,
• A maximum intake of 200 g of purine/day (avoiding ingestion of liver,
kidney, tongue, herring, mussel, hunted meat, lamb, chicken, chocolate,
cocoa, etc).
• Low fat diet (maximum 60 g/day)
• Low sodium intake (max. 2 grams of Natrium per day);
• Normal carbohydrate intake, avoiding high-concentrated carbohydrate
foods and fructose sweetened drinks
• Avoidance of excessive alcohol consumption (especially beer);
• Low oxalic acid intake (peas, beans, asparagus, spinach, cucumbers,
celery, beet, etc.)
• Hydric intake 2000-2500ml daily, tap water, fruit or vegetable juice
ALGORITHM FOR TREATMENT OF HYPERURICEMIA
ALGORITHM FOR TREATMENT OF HYPERURICEMIA
MANAGEMENT OF AN ACUTE GOUT ATTACK