Endocrine system Flashcards
Diabetes mellitus
Diabetes mellitus (DM) describes a group of metabolic diseases that are characterized by chronic hyperglycemia (elevated blood glucose levels). The two most common forms are type 1 and type 2 diabetes mellitus. Type 1 is the result of an autoimmune response that triggers the destruction of insulin-producing β cells in the pancreas and results in an absolute insulin deficiency. Type 2, which is much more common, has a strong genetic component as well as a significant association with obesity and sedentary lifestyles. Type 2 diabetes is characterized by insulin resistance (insufficient response of peripheral cells to insulin) and pancreatic β cell dysfunction (impaired insulin secretion), resulting in relative insulin deficiency. This form of diabetes usually remains clinically inapparent for many years. However, abnormal metabolism (prediabetic state or impaired glucose intolerance), which is associated with chronic hyperglycemia, causes microvascular and macrovascular changes that eventually result in cardiovascular, renal, retinal, and neurological complications. In addition, type 2 diabetic patients often present with other conditions (e.g. hypertension, dyslipidemia, obesity) that increase the risk of cardiovascular disease (e.g., myocardial infarction). Renal insufficiency is primarily responsible for the reduced life expectancy of patients with DM. Because of the chronic, progressive nature of type 1 and type 2 diabetes mellitus, a comprehensive treatment approach is necessary. The primary treatment goals for type 2 diabetes are the normalization of glucose metabolism and the management of risk factors (e.g., arterial hypertension). In theory, weight normalization, physical activity, and a balanced diet should be sufficient to prevent the manifestation of diabetes in prediabetic patients or delay the progression of disease in diabetic patients. Unfortunately, these general measures alone are rarely successful, and treatment with oral antidiabetic drugs and/or insulin injections is often required for optimal glycemic control. In type 1 diabetes, insulin replacement therapy is essential and patients must learn to coordinate insulin injections and dietary carbohydrates. Both type 1 and type 2 diabetic patients require regular self-management training to improve glycemic control, reduce the risk of life-threatening hypoglycemia or hyperglycemia, and prevent diabetic complication
Diabetes mellitus type 1 Dr Deac Pimp
Epidemiology:
∼ 5% of all patients with diabetes
Childhood onset: typically < 20 years but can occur at any age; peaks at age 4–6 years and 10–14 years
Highest prevalence in non-Hispanic whites
Aetiiology of type 1:
Type 1
Autoimmune β cell destruction in genetically susceptible individuals
HLA association. HLA-DR3 and HLA-DR4 positive patients are 4–6 times more likely to develop type 1 diabetes.
Association with other autoimmune conditions
Hashimoto thyroiditis
Type A gastritis
Celiac disease
Primary adrenal insufficiency
Pathophysiology:
Normal insulin physiology
Secretion: Insulin is synthesized in the β cells of the islets of Langerhans. The cleavage of proinsulin (precursor molecule of insulin) produces the C-peptide (connecting peptide) and insulin, which consists of two peptide chains (A and B chains).
Action: Insulin has a variety of metabolic effects on the body, primarily contributing to the generation of energy reserves and glycemic control.
Carbohydrate metabolism: Insulin is the only hormone in the body that lowers the blood glucose level.
Protein metabolism: stimulates protein synthesis Stimulates amino acid uptake into cells; inhibits proteolysis
Lipid metabolism: maintains a fat depot and has an antiketogenic effect
Electrolyte regulation: stimulates intracellular potassium accumulation
Type 1 diabetes
Genetic susceptibility
Environmental trigger (often associated with previous viral infection)
→ Autoimmune response with production of autoantibodies, e.g., Anti-glutamic acid decarboxylase antibody (Anti-GAD), that target insulin-producing cells → progressive destruction of insulin-producing β cells in the pancreatic islets by autoreactive T cells → destruction of 80–90% of β cells
→ Absolute insulin deficiency → elevated blood glucose levels
Clinical features:
Onset for type 1: sudden, diabetic ketoacidosis is often the first manifestation.
Alternatively, children may present with acute illness and classic symptoms.
-Classic: polyuria, secondary enuresis and nocturia in children.
-Polydipsia
-Polyphagia
Nonsepecific:
-Fatigue
-Visual disturbances: blurred vision
-Calf cramps
-Poor wound healing
-Pruritis
Weight loss: a thin appearance is typical for type 1 diabetic patients.
Diabetes mellitus should be suspected in patients with recurrent cellulitis, candidiasis, dermatophyte infections, gangrene, pneumonia (particularly TB reactivation), influenza, genitourinary infections (UTIs), osteomyelitis, and/or vascular dementia.
Investigations :
Hyperglycemia: elevated blood glucose levels
Diagnostic criteria for patients
A single random blood glucose level ≥ 200 mg/dL is sufficient for diagnosis.
Alternatively, a pathological fasting plasma glucose (FPG) test, oral glucose tolerance test (OGTT) , or hemoglobin A1C (HbA1C) test establishes the diagnosis (see table below)
If hyperglycemia is high enough to suggest but not confirm a diagnosis of DM, two similar test results, either from the same sample or from a separate test sample, will confirm the diagnosis.
Symptomatic patients need to be tested.
Asymptomatic patients wih younger than 45 years of age who are obese and have one other risk factor for diabetes.
Also need to be tested if >45 years of age.
For diabetes mellitus, fasting plasma glucose level should be greater than or equal to 126
2 hour glucose value after OGTT is greater than 200.
Hemoglobin is greater than 6.5.
Prediabetes:
FPG: 100-125 (5.6-6.9)
2hour OGTT: 140-199
Hb A1C: 5.7-6.4
Healthy:
FPG: <100 (<5.6)
2 hour OGTT: <140 (<7.8)
Hb A1C In % <5.7
Additional tests
Specific autoantibodies for diabetes mellitus type 1
Anti-GAD antibodies
Anti-tyrosine phosphatase-related islet antigen (IA-2)
Islet cell surface antibody (ICSA; against ganglioside)
C-peptide
↓ C-peptide levels indicate an absolute insulin deficiency → type 1 diabetes
↑ C-peptide levels may indicate insulin resistance and hyperinsulinemia → type 2 diabetes
Urine analysis
Microalbuminuria: an early sign of diabetic nephropathy
Glucosuria: Testing urine for glucose does not suffice to establish the diagnosis of diabetes mellitus.
Ketone bodies (usually accompanied by glucosuria): positive in acute metabolic decompensation in diabetes mellitus (diabetic ketoacidosis).
Ddx:
Glucagonoma
Definition: a rare neuroendocrine tumor of the pancreas that secretes glucagon. In > 50% of cases, metastasis is present at diagnosis.
Clinical findings: nonspecific symptoms, weight loss (80%), necrolytic migratory erythema (70%), impaired glucose tolerance or diabetes mellitus (75–95%), chronic diarrhea (30%), deep vein thrombosis, and depression
Necrolytic migratory erythema
A cutaneous paraneoplastic syndrome that is mainly associated with pancreatic tumors secreting glucagon, but also hepatitis B, C, and bronchial carcinoma
Occurrence of multiple areas of centrifugally spreading erythema, located predominantly on the face, perineum, and lower extremities
Develop into painful and pruritic crusty patches with central areas of bronze-colored induration
Tend to resolve and reappear in a different location
Skin biopsy shows epidermal necrosis
Diagnostics: requires a high index of suspicion to make the diagnosis
Laboratory findings: ↑ glucagon, ↑ blood glucose levels, normocytic normochromic anemia (90%)
Imaging (CT): locate the tumor
Treatment
Glycemic control
Octreotide (somatostatin)
Pancreatic resection
Somatostatinoma
Definition: a rare neuroendocrine tumor of δ-cell (D-cell) origin that is usually located in the pancreas or gastrointestinal tract and secretes somatostatin.
Clinical findings
Abdominal pain
Weight loss
Classic triad
Glucose intolerance
Cholelithiasis
Steatorrhea
Achlorhydria
Diagnostics
Laboratory findings: ↑ somatostatin, ↑ blood glucose levels
Imaging: locate the tumor
Treatment
Octreotide → inhibition of somatostatin secretion
Pancreatic resection: curative if no metastases are present
Chemotherapy.
Treatment
Individual treatment targets
Blood glucose control and regular glycemic monitoring: A1C values
Weight loss : Type 2 diabetic patients with a BMI of 27–35 benefit from a weight reduction of 5%; in patients with a BMI > 35 kg/m2, weight reduction of > 10% is recommended.
Blood pressure control
Improved blood lipid profile with statin therapy
Low dose aspirin for men > 50 years and women > 60 years with cardiovascular risk factors.
Lifestyle modification:
↑ Physical activity → ↓ blood glucose and ↑ insulin sensitivity
Smoking cessation
Balanced diet and nutrition
Small, frequent meals
Diet: ∼ 55% carbohydrates (replace simple carbohydrates such as glucose and sucrose with complex carbohydrates), 30% fat, 15% protein
High-fiber diet
Alcohol should (if possible) be consumed with carbohydrates to avoid hypoglycemia
complications
Hyperglycemic crisis: undiagnosed or insufficiently treated diabetes mellitus may result in severe hyperglycemia, potentially culminating in a coma
Hyperosmolar hyperglycemic state (HHS)
Diabetic ketoacidosis (DKA)
Life-threatening hypoglycemia: secondary to inappropriate insulin therapy
Diabetic cardiomyopathy
Diabetic fatty liver disease
Hyporeninemic hypoaldosteronism
Limited joint mobility (formerly known as diabetic cheiroarthropathy)
Sialadenosis
Increased risk of infection
Strict glycemic control is crucial in preventing microvascular disease.
Prognosis
Diabetes mellitus is one of the leading causes of death in the US; common complications that result in death are myocardial infarction and end stage renal failure.
One of the leading causes of blindness, nontraumatic lower limb amputation, end stage renal failure, and cardiovascular disease
The prognosis primarily depends on glycemic control and treatment of comorbidities (e.g., hypertension, dyslipidemia).
References:[7]
Diabetes mellitus type 2 Dr Deac Pimp
Epidemiology
Type 2:
The estimated prevalence in the US is 9.1%.
Adult onset: typically > 40 years ; mean age of onset is decreasing
Highest prevalence in Hispanics, Native Americans, Asian Americans, African Americans, and Pacific Islanders
Aetiology type 2 Hereditary and environmental factors Association with metabolic syndrome Risk factors Obesity, high-calorie diet High waist-to-hip ratio (visceral fat accumulation) Physical inactivity First-degree relative with diabetes Ethnicity Hypertension Dyslipidemia History of gestational diabetes.
Pathophysiology:
Type 2 diabetes
Two major mechanisms:
Peripheral insulin resistance
Numerous genetic and environmental factors
Central obesity → increased plasma levels of free fatty acids → impaired insulin-dependent glucose uptake into hepatocytes, myocytes, and adipocytes
Increased serine kinase activity in liver, fat and skeletal muscle cells → phosphorylation of insulin receptor substrate (IRS)-1 → decreased affinity of IRS-1 for PI3K → decreased expression of GLUT4 channels → decreased cellular glucose uptake
Pancreatic β cell dysfunction
Accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas → decreased endogenous insulin production
Initially, insulin resistance is compensated by increased insulin and amylin secretion.
Over the course of the disease, insulin resistance progresses, while insulin secretion capacity declines.
After a period of impaired glucose tolerance with isolated postprandial hyperglycemia, diabetes manifests with fasting hyperglycemia.
Type 2 clinical features:
Onset: Gradual; the majority of patients are asymptomatic
Hyperosmolar hyperglycemic state (in elderly especially, signs of dehydration)
Symptoms of complications may be the first clinical sign of disease.
Characteristic features
Classic
Polyuria
Secondary enuresis and nocturia in children
Polydipsia
Polyphagia
Nonspecific
Fatigue
Visual disturbances: blurred vision
Calf cramps
Poor wound healing
Pruritus
Benign acanthosis nigricans
Diabetes mellitus should be suspected in patients with recurrent cellulitis, candidiasis, dermatophyte infections, gangrene, pneumonia (particularly TB reactivation), influenza, genitourinary infections (UTIs), osteomyelitis, and/or vascular dementia.
For diabetes mellitus, fasting plasma glucose level should be greater than or equal to 126
2 hour glucose value after OGTT is greater than 200.
Hemoglobin is greater than 6.5.
Prediabetes:
FPG: 100-125 (5.6-6.9)
2hour OGTT: 140-199
Hb A1C: 5.7-6.4
Healthy:
FPG: <100 (<5.6)
2 hour OGTT: <140 (<7.8)
Hb A1C In % <5.7
Additional tests
Specific autoantibodies for diabetes mellitus type 1
Anti-GAD antibodies
Anti-tyrosine phosphatase-related islet antigen (IA-2)
Islet cell surface antibody (ICSA; against ganglioside)
C-peptide
↓ C-peptide levels indicate an absolute insulin deficiency → type 1 diabetes
↑ C-peptide levels may indicate insulin resistance and hyperinsulinemia → type 2 diabetes
Urine analysis
Microalbuminuria: an early sign of diabetic nephropathy
Glucosuria: Testing urine for glucose does not suffice to establish the diagnosis of diabetes mellitus.
Ketone bodies (usually accompanied by glucosuria): positive in acute metabolic decompensation in diabetes mellitus (diabetic ketoacidosis)
Glucagonoma
Definition: a rare neuroendocrine tumor of the pancreas that secretes glucagon. In > 50% of cases, metastasis is present at diagnosis.
Clinical findings: nonspecific symptoms, weight loss (80%), necrolytic migratory erythema (70%), impaired glucose tolerance or diabetes mellitus (75–95%), chronic diarrhea (30%), deep vein thrombosis, and depression
Necrolytic migratory erythema
A cutaneous paraneoplastic syndrome that is mainly associated with pancreatic tumors secreting glucagon, but also hepatitis B, C, and bronchial carcinoma
Occurrence of multiple areas of centrifugally spreading erythema, located predominantly on the face, perineum, and lower extremities
Develop into painful and pruritic crusty patches with central areas of bronze-colored induration
Tend to resolve and reappear in a different location
Skin biopsy shows epidermal necrosis
Diagnostics: requires a high index of suspicion to make the diagnosis
Laboratory findings: ↑ glucagon, ↑ blood glucose levels, normocytic normochromic anemia (90%)
Imaging (CT): locate the tumor
Treatment
Glycemic control
Octreotide (somatostatin)
Pancreatic resection
Somatostatinoma
Definition: a rare neuroendocrine tumor of δ-cell (D-cell) origin that is usually located in the pancreas or gastrointestinal tract and secretes somatostatin.
Clinical findings
Abdominal pain
Weight loss
Classic triad
Glucose intolerance
Cholelithiasis
Steatorrhea
Achlorhydria
Diagnostics
Laboratory findings: ↑ somatostatin, ↑ blood glucose levels
Imaging: locate the tumor
Treatment
Octreotide → inhibition of somatostatin secretion
Pancreatic resection: curative if no metastases are present
Chemotherapy.
Treatment
Treatment
Individual treatment targets
Blood glucose control and regular glycemic monitoring: A1C values
Weight loss : Type 2 diabetic patients with a BMI of 27–35 benefit from a weight reduction of 5%; in patients with a BMI > 35 kg/m2, weight reduction of > 10% is recommended.
Blood pressure control
Improved blood lipid profile with statin therapy
Low dose aspirin for men > 50 years and women > 60 years with cardiovascular risk factors.
Lifestyle modification:
↑ Physical activity → ↓ blood glucose and ↑ insulin sensitivity
Smoking cessation
Balanced diet and nutrition
Small, frequent meals
Diet: ∼ 55% carbohydrates (replace simple carbohydrates such as glucose and sucrose with complex carbohydrates), 30% fat, 15% protein
High-fiber diet
Alcohol should (if possible) be consumed with carbohydrates to avoid hypoglycemia
complications
Hyperglycemic crisis: undiagnosed or insufficiently treated diabetes mellitus may result in severe hyperglycemia, potentially culminating in a coma
Hyperosmolar hyperglycemic state (HHS)
Diabetic ketoacidosis (DKA)
Life-threatening hypoglycemia: secondary to inappropriate insulin therapy
Diabetic cardiomyopathy
Diabetic fatty liver disease
Hyporeninemic hypoaldosteronism
Limited joint mobility (formerly known as diabetic cheiroarthropathy)
Sialadenosis
Increased risk of infection
prognosis
Diabetes mellitus is one of the leading causes of death in the US; common complications that result in death are myocardial infarction and end stage renal failure.
One of the leading causes of blindness, nontraumatic lower limb amputation, end stage renal failure, and cardiovascular disease
The prognosis primarily depends on glycemic control and treatment of comorbidities (e.g., hypertension, dyslipidemia).
References:[7]
Antihyperglycemic therapy algorithm for type 2 diabetes
HbA1C target for adults: < 7% (53 mmol/mol)
The guidelines for the treatment of DM recommend an individualized treatment strategy.
If the target A1C is not reached within 3 months with conservative measures (e.g., diet, exercise), the next step in the therapeutic algorithm should be initiated.
Oral antidiabetic drugs should be avoided in patients undergoing surgery or suffering from severe illness. Instead, insulin therapy should be initiated!
General measures: weight reduction, exercise, medical nutrition therapy, self-management education.
Monotherapy: drug of choice is metformin.
Dual therapy: Metformin + a second oral antidabetic drug:
Metformin +
A second oral antidiabetic drug: dipeptidyl peptidase-4 inhibitor, sulfonylureas, thiazolidinedione, meglitinides, SGLT-2 inhibitors, alpha-glucosidase inhibitors, amylin analogs
GLP-1 receptor agonists (incretin mimetics)
Basal insulin
Triple therapy
Add a third oral antidiabetic drug, nightly basal insulin, or injectable GLP-1 receptor agonist
Combination injectable therapy Metformin + basal insulin + mealtime insulin or GLP-1 receptor agonist
Only consider the substitution of drugs in cases in which the drug is not tolerated or side effects occur.
Oral antidiabetic drugs should be avoided in patients undergoing surgery or suffering from severe illness. Instead, insulin therapy should be initiated!
References:[7][20]
complicat
Principles of insulin therapy
Total daily requirement of insulin
On average, the body requires 40 USP units of insulin daily.
20 units for basic metabolism → basal insulin
20 units for calorie consumption → bolus insulin
Insulin correction factor
1 unit of insulin lowers the blood glucose level by 30–40 mg/dL (1.7–2.2 mmol/L)
Carbohydrate counting
10 g of carbohydrates increases the blood glucose level by 30–40 mg/dL (1.7–2.2 mmol/L).
Insulin-to-carbohydrate ratio
On average, 1 unit of insulin is required for 15 g carbs = 1 carb serving (carb unit); however, this varies greatly from patient to patient.
Insulin sensitivity fluctuates over the course of a day → Insulin-to-carbohydrate ratio changes over the course of a day.
Morning hours: 2 units insulin, lunchtime: 1 unit, evening hours: 1.5 units
Type 1 diabetes
Insulin replacement therapy: The exogenous insulin requirement depends on the residual insulin production of the pancreas.
The initial total daily dose (TDD) of insulin should be 0.6–1.0 U/kg.
After beginning insulin treatment, there is often a temporary reduction in exogenous insulin demand.
Type 2 diabetes
Residual endogenous insulin production is augmented with exogenous insulin, depending on the extent of insulin resistance (which in turn depends on the level of obesity).
The TDD of insulin should be 0.1–0.2 U/kg
Hypoglycaemia
D: Hypoglycemia, or low blood glucose, has many causes, but it most commonly occurs in diabetic patients as a consequence of insulin therapy or other drugs. The onset of hypoglycemic symptoms depends largely on the individual’s physiological adaptation mechanisms, although symptoms can start to occur when blood glucose falls below 70 mg/dL. Hypoglycemia manifests with autonomic symptoms (i.e., hunger, sweating, tachycardia) and neuroglycopenic symptoms (i.e., confusion, behavioral changes, somnolence). Since prolonged hypoglycemia can result in acute brain damage, changes in a patient’s mental status should prompt immediate fingerstick blood glucose measurement and treatment. Treatment in patients who are still conscious consists of a fast-acting carbohydrate such as glucose tablets, candy, or juice. Unresponsive patients are treated with intravenous dextrose or intramuscular glucagon.
Defining cutoff: There is no specific cutoff that defines hypoglycemia, as there is considerable variability in the serum glucose level at which a person will experience symptoms of hypoglycemia.
In patients with diabetes: generally described as ≤ 70 mg/dL (≤ 3.9 mmol/L). [1]
Whipple triad [1][2]
Low plasma glucose concentration
Signs or symptoms consistent with hypoglycemia (see “Clinical features” below)
Relief of symptoms when plasma glucose increases after treatment.
Causes of hypoglycaemia Insulin-related Insulin excess Accidental overdose of insulin or noninsulin drugs (e.g., sulfonylureas, meglitinides) Wrongly timed medication Drug interactions Factitious disorder Increased sensitivity to insulin Weight loss Increase in activity/exercise Decreased insulin clearance Renal failure
Glucose-related
Fasting/missed meals
Chronic alcohol use
Exercise
Acute illness Sepsis Trauma Burns Organ failure
(Relative) overdose of insulin or a noninsulin drug is by far the most common cause of hypoglycemia.
Consider factitious disorder in patients with access to insulin and other diabetes medications (e.g., healthcare professionals), for whom there is no other obvious explanation for hypoglycemia.
Non diabeteic patients hypoglycaemia causes Critical illness Hepatic disease Renal failure Heart failure Malnutrition Sepsis Trauma Burns
Drugs that cause hypoglycemia: Nonselective beta blockers Hormone deficiencies: Hypopituitarism Adrenal insufficiency
Endogenous hyperinsulinaemia or IGF
Insulinoma
Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS)
Gastric bypass surgery (late dumping syndrome)
Nonislet cell tumor hypoglycemia
Exogenous hyperinsulinism
Factitious disorder
Accidental insulin use
Autoimmune causes
Insulin autoimmune syndrome (IAS)
Anti-insulin receptor autoantibodies
Genetic and congenital disorders Genetic and congenital disorders [4] Congenital hypopituitarism Glycogen storage diseases Fructose intolerance
Clinical features
Threshold for symptoms
Varies greatly, but symptoms have usually occurred by the time serum glucose concentration is < 50 mg/dL (2.8 mmol/L)
The threshold at which symptoms may appear in patients with chronic diabetes is especially variable due to hypoglycemia-associated autonomic failure (HAAF). [1]
Recurrent hypoglycemia → changes in the counterregulatory response (e.g., decreased epinephrine release) → lower glucose threshold needed to trigger symptoms → asymptomatic hypoglycemia
For this reason, the initial symptom of hypoglycemia in patients with HAAF is often confusion.
The threshold can also vary due to medication: Beta blockers can mask signs of hypoglycemia.
Signs and symptoms
Neurogenic/autonomic
Increased sympathetic activity: tremor, pallor, anxiety, tachycardia, sweating, and palpitations
Increased parasympathetic activity: hunger, paresthesias, nausea, and vomiting
Neuroglycopenic
Agitation, confusion, behavioral changes
Fatigue
Seizure, focal neurological signs
Somnolence → obtundation → stupor → coma
Beta blockers can mask signs of hypoglycemia.
Diagnostics:
General diagnostic approach
Confirm low blood glucose (via fingerstick or BMP) and check for Whipple triad.
Rule out acute illness as a cause (e.g., infection, sepsis, burns).
Review the patient’s medications to rule out medication as a cause (see drugs that cause hypoglycemia).
Perform diagnostic workup based on the leading differential diagnosis and whether the patient has diabetes or not.
Diabetic patients [1]
Hypoglycemia in diabetic patients is almost always due to acute illness and/or medications (e.g., insulin) and further workup is generally not indicated.
Initial workup if no obvious trigger identified:
Labs: CBC, BMP, LFTs, urinalysis
Imaging: X-ray chest
Infectious workup
Consider sulfonylurea and exogenous insulin levels.
Nondiabetic patients [2]
Rule out acute illness and medication as a cause.
Further diagnostic testing should only be pursued if the cause is not evident based on history and examination.
The goal is to determine if the hypoglycemia is due to hyperinsulinemia (e.g., insulinoma).
Laboratory studies
The following labs should be obtained during a hypoglycemic episode (or 72-hour fast if no spontaneous hypoglycemic episode is documented):
Insulin antibodies
Sulfonylurea level (and any other oral antidiabetic agents)
β-hydroxybutyrate
Proinsulin
C-peptide
Glucose
Insulin
Glucagon tolerance test (see below)
Consider also: anti-insulin receptor antibodies, IGF-1/IGF-2, cortisol, glucagon, growth hormone
72-hour fast [2]
Procedure: The patient fasts for 72 hours, only drinking noncaloric beverages, and all nonessential medications are discontinued.
Measure insulin, C-peptide, and glucose every 4–6 hours.
Once plasma glucose < 45 mg/dL or < 55 mg/dL with documented Whipple triad, obtain serum studies (see “Laboratory studies” above).
After serum studies have been obtained, continue with a glucagon tolerance test and end the fast.
Glucagon tolerance test
Procedure: After the 72-hour fast has ended, inject glucagon.
Measure serum glucose and insulin at baseline, then at 10, 20, and 30 minutes after glucagon injection.
Nonsuppressed serum insulin concentrations with decreased serum C-peptide and proinsulin concentrations are consistent with exogenous insulin use.
Imaging
Indications: labs consistent with endogenous hyperinsulinism (e.g., insulinoma) [5]
Usually, combined imaging is required to confirm the diagnosis of insulinoma (CT scan and MRI
Hypoglycaemia without hyperinsulinism: glucose: low insulin: low normal Proinsulin/C peptide, low normal β-hydroxybutyrate: normal Glucose response to glucagon: diminished response. Hyperinsulinism or increase IGF glucose: low insulin: ELEVATED Proinsulin/C peptide: Exogenous: low, endogenous: normal/high β-hydroxybutyrate: low Glucose response to glucagon: normal response
treatment
If the patient is conscious:
Oral glucose 15–20 g
Fast-acting carbohydrates (such as glucose tablets, candy, or juice)
If the patient is unconscious (or unable to ingest glucose): [2]
IV dextrose
IM glucagon: if neither oral or IV routes of administering glucose are feasible
Monitoring
Recheck POC glucose after 15 minutes.
Suspected severe hypoglycemia should be treated immediately, without waiting for the results of blood glucose testing!
Adrenal crisis (Addisonian crisis)
Description: Acute, severe glucocorticoid deficiency that requires immediate emergency treatment.
Causes
Stress (e.g., infection, trauma, surgery) in a patient with underlying adrenal insufficiency
Sudden discontinuation of glucocorticoids after prolonged glucocorticoid therapy
Bilateral adrenal hemorrhage or infarction (e.g., Waterhouse-Friderichsen syndrome)
Pituitary apoplexy
Clinical features
Hypotension, shock
Impaired consciousness, coma
Fever
Vomiting, diarrhea
Severe abdominal pain (which resembles peritonitis)
Hypoglycemia, hyponatremia, hyperkalemia, and metabolic acidosis
Therapy
Administration of high doses of hydrocortisone: 100 mg IV every 8 hours
Alternatively: dexamethasone
4 mg IV every 12 hours
Does not interfere with testing, as opposed to hydrocortisone [14]
Fluid resuscitation with normal saline to treat hypotension and hyponatremia
Correct hypoglycemia with 50% dextrose
Intensive care monitoring
In order to avoid the development of secondary and tertiary adrenal insufficiency, prolonged steroid therapy must be tapered slowly and should never be stopped abruptly.
The 5 S’s of adrenal crisis treatment are: Salt: 0.9% saline, Sugar: 50% dextrose, Steroids: 100 mg hydrocortisone IV every 8 hours, Support: normal saline to correct hypotension and electrolyte abnormalities, Search for underlying disorder
Adrenal crisis can be life-threatening. Therefore, treatment with high doses of hydrocortisone should be started immediately without waiting for diagnostic confirmation of hypocortisolism!
Hypercalcaemia
Hypercalcemia is a condition of high calcium levels (total Ca2+> 10.5 mg/dL or ionized Ca2+> 5.25 mg/dL) in the blood serum. For information regarding the physiology and homeostasis of calcium, please see the hypocalcemia article. The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy with paraneoplastic production of parathyroid hormone-related protein (PTHrP). Symptoms of hypercalcemia include nephrolithiasis, bone pain, abdominal pain, and polyuria. Management depends on the severity of calcium imbalance. Mild and asymptomatic moderate hypercalcemia is treated with oral rehydration and low calcium intake, while symptomatic moderate cases and severe cases require IV rehydration and calcitonin administration. Hypercalcemic crisis is a life-threatening complication that manifests with dehydration, oliguria, and altered consciousness and requires immediate forced diuresis.
Hypercalcaemia Dr Deac Pimp
Definition
Hypercalcemia = total serum calcium concentration > 10.5 mg/dL (> 2.62 mmol/L), or ionized (free) calcium concentration > 5.25 mg/dL (> 1.31 mmol/L) [1]
Aetiology PTH mediated: Primary hyperparathyroidism Secondary hyperparaathyroidism Tertiary hyperparaathyroidism Familial hypocalciuric hypercalcaemia
Non-PTH mediated
Hypercalcaemia of malignancy
Granulomatous disorders (e.g sarcoidosis)
Other Medications Hyperthyroidism Long periods of immobilization Milk-alkali syndrome Paget disease of the bone Adrenal insufficiency
Primary hyperparathyroidism and hypercalcemia of malignancy account for > 90% of cases of hypercalcemia. Compared to primary hyperparathyroidism, serum calcium is typically higher in hypercalcemia of malignancy (> 13 mg/dL, or > 3.25 mmol/L), and patients, therefore, exhibit more severe symptoms.
Clinical features
The clinical presentation is variable and may be asymptomatic.
Nephrolithiasis, nephrocalcinosis (calcium oxalate > calcium phosphate stones)
Bone pain, arthralgias, myalgias, fractures
Constipation
Abdominal pain
Nausea and vomiting
Anorexia
Peptic ulcer disease [5]
Pancreatitis
Neuropsychiatric symptoms such as anxiety, depression, fatigue, and cognitive dysfunction
Somnolence
Obtundation and coma indicate progression to hypercalcemic crisis
Diminished muscle excitability
Cardiac arrhythmias
Muscle weakness, paresis
Polyuria and dehydration
Hypercalcemic crisis: life-threatening condition that should be suspected at total calcium levels > 14 mg/dL (3.5 mmol/L) or ionized calcium > 10 mg/dL (2.5 mmol/L); patients present with
Dehydration (due to ADH resistance and vomiting)
Oliguria/anuria
Altered consciousness
Psychosis
Hypercalcemia can cause pancreatitis. Hypocalcemia in patients with pancreatitis suggests pancreatic necrosis.
The presentation of hypercalcemia includes stones (nephrolithiasis), bones (bone pain, arthralgias), thrones (increased urinary frequency), groans (abdominal pain, nausea, vomiting), and psychiatric overtones (anxiety, depression, fatigue). Note that these are also the findings of vitamin D overdose!
Investigations:
Approach [7]
Evaluate calcium imbalance
Initial test: serum calcium concentration
Confirm true hypercalcemia: measure ionized calcium or use serum albumin to calculate corrected calcium.
Corrected calcium (mg/dL) = measured total Ca2+ (mg/dL) + [0.8 x (4.0 - albumin concentration in g/dL)]
Increased ionized calcium, regardless of total calcium levels → true hypercalcemia (potentially symptomatic)
Increased total calcium with normal ionized (active) calcium → factitious hypercalcemia (asymptomatic finding)
Differentiate between low PTH and high PTH: to determine the underlying cause of hypercalcemia
PTH: the most important test for patients with disorders of calcium balance
Further laboratory tests to confirm the diagnosis (e.g., creatinine in suspected CKD)
Further tests
ECG
QT interval shortening
In severe hypercalcemia: J wave
Further evaluation of bone disorders: See laboratory evaluation of bone diseases.
The corrected calcium concentration calculated using serum albumin may not be accurate when major pH changes have taken place in the body (e.g., following surgery). In these cases, it is better to measure ionized calcium directly.
Treatment
Treatment of any underlying disorder (e.g., glucocorticoids in sarcoidosis or any other granulomatous disease → reduction in activity of mononuclear cells producing calcitriol)
Mild or asymptomatic hypercalcemia: total calcium < 12 mg/dL (< 3 mmol/L) or ionized calcium < 8 mg/dL (< 2 mmol/L)
Encourage adequate oral hydration
Reduce dietary intake of calcium
Avoid thiazide diuretics, lithium, high-calcium diet
Moderate hypercalcemia: total calcium 12–14 mg/dl (3–3.5 mmol/L)
Asymptomatic: same treatment as for mild hypercalcemia (see above)
Symptomatic: same treatment as described for severe hypercalcemia (see below)
Severe or symptomatic hypercalcemia: total calcium > 14 mg/dL (> 3.5 mmol/L) or ionized calcium > 10 mg/dL (> 2.5 mmol/L)
Immediate therapy [8]
IV hydration with isotonic saline
Calcitonin [9]
In hypercalcemic crisis: immediate forced diuresis (following volume replacement!)
Cause-based therapy
Excessive bone resorption (e.g., hypercalcemia of malignancy, immobilization): bisphosphonates (zoledronic acid, pamidronate)
Renal insufficiency or heart failure: loop diuretics (with monitoring of serum potassium) to avoid volume overload
Dialysis in very severe cases (total calcium > 18 mg/dL; ionized calcium > 4.5 mmol/L) or concomitant renal failure
Thiazide diuretics enhance Tubular calcium resorption → Discontinue them in hypercalcemia. Loop diuretics Lose calcium → Administer them in hypercalcemia.
Hypocalcaemia
Hypocalcemia is a state of low serum calcium levels (total Ca2+ < 8.5 mg/dL or ionized Ca2+ < 4.65 mg/dL). Total calcium comprises physiologically-active ionized calcium as well as anion-bound and protein-bound, physiologically-inactive calcium. Calcium plays an important role in various cellular processes in the body, such as stabilizing the resting membrane potential of cells, cell signaling, coagulation, and hormone release. In addition to hormonal control by parathyroid hormone (PTH) and calcitriol, calcium homeostasis is also influenced by serum protein levels and acid-base status, both of which impact the ratio of protein-bound Ca2+ to ionized Ca2+ in the serum. Severity and chronicity of calcium deficiency in addition to the patient’s age and comorbidities contribute to the overall clinical presentation of hypocalcemia. Symptoms are variable; the most characteristic features include prolongation of the QT interval and signs of neuromuscular excitation (e.g., tetany, carpopedal spasm, paresthesias). Management consists of calcium supplementation and identifying and treating the underlying cause.
Hypocalcaemia Dr DEAC PIMP
D: Hypocalcemia: total serum calcium concentration < 8.5 mg/dL (< 2.12 mmol/L), or ionized (free) calcium concentration < 4.65 mg/dL (< 1.16 mmol/L) [1]
Severe hypocalcemia: total serum calcium concentration ≤ 7.5 mg/dL (< 1.9 mmol/L), or ionized (free) calcium concentration < 3.6 mg/dL (< 0.9 mmol/L) [2]
Factitious hypocalcemia: an asymptomatic decrease in total calcium with a normal ionized Ca2+ level (typically occurs due to low serum protein levels)
Aetiology:
Low PTH –> Hypoparathyroidism
High PTH: Vit D deficiency, chronic kidney disease, pseudopoparathyroidism, hyperphosphatemia, acute necrotizing pancreatitis.
OtherL medications, multiple blood transfusions and hemolysis
Hypomagnesemia, Hyperventilation, osteoblastic metastases, renal tubular disorders
pseudohypocalcemia
Hypocalcemia is most often due to hypoparathyroidism or vitamin D deficiency (e.g., malabsorption, chronic kidney disease).
Suspect hypocalcemia in the postoperative thyroidectomy patient with new-onset paresthesias and muscle spasms or cramping.
Clinical features:
Manifestations of hypocalcemia are influenced by the severity and chronicity of the hypocalcemia as well as by the patient’s age and comorbidities.
Neurological manifestations [12][13][14][1]
Tetany: increased neuromuscular excitability (when caused by respiratory alkalosis = hyperventilation-induced tetany)
Paresthesias: typically tingling or pins-and-needles sensation in extremities and/or in the perioral area
Spasms (e.g., carpopedal spasm , bronchospasm or laryngospasm ), and cramps (possible in any muscle)
Stiffness, myalgia
Maneuvers to elicit latent tetany on physical exam
Chvostek sign: short contractions (twitching) of the facial muscles elicited by tapping the facial nerve below and in front of the ear (∼ 2 cm ventral to the ear lobe) [1]
Trousseau sign: ipsilateral carpopedal spasm occurring several minutes after inflation of a blood pressure cuff to pressures above the systolic blood pressure [1]
Seizure: may be the initial or only symptom [13]
Signs of neuromuscular irritability (e.g., paresthesias, spasms and cramps) are the most characteristic features of hypocalcemia.
Cardiovascular manifestations [12][13][14][1]
Congestive heart failure
Hypotension
Cardiac arrhythmias (symptoms may include palpitations, irregular pulse, syncope)
Manifestations of chronic hypocalcemia [12][13][14][1]
Psychological/psychiatric manifestations (variable and reversible, usually mild)
Ophthalmologic manifestations: papilledema (in severe cases), cataracts, calcifications of the cornea
Neurological manifestations: pseudotumor cerebri, paradoxical CNS calcifications
Dental changes: altered morphology, dental enamel hypoplasia
Growth plate abnormalities and osteomalacia
Diagnostics:
Laboratory studies [12][2]
Confirm true hypocalcemia
Measure total and ionized calcium
AND/OR check serum albumin and calculate corrected calcium
Evaluate for other electrolyte abnormalities
BMP
Serum phosphate and magnesium
Calcium correction for hypoalbuminemia
Serum intact PTH:
Indication: best initial study for confirmed hypocalcemia with no clear etiology
Interpretation
Low (or normal) PTH suggests hypoparathyroidism
High PTH suggests parathyroid gland function is preserved
Further serum studies: conducted based on clinical suspicion
Alkaline phosphatase
Amylase
25-hydroxyvitamin D (calcidiol)
Urine studies: 24-hour urinary excretion of calcium and magnesium
Additional diagnostics
ECG
Indication: acute, severe, and/or symptomatic hypocalcemia
Findings may include: [13]
Prolonged QT interval
Ventricular arrhythmias: torsades de pointes, ventricular tachycardia, ventricular fibrillation
QRS complex and ST-segment changes (may mimic myocardial infarction)
AV block
Fundoscopy
Recommended in severe/symptomatic cases
Possible findings: papilledema [14]
Treatment
The mainstay of therapy of hypocalcemia consists of calcium supplementation and the treatment of the underlying cause.
Calcium supplementation [2]
Severe and/or symptomatic hypocalcemia: e.g., tetany, seizures, prolonged QT interval, serum calcium ≤ 7.5 mg/dL (< 1.9 mmol/L)
IV calcium supplementation: calcium gluconate or calcium chloride
Continuous telemetry [2]
Consider transfer to critical care unit
Mild and/or chronic hypocalcemia: no symptoms or only mild neuromuscular irritability (e.g., paresthesias), serum calcium 7.6–8.4 mg/dL (1.9–2.12 mmol/L)
Oral calcium supplementation: calcium citrate, calcium carbonate
IV calcium can trigger life threatening arrhythmias in patients simultaneously receiving cardiac glycosides (digoxin or digitoxin). [1]
Treatment of the underlying condition
Hypoparathyroidism
Calcium supplementation
PLUS vitamin D supplementation
Secondary to loop diuretics: consider discontinue loop diuretic and change medication to thiazides
Vitamin D deficiency: vitamin D supplementation
Hypomagnesemia-induced hypocalcemia: magnesium supplementation
Hyperphosphatemia in chronic kidney disease: calcium supplementation
Loop diuretics Lose calcium. Discontinue them in hypocalcemia.
Total and ionized calcium concentrations
Total and ionized calcium concentrations
Total calcium: the total amount of calcium circulating in the serum, comprising protein-bound, anion-bound, and ionized calcium
Approx. 40% of the total serum calcium is bound to proteins (mostly albumin) and is physiologically inactive.
Hypoproteinemia (due to, e.g., nephrotic syndrome, liver cirrhosis, severe malnutrition, malabsorption) → ↓ total Ca2+ level but ionized Ca2+ level is unaffected → factitious hypocalcemia
pH influences the binding of calcium to serum proteins.
↑ pH → ↓ H+ in serum binding to proteins → ↑ Ca2+ binding to proteins → ↓ ionized Ca2+ concentration compensatory ↑ PTH
↓ pH → ↑ H+ in serum binding to proteins → ↓ Ca2+ binding to proteins → ↑ ionized Ca2+ concentration compensatory ↓ PTH
Ionized calcium: the calcium fraction that is not bound to any proteins but is physiologically active
Approx. 45% of the total serum calcium
Functions as the main regulator of PTH secretion
PTH secretion is influenced by pH variations but not by changes in albumin levels.
An excess causes true hypercalcemia whereas a deficiency causes true hypocalcemia
To remember the changes in PTH depending on pH, think: ↑ pH = ↑ PTH and ↓ pH = ↓ PTH
The physiological role of calcium
The physiological role of calcium [3]
Ionized Ca2+ is responsible for stabilizing the resting membrane potential of cells.
↓ Serum Ca2+ → ↑ membrane excitability
↑ Serum Ca2+ → ↓ membrane excitability
Acts as a second messenger in signaling pathways
Cofactor for several enzymes (e.g., phospholipase A, gamma-glutamyltransferase)
Required for the promotion of coagulation pathways
PCOS DR DEAC PIMP
D: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hyperandrogenism, oligoovulation/anovulation, and/or the presence of polycystic ovaries. The diagnosis of PCOS is made following exclusion of disorders that may present with a similar clinical picture (e.g., congenital adrenal hyperplasia), most commonly by hormone analysis. Up to 50% of PCOS patients have metabolic syndrome, which is associated with obesity, insulin resistance, hypercholesterolemia, and an increased risk for endometrial cancer. PCOS primarily manifests with hirsutism, acne, and virilization. Diagnostic methods include a pelvic exam, blood tests for specific hormones, and ultrasound. Management consists of weight loss via lifestyle changes, and oral contraception pills are indicated in women who do not wish to conceive. The aim of treatment in women who desire to conceive is to normalize ovarian function and stimulate follicular growth (e.g., with clomiphene).
R:
D: All conditions that are associated with menstrual cycle changes and signs of virilization should be ruled out before diagnosing PCOS: Pregnancy Thyroid disorder Follicular insufficiency Hyperprolactinemia Congenital adrenal hyperplasia Cushing's disease Pituitary adenoma Androgen-secreting tumors Exogenous androgen intake Exogenous steroid intake
E: Frequency: 6–10% of women in their reproductive years.
A:
C: Onset typically during adolescence
Menstrual irregularities (primary or secondary amenorrhea, oligomenorrhea)
Difficulties conceiving or infertility
Obesity and possibly other signs of metabolic syndrome
Hirsutism
Androgenic alopecia
Acne vulgaris and oily skin
Acanthosis nigricans: hyperpigmented, velvety plaques (axilla, neck)
Premature adrenarche
Voice change may occur in severe forms of PCOS. However, it typically suggests a different underlying cause of hyperandrogenism!
P:
The histological characteristics of PCOS are:
Ovarian hypertrophy with thick capsule
Stromal hyperplasia and fibrosis
Enlarged, multiple cystic follicles, which are sclerotic
Hyperluteinized theca cells
Decreased granulosa cell layer.
The exact pathophysiology is unknown.
Reduced insulin sensitivity (peripheral insulin resistance) is present in PCOS, as in metabolic syndrome → hyperinsulinemia
Hyperinsulinemia results in:
Obesity
Epidermal hyperplasia and hyperpigmentation (acanthosis nigricans)
Increased androgen production in ovarian theca cells → imbalance between androgen precursors and the resulting estrogen produced in granulosa cells
Increased LH secretion disrupts the LH/FSH balance → impaired follicle maturation and anovulation/oligoovulation
Increased androgen precursor release → virilization and a reactive increase in estrogen production in adipose tissue
Inhibits the production of SHBG (sex hormone-binding globulin) in the liver → ↑ free androgens and estrogens
Hyperandrogenism in women is most commonly caused by PCOS!
I:
According to the American Association of Clinical Endocrinologists, at least two of three of the criteria below are required for diagnosis of PCOS after excluding other causes of irregular bleeding and elevated androgen levels.
Hyperandrogenism (clinical or laboratory)
Oligo- and/or anovulation
Polycystic ovaries on ultrasound
Diagnosis of PCOS is possible without the presence of ovarian cysts!
Rule out any other causes of hyperandrogenism and anovulation (see “Differential diagnoses” below).
Blood hormone levels
↑ Testosterone (both total and free) or free androgen index
↑ LH (LH:FSH ratio > 2:1)
Estrogen is normal or slightly elevated
A clinical picture of hyperandrogenism overrules any normal hormone levels and can fulfill a diagnostic criterium of PCOS!
Evaluate for metabolic disease
Test for hypertension
Monitor BMI
Assess for insulin resistance or type 2 diabetes mellitus → oral glucose tolerance test
Assess for hyperlipidemia → measure serum lipids and cholesterol
Transvaginal ultrasound
Enlarged ovaries with numerous anechoic cysts (polycystic ovaries)
“String of pearls” appearance
M:
The therapeutic approach in PCOS is broadly based on whether or not the patient is seeking treatment for infertility.
If treatment for infertility is not sought: therapy aimed at controlling menstrual, metabolic, and hormonal irregularities
If the patient is overweight (BMI ≥ 25 kg/m2)
First-line: weight loss via lifestyle changes (e.g., dietary modifications, exercise)
Second-line (as an adjunct): combined oral contraceptive therapy
If the patient is not overweight: combined oral contraceptive therapy
If seeking treatment for infertility
First-line
Ovulation induction with clomiphene citrate or letrozole
Clomiphene inhibits hypothalamic estrogen receptors, thereby blocking the normal negative feedback effect of estrogen → increased pulsatile secretion of GnRH → increased FSH and LH, which stimulates ovulation
If the patient is overweight: advise weight loss
Second-line: ovulation induction with exogenous gonadotropins or laparoscopic ovarian drilling
P/C: Cardiovascular events Type 2 diabetes mellitus Endometrial cancer Increased miscarriage rate
Hirsutism
Hirsutism
A condition of excessive male pattern hair growth in women (e.g., on the chin, above the upper lip, and around the umbilicus) that is most commonly idiopathic but associated with excess androgen in 10% of cases.
