Hormone Havoc

MICU interesting case

Presented by – Dr Ravi Singh
Moderator - Dr Nitin Sarate
Dr Rajendra Singh
History
• Patient N , 17 Years/ Male/ 11th standard/ Right-Handed/ mixed diet

• Chief complaints –
• 1. Diminution of vision of left eye x 1 year
• 2. decrease in sensorium x 8 months
• 3. Slurring of speech x 2 months
History
1. Diminution of vision x 1 year
• Insidious and gradually progressive
• Painless
• Unable to identify people in the periphery and recurrent history of
bumping into doors especially at night
• Not A/w limb weakness
• Not A/w nausea and vomiting
• Not A/w headache
• Not A/w discharge from eyes , diplopia
History
2. Decrease in sensorium x 8 months
• Insidious and gradually progressive
• Intermittent
• A/w not waking up in the morning and drowsy even after waking up
• A/w increase in forgetfulness
• A/w giddiness
• A/w tremors, involuntary passage of urine and stool
• A/w increase in sweating while sleeping
• Releived on taking sugary food,
 History
3. Slurring of speech x 2 months
• Insidious and gradually progressive
• Persistent
• Not a/w upper and lower limb weakness
• Not associated with difficulty in swallowing
• Not associated with fever
Hospitalisation history
April 2024 - in view of diminution of vision ophthalmic evaluation was done

And diagnosed as Left eye toxoretinitis [Toxo IgG - 108 (positive > 8.8), Toxo IgM -
negative]

Received TMP SMXDS for 21 days, e/d tobramycin , e/d moxiflox

Hospitalisation history
Was admitted in private hospital ( 14/12/2024 to 21/12/24) I/v/o unresponsiveness and
recurrent seizures episodes

O/E BP - 116/74, PR - 80 , SpO2 97% , HgT 37

GCS E2V3M6

16/12/24 MRI Brain with contrast - Pituitary gland is mildly bulky and it measures
approximately 1.9 x 1.5 x 1.2 cm.

An approximately 1.1 x 0.9 x 0.7 cm sized area of signal abnormality is seen within the
pituitary gland in its right half reaching till the midline. The lesion shows T1 and T2
hyperintense signal with peripheral intermediate signal intensity which on post-contrast study
show minimal enhancement. No obvious blooming is seen within. This may represent benign
lesion possibly a dermoid. Further histopathological evaluation is recommended for same.
Hospitalisation history
18/12/24

Prolactin - 61.99

Testosterone- 105.8 (103-763) T Lacosamide 100mg BD

Tab Clonazepam 0.5 mg BD
Cortisol 8 am - 1 (3-21) Tab Olanzapine 0.5 mg OD
C- peptide - 2.4 (1.1- 4.4) Tab Omnacortil 5 mg OD
Tab Lopez 2mg BD
Insulin - 19.89 (2-23)

T3/T4/TSH- 86.92/6.03/0.881
Family history
History of giant cystic prolactinoma in elder sister at 26 years of age.

Birth history

Full term normal vaginal delivery , born out of non consanguineous marriage ,
cried immediately after birth
On admission
Referred to KEM Hospital in view of persistent complaints

came in ems with loss of consciousness since morning

BP - 120/76

PR- 66

SpO2 - 96 %

HgT - 43 ( 1 pint D25 given after which sensorium improved )

Hypoglycemia
Introduction
Hypoglycemia is most convincingly documented by, Whipple's triad,

1. Symptoms consistent with hypoglycemia

2. Low plasma glucose concentration ~ 70mg/dL (3.9mmol/L)
3. Relief of symptoms when plasma glucose concentration is increased.
Hypoglycemia
However, these thresholds are dynamic.

They shift to higher-than normal glucose levels in people with poorly controlled
diabetes, who can experience symptoms of hypoglycemia when their glucose
levels decline toward the normal range (pseudohypoglycemia).

On the other hand, thresholds shift to lower-than-normal glucose levels in people

with recurrent hypoglycemia
Causes of hypoglycemia in adults
Clinical manifestations

Autonomic Neuroglycopenic Others -

Sweating confusion Nausea

Trembling Drowsiness Tiredness

Palpitations Speech difficulty Headache

Hunger Incoordination

Anxiety
Clinical manifestations
Signs

Pallor

Diaphoresis

↑ Heart rate

↑ systolic BP
Hypoglycemia in Diabetics

Hypoglycemia is most commonly a result of the treatment of diabetes.

It is the limiting factor in the glycemic management of diabetes mellitus it causes

recurrent morbidity in most people with type 1 diabetes (T1DM) and in many with
advanced type 2 diabetes (T2DM), and it is sometimes fatal.

It causes a vicious cycle of recurrent hypoglycemia by producing hypoglycemia-

associated autonomic failure-i.e., the clinical syndromes of defective glucose
counterregulation and of hypoglycemia unawareness
Hypoglycemia in non diabetics
Drugs Critical illness Hormone deficiencies
primary adrenocortical
Insulin renal failure
failure (Addison's disease)
Sulfonylureas
hepatic failure
Quinine hypopituitarism
Pentamidine cardiac failure
Growth hormone deficiency
Salicylates
sepsis can cause hypoglycemia in
Sulfonamides
indomethacin young children.
Starvation
Ethanol
Haloperidol ACE
inhibitors others
Hypoglycemia in non diabetics
Endogenous Hyperinsulinism
Non-Beta-Cell Tumors
(1) a primary B-cell disorder-typically a ẞ-cell
large mesenchymal or
tumor (insulinoma), sometimes multiple
epithelial tumors (e.g.,
insulinomas, or a functional B-cell disorder
hepatomas,
with ẞ-cell hypertrophy or hyperplasia
adrenocortical
carcinomas, carcinoids) (2) an antibody to insulin or to the insulin
receptor;

(3) a ẞ-cell secretagogue such as a

sulfonylurea;

(4) ectopic insulin secretion,

Hypoglycemia in non diabetics
1.Fasting Hypoglycemia:

disorders of glycogenolysis.

These disorders include glycogen storage disease (GSD) of types 0, I, III, and IV
and Fanconi-Bickel syndrome

Defects in fatty acid oxidation also result in fasting hypoglycemia. These defects
can include (1) defects in the carnitine cycle (2) fatty-acid B-oxidation disorders;
(3) electron transfer disturbances; and (4) ketogenesis disorders
Hypoglycemia in non diabetics
2.Postprandial Hypoglycemia: These errors include (1) glucokinase and potassium
channel mutations; (2) congenital disorders of glycosylation; and (3) inherited
fructose intolerance.

3. Exercise-Induced Hypoglycemia: It results in hyperinsulinemia caused by

increased activity of monocarboxylate transporter 1 in ẞ cells.
DIAGNOSIS OF THE HYPOGLYCEMIC MECHANISM

➤ history,

➤ physical examination,

➤ investigation
Laboratory investigations
1) Glucose 8) Sulfonylurea and meglitinide
screen
2) CBC
9) Electrolytes, BUN/Cr, UA
3) Insulin
10) liver function tests
4) C-peptide
11) Hormones- cortisol and thyroid
5) Beta-hydroxybutyrate
levels, growth hormone level
6) Proinsulin
12) Other tests: CT and MRI
7) Antibodies for insulin and its receptors
Urgent Treatment
● Oral treatment with glucose tablets or glucose containing fluids, candy or food
is appropriate if the patient is able & willing to take these.
● Initial dose = 20 g of glucose
● Unable to take oral foods→ parenteral therapy IV glucose 25 g bolus
followed by infusion guided by serial plasma glucose measurements.

● Or, Inj.Glucagon 1.0 mg sc/im can be used esp in T1DM. (it has no role in
alcohol induced hypoglycemia)
Treatment
● Non-diabetic hypoglycemia definitive management dep on the underlying
etiology.
● A Offending drugs can be discontinued or their doses reduced.
● Underlying critical illnesses should be treated.
● Cortisol and growth hormone can be replaced if levels are deficient.
● Surgical, radiotherapeutic, or chemotherapeutic reduction of a non-islet cell
tumor.
● Surgical resection of an insulinoma is curative; medical therapy with diazoxide
or octreotide can be used if resection is not possible and in patients with a
nontumor B-cell disorder.
Ward course
Endocrine reference was taken

Advised for fast test and to send RBS, Sr Insulin, sr, C peptide and Beta
hydroxybutyrate when HgT less than 55

And to do hormone panel

Neurosurgery reference was taken in view of outside MRI changes

And advised for repeat MRI P+C

Ward course
Hormone panel Fast test
● 3/2/25. T3/T4TSH- 101/4.6/0.96 ● RBS - 45
● FSH 14.72 (2.5 - 10) ● Sr Insulin- 0.58(2-25)
● LH 2.39 (2.5- 10) ● sr C peptide- 0.45(1.1-4.4)
● Prolactin- 4.08(5-25) ● Beta hydroxybutyrate below
● HbA1c 4.2 0.01(0.02-0.27)
● PTH- 35.5
● Basal ACTH <1.60 (0- 46)

Calcium 11.2
MRI Brain P+C- suggestive
Corrected Calcium - 11.5 of pituitary macroadenoma
Ward course
Labelled as clinically MEN 1 syndrome

Hypercalcemia ( primary hyperparathyroidism)

Hypoglycemia (likely insulinoma)

Non functioning pituitary adenoma

Planned for-

CECT NET protocol

Ga exendin scan PET CT

 Ga exendin
scan PET CT
Ward course
CT NET protocol -

There is well-defined homogeneously enhancing hypodense lesion arising from

the tail of the pancreas, measuring 3.3x3.1x2.7cm with no areas of calcification or
necrosis. It is seen in close proximity to the convexity of interpolar region of left
kidney and inferior pole of spleen. Inferiorly extending till the descending colon.
Fat planes with adjacent structures are maintained. It is arterially supplied by
ramifications of the splenic artery.

In a known cas elf MEN syndrome with pancreatic tail insulinoma features are
consistent with same
Ward course
Surgery reference was taken and insulinoma excision done
MEN syndrome
MEN syndrome
MEN Syndromes (Types 1-4):

Characterized by tumors in ≥2 endocrine glands.

Inherited as autosomal dominant or occur sporadically.

Associated Syndromes with Multiple Endocrine and Organ Neoplasias (MEONs):

Hyperparathyroidism-jaw tumor (HPT-JT) syndrome Carney complex Von Hippel-
Lindau disease Neurofibromatosis type 1 Cowden's syndrome (CWS) McCune-
Albright syndrome (MAS)
MEN 1 Syndrome
Triad of Tumors: Parathyroids (hyperplastic adenomas) Pancreatic Islets (e.g., gastrinomas,
insulinomas) Anterior Pituitary (e.g., prolactinomas) Additional Tumors in MEN 1: Adrenal cortical
tumors Carcinoid tumors (usually foregut) Meningiomas Facial angiofibromas Collagenomas
Lipomas

Epidemiology: Prevalence: ~0.25% in postmortem studies Seen in 1-18% of primary

hyperparathyroidism cases 16-38% in pancreatic islet tumors <3% in pituitary tumors Genetics &
Risk: Autosomal dominant inheritance De novo mutations in ~10% of cases Sporadic form in 8-
14% of cases Clinical Insights: Symptoms develop in majority by the fifth decade

Treatment Challenges: MEN 1 tumors are often: Multiple Larger, more aggressive, and resistant
to treatment Occult metastatic disease is more prevalent
Multiple Endocrine Neoplasia
 Multiple Endocrine Neoplasia

•Characterized by tumors in two or more endocrine glands.

•Four types of MEN (MEN 1–4), inherited as autosomal dominant or sporadically.

•MEON Syndromes:
•Includes at least six other conditions (HPT-JT, Carney complex, von Hippel–Lindau disease,
• neurofibromatosis type 1, Cowden’s syndrome, McCune-Albright syndrome).
•Most are autosomal dominant except McCune-Albright syndrome (mosaic mutation).

•Diagnosis Criteria:
1.Clinical Features: Two or more tumors/lesions in an individual.
2.Familial Pattern: One tumor/lesion in a first-degree relative.
3.Genetic Analysis: Germline mutation identified in the individual, affected or asymptomatic.
•Genetic Testing Benefits:
1.Confirms diagnosis.
2.Identifies family members at risk for tumors.
3.Helps identify mutation-free family members, reducing unnecessary tests and healthcare costs.
MEN 1 syndrome

•Triad of Tumors:
•Parathyroids
•Pancreatic islets
•Anterior pituitary
•Other Associated Tumors:
•Adrenal cortical tumors, carcinoid tumors (foregut), meningiomas, facial angiofibromas,
collagenomas, lipomas.
•Genetic and Familial Aspects:
•Sporadic form in 8-14% of cases; de novo MEN1 gene mutations in ~10% of patients.
•Variability in affected glands and pathologic features within families, including identical twins.
•Prevalence:
•0.25% in postmortem studies; higher in specific patient groups:
• 1–18% in primary hyperparathyroidism
• 16–38% in pancreatic islet tumors
• <3% in pituitary tumors
MEN 1 syndrome

•Age of Onset:
•Clinical manifestations typically develop by the 5th decade, with a
range from 5–81 years.
•Clinical Impact:
•Endocrine tumors often result in early mortality, with a 50% chance of
death by age 50, usually from malignant tumors like pancreatic
neuroendocrine tumors (NETs) or foregut carcinoids.
•Challenges in Treatment:
•Tumors are often multiple, making surgical cures difficult.
•Higher prevalence of occult metastatic disease, larger tumor sizes, and
increased resistance to treatment compared to non-MEN 1 tumors.
Parathyroid

•Primary Hyperparathyroidism:
•Occurs in ~90% of MEN 1 patients, most common feature.
•Symptoms may include asymptomatic hypercalcemia or vague symptoms (polyuria, polydipsia,
• constipation, malaise, dyspepsia).
•Less common symptoms: nephrolithiasis, osteitis fibrosa cystica.
•Biochemical Findings:
•Hypercalcemia with elevated parathyroid hormone (PTH) levels.
•Hypercalcemia is usually mild; severe cases or parathyroid cancer are rare.
•Key Differences from Non-MEN 1 Hyperparathyroidism:
•Earlier onset: 20–25 years (vs. 55 years).
•Male-to-female ratio: 1:1 (vs. 1:3).
•Imaging and Surgery:
•Preoperative imaging (e.g., neck ultrasound, 99mTc-sestamibi parathyroid scintigraphy) is
limited in MEN 1,
•as all parathyroid glands may be involved.
•Neck exploration may be needed regardless of preoperative localization studies.
Parathyroid

•Definitive Treatment:
•Surgical removal of overactive parathyroids is the primary treatment.
•Surgical Controversies:
•Debate over whether to perform subtotal (removal of 3.5 glands) or total
parathyroidectomy with or
• without autotransplantation of parathyroid tissue in the forearm.
•Timing of surgery (early vs. late stage) is also controversial.
•Alternative Treatment:
•Calcimimetics (e.g., cinacalcet): Used when surgery is unsuccessful or
contraindicated,
•acting through the calcium-sensing receptor to manage primary
hyperparathyroidism.
Pancreatic tumors

• Pancreatic Tumors in MEN 1

• Incidence of Pancreatic Islet Cell Tumors (NETs):

• Occurs in 30–80% of MEN 1 patients.
• Tumors often produce excessive hormones (e.g., gastrin, insulin, glucagon, VIP), causing clinical syndromes.
• Some tumors are nonfunctioning or nonsecretory.
• Earlier onset in MEN 1 patients compared to non-MEN 1 patients.

• Gastrinoma (Gastrin-Secreting Tumors):

• Associated with Zollinger-Ellison syndrome: marked gastric acid production, recurrent peptic ulcers, and high mortality due
to perforation and cachexia.
• More common in MEN 1 patients >30 years.
• Symptoms: recurrent peptic ulcers, diarrhea, steatorrhea.
• Diagnosis: Elevated fasting serum gastrin and increased gastric acid secretion.
• Challenge: Hypercalcemia in MEN 1 can also cause hypergastrinemia, complicating diagnosis.
Pancreatic tumors

• Tumor Localization:
• Imaging techniques: Ultrasonography, endoscopic ultrasonography, CT, MRI, selective abdominal angiography, venous
sampling, and somatostatin receptor scintigraphy (SRS).
• Prevalence of Gastrinomas:
• Represent >50% of pancreatic NETs in MEN 1.
• ~20% of patients with gastrinomas are diagnosed with MEN 1.
• Gastrinomas are the major cause of morbidity and mortality in MEN 1 patients
Gastrinoma

• Medical and Surgical Treatment of Gastrinomas in MEN 1

• Medical Treatment:
• Goal: Reduce basal acid output to <10 mmol/L.
• H+-K+-ATPase Inhibitors (e.g., omeprazole, lansoprazole) are the drugs of choice.
• H2 Receptor Antagonists (e.g., cimetidine, ranitidine) may be added for some patients.

• Surgical Treatment:
• Controversial: Aims to reduce metastases and improve survival.
• Effective for nonmetastatic pancreatic gastrinomas (small tumors).
• Surgery Recommended for tumors >2–2.5 cm to improve survival.
• Duodenal Gastrinomas: Surgery often successful.
• Surgical outcomes: 15% disease-free immediately post-op; 5% at 5 years for MEN 1 patients (vs. 45% and 40% in non-MEN 1
patients).

• Treatment for Disseminated Gastrinomas:

• Chemotherapy: Streptozotocin + 5-fluorouracil.
• Hormonal therapy: Octreotide, lanreotide (SSAs).
• Other therapies: SIRT, radiofrequency ablation, PRRT, hepatic artery embolization, interferon, and resection of resectable tumors.

• General Approach: Nonsurgical management preferred for most MEN 1 patients with gastrinomas, except for small, isolated lesions.
Insulinoma

•Incidence: 10–30% of pancreatic tumors in MEN 1.

•Symptoms: Hypoglycemia (weakness, headaches, sweating, seizures) after fasting or exertion,
relieved by glucose.
•Diagnosis:
• 72-hour fast: Key test.
• Increased insulin, C peptide, and proinsulin.
• Exclude sulfonylureas.
•Localization:
• Imaging: Endoscopic ultrasound, CT, celiac axis angiography.
• Additional methods: Portal venous sampling, intraoperative ultrasound.
•Clinical Features:
• More common in MEN 1 patients <40 years.
• 10% of MEN 1 cases have insulinomas as the first manifestation.
• Occurs in ~4% of insulinoma patients with MEN 1.
•Co-occurrence: 10% of MEN 1 patients with insulinomas also have gastrinomas.
Insulinoma

•Medical Treatment:
•Frequent carbohydrate meals.
•Medications: Diazoxide or octreotide (often not fully effective).
•Surgical Treatment:
•Optimal treatment: Enucleation, distal pancreatectomy, or partial pancreatectomy.
•Curative in many patients.
•Chemotherapy & Other Options:
•Chemotherapy: Streptozotocin, 5-fluorouracil, doxorubicin.
•PRRT: 177Lu-DOTATATE.
•Hepatic artery embolization for metastatic disease
Glucagonama

•Incidence: <3% of MEN 1 patients.

•Symptoms: Skin rash (necrolytic migratory erythema), weight loss, anemia, stomatitis. May be
asymptomatic and detected via imaging or glucose intolerance and hyperglucagonemia.
•Treatment:
•Surgical removal: Treatment of choice.
•Medical options:
• Somatostatin analogs (e.g., octreotide, lanreotide).
• Chemotherapy (streptozotocin, 5-fluorouracil).
• Hepatic artery embolization for metastases.
VIPomas

Incidence: Rare in MEN 1.

• Symptoms: Watery diarrhea, hypokalemia, achlorhydria (WDHA syndrome / Verner-Morrison syndrome).
• Diagnosis: Exclude laxative/diuretic abuse, confirm stool volume >0.5-1.0 L/day, and increased plasma VIP concentration.
• Treatment:
• Surgical removal: Curative if resectable.
• Medical options:
• Somatostatin analogs (e.g., octreotide, lanreotide).
• Chemotherapy (streptozotocin, 5-fluorouracil).
• Hepatic artery embolization for metastases.
Pancreatic Polypeptide-Secreting Tumors (PPomas) and Nonfunctioning Pancreatic NETs

PPomas & Nonfunctioning Pancreatic NETs in MEN 1

•PPomas:
• Common in MEN 1 but with no apparent symptoms or clinical significance.
•Nonfunctioning Pancreatic NETs:
• Often asymptomatic, leading to delayed diagnosis and worse prognosis.
• Detected via endoscopic ultrasound (sensitive) and SRS (for metastases).

Treatment:
•Surgery: Recommended for tumors >1-2 cm; pancreatoduodenal
surgery has 80% success, but complications are common.
•Metastatic Disease: Treated with TKR inhibitors, mTOR
inhibitors, PRRT, chemotherapy, and other techniques like SIRT.
Pituitary tumor

•Prevalence: 15-50% of MEN 1 patients; typically microadenomas.

•Hormones Secreted: Prolactin (60%), GH (25%), ACTH (<5%),
or nonfunctional.
•Symptoms: Depending on hormone secreted, can include
hyperprolactinemia (e.g., amenorrhea, impotence), acromegaly, or
Cushing's syndrome. Enlarging tumors can cause visual
disturbances or hypopituitarism.
•Treatment: Medical (bromocriptine for prolactinomas, octreotide
for somatotrope tumors), surgery (transsphenoidal
adenomectomy), and radiotherapy for residual tumors.
Carcinoid tumor

•Prevalence: Occurs in >3% of MEN 1 patients; commonly in the

thymus, pancreas, bronchi, or gastrointestinal tract.
•Symptoms: Often asymptomatic at diagnosis; no consistent
biochemical markers for thymic/bronchial carcinoids.
•Screening: CT, MRI, and octreotide scintigraphy for tumor
detection.
•Treatment: Surgical resection for resectable tumors. For
metastatic tumors: SSAs (octreotide), chemotherapy (fluorouracil,
cisplatin), mTOR inhibitors (everolimus), and PRRT.
Adrenocortical tumors

• Prevalence: 20-70% of MEN 1 patients

• Types of Tumors: Adenomas, hyperplasia, cysts, carcinomas

• Hormonal Activity: <10% are hormonally active (hyperaldosteronism, Cushing’s syndrome)

• Diagnosis:
• Biochemical tests (plasma renin, aldosterone, dexamethasone suppression, catecholamines/metanephrines)
• Tumors >1 cm or symptoms suggestive of hormone excess

• Adrenocortical Carcinoma: ~1% incidence, >10% for tumors >1 cm

• Treatment

• Nonfunctioning Tumors:
• Surgery for tumors >4 cm or with suspicious radiologic features or growth

• Functioning Tumors:
• Treated similarly to non-MEN 1 cases
MEN 1 Genetics & Screening Summary

• Gene: MEN1 gene on chromosome 11q13 encodes menin, a tumor suppressor.

• Inheritance: Follows the two-hit hypothesis (germline mutation + somatic mutation).

• Mutations: MEN1 mutations are scattered; ~10% are de novo.

• Other Relevant Genes: CDC73 (HPT-JT), CaSR (FBHH), AIP (FIPA).

• Genetic Testing

• Who to Test:
• Patients with 2+ MEN1-associated endocrine tumors.
• Asymptomatic first-degree relatives of mutation carriers.
• Individuals with symptoms or signs of MEN 1.
MEN 1 Genetics & Screening Summary

• No MEN1 Mutation Found: Test for other related conditions (HPT-JT, FBHH, FIPA).
• Screening Recommendations
• Asymptomatic Individuals: Start at age 5; annual biochemical tests and imaging (MRI/CT) every 1-3 years.
• Biochemical Tests: Calcium, PTH, gastrin, insulin, glucagon, chromogranin A, prolactin, IGF-1.
• Family Members:
• Mutation Carriers: Lifelong screening.
• Non-Carriers: No screening needed.