• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

Support us:

1. Support us by purchasing our book - Click here for more details: Volume 1- THE BEST OF NOTES IN ENDOCRINOLOGY BOOK SERIES
2. Support you by Becoming a YouTube member (Click here)

• Q. What is the definition of NICTH (Non-Islet cell Tumor hypoglycemia) & IGF-2 related hypoglycemia?
  • It denotes hypoglycemia caused by a tumor other than Insulinoma
• Q. Which tumors produce NICTH?
  • Mesenchymal tumor (Fibrosarcoma)
  • Vascular tumor- Hemingopericytoma
  • Fibroma
  • Hepatocellular carcinoma- most common cause
  • Adrenocortical carcinoma- second most common
  • Colorectal cacrinoma
  • Multiple myeloma
  • Carcinoid
  • Lymphoma
  • 
• Q. What are the possible causes of NICTH?
  • Excess of Big IGF-2
  • Extensive destruction of glucose by the liver
  • Insulin antibodies
  • Insulin receptor antibodies
  • Ectopic Insulin or IGF-1 production
• Q. What is Big IGF-2?
  • This is incompletely processed IGF-2
• Q. What are the consequences of IGF-2?
  • 1. Autocrine-Paracrine stimulation of the tumor
  • 2. Spontaneous hypoglycemia- mainly fasting hypoglycemia
  • 3. Acromegaloid features in some patients
  • 
• Q. What type of hypoglycemia is seen with NICTH?
  • Fasting hypoglycemia
• Q. Does the diagnosis of tumor occur first or does hypoglycemia occur first?
  • The tumor is generally diagnosed first before hypoglycemia occurs
  • These are generally large tumors
• Q. Which is the most important tumor which is associated with NICTH (Non-Islet cell Tumor hypoglycemia) & IGF-2 related hypoglycemia?
  • Hepatocellular carcinoma
  • Adrenocortical carcinoma is a distant second
• Q. What is the most common clinical presentation of hypoglycemia in these patients?
  • These patients present with neuroglycopenia symptoms mainly
  • Loss of judgment and changes in behavior are some of the earliest signs of hypoglycemia in these patients
• Q. What is the biochemical picture in NICTH?
  • Glucose – low
  • C peptide- low
  • Insulin- low
  • Proinsulin- low
  • BOHB- low
  • Response to glucagon – present
• Q. What happens to the GH response in these patients?
  • The GH response is blunted because of suppression by IGF-2
• Q. Which test is a part of biochemical tests in the critical sample- give a hint of possible IGF-2-related hypoglycemia?
  • These patients have a picture of insulin-independent hypoglycemia- Insulin, C-peptide, and Proinsulin are all low
  • The key differentiating factors are two folds:
    • beta-hydroxybutyrate is low -
      • If this was high- it would suggest a variation of normal or extreme starvation
    • GH's response is blunted
      • the absence of raise in GH levels
• Q. Which other electrolyte imbalance is seen in these patients?
  • Hypokalemia is often seen
• Q. Why do some of these patients develop postprandial hyperglycemia?
  • This is because IGF-2 suppresses the pancreatic beta-cell function
  • Hence some of these patients may have fasting hypoglycemia but postmeal hyperglycemia
• Q. Summarize the physiology of IGF-2
  • 
• Q. Which are specific tests done for diagnosis of NICTH?
  • Big IGF-2 measurement
  • IGF-2 IGF1 ratio
• Q. Which tumors produce insulin autoimmune syndrome?
  • Multiple myeloma
  • Hodgkin’s lymphoma
• Q. What is the management of NICTH?
  • Removal of the tumor
  • Glucocorticoids – reduce IGF-2
• Q. What are the conditions in which hypoglycemia and Acromegaloid features coexist?
  • 1. IGF-2 related hypoglycemia
  • 2. MEN1 syndrome
• Q. What is "Rhinophyma"? This is a feature of which possible endocrine condition?
  • Rhinophyma is a condition characterized by the thickening of the skin of the nose, resulting in a bulbous, red appearance
  • This may be seen in Acromegaly
  • 
• Q. What are the conditions that lead to "pseudohypoglycemia"?
  • In patients with Leukemia or Polycythemia- may have pseudohypoglyemia
  • This is because of the increased RBC consumption the glucose leading to low glucose reading in the lab
• Q. Within what period in a 72-hour fast test do patients with Insulinoma manifest the features of hypoglycemia?
  • Hypoglycemia is manifested within 24-36 hours of a 72-hour-fast test in patients with Insulinoma
• Q. What is a good clinical way of judging hypoglycemia symptoms during a 72-hour fast test?
  • Asking the patient to perform serial 7 subtraction test regularly is a good way of assessing for developing hypoglycemia
• Q. What happens to IGF-2 levels in NICTH (Non-Islet cell Tumor hypoglycemia) & IGF-2-related hypoglycemia ?
  • IGF-2 levels may be elevated or normal
  • If they are elevated - it confirms the diagnosis
  • but normal value - may not rule it out
• Q. Which other test is useful in this situation?
  • The molar ratio of IGF-2:IGF-1 is useful
  • Ratio 10:1 is diagnostic of this condition
    • Upto 3:1 ratio is normal
• Q. In which other condition is the IGF-2:IGF-1 ratio significantly elevated?
  • Sepsis
  • Severe cachexia
• Q. What happens to the IGFBP levels?
  • IGFBP1 and IGFBP2 are elevated
  • IGFBP3 is reduced
• Q. Summarize the impact of IGF-2 on liver products.
  • Reduced glucose
  • Reduced IGF-1
  • Reduced ALS (acid labile subunit)
  • Reduced IGFBP3
  • Increased IGFBP2
• Q. Which other IGF-2-like component can be measured if IGF-2 is normal?
  • Pro-IGF-2 can be measured
  • There is an assay developed for the same
• Q. Can non-islet cell tumors produce some other components which can cause hypoglycemia?
  • Yes
  • Rare cases of IGF-1 and Insulin-producing tumors have been reported
• Q. Summarize the biochemical diagnosis of NICTH (Non-Islet cell Tumor hypoglycemia) & IGF-2 related hypoglycemia
  • 
• Q. Which organ produces IGF-2 in normal circumstances?
  • It is produced by the liver
• Q. What is the timing of hypoglycemia seen in NICTH (Non-Islet cell Tumor hypoglycemia) & IGF-2 related hypoglycemia?
  • It is mainly fasting hypoglycemia
• Q. What is the difference in IGF-2-related complexes in normal patients versus those having NICTH (Non-Islet cell Tumor hypoglycemia) & IGF-2-related hypoglycemia?
  • In Normal people 80% of the IGF2 is in form of a complex of IGF-2-IGFBP3-ALS. This is a 150 kDa ternary complex
  • In NICTH (Non-Islet cell Tumor hypoglycemia) & IGF-2 related hypoglycemia - 80% of the complex is in form of IGF-2 with IGFBP3. This is a smaller 50 KDA binary complex
    • This is formed because of suppression of ALS production by IGF-2
  • 
• Q. Can you tell me the sequence of conversion from Prepro IGF2 complex to IGF2?
  • See the picture below
  • 
• Q. Of the above, which component primarily causes hypoglycemia?
  • The interaction of the Big IGF2 (1-87) with the insulin receptor is mainly responsible for the hypoglycemia seen in this condition
• Q. Which other endocrine disorder is seen because of IGF-2?
  • Big IGF-2 produces Hepatitis-C associated osteosclerosis
• Q. Do patients with Hepatitis-C associated osteosclerosis also have hypoglycemia?
  • Interestingly, no
  • Patients with this condition do not have hypoglycemia while patients with IGF-2-related hypoglycemia do not have osteosclerosis!
  • This is because both are caused by a distinct isoform of Big-IGF2
• Q. What is the treatment for this condition?
  • Treatment is directed towards two things:
    • 1. Treatment of the underlying tumor
      • Resection of the underlying tumor often resolves the symptoms
      • In some cases where the tumor may not be completely resectable, debulking is also helpful
    • 2. Management of hypoglycemia
      • Glucocorticoids are the first line of therapy geared towards correcting hypoglycemia in this condition and are found to be very useful
      • Interestingly, growth hormone therapy is the second line of therapy in this condition (despite the theoretical risk of tumor progression)
      • It is also interesting to note that Somatostatin analogs are NOT useful in this condition
• Q. How does growth hormone help in this condition?
  • Growth hormone increases the production of IGFBP3 and ALS leading to increase binding of the Free IGF2 and its removal from the circulation
• Q. Can you give some landmarks in the discovery of hypoglycemia and IGF2-related disease?
  • 
• Q. Who was the first person to give the concept of hypoglycemia?
  • The concept of Hypoglycemia was first understood from the work of Minkowski and von Mering who demonstrated fatality in animals after hepatectomy
  • They also demonstrated that the pancreas was the source of antidiabetic agent (insulin) that later led to the discovery of insulin
• Q. How was hypoglycemia discovered in humans?
  • Hypoglycemia was first demonstrated in humans having Addison's disease by Porges, in patients operated from the pituitary tumor by Cushing, and in emaciated diabetics by Joslin
• Q. In which condition was hypoglycemia used as a form of therapy?
  • Insulin shock therapy was a form of treatment for patients with schizophrenia
  • Typically 100-150 units of insulin were used to produce severe hypoglycemia
  • This treatment was later replaced

Reference:

Dynkevich Y, Rother KI, Whitford I, Qureshi S, Galiveeti S, Szulc AL, Danoff A, Breen TL, Kaviani N, Shanik MH, LeRoith D. Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive. Endocrine Reviews. 2013 Dec 1;34(6):798-826.