Discussion
NICTH is the syndrome of hypoglycemia associated with any tumor other than an insulinoma. This syndrome is relatively uncommon and may be under-diagnosed.
It is explained by overproduction by the tumor of incompletely processed forms of IGF-2: pro-IGF-2. Both IGF-2 and pro-IGF-2 stimulate insulin receptors, resulting in increased glucose utilization. Pro-IGF-2 and IGF-2 suppress not only insulin but also growth hormone which likely exacerbate hypoglycemia1,2,4.
In a non diabetic patient, fasting hypoglycemia is rare and warrants thorough evaluation.
This case is about a psychiatric patient with long history of alcohol use who presented with severe hypoglycemia.
Drug-induced hypoglycemia was first considered. However serum insulin was suppressed, thus excluding self-administration of insulin secretagogues.
Ethanol inhibits gluconeogenesis in the liver, contributing to hypoglycemia but our patient didn’t drink alcohol since one month. In addition, the frequency of hypoglycemia didn’t improve during hospitalization. Therefore, alcohol or drug-induced hypoglycemia was considered unlikely.
Furthermore, during hypoglycemia, cortisol level was normal and insulin level was very low excluding respectively the diagnosis of adrenal insufficiency and insulinoma.
In addition to the presence of a metastatic liver tumor, IGF-I was suppressed, and IGF-2 to IGF-1 ratio was elevated. Given these findings, the diagnosis of NICTH due to HCC was made.
The diagnosis of NICTH is suspected when hypoglycemia is associated with low insulin and C‑peptide levels together with an inappropriate increase in the ratio of IGF‑2 to IGF‑1. Total IGF-2 may be elevated or normal, but levels of pro-IGF 2 are elevated. Measuring pro IGF-2 in clinical practice is difficult. Unfortunately, it is not available in our country.
The ratio of IGF-2/IGF-1 is helpful when levels of IGF-2 are normal like for our patient. A ratio greater than 10: 1 is virtually diagnostic2, 5-7.
In about half of patients with NICTH, hypoglycemia present, often long, after the diagnosis of the neoplasm. About half of them present with hypoglycemia as first manifestation of the disease2.
Unfortunately, our patient had presented late at an advanced stage of his disease with severe hypoglycemia.
The present patient had hepatocellular carcinoma with a liver failure. We suggested that in addition to NICTH, the decrease in glycogen storage due to the decreased liver function had made hypoglycemia more frequent and severe.
Initial treatment of NICTH aims at maintaining euglycemia. Most of these patients are managed with parenteral dextrose infusion. However, the majority of them fail to maintain adequate glucose levels and require a second modality to treat hypoglycemia with varying degrees of success.
The most effective treatment of hypoglycemia with IGF-2 producing tumor remains surgical resection2,8. Chemotherapy, radiation, and selective embolization are other therapeutic options reported for patients with advanced disease9.
When hypoglycemia persists after surgery, radiation, and/or chemotherapy, multiple palliative treatments have been employed. Glucocorticoids have been the most effective agents. They prevent hypoglycemia by increasing gluconeogenesis, inhibition of peripheral glucose uptake, and modulating the growth hormone-IGF axis. Glucocorticoids also have been shown to decrease the production of pro-IGF-2. But, the effects of glucocorticoids vary among patients, requiring close titration, and they are ineffective after reduction or cessation of therapy2, 10.
Our patient was put on predniso­lone 30 mg per day and 2-3 hourly frequent high-carbohy­drate feeds.
Other possible treat­ment options include Recombinant GH, somatostatin analogs, diazoxide and glucagon2,4.
In conclusion, there is a well-established association between solid tumors and production of IGF-2. Although rare, NICTH should be considered in patients with recurrent hypoglycemia especially in those with risk factors for HCC.
Declaration of interest: there is no conflict of interest
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.