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.