Chapter 096. Paraneoplastic Syndromes: Endocrinologic/Hematologic (Part 6)

Tumor-Induced Hypoglycemia Caused by Excess Production of IGF-II (See also Chap. 339) Mesenchymal tumors, hemangiopericytomas, hepatocellular tumors, adrenal carcinomas, and a variety of other large tumors have been reported to produce excessive amounts of insulin-like growth factor type II (IGF-II) precursor, which binds weakly to insulin receptors and strongly to IGF-I receptors, leading to insulin-like actions. The gene encoding IGF-II resides on a chromosome 11p15 locus that is normally imprinted (that is, expression is exclusively from a single parental allele). Biallelic expression of the IGF-II gene occurs in a subset of tumors, suggesting loss of methylation and loss of...
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Chapter 096. Paraneoplastic Syndromes: Endocrinologic/Hematologic (Part 6) Chapter 096. Paraneoplastic Syndromes: Endocrinologic/Hematologic (Part 6) Tumor-Induced Hypoglycemia Caused by Excess Production of IGF-II (See also Chap. 339) Mesenchymal tumors, hemangiopericytomas,hepatocellular tumors, adrenal carcinomas, and a variety of other large tumorshave been reported to produce excessive amounts of insulin-like growth factortype II (IGF-II) precursor, which binds weakly to insulin receptors and strongly toIGF-I receptors, leading to insulin-like actions. The gene encoding IGF-II resideson a chromosome 11p15 locus that is normally imprinted (that is, expression isexclusively from a single parental allele). Biallelic expression of the IGF-II geneoccurs in a subset of tumors, suggesting loss of methylation and loss of imprintingas a mechanism for gene induction. In addition to increased IGF-II production,IGF-II bioavailability is increased due to complex alterations in circulatingbinding proteins. Increased IGF-II suppresses growth hormone (GH) and insulin,resulting in reduced IGF binding protein 3 (IGFBP-3), IGF-I, and acid-labilesubunit (ALS). The reduction in ALS and IGFBP-3, which normally sequesterIGF-II, causes it to be displaced to a small circulating complex that has greateraccess to insulin target tissues. For this reason, circulating IGF-II levels may notbe markedly increased, despite causing hypoglycemia. In addition to IGF-II–mediated hypoglycemia, tumors may occupy enough of the liver to impairgluconeogenesis. In most cases, the tumor causing hypoglycemia is clinically apparent andhypoglycemia develops in association with fasting. The diagnosis is made bydocumenting low serum glucose and suppressed insulin levels in association withsymptoms of hypoglycemia. Serum IGF-II levels may not be increased (IGF-IIassays may not detect IGF-II precursors). Increased IGF-II mRNA expression isfound in most of these tumors. Any medications associated with hypoglycemiashould be eliminated. Treatment of the underlying malignancy, if possible, mayreduce the predisposition to hypoglycemia. Frequent meals and IV glucose,especially during sleep or fasting, are often necessary to prevent hypoglycemia.Glucagon, GH, and glucocorticoids have also been used to enhance glucoseproduction. Human Chorionic Gonadotropin hCG is composed of α and β subunits and can be produced as intacthormone, which is biologically active, or as uncombined biologically inertsubunits. Ectopic production of intact hCG occurs most often in association withtesticular embryonal tumors, germ cell tumors, extragonadal germinomas, lungcancer, hepatoma, and pancreatic islet tumors. Eutopic production of hCG occurswith trophoblastic malignancies. Low levels of hCG or its uncombined α or βsubunits have been reported in a wide array of tumors. hCG α subunit productionis particularly common in lung cancer and pancreatic islet cancer. In men, highhCG levels stimulate steroidogenesis and aromatase activity in testicular Leydigcells, resulting in increased estrogen production and the development ofgynecomastia. Precocious puberty in boys or gynecomastia in men should promptmeasurement of hCG and consideration of a testicular tumor or another source ofectopic hCG production. Most women are asymptomatic. hCG is easily measured.Treatment should be directed at the underlying malignancy. Oncogenic Osteomalacia Hypophosphatemic oncogenic osteomalacia, also called tumor-inducedosteomalacia (TIO), is characterized by markedly reduced serum phosphorus andrenal phosphate wasting, leading to muscle weakness, bone pain, andosteomalacia. Serum calcium and PTH levels are normal and 1,25-dihydroxyvitamin D is low. Oncogenic osteomalacia is usually caused by benign mesenchymal tumors,such as hemangiopericytomas, fibromas, or giant cell tumors, often of the skeletalextremities or head. It has also been described in sarcomas and in patients withprostate and lung cancer. Resection of the tumor reverses the disorder, confirming its humoral basis.The circulating phosphaturic factor is called phosphatonin—a factor that inhibitsrenal tubular reabsorption of phosphate and renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Phosphatonin has been identified as fibroblast growth factor 23 (FGF23).FGF23 levels are increased in some, but not all, patients with osteogenicosteomalacia. The disorder exhibits biochemical features similar to those seenwith inactivating mutations in the PHEX gene, the cause of hereditary X-linkedhypophosphatemia. The PHEX gene encodes a protease that activates FGF23. Treatmentinvolves removal of the tumor, if possible, and sup ...