Laboratory Interpretation -- Hypercalcemia

Adrenocorticotropic Hormone (ACTH)

Plasma ACTH (also called Adrenal Corticotropin or Corticotropin) determination is used as an indicator of piuitary function and is useful in the differential diagnosis of Cushing's disease, ectopic ACTH syndrome (eg. carcinoma of the lung, islet cell tumors, carcinoid tumors, medullary carcinoma of the thyroid), adrenal insufficiency, Addison's disease, hypopituitarism, ACTH-producing tumors (Nelson's syndrome), and andrenogenital syndrome.

ACTH shows a diurnal variation, with most secretion occuring in the AM. Late PM levels are approximately 50% of early AM levels. The levels can also be elevated by stress. ACTH is generally measured in conjunction with plasma cortisol levels.

ACTH levels are shown below along with cortisol levels in various clinical states.

DiseaseACTH LevelPlasma Cortisol Level
Cushings DiseaseElevated to High Normal
Ectopic ACTH SyndromeMarkedly Elevated
Adrenal Carcinoma or AdenomaLow to Non-detectableElevated
Addison's DiseaseConsistently ElevatedDecreased
Nelson's DiseaseConsistently ElevatedDecreased
Andrenogenital SyndromeElevatedDecreased

Alpha-Fetoprotein (AFP)

AFP is an oncofetal antigen which is used primarily as a tumor marker for hepatocellular carcinoma and nonseminomatous germ cell tumors.


Calcitonin is used to detect and confirm medullary carcinoma of the thyroid, especially in patients with hyperparathyroidism, pheochromacytoma, Cushing’s, Multiple Endocrine Neoplasia Type II, and as a marker for oat cell carcinoma of the lung.

The concetration of calcitonin may be increased in patients with medullary carcinoma of the thyroid, of the lung, breast cancer, small cell (oat cell) carcinoma, pancreatic cancers, chronic renal failure, Zollinger-Ellison syndrome, pernicious anemia, women with pregnancy at term, and in newborns. Pentagastrin and Calcium infusion are used as provactive challenge tests, and in medullary carcinoma of the thyroid gland levels greater than 1000 are often seen. In patients with microscopic medullary carcinoma or C-cell hyperplasia an normal basal calcitonin will be seen. Provactive challenge testing will be needed to see increased levels.

Carcinoembryonic Antigen (CEA)

CEA is an oncofetal glycoprotein antigen present in embryonic tissues and some epithelial malignancies.

It is most frequently used as a monitoring tool to detect recurrence of a perviously diagnosed malignancy in patients with gastrointestinal carcinomas, especially colorectal neoplasms, following surgery and/or during therapy.

CEA is also useful for other primary carcinomas of entodermal origin, such as stomach and pancreas. Significant elevations may be found with primary site tumors of the breast, lung, ovary,and medullary carcinoma of the thyroid. Increases have been seen with giant cell carcinoma of the thyroid and with neuroblastoma. The highest levels are associated with metastasis of the primary site tumor to the liver and bone.

C Peptide

Proinsulin secreted by the islets of Langerhans is cleaved to form insulin and C-Peptide. Since virtually all diabetics who receive insulin develop insulin antibodies after several months, the direct assay of insulin becomes unreliable. The measurement of C-Peptide is more useful in evaluating glycemic status in these patients.

Patients with insulin-dependent diabetes mellitus (Type I) usually have very low to nondetectable levels of C-Peptide. Patients with noninsulin dependent diabetes mellitus (Type II) will have normal to elevated levels of C-Peptide. Additionally C-Peptide and insulin levels will be increased in insulinoma cases, while in factitious hypoglycemia, insulin will be increased but C-Peptide levels will be low since exogenous insulin contains no C-Peptide.


Gastrin is secreted by antral G cells and stimulates gastric acid production, antral mobility, and secretion of pepsin and intrinsic factor. Elevated gastrin levels should be combined with data on gastric acid secretion.

Neuroendocrine tumors associated with Zollinger-Ellison syndrome often show elevated rates of gastric HCl secretion and upper gastrointestinal ulcer disease. Gastrin levels > 500 - 600 pg/mL in patients with basal acid hypersecretion are often indicative of gastrinoma, but antral G-cell hyperplasia cases can have gastrin levels > 500 pg/mL and hyperchlorhydria. If gastrinoma is likely but fasting gastrin levels are not diagnostic, the secretin test is the provactive test of choice. I.V. secretin normally diminishes gastrin, but in gastrinomas the gastrin will be increased.

Note that gastric ulcer, chronic renal failure, hyperparathyroidism, pyloric obstruction, carcinoma of the stomach, vagotomy without gastric resection, retained gastric antrum, and short bowel syndrome have all been associated with moderate gastrin elevations.


Glucagon is secreted from the a-cells of the pancreatic islets into the hepatic portal circulation and is commonly held to act exclusively on the liver under physiologic conditions. It is a potent activator of glycogenolysis and gluconeogenesis and increases hepatic glucose production within minutes. This increase is transient. Despite ongoing hyperglucagonemia, hepatic glucose production returns toward basal rates over about 90 minutes, although the hormone continues to support glucose production; i.e., withdrawal of glucagon results in a further decrease in glucose formation thereafter. Glucagon-induced hyperglycemia is also transient because glucagon-induced increase in glycogenolysis does not persist; during sustained hyperglucagonemia, gluconeogenesis increases progressively, at least over four hours in dogs. The transient glycogenolytic response to sustained hyperglucagonemia is not the result of glycogen depletion; a further increase in glucagon causes a further increase in glucose release. It is probably the result of glucose-induced insulin secretion coupled with the autoregulatory effect of hyperglycemia, although other factors may be involved.

Glucagonoma has been reported in association with MEN I. A fasting plasma glucagon of more than 1000 ng/L (more than 1000 pg/mL), establishes the diagnosis. More modest elevations of plasma glucagon levels may occur in diabetic ketoacidosis, renal failure, hepatic failure, sepsis, prolonged fasting, and gluten-sensitive enteropathy. Hypocholesterolemia and hypoaminoacidemia are common, with alanine, glycine, and serine levels usually less than 25 % of normal. Glucagonoma may be distinguished from other hyperglucagonemic syndromes by the failure of glucose to suppress and the failure of arginine to enhance serum glucagon concentrations.

Pancreatic Polypeptide

The physiologic importance of pancreatic polypeptide has not been established. The peptide's capacity to inhibit the effect of cholecystokinin may play a role in pancreatic exocrine function and gallbladder motility. Patients with high circulating levels of PP do not display a particular clinical syndrome. In one patient a PP-containing pancreatic tumor with liver metastases was associated with secretory diarrhea. However, PP has not been shown to be an intestinal secretagogue in small bowel perfusion experiments. Since about half of pancreatic endocrine tumors contain PP, this peptide has been used as a marker for the diagnosis of pancreatic endocrine tumors and for monitoring the response to treatment. PP has also been used to follow subjects at risk because of a family history of MEN I. While in most patients an elevated basal plasma level of PP is indicative of islet cell tumor, in some patients an exxagerated plasma PP response to post-prandial stimulation is indicative of MEN I trait and islet cell hyperplasia. The usefulness of PP as a marker for endocrine pancreatic tumors is limited because plasma PP may not originate from the tumors and because high levels have been found in certain inflammatory diseases, renal dysfunction, and even laxative abuse.


Evaluation of patients with clinical features of carcinoid syndrome is based on the observation that serotonin is secreted by the large majority of functional carcinoid tumors. Serotonin (5-HT) is metabolized in the liver to 5-hydroxyindoleacetic acid (5-HIAA), which is cleared by the kidneys. Plasma and platelet serotonin and urinary 5-HIAA levels are usually elevated in the setting of carcinoid syndrome. Measurement of urinary 5-HIAA excretion is the most useful diagnostic test, and approximately 75 % of patients excrete more than 80 umol/day (15 mg/day). Specificity of this test approaches 100 % after exclusion of ingested substances known to elevate 5-HIAA levels; these include bananas, plantain, pineapple, kiwi fruit, walnuts, plums, pecans, avocados, guiafenesin, and acetaminophen. Conversely, aspirin and levodopa ingestion can cause a falsely depressed 5-HIAA level. In some patients with carcinoid syndrome and normal urinary 5-HIAA, documentation of elevated plasma or platelet serotonin concentrations may establish the diagnosis. However, many gastric carcinoid tumors lack the aromatic L-amino acid decarboxylase and convert 5-hydroxytrptophan (5-HT/serotonin) with low efficiency. Since 5-HTP is not metabolized to 5-HIAA, urinary studies may be misleading. These patients may have elevated urinary serotonin levels, since renal cells contain aromatic L-amino acid decarboxylase. Diagnosis in these cases may be confirmed by demonstrating elevated plasma 5-HTP, histamine, or peptide hormone levels, although it frequently rests on the anatomic detection of the tumor itself.

Intact Parathyroid Hormone (PTH)

Parathyroid hormone plays a major role in calcium homeostasis by maintaining the concentration of ionized calcium within the narrowly defined range necessary to maintain metabolic and neuroregulatory function. At low levels of serum calcium associated with inadequate dietary intake the parathyroid gland will increase the secretion of PTH. This will result in the mobilization of calcium from the large skeletal bones into the extracellular fluid, increased absorption of dietary calcium, and decreased renal clearance of urinary calcium. As serum calcium levels increase smaller amounts of PTH are secreted by the parathyroid gland.

The measurement of PTH is an important aid in the assessment of disorders of calcium metabolism. When evaluated along with calcium levels, the quantitation of PTH has proven useful in distinguishing normal individuals from patients with primary hyperparathyroidism, hypoparathyroidism, and patients with tumor hypercalcemia.

The high and variable concentrations of biologically inactive PTH fragments have interfered with the use of the C-Terminal and midregion PTH assays to evaluate parathyroid function in patients with compromised renal function. Intact and N-terminal specific assays, which measure only the biologically active hormone, provide a more precise assessment of parathyroid function in these patients. The availability of assays for measurement of intact PTH has made assays for PTH fragments obsolete.

Catecholamines (epinephrine, norepinephrine, dopamine)

The conversion of the catecholamine norepinephrine to epinephrine occurs in the adrenal medulla. Therefore, fractionation of catecholamines can be useful in determining the site of a pheochromocytoma. It is also useful to diagnose and treat patients suspected of having neural crest tumors of the adrenal medulla and extra medullary tissues (pheochromocytoma, neuroblastoma, ganglioneuroma) and to evaluate patients with orthostatic hypotension.

Norepinephrine may be significantly more elevated than epinephrine in extra-adrenal pheochromocytoma. In the adrenals, pheochromocytomas may secrete norepinephrine, epinephrine, or a combination of both.

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