Q & A: Hypoglycemia in a Dog with Hepatocellular Carcinoma

My patient is a 10-year-old, male, Husky that presented with hypoglycemic seizures and a large intra-abdominal tumor a year ago. Physical examination at that time showed cachexia and a palpable mass in the cranial aspect of the abdomen. The major laboratory abnormalities included hypoglycemia (32 mg/dl) and high enzyme activities for both alanine aminotransferase (ALT) and alkaline phosphate (AP). Fasting and postprandial serum bile acid concentrations were high. Insulinoma was considered but the serum concentrations of both insulin and insulin-like growth factor I (IGF-1) were found to bee low at that time.

Abdominal radiographs and abdominal ultrasonography confirmed that the intraabdominal mass was of liver origin. At surgery, the liver tumor appeared isolated to the left liver lobe and was removed. Biopsy confirmed hepatocellular carcinoma. Postoperatively, the hypoglycemia resolved and the dog did well.

Recently, the dog has presented again for generalized hypoglycemic seizures; my workup shows that the tumor now has diffusely infiltrated all the remaining liver lobes. The laboratory workup again shows severe hypoglycemia (35 mg/dl) and high ALT and AP activities. The serum concentrations of total bilirubin, total protein, albumin, and urea nitrogen all remain within reference range limits.

My questions are the following:

1. Can I assume that the hypoglycemia is secondary to the hepatic tumor secreting insulin or another insulin-like factor? I originally measured both serum insulin and IGF-1 but both concentrations were normal.
2. Or should I assume that the hypoglycemia is from the liver failing? If that is the case, I thought it odd to not have a concurrent hypoalbuminemia or a high total bilirubin concentration.

I'd appreciate your input on this case.

My Response:

If the etiology of this dog's hypoglycemia was purely from liver failure, then yes, it would be odd to see severe hypoglycemia from liver failure without also seeing a low serum albumin and urea nitrogen. Like you indicated, canine hepatocellular carcinomas can also produce hypoglycemia via paraneoplastic means — these tumors can make an insulin-like substance that causes the blood glucose to fall (1,2). Since it's not insulin being secreted, the serum insulin levels will be low concurrent with the hypoglycemia. The insulin concentrations would never be high, as would be expected with an insulinoma.

Hypoglycemia can be caused by non-insulinoma tumors in the retroperitoneum, thorax, or abdomen. Intra-abdominal tumors that may cause hypoglycemia include hepatocellular carcinoma (the most common primary liver tumor in the dog), hepatoma, leiomyoma, leiomyosarcoma, melanoma, and hemangiosarcoma (1-4). Large mammary gland tumors have also been associated with hypoglycemia in dogs (5).

Large non-islet cell tumors in the abdomen have been previously been associated with hypoglycemia. There may be more than one cause, but the most common is believed to be tumor production of insulin-like growth factors, especially IGF-2 (1,2,4). The tumor may produce excessive IGF-2 or impair IGF-2 binding to serum proteins. Other contributing factors may be rapid glucose utilization by the tumor or deficiency of insulin antagonists. A consistent finding is suppressed serum concentrations of insulin (and IGF-1), like you found in this case.

Sucessful removal of a hepatocellular carcinoma (or other non-non-islet cell tumors) associated with hypoglycemia should correct the hypoglycemia, like it originally did in this dog (1). Due to the widespread tumor infiltration through the liver, this dog's long-term prognosis is guarded at this time. However, use of frequent feedings and treatment with glucocorticoids may help control signs of hypoglycemia, at least temporarily.

References:

1. Sakai M, Asano K, Nakata M, et al. Diabetes mellitus after resection of hepatocellular carcinoma with hypoglycemia in a dog. The Journal of Veterinary Medical Science 2006;68:765-767.
2. Liptak JM, Dernell WS, Monnet E, et al. Massive hepatocellular carcinoma in dogs: 48 cases (1992-2002). Journal of the American Veterinary Medical Association 2004;225:1225-1230.
3. Zini E, Glaus TM, Minuto F, et al. Paraneoplastic hypoglycemia due to an insulin-like growth factor type-II secreting hepatocellular carcinoma in a dog. Journal of Veterinary Internal Medicine 2007;21:193-195.
4. Leifer CE, Peterson ME, Matus RE, et al: Hypoglycemia associated with nonislet cell tumor in 13 dogs. Journal of the American Veterinary Medical Association 1985; 186:53-5.
5. Rossi G, Errico G, Perez P, et al. Paraneoplastic hypoglycemia in a diabetic dog with an insulin growth factor-2-producing mammary carcinoma. Veterinary Clinical Pathology 2010;39:480-484.