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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Insulin

Last Update: April 26, 2018.

OVERVIEW

Introduction

Insulin is a pancreatic hormone that plays an essential role in regulation of blood glucose as well as lipid and carbohydrate metabolism. Both natural and recombinant forms of insulin are used therapeutically to treat type 1 diabetes. While insulin itself is not hepatotoxic and has not been linked to serum enzyme elevations or instances of clinically apparent liver injury, high doses including overdoses of insulin and glucose can result in hepatic glycogenosis and serum aminotransferase elevations.

Background

Insulin (in' su lin) is a polypeptide hormone produced by pancreatic islet β cells that is primarily responsible for regulation of blood glucose and storage of carbohydrates and lipids. Type 1 diabetes is due to inadequate production of insulin caused by destruction and loss of insulin producing pancreatic islet β cells. Type 2 diabetes is due to relative insulin resistance. Initial forms of insulin were isolated from pancreas tissue harvested from swine and cattle, and thus referred to as pork and beef insulins. More recently, human insulins have been produced by recombinant techniques. Since its first use in the 1930s, insulin has been the mainstay of therapy of type 1 diabetes. Insulin is also used in patients with type 2 diabetes that is refractory to lifestyle interventions (diet, physical activity, weight loss) and use of oral hypoglycemic agents. Multiple formulations of insulin are available including short-acting (regular), rapid-acting (aspart, glulisine, lispro) and medium- or long-acting (NPH, glargine, detemir) forms generically and under brand names such as Apidra, Basaglar, Humalog, Humulin, Lantus, Levemir, Novolin, Novolog and Tresiba. Commercial combination products with several forms of insulin or insulin with other agents are also available. Insulin can be given intravenously, intramuscularly and subcutaneously and the dose and frequency of administration varies by formulation and the individual being treated. Adverse events from insulin are largely due to hypoglycemia. Insulin therapy often results in weight gain. Local injection reactions (lipoatrophy) and hypersensitivity reactions are uncommon, particularly with newer recombinant forms of insulin.

Hepatotoxicity

Insulin in typical therapeutic doses is not associated with serum enzyme elevations or with episodes of clinically apparent liver injury. However, use of insulin in poorly controlled type 1 diabetes can result in a clinical syndrome known as glycogenosis or glycogenic hepatopathy, marked by varying degrees of hepatomegaly, abdominal pain and serum aminotransferase elevations. Serum ALT and AST levels range from normal to 20 to 30 times the upper limit or normal. Alkaline phosphatase and bilirubin levels are minimally increased or normal. Serum glucose and hemoglobin A1c levels are invariably elevated, and the liver and metabolic abnormalities resolve rapidly with better glycemic control. A severe form of glycogenosis associated with hepatomegaly, growth retardation, delayed puberty and Cushingoid facies in children is known as Mauriac syndrome. Glycogenosis with serum enzyme elevations can also occur in patients with insulin overdose during treatment with high doses of intravenous glucose (Case 1). Glycogenosis has also been reported in patients recieving short-term, high-dose corticosteroids..

The diagnosis of glycogenosis can be confirmed by liver biopsy which typically shows slightly swollen hepatocytes with pale cytoplasm and accentuated cell membranes, which with periodic acid Schiff (PAS) staining demonstrates intracytoplasmic accumulation of glycogen. Imaging by CT usually shows an enlarged and hyper-dense liver in contrast to hepatic steatosis which generally causes a hypo-dense pattern. The condition can be relapsing, accompanying repeated episodes of hyperglycemia, but it does not appear to result in chronic liver injury, fibrosis or cirrhosis. Thus, the serum enzyme elevations are due to the combination of marked hyperglycemia and intermittent or high levels of insulin and not to intrinsic hepatotoxicity or an idiosyncratic reaction to insulin. The syndrome occurs most commonly in children or young adults with poorly controlled type 1 diabetes.

Likelihood score: A[H] (known cause of liver injury, but only when administered in high or intermittent doses and in the presence of hyperglycemia).

Mechanism of Liver Injury

Insulin acts to increase uptake of glucose in the liver, decreasing gluconeogenesis and promoting glycogen synthesis. Thus, the hyperglycemia in the presence of high doses of insulin cause excessive production and storage of glycogen in the liver. Glycogenosis can cause serum enzyme elevations, but does not seem to injure hepatocytes and is not associated with permanent liver damage or fibrosis. Glycogenosis reverses rapidly when insulin and glucose are discontinued. Glycogenosis can also result from hyperglycemia caused by high doses of corticosteroids.

Outcome and Management

The liver injury associated with insulin use or overdose is likely due to glycogenosis rather than inherent injury from insulin, and reverses rapidly when insulin and glucose are discontinued.

Drug Class: Hormonal Agents; Antidiabetic Agents

CASE REPORT

Case 1. Hepatic glycogenosis developing after overdose of insulin and high doses of intravenous glucose.

[Modified from: Tsujimoto T, Takano M, Nishiofuku M, Yoshiji H, Matsumura Y, Kuriyama S, Uemura M, et al. Rapid onset of glycogen storage hepatomegaly in a type-2 diabetic patient after a massive dose of long-acting insulin and large doses of glucose. Intern Med 2006; 45: 469-73. PubMed Citation]

A 41 year old man with poorly controlled type 2 diabetes took an overdose of insulin (~180 units) and was admitted to hospital in coma with severe hypoglycemia (glucose 9 mg/dL). He was given continuous infusions of glucose, but hypoglycemia persisted for 36 hours. On day 3 after admission he developed upper abdominal pain and was found to have tender hepatomegaly and marked elevations in serum enzymes with ALT 1024 U/L, AST 1064 U/L, LDH 1751 U/L, alkaline phosphatase 202 U/L, GGT 181 U/L and total bilirubin 2.3 mg/dL. His serum enzymes had been normal on admission immediately after the overdose (Table). Abdominal CT scanning demonstrated marked hepatomegaly and increased attenuation (hyper-dense liver compared to spleen and kidneys). A liver biopsy showed glycogenosis with minimal cellular infiltration and no necrosis, mild steatosis and no fibrosis. The presence of glycogen was documented by PAS staining with and without diastase. Doses of glucose were decreased and he was switched to oral intake only. Serum enzymes improved rapidly and were normal 2 weeks later. Repeat CT scanning showed a decrease in liver size and in hepatic attenuation. Repeat liver biopsy showed slight ballooning of hepatocytes and minimal residual intracytoplasmic glycogen accumulation.

Key Points

Medication:Insulin glargine overdose treated with glucose infusions
Pattern:Hepatocellular (R=~16.5)
Severity:1+ (enzyme elevations without jaundice)
Latency:3 days
Recovery:2 weeks
Other medications:Voglibose (alpha glucosidase inhibitor)

Laboratory Values

Time After Overdose (days)TherapyALT
(U/L)		Alk P
(U/L)		Bilirubin (mg/dL)Other
1iv Glucose [326 g]231250.4Coma
2iv Glucose [811 g]18
3iv Glucose [926 g]10642022.3Abdominal Pain
4iv Glucose [531 g]708
5iv Glucose [200 g]274Liver biopsy (1)
6iv Glucose [52 g]214
7Oral intake only135
1041
1424
1816
2119Liver biopsy (2)
Standard Normal Values <40 <130 <1.2

Comment

The sudden onset of hepatomegaly with abdominal pain and marked serum aminotransferase elevations within days of starting glucose infusions after an overdose of insulin is typical of acute glycogenosis and dramatically demonstrates how rapidly the condition can develop and how rapidly it resolves. The clinical features resemble those of the hepatic glycogenosis that occurs in poorly controlled type 1 diabetes when insulin is being administered at a time that significant hyperglycemia is present. The diagnosis can be made based upon the clinical history and the finding of a hyper-dense liver by CT scanning. However, similar serum enzyme elevations can occur due to shock or ischemia and some degree of liver test abnormalities are common in patients with diabetes and fatty liver. The histologic findings of slightly swollen hepatocytes with pale cytoplasm and accentuation of plasma membranes suggests glycogenosis, which can be proven by PAS staining with and without diastase (an enzyme that digests glycogen demonstrating that the PAS-positive granules are composed of glycogen). Thus, insulin is not the direct cause of the liver abnormalities, but does allow for the excess circulating glucose to be taken up by hepatocytes producing amounts of intracytoplasmic glycogen that cause hepatocyte swelling, liver enlargement and release of hepatic enzymes.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Insulin – Generic, Lantus, Humulin®

DRUG CLASS

Hormonal Agents; Antidiabetic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Insulin 11061-68-0 C257-H383-N65-O77-S6
Insulin Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 26 April 2018

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