eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Lithium

Author: David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School
Coauthor(s): Amit Gupta, MD, Fellow, Department of Toxicology, North Shore Hospital
Contributor Information and Disclosures

Updated: Mar 24, 2009

Introduction

Background

Lithium has been in use since the 1870s. Lithium was initially used to treat depression, gout, and neutropenia, and for cluster headache prophylaxis, but it fell out of favor because of its side effects. In the 1940s, the US Food and Drug Administration (FDA) banned the use of lithium because of fatalities but lifted the ban in 1970. Presently, lithium is commonly used as maintenance treatment of bipolar disorder. Lithium poisoning occurs frequently, since it is used in a population at high risk for overdose. Furthermore, lithium has a relatively narrow therapeutic index that predisposes patients on chronic lithium maintenance treatment to poisoning with relatively minor changes in medications or health status.

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Pathophysiology

The central nervous system (CNS) is the major organ system affected, although the renal, gastrointestinal (GI), endocrine, and cardiovascular (CV) systems also may be involved.

Lithium is available only for oral administration. It is almost completely absorbed from the GI tract. Peak levels occur 2-4 hours postingestion, although absorption can be much slower in massive overdose or with ingestion of sustained-release preparations.

Lithium dosing

Lithium is minimally protein bound (<10%) and has an apparent volume of distribution of 0.6-1 L/kg. The therapeutic dose is 300-2700 mg/d with desired serum levels of 0.6-1.2 mEq/L.

Lithium clearance is predominantly through the kidneys. Because it is minimally protein bound, lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate (GFR). Consequently, dosing must be adjusted based on renal function. Individuals with chronic renal insufficiency must be closely monitored if placed on lithium therapy.

Most filtered lithium is reabsorbed in the proximal tubule; thus, drugs known to inhibit proximal tubular reabsorption, such as carbonic anhydrase inhibitors and aminophylline, may increase excretion. Diuretics acting distally to the proximal tubule, such as thiazides and spironolactone, do not directly affect the fractional excretion of lithium (although they may affect serum lithium levels indirectly through their effects on volume status). Reabsorption of lithium is increased and toxicity is more likely in patients who are hyponatremic or volume depleted, both of which are possible consequences of diuretic therapy.

Lithium half-life

The plasma elimination half-life of a single dose of lithium is from 12-27 hours (varies with age). The half-life increases to approximately 36 hours in elderly persons (secondary to decreased GFR). Additionally, half-life may be considerably longer with chronic lithium use.

Frequency

United States

An estimated 10,000 toxic exposures occur per year. These data indicate a gradual increase over the past 10 years.

Mortality/Morbidity

An estimated 2000 moderate-to-severe outcomes occur in the United States each year; lethal outcomes are generally secondary to severe CNS effects with subsequent cardiovascular collapse.

Race

No predilection exists.

Age

Approximately 10% of toxic lithium exposures occur in children younger than 19 years.

Clinical

History

As with all toxic ingestions, it is important to determine the amount, time, co-ingestants, and reason for ingestion. Toxicity does not often correlate with the measured lithium level since clinical toxicity is affected by the type of the poisoning.   

Clinical features

• Three main categories of patients who are poisoned are as follows: acute, acute-on-chronic, and chronic.
  • Acute: These patients usually do not have a tissue body burden and symptoms are predominately GI including nausea, vomiting, cramping, and sometimes diarrhea. Progression of acute toxicity can involve neuromuscular signs such as tremulousness, dystonia, hyperreflexia, and ataxia. Cardiac dysrhythmias have been reported but rarely occur. The most common ECG finding is T-wave flattening.
  • Acute-on-chronic: These patients take lithium regularly and have taken a larger dose recently. These patients may display both GI and neurologic symptoms, and serum levels can be difficult to interpret. Patients should be treated according to their clinical manifestations.  
  • Chronic: These patients typically have a large body burden of lithium and may be difficult to treat. Chronic lithium toxicity is usually precipitated with introduction of new medication that may impair renal function/excretion or cause a hypovolemic state. Symptoms are primarily neurologic. Mental status is often altered and can progress to coma and seizures if the diagnosis is unrecognized. Many severely poisoned patients can develop a syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) such as cognitive impairment, sensorimotor peripheral neuropathy, and cerebellar dysfunction.  

Drug interactions
 
Three major drug classes have been identified as potential precipitants of lithium toxicity. 

• Diuretics that promote renal sodium wasting
• Angiotensin-converting enzyme (ACE) inhibitors that reduce glomerular filtration rate (GFR) and enhance the tubular reabsorption of lithium 
• Nonsteroidal anti-inflammatory drugs (NSAIDs) that reduce GFR and interrupt of renal prostaglandin synthesis

Systemic effects 

• Renal toxicity is common with chronic lithium therapy, with nephrogenic diabetes insipidus being the most severe manifestation. Lithium inhibits the action of antidiuretic hormone (ADH) on the distal renal tubule, impairing sodium and water reabsorption. Other manifestations of lithium toxicity on the kidney include renal tubular acidosis, chronic tubulointerstitial nephritis, and nephrotic syndrome. 
• The most common endocrine disorder secondary to chronic toxicity is hypothyroidism. Lithium is taken up avidly by thyroid cells and blocks thyroid hormone release from thyroglobulin, which inhibits adenylate cyclase and prevents thyroid-stimulating hormone (TSH) from activating thyroid cells via the TSH receptor. It may also affect thyroid hormone synthesis. Myxedema coma has been reported as a complication of toxicity. 
• Acute exposure to lithium can cause leukocytosis, whereas chronic exposure can produce aplastic anemia.
• Patients who are on chronic lithium therapy can develop localized edema, dermatitis, and skin ulcers.

Physical

• Neurologic effects of lithium toxicity include tremors, lethargy, confusion, seizures, and coma. 
• GI effects of lithium toxicity include nausea, vomiting, crampy abdominal pain, and diarrhea. 
• Mild-to-moderate lithium toxicity is characterized by tremor, weakness, and mild confusion. 
• Moderate-to-severe lithium toxicity is characterized by altered mental status, muscle fasciculations, stupor, seizures, coma, hyperreflexia, and cardiovascular collapse.

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