Long-Term Lithium Use: More Evidence Needed to Associate With Cancer Risk

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The European Medicine Agency has reported that there may be an association between long-term lithium use and reports of both renal tumors and thyroid cancer.
The European Medicine Agency has reported that there may be an association between long-term lithium use and reports of both renal tumors and thyroid cancer.

In 2015, the European Medicine Agency sounded an alarm among long-term lithium users when it released a report detailing evidence of renal tumors in patients receiving chronic lithium.1,2 The EMA report, followed by a case report a few months later of a woman who developed both renal and thyroid cancer after taking lithium for 18 years, caused widespread concern.1

Ubiquity of Lithium

Since 1949, lithium has been a mainstay for patients with bipolar disorder and depression because it is among the most effective agents at preventing suicide deaths.1 As such, it is considered first-line treatment for patients with bipolar disorder.

Because the report was based on only 2 studies, Ambrosiani and colleagues broadened the scope of their investigation to determine the risk to patients who need to take long-term lithium by analyzing data from several sources1,3-4:

  • retrospective analysis of patient records from the researchers' own lithium clinic,
  • retrospective analysis of the causes of death from clinic patients,
  • analysis of lithium adverse events from the European and World Health Organization pharmacovigilance databases, and
  • a literature review of the thyroid and renal tumors in patients treated with lithium.

Of the 1871 patients treated with lithium who had visited the clinic between 1980 and 2013, 562 patients were followed-up for at least 5 years, and 345 patients were followed-up for at least 10 years.1 In that patient population, there were 19 thyroidectomies, and 9 patients were diagnosed with thyroid cancer.1 The other cases were caused by adenoma and multinodal goiters.

In examining the death certificates of 375 patients who had visited the lithium clinic from 1980 to 2013, only 1 case of renal tumor was listed as the primary cause of death.1

The pharmacovigilance databases of lithium-related adverse events included 22,280 cases in VigiAccess, which found 29 and 14 cases of renal and thyroid tumors, respectively.1 The EudraVigilance database had 9833 cases of lithium-related adverse events, which resulted in 21 renal and 8 thyroid neoplasms.1

A literature review of thyroid cancers turned up 4 relevant articles, which yielded 6 cases of patients treated with lithium who developed tumors.1 In a literature search for renal tumors, the researchers found 6 articles that amounted to 25 cases of kidney tumors.1

Despite the exhaustive research, Ambrosiani and colleagues could not definitely state that lithium had caused the thyroid cancers. Thyroid papillary carcinoma is also the most frequently occurring thyroid cancer in the general population.1 The evidence has yet to yield an epidemiologic study.

The association of chronic lithium use and renal cancer is still inconclusive. Thus far, 2 population studies have not shown a connection between long-term lithium use and renal cancer.1

End of the Lithium-Renal Cancer Debate?

In 1 of the more robust studies examining the association of long-term lithium use with renal cancers, Pottegård and colleagues analyzed data from the Danish Cancer Registry from 1995 to 2012, alongside long-term lithium use data from the Danish Prescription Registry.5 Data from 259,080 age- and sex-matched cancer-free control patients were matched with data from 6477 renal and upper urinary tract cancer cases. Long-term lithium use was considered to be 5 or more years of adherent therapy.5

In the cancer registry, long-term lithium use was identified in 0.22% of cases and in 0.17% of the control group.5 The odds ratio (OR) for upper urinary tract cancer associated with long-term lithium use was 1.3 (95% CI, 0.8-2.2). Even when the analysis was adjusted for cancer stage and subtype, there was a slight but still nonsignificant increase in the OR for localized disease (OR, 1.6; 95% CI, 0.8-3.0), and for renal pelvis/ureter cancers (OR, 1.7; 95% CI, 0.5-5.4).5

"We undertook the study of lithium and urinary tract cancers based on a debate spurred by a case-series from France (Zaidan et al3) indicating a markedly increased risk for renal cancer," explained Anton Pottegård, PhD, associate professor of clinical pharmacology and pharmacy at the University of Southern Denmark in Odense, Denmark. "This was worrying, as many patients use lithium long-term, because there is really no alternative (at least not as well tolerated). Luckily, we found no evidence of an increased risk. As such, I hope that physicians and patients will use our results as a reason to do absolutely nothing; that is, continue the use of lithium if it's working well for the patient, without worrying about the risk for renal cancer."

Patient Awareness of Lithium Toxicity

One of the key elements in keeping patients healthy while they take lithium is continual patient education regarding the drug's narrow therapeutic index. Patients need to know why they are taking it, how to take the drug, potential adverse effects, and the importance of having their blood levels monitored.6

To determine patients' awareness and their potential for lithium toxicity, Zolezzi and colleagues analyzed the literature on patient education for lithium. In their 12-study analysis, they found a positive correlation between the patients' knowledge about lithium and safe levels of the drug, as measured by the self-reported Lithium Knowledge Test and Lithium Attitudes Questionnaire.6

"It is not sufficient that clinicians are aware of the therapeutic drug monitoring required for lithium; we wanted to stress that they must ensure their patients are well educated on lithium toxicity, its prevention, and symptom recognition," said Monica Zolezzi, BPharm, MSc, ACPR, PhD, assistant professor in the College of Pharmacy at the Qatar University in Doha. "We have patients from different parts of the world who speak different languages and have different cultures and need specific education regarding lithium treatment. We hoped to be able to address this by looking at the literature for evidence in studies evaluating the relationship between patients' lithium knowledge and safer utilization patterns of lithium."

Summary and Clinical Applicability

When the European Medicines Agency released a statement in 2015 about the potential for renal and thyroid tumors in patients taking lithium for more than 10 years, it unleashed a global debate about the need for routine screening of such patients. Given lithium's first-line therapy status in patients with mood disorders, researchers needed to investigate whether patients receiving long-term lithium were at substantial risk. Subsequent evidence, however, did not show the same signals.

Limitations and Disclosures

None.

References

  1. Ambrosiani L, Pisanu C, Deidda A, Chillotti C, Stochino ME, Bocchetta A. Thyroid and renal tumors in patients treated with long-term lithium: case series from a lithium clinic, review of the literature and international pharmacovigilance reports. Int J Bipolar Disord. 2018;6(1):17.
  2. European Medicine Agency. Pharmacovigilance Risk Assessment Committee (PRAC). PRAC recommendations on signals adopted at the PRAC meeting of 6-9 January 2015. https://www.ema.europa.eu/documents/prac-recommendation/prac-recommendations-signals-adopted-prac-meeting-6-9-january-2015_en.pdf Accessed December 3, 2018.
  3. Zaidan M, Stucker F, Stengel B, et al. Increased risk of solid renal tumors in lithium-treated patients. Kidney Int. 2014;86(1):184-190.
  4. Rookmaaker MB, van Gerven HA, Goldschmeding R, Boer WH. Solid renal tumours of collecting duct origin in patients on chronic lithium therapy. Clin Kidney J. 2012;5(5):412-415.
  5. Pottegård A, Hallas J, Jensen BL, Madsen K, Friis S. Long-term lithium use and risk of renal and upper urinary tract cancers. J Am Soc Nephrol. 2016;27(1):249-255.
  6. Zolezzi M, Eltorki YH, Almaamoon M, Fathy M, Omar NE. Outcomes of patient education practices to optimize the safe use of lithium: a literature review. Ment Health Clin. 2018;8(1):41-48.
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