Chronic Lithium Therapy Research Articles

Lithium-associated primary hyperparathyroidism:: An evaluation of screening and referral patterns in a southeastern veteran population

BackgroundLong-term lithium therapy has a well-established but under-recognized association with primary hyperparathyroidism. Rates of hypercalcemia, screening for primary hyperparathyroidism, and referral for parathyroidectomy were evaluated among United States veterans on long-term lithium therapy. MethodsPatients undergoing chronic long-term lithium therapy (>12 months) were identified from 1999 to 2022. Demographics, long-term lithium therapy duration, post-treatment calcium, parathyroid hormone, creatinine, and vitamin D levels were abstracted. Rates of screening for hypercalcemia (calcium ≥10.2 mg/dL), primary hyperparathyroidism (parathyroid hormone ≥30 pg/mL in the setting of hypercalcemia), referral for parathyroidectomy, and outcomes were evaluated. ResultsA total of 1,356 patients underwent long-term lithium therapy, 514 of whom received chronic long-term lithium therapy. Baseline characteristics of patients with and without post-treatment hypercalcemia were compared. Of 148 patients with post-treatment hypercalcemia, 112 (74.7%) underwent no further evaluation for primary hyperparathyroidism, while 36 (25.3%) patients had a parathyroid hormone level recorded. Although 33 (91.7%) hypercalcemic patients screened positive for primary hyperparathyroidism, only 5 (13%) were referred for parathyroidectomy. Of the 4 patients who underwent parathyroidectomy, mean calcium was 11.2 mg/dL (range 11.1–11.4), and mean parathyroid hormone was 272 pg/mL (range 108–622). Three patients were localized on preoperative imaging, 2 of whom underwent unilateral exploration with cure, with 1 experiencing recurrence at 31 months. The remaining patient who localized preoperatively underwent bilateral exploration and had 2 ipsilateral glands resected and persistence. The patient who did not localize preoperatively underwent bilateral exploration with 3 gland resection and cure. ConclusionsScreening for primary hyperparathyroidism and referral for parathyroidectomy are underutilized in United States veterans undergoing chronic long-term lithium therapy. Institutional protocols to standardize screening, surveillance, and referrals to endocrinology/endocrine surgery could benefit this population at increased risk for primary hyperparathyroidism.

Abstract #1183839: Challenges in management of lithium induced hyperparathyroidism: An interesting case

Lithium induced hyperparathyroidism occurs in 4.3% - 6.3% of patients on chronic lithium therapy compared to 0.5% -1% in general population. Lithium induced hyperparathyroidism is often an under appreciated finding and its pathophysiology often mimics other hypercalcemic disorders. Further, both medical and surgical therapy results are not very successful in long term.

P192. Can We Predict Lithium Response Status in Bipolar Disorder Using Total Brain Volumetric Parameters?

Patients with bipolar disorder (BD) demonstrate a differential response to prophylactic lithium therapy. Neuroimaging studies have found various volumetric alterations in BD, but whether these are related to lithium response is not clear. Further, chronic lithium therapy has been associated with an increment of gray matter.

Chronic Lithium Therapy and Urine-Concentrating Ability in Individuals With Bipolar Disorder: Association Between Daily Dose and Resistance to Vasopressin and Polyuria

IntroductionLithium treatment can induce nephrogenic diabetes insipidus (NDI), but no consensus intervention is offered to date. We evaluated in these patients patterns of urine concentration and the correlates of 24-hour urine output.MethodsProspective, single-center, observational study of 217 consecutive lithium-treated individuals, with 24-hour urine collection, desmopressin (1-deamino-arginine vasopressin [DDAVP]) concentrating test, fasting plasma vasopressin measurement (copeptin measurement in n = 119), and measured glomerular filtration rate (mGFR). Maximal urine osmolality (MaxUosm) was the highest level during the DDAVP test.ResultsOf the individuals, 21% displayed polyuria (>3 l/d), but 55% displayed elevated fasting vasopressin level (>5 pg/ml). Uosm was significantly lower and urinary output and free water clearance were significantly higher in individuals treated for >10 years. MaxUosm was >600 mOsm/KgH2O in 128 patients (59%), among which vasopressin was increased in 51%, associated with higher lithium dose (950 [750–1200] vs. 800 [500–1000] mg/d, P < 0.001). All patients with lithium daily dose ≥1400 mg/d had high vasopressin levels. In multivariable analysis, 24-hour urine output was associated with higher lithium daily dose (β 0.49 ± 0.17, P = 0.005), female sex (β −359 ± 123, P = 0.004), daily osmolar intake (β 2.21 ± 0.24, P < 0.001), MaxUosm (β −2.89 ± 0.35, P < 0.001), and plasma vasopressin level (β 10.17 ± 4.76, P = 0.03).ConclusionHigher lithium daily dose was associated with higher vasopressin levels and higher urine output, independently of other factors. Daily osmolar intake was also associated with higher 24-hour urine output. These results suggest that controlled salt and protein intake and lithium dose might reduce polyuria in these patients.

Renal function after withdrawal of lithium.

Patients on chronic lithium therapy sometimes develop chronic kidney disease. For clinical decision-making, it is important to know whether discontinuation of lithium can lead to improvement of renal function. We studied the trajectory of renal function in a population previously on chronic lithium therapy. From a large database of patients on chronic lithium therapy, we selected a group of patients who stopped using lithium and whose creatinine values at least half a year after lithium withdrawal were available. We measured the slope of renal function (eGFR) before and after discontinuation of lithium. We compared the subgroup of patients with improvement of the renal function with those who showed further deterioration of the eGFR. eGFR slope significantly improved after discontinuation of lithium. Of patients with chronic kidney disease stage 3 or more (eGFR<60ml/min), the vast majority showed an increase of eGFR or a decrease in the rate of decline after lithium withdrawal. The group of patients with further deterioration of the renal function had a mean eGFR of 32ml/min, which was significantly lower than the patients with an improvement of the kidney function. Discontinuation of lithium leads in the majority of patients to improvement in renal function or at least less rapid deterioration.

Nephrogenic diabetes insipidus in children (Review).

Nephrogenic diabetes insipidus (NDI) is characterized by impaired urinary concentrating ability, despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). NDI can be inherited or acquired. NDI can result from genetic abnormalities, such as mutations in the vasopressin V2 receptor (AVPR2) or the aquaporin-2 (AQP2) water channel, or acquired causes, such as chronic lithium therapy. Congenital NDI is a rare condition. Mutations in AVPR2 are responsible for approximately 90% of patients with congenital NDI, and they have an X-linked pattern of inheritance. In approximately 10% of patients, congenital NDI has an autosomal recessive or dominant pattern of inheritance with mutations in the AQP2 gene. In 2% of cases, the genetic cause is unknown. The main symptoms at presentation include growth retardation, vomiting or feeding concerns, polyuria plus polydipsia, and dehydration. Without treatment, most patients fail to grow normally, and present with associated constipation, urological complication, megacystis, trabeculated bladder, hydroureter, hydronephrosis, and mental retardation. Treatment of NDI consist of sufficient water intake, low-sodium diet, diuretic thiazide, sometimes in combination with a cyclooxygenase (COX) inhibitor (indomethacin) or nonsteroidal anti-inflammatory drugs (NSAIDs), or hydrochlorothiazide in combination with amiloride. Some authors note a generally favorable long-term outcome and an apparent loss of efficacy of medical treatment during school age.

Chronic Lithium Neurotoxicity Presenting as Dementia: A Case Report

<h3>Introduction</h3> Treatment with Lithium can be associated with a continuum of neurological side effects, ranging from benign tremors to early reversible lithium neurotoxicity, to chronic irreversible lithium neurotoxicity. Among chronic systemic adverse effects of Lithium, neurotoxicity has been reported to be the most common, followed by renal and cardiovascular toxicity (Sunn et al). Data on lithium toxicity in the elderly is limited but available data indicates that adverse effects occur more commonly in the context of chronic therapeutic administration of lithium rather than instances of overdose (Oakly et al). EEG and nerve conduction studies show notable changes that correlate with the increased duration of Li therapy (Fountoulakis et al). Older adults are more susceptible to side effects even with "normal" lithium levels for reasons such as declined renal function, reduced volume of distribution, medical comorbidities, concomitant medications, and drug interactions. Here we present a case of an elderly man with chronic lithium neurotoxicity associated with significant cognitive changes and severe disability. This will be followed by a review of literature of chronic lithium neurotoxicity in the geriatric population. <h3>Methods</h3> Case of Mr. A: We present the case of a 72 year old man who presented to the Memory Clinic with a diagnosis of Alzheimer's disease (AD) since the age of 55. His presentation was also notable for progressive aphasia and he had a PEG tube placed for feeding. His cognitive deficits were most significant in the domains of executive and visuospatial functioning, memory, and language. Physical exam findings were notable for mild left hand tremor, difficulties with balance, slow gait with short steps and a decreased arm swing, limited vertical gaze, and dysphagia. He was independent with his ADLs but dependent on IADLs due to aforementioned cognitive and physical findings. Other psychiatric diagnoses included Bipolar Disorder, Substance Use Disorder in remission. At the time of his evaluation, Mr. A had been on Lithium for over 20 years with records for the past three years showing therapeutic levels .5-1.1mmol/L. Although the patient had been previously diagnosed with AD, his relatively stable neuropsychological profile over the last 15 years called the diagnosis of AD into question and this was confirmed by negative amyloid imaging. The patient had yearly therapeutic levels of Lithium until his wife's concern for further insidious cognitive decline in the domains of language and memory, along with worsening gait and tremor prompted checking a Lithium level which was 1.8. Patient was subsequently weaned off Lithium over several months. At the time of this writing this abstract, Mr. A's cognition and motor function are significantly improving, to the extent of no longer requiring PEG for dysphagia. Electronic searches of The Cochrane Central Register of Controlled Trials and the standard bibliographic databases PubMed, MEDLINE, EMBASE, and PsycINFO will be performed for papers focusing on chronic lithium neurotoxicity in older adults. Keywords include "lithium" and "adverse effects" or neurotoxicity" or "neurological manifestations." Original research, case reports, and reviews will be included. Data focusing on older adults will be extracted and presented. <h3>Results</h3> Initial search for literature focusing on chronic lithium neurotoxicity yielded 4 papers. Data from these papers will be extracted. The range of neurological adverse effects, both physical and mental, will be described. This will be followed by a discussion of risk and precipitating factors for lithium neurotoxicity. Association with lithium doses, duration of treatment, and serum lithium levels will be elucidated. Lastly, diagnosis and treatment considerations will be highlighted. <h3>Conclusions</h3> Chronic lithium Neurotoxicity is more common in the elderly and can occur at normal to even sub therapeutic doses. It is imperative to have an optimal index of suspicion if an individual on chronic lithium therapy presents with cognitive deficits. <h3>Funding</h3> not applicable

Lithium-associated hyperparathyroidism.

Lithium is a mood stabiliser widely used in the treatment and prophylaxis of mania, bipolar disorders and recurrent depression. Treatment with lithium can give rise to various endocrine and metabolic abnormalities, including thyroid dysfunction, nephrogenic diabetes insipidus and hypercalcaemia. Lithium may induce hypercalcaemia through both acute and chronic effects. The initial acute effects are potentially reversible and occur as a result of lithium's action on the calcium-sensing receptor pathway and glycogen synthase kinase 3, giving rise to a biochemical picture similar to that seen in familial hypocalciuric hypercalcaemia. In the long term, chronic lithium therapy leads to permanent changes within the parathyroid glands by either unmasking hyperparathyroidism in patients with a subclinical parathyroid adenoma or possibly by initiating multiglandular hyperparathyroidism. The latter biochemical picture is identical to that of primary hyperparathyroidism. Lithium-associated hyperparathyroidism, especially in patients on chronic lithium therapy, is associated with increased morbidity. Hence, regular monitoring of calcium levels in patients on lithium therapy is of paramount importance as early recognition of lithium-associated hyperparathyroidism can improve outcomes. This review focuses on the definition, pathophysiology, presentation, investigations and management of lithium-associated hyperparathyroidism.

Genetic Deletion of P2Y2 Receptor Offers Long-Term (5 Months) Protection Against Lithium-Induced Polyuria, Natriuresis, Kaliuresis, and Collecting Duct Remodeling and Cell Proliferation.

Chronic lithium administration for the treatment of bipolar disorder leads to nephrogenic diabetes insipidus (NDI), characterized by polyuria, natriuresis, kaliuresis, and collecting duct remodeling and cell proliferation among other features. Previously, using a 2-week lithium-induced NDI model, we reported that P2Y2 receptor (R) knockout mice are significantly resistant to polyuria, natriuresis, kaliuresis, and decrease in AQP2 protein abundance in the kidney relative to wild type mice. Here we show this protection is long-lasting, and is also associated with significant amelioration of lithium-induced collecting duct remodeling and cell proliferation. Age-matched wild type and knockout mice were fed regular (n = 5/genotype) or lithium-added (40 mmol/kg chow; n = 10/genotype) diet for 5 months and euthanized. Water intake, urine output and osmolality were monitored once in every month. Salt blocks were provided to mice on lithium-diet to prevent sodium loss. At the end of 5 months mice were euthanized and serum and kidney samples were analyzed. There was a steady increase in lithium-induced polyuria, natriuresis and kaliuresis in wild type mice over the 5-month period. Increases in these urinary parameters were very low in lithium-fed knockout mice, resulting in significantly widening differences between the wild type and knockout mice. Terminal AQP2 and NKCC2 protein abundances in the kidney were significantly higher in lithium-fed knockout vs. wild type mice. There were no significant differences in terminal serum lithium or sodium levels between the wild type and knockout mice. Confocal immunofluorescence microscopy revealed that lithium-induced marked remodeling of collecting duct with significantly increased proportion of [H+]-ATPase-positive intercalated cells and decreased proportion of AQP2-positive principal cells in the wild type, but not in knockout mice. Lithium-induced collecting duct cell proliferation (indicated by Ki67 labeling), was significantly lower in knockout vs. wild type mice. This is the first piece of evidence that purinergic signaling is potentially involved in lithium-induced collecting duct remodeling and cell proliferation. Our results demonstrate that genetic deletion of P2Y2-R protects against the key structural and functional alterations in Li-induced NDI, and underscore the potential utility of targeting this receptor for the treatment of NDI in bipolar patients on chronic lithium therapy.

Abstract #728 Recurrent Hypercalcemia Secondary to Sarcoidosis in the Setting of Chronic Lithium Therapy

Abstract #728 Recurrent Hypercalcemia Secondary to Sarcoidosis in the Setting of Chronic Lithium Therapy

Fatal 251-NBOMe Intoxication: A New Recreational Risk

Abuse of synthetic drugs is an emerging trend in substance abuse. Identification of exposure to such chemicals is often difficult due to the paucity of specific laboratory assays. One such group of compounds is the 2C class of phenethylamines that include 2-(4-lodo-2, 5-dimethoxyphenyl)-N-I[(2-methyoxyphenyl)methyl]ethanamine, known as 251-NBOMe or the street names “Smiles” and “N-Bomb.” This family of compounds consists of relatively new synthetic drugs, a two-carbon substitute of phenethylamine, which is a highly potent serotonin receptor 2A(5-HT2A) agonist. There are limited data on 251-NBOMe poisoning. We report a 17-year-old girl with mood disorders who died following 251-NBOMe ingestion, revealing its lethality. She presented in status epilepticus shortly after ingesting a substance on a blotter paper at a concert. She then acutely developed hyperthermia, metabolic acidosis, rhabdomyolysis, elevated transaminases, acute kidney injury, hypokalemia, hypocalcemia, and irreversible cerebral edema, and was declared brain dead on hospital day seven. Specific toxicological testing revealed exposure to 251-NBOMe from antemortem whole blood liquid chromatography/time-of-flight mass spectrometry at concentrations above 0.25 ng/mL. We suggest that the patient died from fulminant serotonin syndrome following acute 251-NBOMe intoxication with a possible contribution from chronic lithium therapy.

Imaging findings of renal toxicity in patients on chronic lithium therapy

Lithium salts are the mainstay of treatment of bipolar disorder. However, the therapeutic index of lithium is narrow, and severe side effects may be seen. Nephrotoxicity is the most important side effect, which may progress to chronic renal failure. In this pictorial essay, we present ultrasonography, computed tomography, and magnetic resonance imaging findings of renal toxicity secondary to chronic lithium use. We believe that imaging could be extremely helpful for the evaluation of renal toxicity and may even detect preclinical stages of renal parenchymal injury. A combination of different imaging modalities may help clarify findings detected on one modality.

2689 – MRI findings and renal function in patients on long-term lithium therapy

Nephrotoxicity is a well-known pharmacological side effect in patients under long-term treatment with lithium. About 20% may develop renal insufficiency and in 33-62.5% of these patients renal cysts are seen. Some prior studies report MRI findings in patients undergoing chronic lithium therapy. To compare Magnetic resonance imaging (MRI) findings of the kidney in patients undergoing chronic lithium therapy with renal function to determine if MRI findings are related to renal function impairment. Thirty five consecutive patients with mood disorders who were undergoing lithium therapy for at least one year were evaluated with a 1.5 tesla MRI imaging and renal function tests. Renal size and the presence, number and location of renal microcysts were analyzed and compared with renal function. The mean size of kidney was 106.0 mm ± 6.0; 106.0 mm ± 11.0. The mean number of microcysts in both kidney was 6.2. There was a positive correlation between duration of lithium treatment and number of renal microcyst(P< 0.0001, r=0.773). Correlation between MRI findings and renal function tests were not statistically significant.(p> 0.05). The present study reports that longer duration of lithium therapy can increase number of renal microcysts.It seems that increasing renal microcysts are not consistent with renal function impairment and magnetic resonance may not be useful for prediction or diagnosis of lithium-induced nephropathy. Our study results suggest that the relationship between MRI findings and renal function impairment in patients on long-term lithium therapy is not clear and needs further studies.

Kompletter AV-Block unter Lithiumtherapie im therapeutischen Bereich

A 69-year-old man came to the emergency unit because of vertigo and presyncope. A bipolar disorder - known since an age of 15 years - has been treated with 2 × 450 mg lithium and 100 mg perazine per day for several years (no other medications). With the exception of a low heart rate (36/min) clinical examination findings were unremarkable. Electrocardiography revealed a permanent complete atrioventricular block with a heart rate of 36/min. Echocardiography showed a normal left ejection fraction (EF 65 %). Laboratory tests were mainly unremarkable, particularly the lithium levels (0,7 mmol/l) were within the therapeutic range. Continuous treatment with orciprenaline stabilized the heart rate at an average of 52/min. After pacing with a provisional pacemaker a permanent pacemaker was implanted without complications, and the symptoms of vertigo and dizziness disappeared. Pacemaker checkup on the following day still showed a complete atrioventricular block with a heart rate of 28/min. Complete atrioventricular block secondary to chronic lithium therapy even in therapeutic levels is a rare complication with poor prognosis. Therefore it should be treated consequently.

Solid renal tumours of collecting duct origin in patients on chronic lithium therapy.

BackgroundLithium (Li) is an invaluable drug for the treatment of bipolar disorder. Long-term Li use is associated with renal complications including the formation of uncomplicated renal cysts caused by proliferation and expansion of collecting duct (CD) cells. We report six patients with complicated renal cysts in the context of Li nephropathy.MethodsOver a time period of 15 years, we have identified six patients with one or more solid renal tumours in our population of approximately 50 patients with chronic Li nephropathy. In this study we describe the clinical and pathological characteristics of these Li-related tumours.ResultsAll patients were on Li therapy for over 10 years and suffered from varying degrees of Li nephropathy. The tumours were all of CD origin and comprised both oncocytomas and collecting duct carcinomas. The CD carcinomas differed from the very rare “classical” CD cell carcinomas in histological appearance, multifocal presentation and non-aggressive clinical behaviourConclusionsThe increased incidence of CD derived tumours and atypical presentation of CD cell carcinomas in patients with chronic Li nephropathy suggests that Li predisposes to the development of these tumours. We hypothesize that prolonged stimulation of CD cell proliferation and expansion by Li not only causes cyst formation, but can eventually induce the formation of adenomas and carcinomas. Increased awareness of a possible relationship between chronic Li therapy and renal neoplasms, will enhance the knowledge on epidemiology, clinical behavior and optimal therapy for the Li-related renal neoplasms.

Lithium Nephropathy

This case series describes a unique sonographic appearance consisting of numerous microcysts and punctate echogenic foci seen on renal sonograms of 10 adult patients receiving chronic lithium therapy. Clinically, chronic renal insufficiency was present in 6 and nephrogenic diabetes insipidus in 2. Sonography showed numerous microcysts and punctate echogenic foci. Computed tomography in 5 patients confirmed microcysts and microcalcifications, which were fewer in number than on sonography. Magnetic resonance imaging in 2 patients confirmed microcysts in each case. Renal biopsy in 1 patient showed chronic interstitial nephritis, microcysts, and tubular dilatation. The diagnosis of lithium nephropathy should be considered when sonography shows these findings.

MR findings of lithium-related kidney disease: preliminary observations in four patients

To describe MR features of the kidney in patients on chronic lithium therapy and to correlate findings with the level of renal impairment. In this retrospective HIPPA compliant study, a search was performed in our institutional clinical and radiological computerized database for subjects with lithium-related kidney disease between August 1, 2009 and May 30, 2010. Four patients (2 male and 2 females, mean age 64.75 ± 3.5) with a total of eight kidneys fulfilled the search criteria. T2-weighted images were used to evaluate the presence, size, and distribution of renal cysts. T1-weighted images were used to evaluate kidney length, parenchymal thickness, and cortico-medullary differentiation (CMD). All kidneys displayed multiple, very abundant, small size (1-2 mm) cysts. The distribution of the cysts was symmetric in renal cortex and medulla and the number of cysts was similar in both kidneys. Sparse, asymmetrical parenchymal renal cysts >3 mm in diameter were also observed. The size and parenchyma thickness of both kidneys was considered normal in all patients. The CMD differentiation was preserved only in patients with normal laboratory kidney findings (n = 2), but was lost in patients with chronic renal failure. Multi-microcystic kidney disease secondary to long-term lithium therapy can be detected with MR imaging regardless of known renal impairment. Preservation of renal CMD was observed in both patients with normal kidney function. The results of our preliminary study suggest the possible role of MR imaging for the screening of early manifestations of nephropathy in patients undergoing chronic lithium therapy.

Lithium‐Associated Mobitz II Block: Case Series and Review of the Literature

We report two cases of lithium-associated Mobitz II block. Both patients required placement of a permanent pacemaker due to persistent block and symptoms despite attempts at lowering the daily dose of lithium. We then reviewed the literature on this rare complication. Chronic lithium therapy may be associated with development of conduction block at or below the level of the atrioventricular node. Patients taking lithium should be monitored closely for development of cardiovascular complications.

MRI Findings in Chronic Lithium Nephropathy: A Case Report

Patients on long term lithium therapy for affective disorders may develop renal toxicity. It may manifest as nephrogenic diabetes insipidus with renal biopsy showing interstitial fibrosis, sclerotic glomeruli and cyst formation. Magnetic resonance imaging demonstrates the presence of microcysts in patients on long-term lithium therapy, suggesting a possible cause for their nephrotoxicity. We describe the typical magnetic resonance imaging appearance of renal microcysts in a 53 year old woman on chronic lithium therapy.

Long-term results of surgery for lithium-associated hyperparathyroidism

Lithium therapy for affective bipolar disease is frequently associated with hyperparathyroidism (HPT), but the results of surgical treatment are virtually unknown. The aim of this retrospective review was to analyse the long-term outcome after surgery for lithium-induced HPT in a large series of patients. Seventy-one patients on chronic lithium therapy who underwent surgery in three university and three district hospitals in Sweden were followed for a median of 6.3 years. Histopathology, complications of surgery and normocalcaemia at 6 months after surgery and last follow-up were analysed. The primary histopathological diagnoses were adenoma (45 per cent), double adenomas (3 per cent) and hyperplasia (52 per cent). No permanent paresis of the recurrent laryngeal nerve was recorded but 13 per cent of the patients suffered from permanent hypoparathyroidism. At follow-up, the rate of persistent and recurrent HPT was 42 per cent regardless of the histopathological diagnosis. The results of conventional surgery for lithium-associated HPT are poor. The surgical approach should be adjusted for the multiglandular disease that is usually the cause of HPT in patients on chronic lithium therapy.