リチウム中毒株式会社麻生 飯塚病院

　　　　　 総合診療科　坂井 正弘 　　　　　　　監修　 　吉野 俊平

分野：腎臓 テーマ：疾患の臨床徴候、治療

Clinical Question 2015.1.26 J Hospitalist Network

症例　53歳女性

I.D. 高血圧症、躁うつ病、甲状腺機能低下症の既往がある58歳女性 現病歴 来院3日前から倦怠感、咽頭痛、咳嗽を自覚 来院当日に自宅で倒れているところを発見され、救急搬送

既往歴 高血圧症、躁うつ病、甲状腺機能低下症 薬歴 炭酸リチウム、ロラゼパム、レボチロキシン バルサルタン 最近の薬剤変更歴はない 生活歴 喫煙歴 20本/日(18歳から現在まで) 飲酒歴 日本酒2合/日(20歳から現在まで) 生活保護受給者

身体所見 JCSⅠ-3(幻聴や視線恐怖を訴える）、両上肢の ミオクローヌスあり、その他明らかな異常はない 心電図 HR 87 bpm、整、ST-T変化はない 血液検査 血中リチウム濃度 3.3 mEq/l、BUN 32 mg/dl Cre 1.1 mg/dl、肝機能異常なし、アンモニア正常電解質異常なし、低血糖なし、甲状腺機能正常 髄液検査 細胞数の上昇なし

頭部CT 出血性病変やその他頭蓋内の占拠性病変なし 頭部MRI 急性期脳梗塞や脳実質の信号変化なし

まとめ ✤高血圧症、躁うつ病、甲状腺機能亢進症の 既往がある58歳女性

✤来院3日前から感冒症状を自覚し、 意識障害および両上肢のミオクローヌスを 呈して、救急搬送

✤血中リチウム濃度の上昇と腎機能の悪化が 見られる他は、血液検査、髄液検査 頭部CT/MRIで意識障害の原因なし

✤リチウム中毒が疑われて入院

Clinical Question

「血中リチウム濃度が3.3 mEq/l… これで今ある症状は説明できるの？」

そもそも、リチウム中毒の症状って…

リチウム中毒の分類✤ リチウムの毒性には急性と慢性がある ✴ 急性リチウム中毒 　 リチウム加療中ではない患者における誤薬や過量内服 ✴ 長期内服患者における急性リチウム中毒 　 リチウム加療中の患者における誤薬や過量内服 ✴ 慢性リチウム中毒 　 リチウム加療中の患者におけるリチウム投与量の増量や 　 腎機能低下に起因する中毒

J  Am  Soc  Nephrol.  1999; 10: 666-674.

リチウム中毒の臨床症状、合併症は？

Acute on chronic poisoning occurs in patients being treatedwith lithium who take an overdose (3). This ingestion may beaccidental or intentional, especially in patients with bipolardisorders who are manifesting depression. This form of poi-soning is generally more severe than acute poisoning due to theprolongation of the lithium elimination half-life (3). Serumconcentrations above 3 to 4 mEq/L are often associated withsevere symptoms (3) and generally require hemodialysis.Chronic toxicity occurs in patients receiving chronic lithium

therapy (3). Chronic poisoning can occur in patients whoselithium dosage has been increased or in individuals whoserenal function has decreased, resulting in an increase in serumlithium levels (3). The severity of chronic lithium intoxicationcorrelates directly with the serum lithium concentration andmay be categorized as mild (1.5 to 2.0 mEq/L), moderate (2.0to 2.5 mEq/L), or severe (!2.5 mEq/L) (5). Toxic symptomsmay be present even when concentrations are well within therecommended therapeutic range (3,5). Symptoms associatedwith mild poisoning include lethargy, drowsiness, coarse handtremor, muscle weakness, nausea, vomiting, and diarrhea (Ta-ble 2) (2,5). Moderate toxicity is associated with confusion,dysarthria, nystagmus, ataxia, myoclonic twitches, and ECGchanges (flat or inverted T waves) (2,5). Severe toxicity, whichcan be life-threatening, is associated with grossly impairedconsciousness, increased deep tendon reflexes, seizures, syn-cope, renal insufficiency, coma, and death (2,5). However, theclinical presentation of lithium toxicity is only loosely corre-lated with serum drug concentrations, and there is great vari-ability in severity associated with a given concentration. Thus,management of toxicity should be dictated primarily by patientpresentation and not serum concentrations.The most common manifestation of lithium toxicity is al-

tered mental status (2). Lithium poisoning frequently results inelectrocardiogram (ECG) changes including transient ST seg-ment depression and inverted T-waves in the lateral precordial

leads (2). Occasional patients develop sinus node dysfunctionand syncope (2). Lithium toxicity may also cause GI symp-toms, including nausea, vomiting, diarrhea, bloating, and epi-gastric pain (2). Care must be taken to distinguish GI symp-toms from cardiac symptoms, especially in patients who alsopresent with an abnormal ECG. Lithium can occasionallycause peripheral neuropathy or myopathy (2).Lithium is concentrated within the thyroid and inhibits thy-

roid synthesis and release (3). Thus, lithium can cause hypo-thyroidism and hypothermia (2,3). However, it can also causethyrotoxicosis and hyperthermia (2,3). Lithium may also causehyperparathyroidism and hypercalcemia (3). A recent study ofhyperthyroidism and long-term lithium therapy followed pa-tients for an average of 19 yr and found an increased incidenceand prevalence of hyperthyroidism, with a tendency towardpromotion of parathyroid hyperplasia and hypercalcemia (15).This study also found that the hypercalcemia was either irre-versible or only very slowly reversible (15), in contrast toearlier case reports of patients treated with lithium for 10 d to6 yr in whom serum calcium levels returned to normal valueswithin 1 to 4 wk after lithium therapy was withdrawn. Thesefindings suggest an association between the duration of lithiumtreatment and the degree of persistence of hypercalcemia.Since hypercalcemia can cause nephrogenic diabetes insipidus,it could exacerbate lithium-induced nephrogenic diabetes in-sipidus (see below).Lithium does not always result in hypercalcemia, and some

patients maintain normal calcium levels despite elevated serumparathyroid hormone levels. A recent 2-yr prospective studyfollowed 53 patients and found that their parathyroid hormonelevels increased progressively over the course of the study(16). However, there was no change in serum calcium orphosphorus, or in the tubular reabsorption of phosphate (rela-tive to GFR) (16). The fasting and 24-h urinary calcium ex-

Table 2. Clinical symptoms associated with lithium poisoninga

Organ System Acute Poisoning Chronic Poisoning

Endocrine None HypothyroidismGastrointestinal Nausea, vomiting MinimalHeart Prolonged QT interval, Myocarditis

ST and T wave changesHematologic Leukocytosis Aplastic anemiaNeurologicmild Fine tremor, lightheadedness, weakness Samemoderate Apathy, drowsiness, hyperreflexia, muscle

twitching, slurred speech, tinnitusSame

severe Choreoathetoid movements, clonus, coma,confusion, muscular irritability, seizures

Memory deficits, Parkinson’s diseasePseudotumor cerebri, psychosis

Neuromuscular Myopathy, peripheral neuropathy SameRenal Urine concentrating defect Chronic interstitial nephritis, nephrogenic

diabetes insipidus, renal failureSkin None Dermatitis, localized edema, ulcers

a Data from references 2 through 4.

670 Journal of the American Society of Nephrology J Am Soc Nephrol 10: 666–674, 1999

神経・精神症状にはあまり差はなく、 慢性では腎性尿崩症や腎機能障害、内分泌異常が 問題になってくると考えれば良さそう

J  Am  Soc  Nephrol.  1999; 10: 666-674.

急性リチウム中毒✤ 不整脈、消化器症状、神経・精神症状が 　　　　　　　　　　　　　　　メインとなる- 不整脈 QTcの延長や徐脈が報告されているものの、 致死的な不整脈をきたすことは稀

- 消化器症状 嘔気・嘔吐、下痢などの症状をきたすことがある

- 神経・精神症状 昏迷、失調、錯乱、興奮、振戦、ミオクローヌス 繊維束収縮、けいれんなど

リチウム中毒のリスクは？✤ 長期にリチウムを摂取している患者で、 中毒をきたすリスクとして下記が知られている

★感染症を契機にした脱水や、ACE阻害薬やARB、NSAIDsの使用に注意

J  Am  Soc  Nephrol.  1999; 10: 666-674.

cretion values were significantly decreased over the 2 yr of thestudy, suggesting that bone resorption was reduced (16).

Risk Factors for Lithium IntoxicationFactors that increase the risk for chronic toxicity in previ-

ously stable patients (Table 3) include other medications, ill-ness, and alterations in potassium or sodium levels. Drugs thatalter renal function can increase the risk for chronic lithiumtoxicity (2,17,18). Among these, ACE inhibitors, NSAID, andthiazide diuretics increase the reabsorption of lithium andresult in increased serum lithium concentrations (Table 4). Inone study, after initiation of an ACE inhibitor (lisinopril,captopril, or enalapril), steady-state lithium concentrations in-creased 36%, lithium clearance was reduced by 26%, and fourpatients presented with symptoms suggestive of lithium toxic-ity (19). The authors noted that age was a contributor to thiseffect, and that elderly patients may be uniquely predisposed tothis interaction (19). NSAID pose a special problem becausemany of these compounds are now available without a pre-scription and patients may take them without realizing theirpotential for interaction with lithium.Thiazide diuretics have a significant potential to increase

serum lithium concentrations. These diuretics induce a natri-uresis that leads to a compensatory increase in the reabsorptionof sodium (and lithium) in the proximal tubule (5). This effectof thiazide diuretics has been suggested in many case reports,describing lithium toxicity subsequent to thiazide initiation,and has also been documented in a handful of small controlledstudies (5). In general, therapeutic doses of thiazide diureticsresult in a 25 to 40% decrease in lithium clearance with aconcomitant increase in serum lithium levels (5). The nature ofthis interaction is quite variable and the most conservativeapproach is simply to avoid the use of thiazide diuretics ifpossible.Another risk factor is a concurrent illness that results in

decreased circulating volume, either true volume depletion ordecreased effective circulating volume. A common example isa patient acquiring a viral illness, such as a cold, the flu, orgastroenteritis, that results in decreased oral intake or increasedgastrointestinal losses. The decrease in circulating volume willstimulate proximal tubule sodium reabsorption, similar to theeffect of thiazide diuretics, and also result in an increase inproximal lithium reabsorption and serum lithium levels.Other risk factors include alterations in serum potassium or

sodium concentrations. Sodium restriction enhances the renaltubular reabsorption of lithium (20), thus leading to potentiallytoxic serum levels of lithium. Serum potassium concentrationscan have variable effects on serum lithium levels. For example,acute hyperkalemia increases lithium reabsorption in dogs(21). In dogs, raising plasma potassium from 2.6 to 7.9 mEq/Ldecreases water reabsorption and increases lithium reabsorp-tion without changing GFR (21). However, chronic reductionsin dietary potassium can result in increased lithium reabsorp-tion in the rat (22). In rats fed a low potassium diet, lithium isreabsorbed by an amiloride-sensitive transport mechanism inthe distal nephron, and fractional excretion of lithium is re-

duced by almost 50% compared with that of potassium-repleterats (22).

Diabetes InsipidusThe most frequent side effect of lithium is nephrogenic

diabetes insipidus, with an estimated prevalence of 20 to 70%(2,3,23). Patients present with polyuria, polydipsia, and aninability to concentrate their urine. Chronic treatment with

Table 3. Factors that increase the risk for lithium toxicitya

AnorexiaCystic fibrosisDecreased effective circulating volumecirrhosiscongestive heart failurenephrotic syndrome

Decreased dietary sodium intakeDiabetes insipidusDiabetes mellitusGastroenteritisInfectionsMedicationsangiotensin-converting enzyme inhibitorscyclosporinediuretics: loop diuretics and thiazidesnonsteroidal anti-inflammatory drugstetracycline

OverdoseRenal insufficiencySchizophreniaSurgeryVolume depletiona Data from references 2, 3, and 34.

Table 4. Drug interactions with lithiuma

Drug Effect on LithiumConcentration

Diureticsthiazide Increaseloop diuretics Decreaseosmotic diuretics DecreaseK! sparing Decreasemethyl xanthine Decreaseacetazolamide Decrease

ACE inhibitors IncreaseNSAIDindomethacin Increaseibuprofen Increasemefenamic acid Increasenaproxen Increasesulindac Noneaspirin None

a Modified from reference 5. ACE, angiotensin-convertingenzyme inhibitors; NSAID, nonsteroidal anti-inflammatory drugs.

J Am Soc Nephrol 10: 666–674, 1999 Lithium Intoxication 671

慢性リチウム中毒についての補足①

✤ 腎性尿崩症は長期にリチウムを摂取している患者の20～40％に合併しうる

Am  J  Kidney  Dis. 1987; 10(5): 329.

Nat  Rev  Nephrol. 2009; 5(5): 270.

✤ 腎機能障害はGFRの低下が0～5 ml/min/年 　程度の軽微なものとする報告もあれば、 　15年以上の長期投与群では末期腎不全に 　至った症例が増加したとする報告もある

Lancet. 1987; 10(5): 329.

Kidney  Int. 2010; 77: 219-24.

慢性リチウム中毒についての補足②✤ 甲状腺機能低下症は、約6倍の頻度で見られる ✤ 原発性副甲状腺機能亢進症合併の絶対リスクは、一般人口0.1％に比して、約10％とする報告がある

Lancet. 1987; 10(5): 329.

✤ リチウムを長期に投与する患者では、 1年に1回は少なくとも腎機能、TSH、血清カルシウム値を測定することが推奨されている (内分泌疾患の家族歴がある患者では、より頻回なフォローアップが推奨されている)

Lancet. 1987; 10(5): 329. National  Institute  for  Health  and  Clinical  Excellence. 2006: 1-31.

じゃあ、血中リチウム濃度と症状の関係は？

血中濃度と臨床症状、検査異常✤ 治療域の血中リチウム濃度は 　　　　　　　　　0.8～1.2 mEq/lとされる

Treat  Guidel  Med  Lett. 2006; 4(46): 35.

✤ 急性では、血中リチウム濃度と臨床症状 　　　　　　　　　検査異常との関連は乏しい - 血中濃度が治療域の患者が、嘔吐や徐脈など 重篤な臨床症状を合併した報告がある

Br  Med  J.  1978; 1(6116): 815.

Int  J  Clin  Pharmacol  Ther. 2011; 49(5): 336-8.

- 4 mEq/l以上にも関わらず、無症候の患者もいた

血中濃度と臨床症状、検査異常✤ 慢性では、血中リチウム濃度と臨床症状、 検査異常との関連があるとされる

Med  Toxicol  Adverse  Drug  Exp.  1988;3(1):18.

✴ Mild (1.5～2.0 mEq/l) 　傾眠、振戦、筋力低下、嘔気・嘔吐、下痢

✴ Moderate (2.0～2.5 mEq/l) 　昏迷、興奮、構音障害、失調、ミオクローヌス、心電図変化

✴ Severe (>2.5 mEq/l) 　昏睡、けいれん、失神

J  Am  Soc  Nephrol.  1999; 10: 666-674.

血中濃度と臨床症状、検査異常

✤ 　　　　では ✴ Mild (1.5～2.5 mEq/l)

　振戦、構音障害、軽度の嗜眠 ✴ Moderate (2.5～3.5 mEq/l)

　重度の嗜眠、粗大な振戦、ミオクローヌス ✴ Severe (>3.5 mEq/l)

　けいれん、非けいれん性てんかん重積

血中濃度と症状の現れ方には幅がある

ここで、もう1つのClinical Questionが

Clinical Question

「この患者さんでの治療は？」

NEW

リチウム中毒の治療

✤ 基本は輸液を含む支持療法 J  Am  Soc  Nephrol.  1999; 10: 666-674.

✤ 活性炭は無効 ✤ 急性中毒ではポリエチレングリコール (日本ではニフレック®) が有効だとする 　報告はあるが、慢性中毒では無効

Am  J  Med.  1994; 97: 383-389.

✤ 症例によっては血液浄化療法の適応がある

そもそも、血液浄化療法の有効性は？

✤ 低分子であり、蛋白結合能が低いことから 　血液浄化療法の良い適応である

J  Am  Soc  Nephrol.  1999; 10: 666-674.

✤ 正常腎で10～40 ml/分程度のクリアランスだが、透析療法では70～170 ml/分程度のクリアランスが得られる

Am  J  Med.  1994; 97(4): 383.

✤ 4時間の透析療法で、1 mEq/l程度低下する   Medical  Toxicology:  Diagnosis  and  Treatment  of  Human  Poisoning.  1997; p 1597.

血液浄化療法の適応

J  Am  Soc  Nephrol.  1999; 10: 666-674.

maintain a good level of urine output. While receiving normalsaline, patients must be monitored to prevent hypernatremia(2), especially in those with underlying diabetes insipidus.After stabilizing the patient, management shifts to increasing

lithium removal from the patient. In patients with normal renalfunction, the kidneys can clear lithium at a rate of 10 to 40ml/min (2). In theory, forced diuresis using normal salineshould increase lithium clearance by decreasing proximal re-absorption. However, clinical studies have shown no increasein lithium clearance with forced diuresis, except in patientswho present with true volume depletion (2). Thus, this therapyis not recommended. Another approach is the use of the cationexchange resin, sodium polystyrene sulfonate, to remove lith-ium in exchange for sodium (3,29). This approach has shownsome benefit in limited clinical studies (29). However, theeffectiveness of repeated doses has not been studied and mayproduce hypokalemia (4).

DialysisThe primary modality for removing lithium is hemodialysis.

Peritoneal dialysis clears only 9 to 15 ml/min of lithium and isnot recommended for treating lithium poisoning (2,3). Con-ventional hemodialysis can reduce plasma lithium by 1 mEq/Lper 4 h of treatment (3). High flux should be capable ofremoving more lithium per hour of hemodialysis, but publishedvalues are not available. The hemodialysis catheter should beleft in place because treatment must often be repeated sincehemodialysis does not clear intracellular lithium effectively.Thus, serum lithium levels often rebound after hemodialysis asthe intracellular lithium exits cells and reenters the blood-stream. Lithium levels may also rise in patients who ingested asustained-release lithium preparation due to continued lithiumabsorption from the GI tract. Thus, lithium levels must bechecked frequently, even after hemodialysis (3).

Indications for HemodialysisHemodialysis should be performed in any patient with lith-

ium intoxication who presents with coma, convulsions, respi-

ratory failure, deteriorating mental status, or renal failure (Ta-ble 4) (3). Hemodialysis should also be performed in anyonewhose lithium excretion is impaired (3); this is assessed bymeasuring serial lithium levels. If the lithium level fails todecrease despite conservative therapy, whether due to contin-ued GI absorption or diffusion of lithium from cells, thenhemodialysis should be performed (3). Another kinetic crite-rion for instituting hemodialysis is if more lithium can becleared by a single hemodialysis treatment than by the kidneysin 24 h (3).One should also strongly consider hemodialysis for any

patient on chronic lithium therapy with serum lithium levelsexceeding 4 mEq/L, or for patients with lithium levels between2.5 and 4 mEq/L who develop serious cardiac or neurologicsymptoms (3). Patients on chronic lithium therapy are at higherrisk for permanent deficits from lithium poisoning than patientswith acute poisoning since intracellular lithium levels arethought to be responsible for irreversible toxicity (4). Thus,acutely poisoned individuals may not need hemodialysis untillithium levels reach 6 to 8 mEq/L (3). Dialysis is rarelyindicted in patients with serum lithium levels below 2.5 mEq/L(3). However, several lithium levels must be measured as thelevel may rise after admission.A decision to initiate hemodialysis should be made approx-

imately 8 to 12 h after admission. This decision should bemade based on serial lithium levels, the level of renal function,and the patient’s overall clinical condition. Because hemodi-alysis is very effective at removing lithium from the blood andhas minimal side effects, it should be undertaken whenever thenephrologist has any doubts about not performing hemodialy-sis. Hemodialysis should be performed using a bicarbonatebath and not with an acetate bath, as lithium clearance fromintracellular stores is reduced when an acetate bath is used (2).A case report describes the use of a high phosphorus bath toprevent hypophosphatemia after hemodialysis for lithium in-toxication (30). Alternatively, serum phosphorus should bechecked after hemodialysis and hypophosphatemia correctedorally.After initiating hemodialysis, lithium levels must continue to

be checked frequently, because they often rebound. Typically,at least two hemodialysis treatments are necessary in patientsrequiring hemodialysis (2,3). Serum lithium levels can rise forup to 3 to 4 d after admission (31,32). In one case report,lithium levels began to increase after the patient was allowed toresume eating due to absorption of residual lithium from the GItract (32). These experiences emphasize the need for pro-longed, close monitoring of lithium-poisoned patients, espe-cially those receiving sustained-release lithium preparations(31,32).Continuous renal replacement therapies have been used on a

limited basis for treating lithium poisoning (33). Continuousarteriovenous hemodialysis and continuous venovenous hemo-dialysis can clear 60 to 85 L/d of lithium (33); their continuousnature decreases concerns about lithium rebound. Continuoustherapies do not reduce lithium levels as quickly as hemodial-ysis and are often limited by the need for anticoagulation. Theymay be particularly useful for patients with chronic poisoning

Table 5. Treatment of lithium poisoning

Protect oral airway if consciousness is impairedIntravenous normal saline if volume depletedWhole bowel irrigation with polyethylene glycolSodium polystyrene sulfonateHemodialysislithium level !6 mEq/L: any patientlithium level !4 mEq/L: any patient on chronic lithiumtherapy

lithium level between 2.5 and 4 mEq/L: any patient withsevere neurologic symptoms, renal insufficiency, orunstable hemodynamically or neurologically

lithium level "2.5 mEq/L: hemodialysis indicated only forpatients with end-stage renal disease or patients whoselithium levels increase after admission or who fail toreach a lithium level below 1 mEq/L in 30 h

Data from references 2 through 4.

J Am Soc Nephrol 10: 666–674, 1999 Lithium Intoxication 673

2.5～4 mEq/lでは、重度の神経症状、腎不全、不安定な 血行動態や神経症状があれば透析療法を施行するとある

血液浄化療法の適応✦ 血中リチウム濃度 > 4 mEq/l 　透析療法を施行 ✦ 血中リチウム濃度 > 2.5 mEq/l 　重度のリチウム中毒症状（けいれん、昏睡など） 　腎不全やその他リチウムの排泄遅延に関わる要因がある 　場合、非代償性心不全など大量輸液が困難な患者長期に 　リチウムを摂取している患者で透析療法を考慮 ✦ 血中リチウム濃度 < 2.5 mEq/l 　上記の濃度にも関わらず、中等度から重度のリチウム中毒 　症状がある場合は、中毒を専門とする医師と相談

✤ 血中リチウム濃度 < 4 mEq/l の症例では 　透析療法の適応はやや不明瞭 ✤ 本症例では、重度の神経症状はなく、入院後 　1 ml/kg/hrの尿量が得られたことから 　腎臓内科と協議し、緊急の透析療法を 　施行しない方針とした ⇨ 輸液をしながら、様子を見ていれば良い？ 　 血中リチウム濃度のフォローアップは？

本症例では…

血中濃度モニタリング✤ 血中濃度のピークは即放性製剤では1～2時間後 　徐放性製剤では4～6時間後とされる ✤ 過量内服の症例では、ピークが12時間後となる 　報告があり、注意が必要

J  Clin  Pharmacol. 1994; 34(4): 280.

Ann  Pharmacother. 1996; 30(4): 356.

✤ 血中リチウム濃度はピーク値を確認するまでは 　2～4時間ごとに測定を繰り返し、ピークを 　むかえた後は、6～12時間ごとの測定が 　望ましいとされる

✤ 本症例では、血中リチウム濃度は来院時を 　ピークに低下し第3病日にはミオクローヌス 　は消失し、第6病日頃から幻聴や視線恐怖等 　の精神症状の改善が見られた ✤ 神経・精神症状の後遺症なく、退院

その後…

終わり 最後までありがとうございました