Case Discussion < Brief History >     A 55-year-old woman who has had bipolar disorder with regular medical control with Depakine for 7 years presented with easy fatigability, thirsty, urinary frequency, diuresis, and tremor over bilateral hands one month earlier before admission. The daily urine amount could reach 3 liters. Her family also noted that her consciousness became drowsy gradually one week prior to this admission. Two days before admission, she was found to have incoherent speech, unsteady gait and weird behaviors such as treating kitchen as restroom or going out without clothes. Because of these strange behaviors, her family increased the drug dosage because they thought the drug level was not adequate. However, these weird symptoms became worse. She was brought to our emergency service. At the emergency service, she was in delirium status and the Glasgow coma scale was E2M4V3. Her body temperature was 37.4 oC, blood pressure 144/84 mmHg, and pulse rate was 112 beat per minute. Upon physical examinations, skin turgor was poor and oral mucosa was dry. There was no focal neurologic deficit or other abnormal physical findings. < Laboratory and Image Study >  1. CBC/DC & coagulation profiles: Day after admission WBC K/μL Hgb g/dL Hct % MCV fL Plt K/μL 0 7.51 11.8 35.4 92.3 470 2nd 7.33 11.3 34.0 92.2 461 5th 7.22 11.1 33.9 92.2 458 2. Biochemistry Day after admission BUN mg/dl Cre mg/dl Na mmol/l K mmol/l GOT U/l T-Bil mg/dl Alb g/dL Li mmole/l 0 39.8 2.9 130 3.5 34 0.8 3.8 3.48 2nd 39.7 2.8 132 3.7       3.34 3rd 25 2.0 135 3.8       1.85 5th 25.4 2.1 138 4.1 33 0.9   2.18  3. Urine analysis: Day after admission Appearance Sp. gr pH Protein mg/dL Glu g/dL Ketones O.B Urobil EU/dL Bil 0 Y;C 1.05 7.0 － － － － 0.1 － 3rd Y;C 1.05 7.0 － － － － 0.1 － Day after admission Nitrite WBC RBC /HPF WBC /HPF EpithCell /HPF Cast /LPF Crystal Bact   0 － － 0-1 0-1 0-3 － － － 3rd － － 0-1  0 3-5 － － － 4. Artery blood gas: PH:7.36, PaCO2: 42.3, PO2: 95, HCO3-: 22.6 5. EKG: Normal sinus rhythm 6. CXR: Normal heart size and clear lung fields. 7. Renal echo:  Size R't 10.3 cm ; L't 10.9 cm Shape Bilaterally normal Cortical thinkness R't: 8 mm; L't: 9 mm (within normal limit) Central sinus No hydronephrosis Solid or cystic lesion Nil   < Course and Treatment >      Based on the history, lithium (Li) intoxication was suspected. The patient was treated with fluid replacement and the Li level was checked with a level of 3.48 mmole/l. Besides, acute renal failure was also noted. Because this patient already had CNS depression and acute renal failure, hemodialysis was initiated immediately. After emergent hemodialysis, her consciousness improved gradually with decreases of Li levels. Because a rebound of Li concentration after hemodialysis was not uncommon, she was weaned from hemodialysis gradually after Li levels was stablized. She was then transferred back to the local hospital one week after admission. During the follow-up period, her renal function returned to normal, and there was no neurologic sequelae. < Analysis >            Lithium (Li) is am important treatment for bipolar disorders, but this therapy is associated with many side effects due to its narrow therapeutic range. The side effects mainly involve the kidneys and central nervous system (CNS). The therapeutic dose is 300-2700 mg/d with desired serum levels of 0.7-1.2 mEq/L. Li is minimally protein bound and its clearance is predominantly through the kidneys. Li 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 Li therapy. Most filtered Li is reabsorbed in the proximal tubule and enhanced reabsorption of Li when patients are hyponatremic and volume depleted. Toxicity does not necessarily correlate with the measured Li level because toxicity is affected by the nature and type of the poisoning. Acute poisoning is due to voluntary or accidental ingestion in a previously untreated patient; acute-on-chronic poisoning is due to voluntary or accidental ingestion in a patient currently using lithium; and chronic or therapeutic poisoning is progressive lithium toxicity, generally in a patient on lithium therapy.       The clinical symptoms of Li intoxication are non-specific initially, and CNS symptoms develop subsequently, such as nausea, vomiting, diarrhea, weakness and fatigue, lethargy and confusion, tremor and finally seizures. Measurement of serum Li concentration should be performed if any degree of toxicity is suspected; however, the suspicion of toxicity should be high in any patient with known Li use because early toxic symptoms are very vague and nonspecific. A second serum Li level measured 2 hours after the first may disclose any trend and sustained-release Li preparations may take several hours to reach peak concentrations. Electrolyte disturbances, particularly hyponatremia, may predispose an individual to Li toxicity. Li toxicity is one of the few clinical entities that may be associated with a decrease in the anion gap. Treatment for Li intoxication is to enhance elimination by volume resuscitation with normal saline or one-half isotonic sodium chloride solution and hemodialysis. Continuous venovenous hemodiafiltration also effectively removes Li and can prevent post-dialysis rebound. In general, dialysis should be considered in patients with chronic toxicity and serum lithium concentrations higher than 4 mEq/L and in unstable chronic patients with lithium levels higher than 2.5 mEq/L. However, guidelines for hemodialysis are controversial in patients with acute lithium intoxication and hemodialysis is generally suggested in patients with higher serum lithium levels despite relatively minor symptoms. Change in mental status assists in determining need for dialysis.     Li may produce nephrogenic diabetes (NDI), renal tubular acidosis, chronic interstitial nephritis and even nephrotic syndrome. In our patient, she suffered from Li-induced polyuria, but it improved gradually before we tested the response to exogenous antidiuretic hormone (ADH). Most patients with Li-induced polyuria are unresponsive to exogenous ADH treatment as a result of abnormalities in the medullary osmotic gradient or direct inhibition of the tubular hydro-osmotic effects of ADH. Chronic administration of Li diminishes the medullary and papillary osmolar gradients as a result of depletion of urea without affecting sodium chloride concentrations. However, Li-induced polyuria is largely due to direct inhibition of the ADH-dependent aspects of water conservation. Although Li-induced NDI usually improves after Li withdrawal, some patients still have persistent concentrating defect for several years. Amiloride rduces urinary volume and enhances the concentrating ability of patients with Li-induced NDI.   < Reference >     Harrison's principles of internal medicine 15 edition Primer on Kidney Disease, 4th edition Optimizing lithium treatment. J Clin Psychiatry. 2000;61 Suppl 9:76-81 eMedicine, Toxicity, Lithium, Last Updated: June 13, 2006                繼續教育考題 1. (C) 一般在已使用Li鹽治療的病患，造成Li intoxication的原因以何居多？ A  Acute intoxication B  Acute on chronic intoxication C  Chronic intoxication D  All of above 2. (D) 可能增加 Li intoxication的原因包括？ A  Impaired renal function B  Dehydration C  Larger dosage prescription D  All of above 3. (C) 有關 Li intoxication 的症狀何者錯誤？ A  Non-specific initially B  Kidney and CNS are involved mainly C  Acute hepatic failure D  Seizure may occur 4. (B) 對Li intoxication的描述何者錯誤？ A  Mainly Kidney and CNS are involved mainly B  Serum Li level correlates with toxicity well C  It might lead to nephrotenic diabetic insipidus (NDI) D  Hyponatremia will potentiate Li toxicity 5. (D) Li intoxication對kidney常見的影響不包括? A  Nephrogenic diabetic insipidus B  Acure renal failure C  Chronic interstitial nephritis D  Papillary necrosis 6. (C) 何者不是Li intoxication 的標準治療？ A  Normal saline infusion to prevent dehydration and hyponatremia B  Hemodialysis C  Plasmaphereis D  All of above 答案解說 (C) Generally, Li intoxication usually develops in patients are already under regular Li therapy, like this case. Chronic or therapeutic poisoning: Progressive lithium toxicity, generally in a patient on lithium therapy. (D)  1) Li 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 Li therapy. 2) Hyponatremia may predispose an individual to Li toxicity, because proximal tubules will enhance Na resorption in hyponatremia and Li will compete with Na for reabsorption. (C)  The clinical symptoms of Li intoxication are non-specific initially and then CNS symptoms develop subsequently, such as nausea, vomiting, diarrhea, weakness and fatigue, lethargy and confusion, tremor and finally seizure. The side effects mainly involve kidneys and CNS. (B)  Toxicity does not necessarily correlate with the measured Li level because toxicity is affected by the nature and type of the poisoning. The side effects mainly involve kidneys and CNS. In kidney, Li may produce nephrogenic diabetes (NDI), and hyponatremia will enhance Li reabsorption. (D)  In kidney, Li may produce nephrogenic diabetes (NDI), renal tubular acidosis, chronic interstitial nephritis and even nephrotic syndrome. (C) Treatment for Li-intoxication is to enhance elimination by volume resuscitation with normal saline or one-half isotonic sodium chloride solution and hemodialysis. Continuous venovenous hemodiafiltration also effectively removes Li.