Short Communication - Neuropsychiatry (2016) Volume 6, Issue 6
Hypothyroidism exacerbating valproate induced hyperammonemic delirium, an unknown clinical concern: Short communication
- Corresponding Author:
- Chung-Chieh Hung, MSc
Department of Psychiatry
China Medical University Hospital, Taichung, Taiwan
Tel: +886-921-067260
Fax: +886-4-22361042
Abstract
From the literature reviews, valproic acid (VPA) induced hyperammonemia is a commonly adverse event and usually asymptomatic. VPA is a well-tolerated and an effective agent for the treatment of epilepsy, bipolar disorder, schizoaffective disorder, off-lable use for the impulsive control problems and etc. However, several case reports have indicated that VPA may induce serious symptomatic hyperammonemia and even lethal. Based on the analysis of susceptible patients, several possible mechanisms and risk factors have been proposed to identify the patients at risk.
Keywords
Delirium, Hypothyroidism, Hyperammonemia, Valproate
Introduction
The hypothyroidism is differentiated preliminarily as primary, secondary and tertiary etiologies according to the causative reasons [1]. Each of the above condition may contribute to neurological and psychiatric manifestations [2]. When the patients suffer from the hypothyroidism, they are easier to be found with anxiety, depression, cognitive and executive dysfunction. These neurological and psychiatric symptoms are more likely to occur in the elderly group [3].
Although it is well known that valproic acid (VPA) can induce hyperammonemia [4], scanty reports concerned of its association or relationship with the hypothyroidism. In the previous case report [5], we presented a bipolar affective patient with hypothyroidism (in fact, merely subclinical hypothyroidism) who experienced from the delayed hyperammonemic delirium during VPA treatment.
In this following reviewed article, we searched for the literature for the VPA-induced consciousness disturbance. In addition, we also updated the delirium cases resulted from hypothyroidism. The aim of this short communication is to address the important issues for the VPA treated patient in the neurological and psychological setting. We should be highly alert when they had the underlying hypothyroidism even merely subclinical.
When the patients have the concomitant clinical pictures, they are prone to suffer from lethal side effect of consciousness disturbance.
Discussion
VPA induced hyperammonaemia can be either asymptomatic or symptomatic. The prevalence of such adverse event remains mysterious but rare in the adulthood population [6]. In addition, it may occur with both therapeutic and supratherapeutic concentrations of the serum VPA drug level, indicating other influence of potential risk factors. The patients who have been on VPA for several years without developing any complications can suddenly develop symptoms of encephalopathy. The acute (outlined in Table 1) [7-14] and the delayed [5] effects of VPA induced hyperammonemia are all documented. Nevertheless, nearly all reports reveal and discuss about the acute onset adverse events. This communication summarized the acute effect cases of VPA induced hyperammonemia in the Table 1. These cases are revealed the onset from 2 days to 10 days. We only found one case report [5] about the delayed onset VPA induced hyperammonemia with the occurrence 4 years later. Though these adverse events are well reviewed, only one retrospective study [15] examines the causative relationship. In the above study, adult patients in the psychiatric setting are treated with a mood stabilizer and checked for hyperammonemia. The 51.2% of the patients receiving VPA (N=123) had asymptomatic hyperammonemia (level >97 μg/dl) [15].
| Authors | Sex | Age | Diagnosis | Substance | Exposure | Symptoms | Recovery | Valproate acid | Elevated ammonia | Co-medications | Image study | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose | level | Level | ratio | ||||||||||
| Settle EC [7] | ♀ | 57 | BD | BZD | 7 days | Coma | <5 days | N/A | 67 | 134 | 1.9 | Clonazepam | Generalized slowing EEG |
| RabyWN[8] | ♀ | 24 | BPD, MDD |
BZD | 10 days | Fatigue, lethargy, nausea | 10 days | 750 | 89.9 | 173 | 2.9 | Clonazepam, Liothyronine, Thioridazine, Tranylcypromine |
None |
| Eze et al. [9] | ♀ | 69 | BD | BZD | 4days | Coma | 5 days | 750 | 107.2 | 244 | 3.1 | Alprazolam, Clonidine, Hydrochloride, Meclizine, Nabumentone, Sertraline, Trazodone, Trimipramine |
Normal brain CT |
| Pannikkar andGilman[10] | ♀ | 53 | BD | Alcohol | 10 days | Lethargy, confusion | 3 days | 1750 | 107 | 135 | 2.2 | Benztropine, Haloperidol |
None |
| Pannikkar andGilman (1999)[10] | ♀ | 23 | SCZA | Alcohol, cocaine |
14 days | Confusion | 2 days | 1500 | 70 | 329 | 5.5 | Olanzapine | None |
| Stewart JC [11] | ♂ | 79 | SCZ, epilepsy | None | 2 days | Lethargy, confusion | 4 days | 2250 | 48500 | 152 | 2.2 | Amlodipine, Aspirin, Finasteride, Olanzapine, Phenytoin, Risedronate |
None |
| Eubanks et al. [12] | ♀ | 33 | BD, BPD, PTSD | BZD | 3days | Confusion | 3 days | 1500 | 120 | 482 | 9.5 | Bupropion, Clonazepam, Hydroxyzine, Mirtazapine, Venlafaxine, |
Normal brain CT |
| Hung. et al. [13] | ♀ | 21 | SCZA | None | 4 days | Vomiting, confusion, ataxia | 2 days | 750 | 107.7 | 228 | 3.3 | None | Intermittent slowing EEG |
| Anupama[14] | ♂ | 46 | BD | None | 18 days | Confusion, lack of orientation | 6 days | 1000 | N/A | 92 | 2.5 | Lorazepam | None |
| ♂ | 53 | BD | None | 2 days | Confusion, lack of orientation, impaired memory | 3 days | 1000 | N/A | 147 | 4.1 | Olanzapine, Lorazepam | None | |
| ♀ | 36 | BD | None | 2 days | Drowsy, loss of consciousness | 3 days | 600 | N/A | 77 | 2 | Lithium, Lorazepam | None | |
Abbreviation: BD: bipolar disorder, BPD: borderline personality disorder, BZD: benzodiazepine, CT: computed topography, EEG: electroencephalogram, MDD: major depressive disorder, PTSD: posttraumatic stress disorder, SCZA: schizoaffective disorder, SCZ: schizophrenia. Valproic acid dose is expressed as mg/d and its levelμg/ml. Elevated ammonia level is expressed asμg/dL.
Table 1: Acute effect cases of VPA induced hyperammonemia.
To the best of our knowledge, one of the reviewed articles reveals and summarizes the neuropsychiatric symptoms as well as the tentative risk factors led to the mechanism of VPA induced hyperammonemia [6]. Regarding the proposed mechanism of action, the animal studies convince in both the role of kidney and liver for the underlying cause [16,17]. The animal model of kidney and the renal uptake of glutamine which increases the serum ammonia would be dangerous to be hyperammonemic [16]. The other potential mechanisms within the liver lead to hyperammonemia. The description of the underlying biochemical pathway shows that the VPA is believed to increase the ammonia by reducing the free carnitine and co-enzyme A. Nevertheless, loss of carnitine prevents importation of long-chain fatty acids into the mitochondrial matrix for metabolism. Loss of co-enzyme A prevents the beta-oxidation of fatty acids into acetyl-co-enzyme A, which is a substrate of N-acetylglutamate, the required activator of the initial enzyme in the urea cycle.
Therefore, the increased ammonia level affects the urea cycle inside the hepatocytes. There is an association between VPA induced hyperammonemia, consciousness disturbance and genetic impairment in the urea cycle [18]. The risk factors exist that urea cycle disorders, infancy (immature hepatic function), carnitine deficiency due to either genetic abnormalities or dietary restrictions [18] effects of nutritional intake such as higher nitrogen load [19], or possibly increased carbohydrate intake [20], polypharmacy, and complicating medical conditions.
We could take a look at the Table 1 [7-14] and summarized the demographic data of the currently acute VPA induced hyperammonemia. We deduced that the other factors that few study notified about the brain image studies. From our review, some cases with VPA induced hyperammonemia are revealed generalized slowing and intermittent slowing electroencephalogram (EEG). As the authors of the reviewed literatures suggest that the patients with pre-existing epilepsy would have their EEG pronounced general slowing, an increase in epileptiform discharges [17]. The unknown pathology inside the brain via EEG testing could be one of mechanism or even consequences of VPA induced hyperammonemia. However, the systematic study of the EEG of the patients without epilepsy but suffering from VPA induced hyperammneomia is lacking.
From the Table 2 [5,21,22], we searched for the three case reports excluding the Hashimoto thyroiditis. We compared the difference among the hypothyroidism cases with consequent consciousness disturbance. As the case [22] demonstrates the relationship between the enzymatic activity of thyroid hormone and the urea cycle enzymes. The passage emphasizes the hyperammonemia associated with hypothyroidism. On the other sides, the case [21] argues that hyperammonemia in the hypothyroidism may be explained by the pathophysiological studies of the urea cycle, especially from the rat liver model. Hence the hyperammonemia occurs on the consequence of discontinuation of levothyroxine and improves after the supplement of the levothyroxine. The current study [5] connects the risk factors of hyperthyroidism and VPA long time therapy in the role of hyperammonemia. We could find out that all these three cases all had the delayed onset consciousness disturbance related to hypothyroidism.
| Authors | Age | Sex | Aggravatingfactor | Onset (years) |
Psychiatric Disease | Neurological outcome | Brain Image |
|---|---|---|---|---|---|---|---|
| DoronRimar et al. [21] | 82 | ♀ | Levothyroxine discontinuation | 10 | None | Coma | High intense globuspallidus and hypothalamus in brain MRI-T1 |
| Seiji Hitoshi et al. [22] | 53 | ♀ | Portal-systemic encephalopathy | 2 | None | Slow speech and intermittent coma | Generalized slowing and triphasic waves |
| Hung C.C. et al. [13] | 41 | ♀ | Valproicacid association | 4 | Bipolar disorder | Delirium | Normal brain CT |
CT: computed topography, EEG: electroencephalogram, MRI: magnetic resonance image
Table 2: Co-morbid hypothyroidism (exclusions of Hashimoto’s thyroiditis) and consciousness disturbance reviewed case series.
The mechanism may be competition between VPA and thyroid hormones [23]. On the other side, VPA treatment didn’t always alter thyroid hormones in another study [24]. More investigation such like cohort study or clinical trials are suggested while the results are controversial.
Conclusions
The exact mechanism of hypothyroidism aggravating VPA induced hyperammonemia remains unknown but still reminds us of a clinical concern. Thyroid hormones are hypothesized to regulate hepatic mitochondrial catabolism [25]. The competition between thyroid hormone and VPA would influence the uric cycle and hence hyperammonemia occured. From the above summary, hypothyroidism could mandate for decompensating liver diseases, hyperammonemia from the production of urea cycle (although obviously in rat but not human), or inefficient urea synthesis.
To answer such clinical concern, we presumed that VPA probably competed with thyroid hormones. Frankly speaking, VPA might be the consequence of hypothyroidism and hypothyroidism predisposed to the hyperammonemia. Besides, the summation of the two risk factors of the hyperammonemia would make this clinical situation worse.
Undoubtedly, we should be more cautious while prescribing VPA in patients with hypothyroidism, even merely subclinical hypothyroidism in our previous case report.
Acknowledgement
This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW105- TDU-B-212-133019).
References
- Querido A, Stanbury JB. The response of the thyroid gland to thyrotropic hormone as an aid in the differential diagnosis of primary and secondary hypothyroidism. J. Clin. Endocrinol. Metab10(10), 1192-1201 (1950).
- Martin JM, Stanbury JB. The response of the I131-treated thyroid gland to thyrotropic hormone. J. Clin. Endocrinol. Metab15(7), 811 (1955).
- Davis JD, Tremont G. Neuropsychiatric aspects of hypothyroidism and treatment reversibility. Minerva. Endocrinol32(1), 49-65 (2007).
- Lewis C, Deshpande A, Tesar GE, et al.Valproate-induced hyperammonemic encephalopathy: a brief review. Curr. Med. Res. Opin28(6), 1039-1042 (2012).
- Hung CC, Lin CH, Lane HY. Hypothyroidism may exacerbate valproate-related hyperammonemic delirium. Biomedicine (Taipei) 6(2), 12 (2016).
- Carr RB, Shrewsbury K. Hyperammonemia due to valproic acid in the psychiatric setting. Am. J. Psychiatry 164(1), 1020-1027 (2007).
- Settle EC, Jr. Valproic acid-associated encephalopathy with coma. Am. J. Psychiatry152(8), 1236-1237 (1995).
- Raby WN. Carnitine for valproic acid-induced hyperammonemia. Am. J. Psychiatry154(8), 1168-1169 (1997).
- Eze E, Workman M, Donley B. Hyperammonemia and coma developed by a woman treated with valproic acid for affective disorder. Psychiatr. Serv49(10), 1358-1359 (1998).
- Panikkar GP, Gilman SM. Valproate-induced hyperammonemia in the psychiatric setting: 2 cases. J. Clin. Psychiatry60(8), 557-559 (1999).
- Stewart JT. Treatment of valproate-induced hyperammonemia. J. Am. Geriatr. Soc53(6), 1080 (2005).
- Eubanks AL, Aguirre B, Bourgeois JA. Severe acute hyperammonemia after brief exposure to valproate. Psychosomatics 49(1), 82-83 (2008).
- Hung CC, Li TM, Wei IH, et al. The real mechanism of VPA-induced hyperammonemia remains unknown. Gen. Hosp. Psychiatry33(1), 84. e3-4 (2011).
- Muraleedharan A, Palappallil DS, Gangadhar R, et al.Valproate Induced Hyperammonemic Delirium. J. Clin. Diagn. Res9(12), FR01-FR03 (2015).
- Raja M, Azzoni A. Valproate-induced hyperammonaemia. J. Clin. Psychopharmacol22(1), 631 (2002).
- Elhamri M, Ferrier B, Martin M, et al.Effect of valproate, sodium 2-propyl-4-pentenoate and sodium 2-propyl-2-pentenoate on renal substrate uptake and ammoniagenesis in the rat. J. Pharmacol. Exp. Ther266(1), 89-96 (1993).
- Verrotti A, Trotta D, Morgese G, et al.Valproate-induced hyperammonemic encephalopathy. Metab.Brain. Dis17(4), 367-373 (2002).
- Raskind JY, El-Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann. Pharmacother34(5), 630-638 (2000).
- Laub MC. Nutritional influence on serum ammonia in young patients receiving sodium valproate. Epilepsia 27(1), 55-59 (1986).
- Warter JM, Marescaux C, Chabrier G, et al.Increase of valproate-induced hyperammonemia in normal subjects by carbohydrate intake. Neurology34(11), 1487-1489 (1984).
- Rimar D, Kruzel-Davila E, Dori G, et al.Hyperammonemic coma-barking up the wrong tree. J. Gen. Intern. Med 22(4), 549-552 (2007).
- Hitoshi S, Terao Y, Sakuta M. Portal-systemic encephalopathy and hypothalamic hypothyroidism: effect of thyroid hormone on ammonia metabolism. Intern. Med32(8), 655-658 (1993).
- Benedetti MS, Whomsley R, Baltes E, et al. Alteration of thyroid hormone homeostasis by antiepileptic drugs in humans: involvement of glucuronosyltransferase induction. Eur. J. Clin. Pharmacol61(12), 863-872 (2005).
- Isojarvi JI, Turkka J, Pakarinen AJ, et al.Thyroid function in men taking carbamazepine, oxcarbazepine, or valproate for epilepsy. Epilepsia 42(7), 930-934 (2001).
- Tajiri J, Shimada T, Naomi S, et al.Hepatic dysfunction in primary hypothyroidism. Endocrinol. Jpn 31(1), 83-91 (1984).