ESPEN Congress Vienna Neglected deficiencies in severe malnutrition: Commentary - Thiamine. E. Doberer (Austria)

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1 ESPEN Congress Vienna 2009 Neglected deficiencies in severe malnutrition: Commentary - Thiamine E. Doberer (Austria)

2 Neglected deficiencies in severe malnutrition: Commentary - Thiamine Edith Doberer Department of Medicine III Medical University Vienna

3 Thiamine Water-soluble vitamin Sources: yeast, pork, rice, cereals Normal serum levels 1,1-1,6 mg/dl Requirements: continuous supplementation required 1,1 mg 1,2 mg/day (0,5 mg per 1000 kcal) 1,4 mg/day pregnancy, lactation

4 Thiamine Metabolism absorbed in small intestine highest concentration in skeletal muscle, liver, heart, kidney, brain excreted in urine (increased loss in loop-diuretic treated patients) Actions: Cofactor for enzymes involved in amino-acid and carbohydrate metabolism Pyruvate dehydrogenase: pyruvate acetyl-coa + CO 2 Transketolase α ketoglutarate dehydrogenase: α ketoglutarate succinyl CoA + CO 2

5 Thiamine deficiency: epidemiology Lindboe CF et al; J Neurol Sci autopsies 52 cases of Wernicke encephalopathy 23 % in non-alcoholics 4 cases clinically diagnosed (all in alcoholics) Prevalence: Necropsy studies: 0,8 2,8 % Prevalence of WE lesions on autopsy of alcoholics: 12,5 % Clinically diagnosed: 0,004 0,13 % Predisposition in female patients Mortality: untreated: 100 % treated: %

6 Thiamine deficiency: population chronic alcoholism (80 %) extracorporeal renal replacement therapy: hemodialysis, peritoneal dialysis Hyperemesis gravidarum, Anorexia nervosa, dieting, prolonged fasting Systemic malignancies Acquired immunodeficiency syndrome Bariatric surgery (Jiang W et al; Am J Psychiatry 2006) within 3-6 months after surgery risk factor: persistent vomiting, rapid weight reduction

7 Thiamine deficiency and unexplained encephalopathy in hemodialysis patients Hung SC et al. Am J Kidney Dis dialysis patients with unexplained encephalopathy diverse clinical symptoms (convulsions, acute visual loss) 5 patients on regular thiamine supplementation (5 mg/die) Laboratory testing: significant low thiamine levels low serum albumin and blood urea nitrogen levels prompt recovery following thiamine supplementation

8 Hyperemesis gravidarum complicated by Wernicke Encephalopathy: case report and review Chiossi G et al. Obstet Gynecol Surv 2006 Combination of poor nutritional intake frequent vomiting increased metabolic demands Mean gestational age: 14,3 ± 3,4 weeks Mean duration of vomiting: 7,7 ± 2,8 weeks Classical triad 46,9% Complete remission rare Pregnancy loss rate: 47,9% Thiamine deficiency often aggravated by hyperthyroidism Symptoms triggered by iv administration of glucose Prophylaxis: vomiting > 3 weeks or prior to administration of parenteral glucose

9 Urinary loss of thiamine is increased by low dose of furosemid in healthy volunteers Rieck J et al. J Lab Clin Med 1999

10 Thiamine deficiency: congestive heart failure Heart failure: elderly patients Inadequate nutrient intake Thiamine deficiency impairs cardiac function Chronic use of (loop) diuretics Prevalence of thiamine deficiency in HF: Zenuk C et al; Can J Clin Pharmacol 2003 Seligmann H et al; Am J Med % (depending on loop diuretic dosage) Improving left ventricular function upon thiamine supplementation Shimon I et al; Am J Med mg thiamine/day for 6 weeks Significant increase of LVEF and diuresis

11 Thiamine deficiency: three disorders Wernicke-Korsakoff syndrome Wernicke encephalopathy (WE): acute neurologic syndrome unless prompt treatment, leading to death or severe neurologic morbidity genetic predisposition Korsakoff syndrome chronic neuropsychiatric condition consequence of WE or slowly developing chronic disease Beriberi (infantile, adult) dry: symmetrical peripheral neuropathy (sensory + motor) of mostly distal extremities wet: neuropathy + signs of cardiac involvement (congestive heart failure, edema etc) Leigh`s syndrome rare, subacute necrotizing encephalomyopathy ataxia, dysarthria, movement disorders

12 Thiamine deficiency: diagnosis 4. Brain Imaging MRI > CT Verification of diagnosis 3. Laboratory testing 2. Clinical signs Classical triad: oculomotor disorders, gait ataxia, desorientation 1. Case history alcoholism, malnutrition, hyperemesis gravidarum, bariatric surgery, weight loss, malignancies, dialysis treatment, etc

13 Thiamine deficiency: Diagnosis Classical triad 1. Encephalopathy (mental status changes): mild delirium global confusion - coma 2. Oculomotor disorders Nystagmus (usually horizontal) Ptosis Papilledema 3. Gait ataxia Mild gait disturbance inability to stand Other clinical signs: Cardiac failure (typically high output) Gastrointestinal complaints (nausea, vomiting) Vestibular dysfunction, deafness

14 Clinical signs in the Wernicke Korsakoff complex Harper CG et al. J Neurol Neurosurg Psychiatry 1986 mental >> eye > ataxia mental/ataxia > mental/eye > eye/ataxia

15 Operational criteria for the classification of chronic alcoholics: identification of Wernicke's encephalopathy Caine D et al. J Neurol Neurosurg Psychiatry 1997 Caine criteria 1. Dietary deficiency (BMI, history of impaired dietary intake) 2. Oculomotor abnormalities (ophthalmoplegia, nystagmus) 3. Cerebellar dysfunction (ataxia or unsteadiness) 4. Altered mental status or mild memory impairment Diagnosis of WE: 2 criteria positive Sensitivity: Classical triad => 22% Caine criteria => 85 %

16 Thiamine deficiency: Diagnosis Laboratory testing Time consuming (several days) and unavailable in most healthcare settings Sensitivity and specificity of tests unclear Blood thiamine concentration Erythrocyte thiamine transketolase (ETKA) before and after addition of thiamine pyrophosphate (TPP) Low ETKA plus 25 % stimulation by TPP => thiamine deficiency Cerebrospinal fluid: normal

17 Severe lactic acidosis related to acute thiamine deficiency Oriot D et al; JPEN 1991 Thiamine deficiency pyruvate pyruvate dehydrogenase acetyl-coa citrate synthase oxaloacetate Citric acid cycle citrate lactatedehydrogenase Cofactor: thiamine pyrophosphate lactate

18 Lactic acidosis in thiamine deficiency Madl C et al. Clin Nutr 1993

19 Thiamine deficiency: Diagnosis Brain imaging CT: low-density abnormalities in the paraventricular regions of the thalamus (enhancement by contrast) Sensitivity: 13 % MRI Abnormal hyperintensity of the mamillary bodies and periaqueductal grey matter Sensitivity 53%, Specificity 93 % Antunez et al; Am J Roentgenol 1998

20 Thiamine deficiency: diagnosis Consideration of diagnosis => initiate treatment undiagnosed mental status, coma, oculomotor disorders or ataxia 100 mg thiamine for 5-7 days parenteral administration: intravenous or intramusculary intestinal absorption unpredictable in malnourished patients and alcoholics Administration of thiamine prior to glucose Continue daily oral administration of 100 mg thiamine No toxicity described Single vitamin deficiency is rare! simple, safe, inexpensive and effective

21 Thiamine deficiency: treatment Clinical course following appropriate treatment: Improvement of clinical signs 1. ocular signs: hours-days => 2. gait ataxia: days weeks => 3. Confusion: weeks MRI: abnormalities of diffusion-weighted imaging become normalized with therapy (48 hours) Chu K et al; Arch Neurol 2002 Prognosis Mortality % Residual deficits despite appropriate treatment 60% nystagmus or ataxia

22 Conclusion 20 % NON-alcoholics acute onset of neurologic symptoms of unknown origin in malnourished patients => consider thiamine deficiency Clinical diagnosis verification of diagnosis with laboratory testing and brain imaging Therapy is safe, easy, inexpensiv Do`s and Dont`s: administer thiamine upon suspicion of thiamine deficiency avoid glucose administration prior to thiamine administration in a thiamine deficient state

23 Thiamine deficiency: pathology Acute WE lesions: Vascular congestion Microglial proliferation Petechial hemorrhages Chronic Korsakoff lesions: Demyelination Gliosis Neuronal loss, atrophy of mamillary bodies Exact pathophysiology unclear: Blood-brain barrier breakdown NMDA receptor mediated excitotoxocitiy Increased reactive oxygen species