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Paradoxical Increase of Plasma Vitamin B12 and Folates with Disease Severity in Anorexia Nervosa

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Paradoxical Increase of Plasma Vitamin B12 and Folates with Disease Severity in Anorexia Nervosa EMPIRICAL ARTICLE Paradoxical Increase of Plasma Vitamin B12 and Folates with Disease Severity in Anorexia Nervosa Fabiola Corbetta, MD1 ABSTRACT values were found in 55 and 20% of 2 Objective: Anorexia nervosa (AN) is a patients, respectively, a linear correlation Lucio Tremolizzo, MD, PhD complex disorder involving severe psy- with both transaminases was present 2 Elisa Conti, PhD chological manifestations and multiple only for vitamin B12 and folates; further- Carlo Ferrarese, MD, PhD2 organ damage, including liver dysfunc- more, H-B12 patients had both higher 1 tion. The primary aim of this study con- AST and ALT values. EDI- 3 subscores sig- Francesca Neri, PrD sisted in assessing plasma levels of nificantly correlated with vitamin B12 and 1 Monica Bomba, MD vitamin B12 and folates with respect to folates plasma values and H-B12 patients Renata Nacinovich, MD1* liver function enzymes considering the displayed EDI-3 higher values. liver-storage properties of this vitamin. Discussion: These data suggest that Method: We recruited 70 restrictive plasma levels of vitamin B12 might be an type AN adolescents and the severity early marker of liver dysfunction, possibly of psychopathological traits was also related to more severe psychopatho- assessed using EDI-3 scale. Plasma lev- logical aspects. The identification of els of vitamin B12, folates, transami- patients with higher fasting plasma vita- nases (AST, ALT), gamma-glutamyl min B12 levels could therefore lead to transpeptidase (GGT), alkaline phospha- earlier and more careful refeeding inter- tase (ALP) and cholinesterase (CHE) ventions. Further studies will clarify the were determined. potential role of this vitamin in AN clini- cal practice. VC 2014 Wiley Periodicals, Inc. Results: About 38.5% of patients dis- played vitamin B12 values (H-B12) above Keywords: anorexia nervosa; vita- the upper range of normal reference; min B12; adolescents; liver dysfunc- 4.3% of patients had increased values of tion; transaminases folates; 20 and 11.4% of patients dis- played ALT and AST values above refer- (Int J Eat Disord 2015; 48:317–322) ence limits; none had GGT values above normal range. Albeit low CHE and ALP Introduction with a peak of incidence in adolescence, and is especially alarming given the associated consider- Anorexia nervosa (AN) is a common eating disor- able mortality rate,2 and other medical complica- der (ED) which presents as a complex psychiatric 3,4 tions. Moreover, refeeding syndrome poses condition associated with severe loss of weight and additional risk to AN patients as a relevant meta- excessive concern about body weight and shape bolic disturbance to nutritional rehabilitation.5,6 In with, sometime, weight-regulatory behaviors. The particular, refeeding-associated liver steatosis with prevalence in young females is relatively high,1 increased expression of associated markers is a problem often encountered in clinical practice.7 Accepted 31 October 2014 Interestingly, more than 10% of AN patients show Supported by University of Milano-Bicocca, Italy. disease-related elevation of aminotransferases.5 Fabiola Corbetta and Lucio Tremolizzo contributed equally to the present work. This abnormality is usually asymptomatic and self- *Correspondence to: Renata Nacinovich, MD, University of limiting, but some cases of acute liver failure have Milano Bicocca, Child and Adolescent Mental Health Clinic, S. been described.8–10 The mechanism of liver Gerardo Hospital, via Pergolesi 33, 20900 Monza (MB), Italy. E-mail: [email protected] enzymes elevation observed during severe malnutri- 1 Department of Child and Adolescent Mental Health, San Ger- tion in patients with AN includes hepatocytes ardo Hospital and Department of Surgery and Translational Medi- hypoxia due to low cardiac output and glycogenic cine, University of Milano-Bicocca, Monza, Italy 2 Neurology Unit, San Gerardo Hospital and Department of Sur- depletion, hepatocellular injury from non-alcoholic 11 gery and Translational Medicine, University of Milano-Bicocca, fatty liver disease (NAFLD). oxidative stress, iron Monza, Italy deposition,12 and starvation-induced autophagy.9 Published online 29 November 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/eat.22371 Body fat and body mass index (BMI) in AN patients VC 2014 Wiley Periodicals, Inc. have been reported as inversely correlated with International Journal of Eating Disorders 48:3 317–322 2015 317 CORBETTA ET AL. plasma levels of alanine aminotransferase (ALT) and whose role and levels are strictly related to each gamma-glutamyl transpeptidase (GGT), suggesting other) in a sample of 70 adolescent females the presence of NAFLD.11 Consistently, the few liver affected by restrictive type AN, concurrently assess- biopsies available from patients with AN presenting ing liver cytolysis, stasis and synthesis enzymes. As with elevated liver enzymes, show moderate peri- secondary aim, we compared these values with portal inflammatory infiltrates, hepatocyte balloon- clinical and demographic data, including the ing, fatty liver and increased glycogen deposits, assessment of the severity of the psychopathologi- possibly suggesting malnutrition-induced apopto- cal traits by administering the Eating Disorder sis.9 Four specific risk factors for hepatic cytolysis Inventory-3 scale. were identified in a population of adults with AN: age <30 years, BMI <12, male, and the pure restric- tive form of the disease.13 Tsukamoto et al.14 Method reported in a cohort of adult ED patients that younger participants presented more pronounced Patient Recruitment metabolic damage deriving from starvation com- Seventy adolescent female inpatients (age between 12 pared with older ones and that lower BMI and and 18 years old) affected by restrictive type AN were shorter disease duration were correlated with ele- diagnosed according to DSM-IV-TR criteria and recruited vated ALT. Montagnese et al.15 further confirmed at the Department of Child and Adolescent Neuropsychia- these findings by identifying a correlation between try of the San Gerardo Hospital, Monza, Italy. Clinical and low BMI and prevalence of hyper-transaminasemia. demographic characteristics are described in Table 1. Moreover, they found an increase in plasma levels Patients with alcohol abuse, cancer (with special attention of lactate dehydrogenase (LDH) and GGT, suggest- to hematological cancers), significant liver or kidney dys- ing generalized liver damage associated with malnu- function, recent infections or surgery were excluded, as trition.15 Low cholinesterase serum levels (CHE, well as patients taking vitamins, steroids or immunosup- marker of hepatocyte function influenced by nutri- pressive drugs, or patients with age <12 and >18 years. tional status) were also found, which inversely cor- Only one patient was taking medications (Sertraline related with hypertransaminasemia.15 50 mg o.d.), while all the others were drug free at the Liver damage is associated not only with hyper- moment of blood withdrawal. Following ethics committee transaminasemia but also with the increase in approval of the study, both parents, and recruited partici- 16,17 pants, gave written informed consent before enrolling in plasma levels of vitamin B12,duetoleakage. the study. Each patient was assessed using the Eating Dis- Normally, the liver stores a vitamin B12 (cobalamin) supply of several milligrams, which is sufficient to order Inventory-3 (EDI-3) in order to have a standardized cover the daily need for several years.18 Diseases that clinical evaluation of symptomatology associated with AN. In the analyses we considered the three eating disor- lead to elevated blood levels of vitamin B12 include hematologic disorders (e.g., acute and chronic der specific scores (DT: drive for thinness; B: bulimia; BD: myelogenous leukaemia), and liver diseases (e.g., body dissatisfaction), the resulting composite (EDRC, eat- acute hepatitis or hepatocellular carcinoma).16–18 ing disorder risk composite), and the composite deriving However, dietary supplementation or integration from the other nine scores not specific for eating disorders (GPMC, general psychological maladjustment composite). that may elevate plasma vitamin B12 should be con- sidered as the primary cause of any increase.18 Disease duration (months), progression rate [defined as The need for predicting liver damage in AN delta BMI (i.e., BMI at disease onset-BMI at current evalu- before full development is strong as it may lead to ation)/disease duration] and BMI were included in the dramatic consequences and influence subsequent analyses as well. weight recovery, especially in younger patients.13 For this reason, the availability of sensitive markers Plasma Determinations of hepatic damage might be crucial for the man- Blood withdrawal for each participant was performed agement of AN in clinical practice. The vitamin B12 on admission or the next day if the admission was during levels of AN patients have never been systemati- the afternoon (in this latter case no drugs were adminis- cally investigated with this aim. This lack of study tered to the patients). Blood was obtained always is due to the general assumptions that, if any differ- between 08.00 and 08.30 AM, following overnight fasting ences were found between the levels of AN patients and immediately sent to the Laboratory of Analyses for and those of the healthy participants, they would plasma separation and the assessment of the variables of be related to the restrictive feeding attitude. Hence, interest.19
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