Liver disease in obesity and underweight: the two sides of the coin. A narrative review.

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Renata Risi, Dario Tuccinardi, Stefania Mariani, Carla Lubrano, Silvia Manfrini, Lorenzo Maria Donini, Mikiko Watanabe

Author Information

Renata Risi: Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161, Rome, Italy.
Dario Tuccinardi: Department of Endocrinology and Diabetes, Department of Medicine, University Campus Bio-Medico of Rome, Via Alvaro del Portillo, 21, 00128, Rome, Italy. d.tuccinardi@unicampus.it. ORCID
Stefania Mariani: Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161, Rome, Italy.
Carla Lubrano: Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161, Rome, Italy.
Silvia Manfrini: Department of Endocrinology and Diabetes, Department of Medicine, University Campus Bio-Medico of Rome, Via Alvaro del Portillo, 21, 00128, Rome, Italy.
Lorenzo Maria Donini: Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161, Rome, Italy.
Mikiko Watanabe: Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161, Rome, Italy.

PMID: 33150534 DOI: 10.1007/s40519-020-01060-w

PURPOSE: Malnutrition, whether characterized by not enough or too much nutrient intake, is detrimental to the liver. We herein provide a narrative literature revision relative to hepatic disease occurrence in over or undernourished subjects, to shed light on the paradox where both sides of malnutrition lead to similar liver dysfunction and fat accumulation.
METHODS: Medline, EMBASE, and Cochrane Library were searched for publications up to July 2020. Articles discussing the association between both chronic and acute liver pathology and malnutrition were evaluated together with studies reporting the dietary intake in subjects affected by malnutrition.
RESULTS: The association between overnutrition and non-alcoholic fatty liver disease (NAFLD) is well recognized, as the beneficial effects of calorie restriction and very low carbohydrate diets. Conversely, the link between undernutrition and liver injury is more complex and less understood. In developing countries, early exposure to nutrient deficiency leads to marasmus and kwashiorkor, accompanied by fatty liver, whereas in developed countries anorexia nervosa is a more common form of undernutrition, associated with liver injury. Weight gain in undernutrition is associated with liver function improvement, whereas no study on the impact of macronutrient distribution is available. We hypothesized a role for very low carbohydrate diets in the management of undernutrition derived liver pathology, in addition to the established one in overnutrition-related NAFLD.
CONCLUSIONS: Further studies are warranted to update the knowledge regarding undernutrition-related liver disease, and a specific interest should be paid to macronutrient distribution both in the context of refeeding and relative to its role in the development of hepatic complications of anorexia nervosa.
LEVEL OF EVIDENCE: Narrative review, Level V.

Anorexia nervosa Diet Eating disorder Liver failure Malnutrition NAFLD Treatment Very low carbohydrate diet

Povsic M, Wong OY, Perry R, Bottomley J (2019) A Structured literature review of the epidemiology and disease burden of non-alcoholic steatohepatitis (NASH). Adv Ther 36(7):1574–1594. https://doi.org/10.1007/s12325-019-00960-3 [DOI: 10.1007/s12325-019-00960-3]

Meex RCR, Watt MJ (2017) Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol 13(9):509–520. https://doi.org/10.1038/nrendo.2017.56 [DOI: 10.1038/nrendo.2017.56]

Chen Z, Yu R, Xiong Y, Du F, Zhu S (2017) A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease. Lipids Health Dis. https://doi.org/10.1186/s12944-017-0572-9 [DOI: 10.1186/s12944-017-0572-9]

Watanabe M, Tozzi R, Risi R et al (2020) Beneficial effects of the ketogenic diet on nonalcoholic fatty liver disease: a comprehensive review of the literature. Obes Rev. https://doi.org/10.1111/obr.13024 [DOI: 10.1111/obr.13024]

Jahoor F, Badaloo A, Reid M, Forrester T (2008) Protein metabolism in severe childhood malnutrition. Ann Trop Paediatr 28(2):87–101. https://doi.org/10.1179/146532808X302107 [DOI: 10.1179/146532808X302107]

Rosen E, Bakshi N, Watters A, Rosen HR, Mehler PS, Watters A (2017) Hepatic complications of anorexia nervosa. Dig Dis Sci 62(11):2977–2981. https://doi.org/10.1007/s10620-017-4766-9 [DOI: 10.1007/s10620-017-4766-9]

Mariani S, Fiore D, Varone L et al (2012) Obstructive sleep apnea and bone mineral density in obese patients. Diabetes Metab Syndr Obes Targets Ther 5:395–401. https://doi.org/10.2147/DMSO.S37761 [DOI: 10.2147/DMSO.S37761]

Palermo A, Tuccinardi D, Defeudis G et al (2016) BMI and BMD: The potential interplay between obesity and bone fragility. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph13060544 [DOI: 10.3390/ijerph13060544]

Okamura T, Hashimoto Y, Hamaguchi M, Obora A, Kojima T, Fukui M (2019) Ectopic fat obesity presents the greatest risk for incident type 2 diabetes: a population-based longitudinal study. Int J Obes 43(1):139–148. https://doi.org/10.1038/s41366-018-0076-3 [DOI: 10.1038/s41366-018-0076-3]

Foster DW, McGarry JD (1982) The regulation of ketogenesis. Ciba Found Symp 87:120–131. https://doi.org/10.1002/9780470720691.ch7 [DOI: 10.1002/9780470720691.ch7]

Pennisi G, Celsa C, Giammanco A, Spatola F, Petta S (2019) The burden of hepatocellular carcinoma in non-alcoholic fatty liver disease: Screening issue and future perspectives. Int J Mol Sci. https://doi.org/10.3390/ijms20225613 [DOI: 10.3390/ijms20225613]

Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M (2016) Global epidemiology of nonalcoholic fatty liver disease—Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64(1):73–84. https://doi.org/10.1002/hep.28431 [DOI: 10.1002/hep.28431]

Dumitrascu DL, Neuman MG (2018) Non-alcoholic fatty liver disease: an update on diagnosis. Clujul Med 91(2):147–150. https://doi.org/10.15386/cjmed-993 [DOI: 10.15386/cjmed-993]

Buzzetti E, Pinzani M, Tsochatzis EA (2016) The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 65(8):1038–1048. https://doi.org/10.1016/j.metabol.2015.12.012 [DOI: 10.1016/j.metabol.2015.12.012]

Ma J, Zhou Q, Li H (2017) Gut microbiota and nonalcoholic fatty liver disease: Insights on mechanisms and therapy. Nutrients. https://doi.org/10.3390/nu9101124 [DOI: 10.3390/nu9101124]

Leung C, Rivera L, Furness JB, Angus PW (2016) The role of the gut microbiota in NAFLD. Nat Rev Gastroenterol Hepatol 13(7):412–425. https://doi.org/10.1038/nrgastro.2016.85 [DOI: 10.1038/nrgastro.2016.85]

Severson TJ, Besur S, Bonkovsky HL (2016) Genetic factors that affect nonalcoholic fatty liver disease: a systematic clinical review. World J Gastroenterol 22(29):6742–6756. https://doi.org/10.3748/wjg.v22.i29.6742 [DOI: 10.3748/wjg.v22.i29.6742]

Karagozian R, Bhardwaj G, Wakefield DB, Baffy G (2016) Obesity paradox in advanced liver disease: obesity is associated with lower mortality in hospitalized patients with cirrhosis. Liver Int 36(10):1450–1456. https://doi.org/10.1111/liv.13137 [DOI: 10.1111/liv.13137]

Donini LM, Pinto A, Giusti AM, Lenzi A, Poggiogalle E (2020) Obesity or BMI paradox? Beneath the tip of the iceberg. Front Nutr. https://doi.org/10.3389/fnut.2020.00053 [DOI: 10.3389/fnut.2020.00053]

Fromenty B (2017) Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity. J Clin Transl Res. https://doi.org/10.18053/jctres.03.2017s1.006 [DOI: 10.18053/jctres.03.2017s1.006]

Townsend LK, Peppler WT, Bush ND, Wright DC (2018) Obesity exacerbates the acute metabolic side effects of olanzapine. Psychoneuroendocrinology 88:121–128. https://doi.org/10.1016/j.psyneuen.2017.12.004 [DOI: 10.1016/j.psyneuen.2017.12.004]

Allard J, Le Guillou D, Begriche K, Fromenty B (2019) Drug-induced liver injury in obesity and nonalcoholic fatty liver disease. Adv Pharmacol 85:75–107. https://doi.org/10.1016/bs.apha.2019.01.003 [DOI: 10.1016/bs.apha.2019.01.003]

Tsai JH, Ferrell LD, Tan V, Yeh MM, Sarkar M, Gill RM (2017) Aggressive non-alcoholic steatohepatitis following rapid weight loss and/or malnutrition. Mod Pathol 30(6):834–842. https://doi.org/10.1038/modpathol.2017.13 [DOI: 10.1038/modpathol.2017.13]

William JH, Tapper EB, Yee EU, Robson SC (2015) Secondary Kwashiorkor: a rare complication of gastric bypass surgery. Am J Med 128(5):e1–e2. https://doi.org/10.1016/j.amjmed.2014.12.002 [DOI: 10.1016/j.amjmed.2014.12.002]

Watanabe M, Risi R, Camajani E et al (2020) Baseline homa IR and circulating FGF21 levels predict NAFLD improvement in patients undergoing a low carbohydrate dietary intervention for weight loss: A prospective observational pilot study. Nutrients 12(7):1–13. https://doi.org/10.3390/nu12072141 [DOI: 10.3390/nu12072141]

Dalvi PS, Yang S, Swain N et al (2018) Long-term metabolic effects of malnutrition: liver steatosis and insulin resistance following early-life protein restriction. PLoS ONE. https://doi.org/10.1371/journal.pone.0199916 [DOI: 10.1371/journal.pone.0199916]

Ravelli ACJ, Van Der Meulen JHP, Osmond C, Barker DJP, Bleker OP (1999) Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 70(5):811–816. https://doi.org/10.1093/ajcn/70.5.811 [DOI: 10.1093/ajcn/70.5.811]

Wang N, Wang X, Han B et al (2015) Is exposure to famine in childhood and economic development in adulthood associated with diabetes? J Clin Endocrinol Metab 100(12):4514–4523. https://doi.org/10.1210/jc.2015-2750 [DOI: 10.1210/jc.2015-2750]

Lussana F, Painter RC, Ocke MC, Buller HR, Bossuyt PM, Roseboom TJ (2008) Prenatal exposure to the Dutch famine is associated with a preference for fatty foods and a more atherogenic lipid profile. Am J Clin Nutr 88(6):1648–1652. https://doi.org/10.3945/ajcn.2008.26140 [DOI: 10.3945/ajcn.2008.26140]

Wang N, Wang X, Li Q et al (2017) The famine exposure in early life and metabolic syndrome in adulthood. Clin Nutr 36(1):253–259. https://doi.org/10.1016/j.clnu.2015.11.010 [DOI: 10.1016/j.clnu.2015.11.010]

Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A (2013) Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients 5(5):1544–1560. https://doi.org/10.3390/nu5051544 [DOI: 10.3390/nu5051544]

Sandboge S, Perälä MM, Salonen MK et al (2013) Early growth and non-alcoholic fatty liver disease in adulthood-the NAFLD liver fat score and equation applied on the Helsinki Birth Cohort Study. Ann Med 45(5–6):430–437. https://doi.org/10.3109/07853890.2013.801275 [DOI: 10.3109/07853890.2013.801275]

Wang N, Chen Y, Ning Z et al (2016) Exposure to famine in early life and nonalcoholic fatty liver disease in adulthood. J Clin Endocrinol Metab 101(5):2218–2225. https://doi.org/10.1210/jc.2016-1076 [DOI: 10.1210/jc.2016-1076]

Chen JP, Peng B, Tang L et al (2016) Fetal and infant exposure to the Chinese famine increases the risk of fatty liver disease in Chongqing, China. J Gastroenterol Hepatol 31(1):200–205. https://doi.org/10.1111/jgh.13044 [DOI: 10.1111/jgh.13044]

Orozco-Solís R, Matos RJB, Guzmán-Quevedo O et al (2010) Nutritional programming in the rat is linked to long-lasting changes in nutrient sensing and energy homeostasis in the hypothalamus. PLoS ONE. https://doi.org/10.1371/journal.pone.0013537 [DOI: 10.1371/journal.pone.0013537]

Erhuma A, Salter AM, Sculley DV, Langley-Evans SC, Bennett AJ (2007) Prenatal exposure to a low-protein diet programs disordered regulation of lipid metabolism in the aging rat. Am J Physiol - Endocrinol Metab. https://doi.org/10.1152/ajpendo.00605.2006 [DOI: 10.1152/ajpendo.00605.2006]

Wolfe D, Gong M, Han G, Magee TR, Ross MG, Desai M (2012) Nutrient sensor-mediated programmed nonalcoholic fatty liver disease in low birthweight offspring. Am J Obstet Gynecol 207(4):308.e1-308.e6. https://doi.org/10.1016/j.ajog.2012.07.033 [DOI: 10.1016/j.ajog.2012.07.033]

Yamada M, Wolfe D, Han G, French SW, Ross MG, Desai M (2011) Early onset of fatty liver in growth-restricted rat fetuses and newborns. Congenit Anom (Kyoto) 51(4):167–173. https://doi.org/10.1111/j.1741-4520.2011.00336.x [DOI: 10.1111/j.1741-4520.2011.00336.x]

Hoffman ML, Peck KN, Forella ME, Fox AR, Govoni KE, Zinn SA (2016) The effects of poor maternal nutrition during gestation on postnatal growth and development of lambs. J Anim Sci 94(2):789–799. https://doi.org/10.2527/jas.2015-9933 [DOI: 10.2527/jas.2015-9933]

Wang Y, Wan H, Chen C et al (2020) Association between famine exposure in early life with insulin resistance and beta cell dysfunction in adulthood. Nutr Diabetes. https://doi.org/10.1038/s41387-020-0121-x [DOI: 10.1038/s41387-020-0121-x]

Spoelstra MN, Mari A, Mendel M et al (2012) Kwashiorkor and marasmus are both associated with impaired glucose clearance related to pancreatic β-cell dysfunction. Metabolism 61(9):1224–1230. https://doi.org/10.1016/j.metabol.2012.01.019 [DOI: 10.1016/j.metabol.2012.01.019]

van Zutphen T, Ciapaite J, Bloks VW et al (2016) Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction. J Hepatol 65(6):1198–1208. https://doi.org/10.1016/j.jhep.2016.05.046 [DOI: 10.1016/j.jhep.2016.05.046]

Black RE, Victora CG, Walker SP et al (2013) Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet 382(9890):427–451. https://doi.org/10.1016/S0140-6736(13)60937-X ([published correction appears in Lancet. 2013. 2013 Aug 3;382(9890):396]) [DOI: 10.1016/S0140-6736(13)60937-X]

Doherty JF, Adam EJ, Griffin GE, Golden MHN (1992) Ultrasonographic assessment of the extent of hepatic steatosis in severe malnutrition. Arch Dis Child 67(11):1348–1352. https://doi.org/10.1136/adc.67.11.1348 [DOI: 10.1136/adc.67.11.1348]

Chaudhuri AD, Bhattacharyya AK, Mukherjee AM (1972) The liver in pre-kwashiorkor and kwashiorkor-marasmus syndromes. Trans R Soc Trop Med Hyg 66(2):258–262. https://doi.org/10.1016/0035-9203(72)90157-5 [DOI: 10.1016/0035-9203(72)90157-5]

Mehanna HM (1969) the Liver in protein-calorie malnutrition. Nutr Rev 27(8):223–225. https://doi.org/10.1111/j.1753-4887.1969.tb05031.x [DOI: 10.1111/j.1753-4887.1969.tb05031.x]

James WP (1977) Kwashiorkor and marasmus: old concepts and new developments. Proc R Soc Med 70(9):611–615 [PMID: 411136]

Palm CVB, Frølich JS, Snogdal LS, Støving RK (2016) Kwashiorkor: an unexpected complication to anorexia nervosa. BMJ Case Rep. https://doi.org/10.1136/bcr-2016-215638 [DOI: 10.1136/bcr-2016-215638]

Tan MCY, Chien JMF, Khor LY, Chea YW, Wong TH (2018) Acute presentation of post-operative kwashiorkor and refeeding syndrome complicated by chronic Strongyloides infection in an elderly patient. ANZ J Surg 88(9):E692. https://doi.org/10.1111/ans.14769 [DOI: 10.1111/ans.14769]

Zadák Z. [Prevention and therapy of sarcopenia in the ageing]. Vnitr Lek. 62(7–8):671–677. https://www.ncbi.nlm.nih.gov/pubmed/27627096 . Accessed 25 Aug 2020

Semba RD (2016) The rise and fall of protein malnutrition in global health. Ann Nutr Metab 69(2):79–88. https://doi.org/10.1159/000449175 [DOI: 10.1159/000449175]

Mclaren DS (1974) The great protein fiasco. Lancet 304(7872):93–96. https://doi.org/10.1016/S0140-6736(74)91649-3 [DOI: 10.1016/S0140-6736(74)91649-3]

Truswell AS, Miller JC (1993) Pathogenesis of the fatty liver in protein-energy malnutrition. Am J Clin Nutr 57(5):695–696. https://doi.org/10.1093/ajcn/57.5.695 [DOI: 10.1093/ajcn/57.5.695]

Treasure J, Claudino AM, Zucker N (2010) Eating disorders. Lancet 375(9714):583–593. https://doi.org/10.1016/S0140-6736(09)61748-7 [DOI: 10.1016/S0140-6736(09)61748-7]

Smink FRE, Van Hoeken D, Hoek HW (2012) Epidemiology of eating disorders: Incidence, prevalence and mortality rates. Curr Psychiatry Rep 14(4):406–414. https://doi.org/10.1007/s11920-012-0282-y [DOI: 10.1007/s11920-012-0282-y]

Hoek HW, van Hoeken D (2003) Review of the prevalence and incidence of eating disorders. Int J Eat Disord 34(4):383–396. https://doi.org/10.1002/eat.10222 [DOI: 10.1002/eat.10222]

American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington D.C. https://doi.org/10.1176/appi.books.9780890425596 . Accessed 18 Aug 2020

Arcelus J, Mitchell AJ, Wales J, Nielsen S (2011) Mortality rates in patients with anorexia nervosa and other eating disorders: a meta-analysis of 36 studies. Arch Gen Psychiatry 68(7):724–731. https://doi.org/10.1001/archgenpsychiatry.2011.74 [DOI: 10.1001/archgenpsychiatry.2011.74]

Harris EC, Barraclough B (1998) Excess mortality of mental disorder. Br J Psychiatry 173(JULY):11–53. https://doi.org/10.1192/bjp.173.1.11 [DOI: 10.1192/bjp.173.1.11]

Zipfel S, Giel KE, Bulik CM, Hay P, Schmidt U (2015) Anorexia nervosa: aetiology, assessment, and treatment. Lancet Psychiatry 2(12):1099–1111. https://doi.org/10.1016/S2215-0366(15)00356-9 [DOI: 10.1016/S2215-0366(15)00356-9]

Karahmadi M, Layegh E, Layegh S, Keypour M (2011) High level increase in liver enzymes and severe thrombocytopenia in a male case of anorexia nervosa. J Res Med Sci 16(10):1378–1381 [PMID: 22973335]

Mickley D, Greenfeld D, Quinlan DM, Roloff P, Zwas F (1996) Abnormal liver enzymes in outpatients with eating disorders. Int J Eat Disord 20(3):325–329. https://doi.org/10.1002/(SICI)1098-108X(199611)20:3%3c325::AID-EAT13%3e3.0.CO;2-Z [DOI: 10.1002/(SICI)1098-108X(199611)20]

Umeki S (1988) Biochemical abnormalities of the serum in anorexia nervosa. J Nerv Ment Dis 176(8):503–506. https://doi.org/10.1097/00005053-198808000-00009 [DOI: 10.1097/00005053-198808000-00009]

Imaeda M, Tanaka S, Fujishiro H et al (2016) Risk factors for elevated liver enzymes during refeeding of severely malnourished patients with eating disorders: a retrospective cohort study. J Eat Disord. https://doi.org/10.1186/s40337-016-0127-x [DOI: 10.1186/s40337-016-0127-x]

Tomita K, Haga H, Ishii G et al (2014) Clinical manifestations of liver injury in patients with anorexia nervosa. Hepatol Res 44(10):E26–E31. https://doi.org/10.1111/hepr.12202 [DOI: 10.1111/hepr.12202]

Rosen E, Sabel AL, Brinton JT, Catanach B, Gaudiani JL, Mehler PS (2016) Liver dysfunction in patients with severe anorexia nervosa. Int J Eat Disord 49(2):153–160. https://doi.org/10.1002/eat.22436 [DOI: 10.1002/eat.22436]

Gaudiani JL, Sabel AL, Mascolo M, Mehler PS (2012) Severe anorexia nervosa: outcomes from a medical stabilization unit. Int J Eat Disord 45(1):85–92. https://doi.org/10.1002/eat.20889 [DOI: 10.1002/eat.20889]

Hanachi M, Melchior JC, Crenn P (2013) Hypertransaminasemia in severely malnourished adult anorexia nervosa patients: risk factors and evolution under enteral nutrition. Clin Nutr 32(3):391–395. https://doi.org/10.1016/j.clnu.2012.08.020 [DOI: 10.1016/j.clnu.2012.08.020]

Harris RH, Sasson G, Mehler PS (2013) Elevation of liver function tests in severe anorexianervosa. Int J Eat Disord 46(4):369–374. https://doi.org/10.1002/eat.22073 [DOI: 10.1002/eat.22073]

Ozawa Y, Shimizu T, Shishiba Y (1998) Elevation of serum aminotransferase as a sign of multiorgan-disorders in severely emaciated anorexia nervosa. Intern Med 37(1):32–39. https://doi.org/10.2169/internalmedicine.37.32 [DOI: 10.2169/internalmedicine.37.32]

Tsukamoto M, Tanaka A, Arai M et al (2008) Hepatocellular injuries observed in patients with an eating disorder prior to nutritional treatment. Intern Med 47(16):1447–1450. https://doi.org/10.2169/internalmedicine.47.0824 [DOI: 10.2169/internalmedicine.47.0824]

Rautou PE, Cazals-Hatem D, Moreau R, Francoz C, Feldmann G, Lebrec D, Ogier-Denis E, Bedossa P, Valla D, Durand F (2008) Acute liver cell damage in patients with anorexia nervosa: a possible role of starvation-induced hepatocyte autophagy. Gastroenterology 135(3):840–848. https://doi.org/10.1053/j.gastro.2008.05.055 [DOI: 10.1053/j.gastro.2008.05.055]

Kheloufi M, Boulanger CM, Durand F, Rautou PE (2014) Liver autophagy in anorexia nervosa and acute liver injury. Biomed Res Int 2014:701064. https://doi.org/10.1155/2014/701064 [DOI: 10.1155/2014/701064]

Rosen E, Bakshi N, Watters A, Rosen HR, Mehler PS (2017) Hepatic complications of anorexia nervosa. Dig Dis Sci 62(11):2977–2981. https://doi.org/10.1007/s10620-017-4766-9 [DOI: 10.1007/s10620-017-4766-9]

Levine B, Mizushima N, Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469(7330):323–335. https://doi.org/10.1038/nature09782 [DOI: 10.1038/nature09782]

Misra M, Klibanski A (2016) Anorexia nervosa and its associated endocrinopathy in young people. Horm Res Paediatr 85(3):147–157. https://doi.org/10.1159/000443735 [DOI: 10.1159/000443735]

Mintziori G, Poulakos P, Tsametis C, Goulis DG (2017) Hypogonadism and non-alcoholic fatty liver disease. Minerva Endocrinol 42(2):145–150. https://doi.org/10.23736/S0391-1977.16.02570-0 [DOI: 10.23736/S0391-1977.16.02570-0]

Takahashi Y (2017) The role of growth hormone and insulin-like growth factor-I in the liver. Int J Mol Sci. https://doi.org/10.3390/ijms18071447 [DOI: 10.3390/ijms18071447]

Letiexhe MR, Scheen AJ, Lefèbvre PJ (1997) Plasma leptin levels, insulin secretion, clearance and action on glucose metabolism in anorexia nervosa. Eat Weight Disord 2(2):79–86. https://doi.org/10.1007/bf03339953 [DOI: 10.1007/bf03339953]

Nozaki T (1994) Insulin response to intravenous glucose in patients with anorexia nervosa showing low insulin response to oral glucose. J Clin Endocrinol Metab 79(1):217–222. https://doi.org/10.1210/jc.79.1.217 [DOI: 10.1210/jc.79.1.217]

Fanin A, Miele L, Bertolini E, Giorgini A, Pontiroli AE, Benetti A (2020) Liver alterations in anorexia nervosa are not caused by insulin resistance. Intern Emerg Med 15(2):337–339. https://doi.org/10.1007/s11739-019-02227-9 [DOI: 10.1007/s11739-019-02227-9]

Mancuso P (2016) The role of adipokines in chronic inflammation. ImmunoTargets Ther 5:47–56. https://doi.org/10.2147/ITT.S73223 [DOI: 10.2147/ITT.S73223]

Larabee CM, Neely OC, Domingos AI (2020) Obesity: a neuroimmunometabolic perspective. Nat Rev Endocrinol 16(1):30–43. https://doi.org/10.1038/s41574-019-0283-6 [DOI: 10.1038/s41574-019-0283-6]

Gardner EM (2005) Caloric restriction decreases survival of aged mice in response to primary influenza infection. Journals Gerontol 60(6):688–694. https://doi.org/10.1093/gerona/60.6.688 [DOI: 10.1093/gerona/60.6.688]

Ritz BW, Aktan I, Nogusa S, Gardner EM (2008) Energy restriction impairs natural killer cell function and increases the severity of influenza infection in young adult male C57BL/6 mice. J Nutr 138(11):2269–2275. https://doi.org/10.3945/jn.108.093633 [DOI: 10.3945/jn.108.093633]

Clinthorne JF, Adams DJ, Fenton JI, Ritz BW, Gardner EM (2010) Short-term re-feeding of previously energy-restricted C57BL/6 male mice restores body weight and body fat and attenuates the decline in natural killer cell function after primary influenza infection. J Nutr 140(8):1495–1501. https://doi.org/10.3945/jn.110.122408 [DOI: 10.3945/jn.110.122408]

Gibson D, Mehler PS (2019) Anorexia nervosa and the immune system—a narrative review. J Clin Med 8(11):1915. https://doi.org/10.3390/jcm8111915 [DOI: 10.3390/jcm8111915]

Genton L, Cani PD, Schrenzel J (2015) Alterations of gut barrier and gut microbiota in food restriction, food deprivation and protein-energy wasting. Clin Nutr 34(3):341–349. https://doi.org/10.1016/j.clnu.2014.10.003 [DOI: 10.1016/j.clnu.2014.10.003]

Roubalová R, Procházková P, Papežová H, Smitka K, Bilej M, Tlaskalová-Hogenová H (2020) Anorexia nervosa: gut microbiota-immune-brain interactions. Clin Nutr 39(3):676–684. https://doi.org/10.1016/j.clnu.2019.03.023 [DOI: 10.1016/j.clnu.2019.03.023]

Solmi M, Veronese N, Manzato E et al (2015) Oxidative stress and antioxidant levels in patients with anorexia nervosa: a systematic review and exploratory meta-analysis. Int J Eat Disord 48(7):826–841. https://doi.org/10.1002/eat.22443 [DOI: 10.1002/eat.22443]

Zenger F, Russmann S, Junker E, Wüthrich C, Bui MH, Lauterburg BH (2004) Decreased glutathione in patients with anorexia nervosa. Risk factor for toxic liver injury? Eur J Clin Nutr 58(2):238–243. https://doi.org/10.1038/sj.ejcn.1601772 [DOI: 10.1038/sj.ejcn.1601772]

Koch M (2016) Gut Microbiota and the Liver. J Clin Gastroenterol 50:S183–S187. https://doi.org/10.1097/mcg.0000000000000699 [DOI: 10.1097/mcg.0000000000000699]

Cichoz-Lach H, Michalak A (2014) Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol 20(25):8082–8091. https://doi.org/10.3748/wjg.v20.i25.8082 [DOI: 10.3748/wjg.v20.i25.8082]

Marcos A, Varela P, Toro O et al (1997) Interactions between nutrition and immunity in anorexia nervosa: a 1-y follow-up study. Am J Clin Nutr. https://doi.org/10.1093/ajcn/66.2.485S [DOI: 10.1093/ajcn/66.2.485S]

Amrein PC, Friedman R, Ellman L, Kosinski K (1979) Hematologic changes in anorexia nervosa. JAMA 241(20):2190–2191. https://doi.org/10.1001/jama.1979.03290460054022 [DOI: 10.1001/jama.1979.03290460054022]

Mustafa A, Ward A, Treasure J, Peakman M (1997) T lymphocyte subpopulations in anorexia nervosa and refeeding. Clin Immunol Immunopathol 82(3):282–289. https://doi.org/10.1006/clin.1996.4310 [DOI: 10.1006/clin.1996.4310]

Michaux I, Lambert M, Hantson P (2001) Anorexia nervosa complicated by pancytopenia and sepsis. Acta Clin Belg 56(1):55–56. https://doi.org/10.1179/acb.2001.010 [DOI: 10.1179/acb.2001.010]

Dobner J, Kaser S (2018) Body mass index and the risk of infection-from underweight to obesity. Clin Microbiol Infect 24(1):24–28. https://doi.org/10.1016/j.cmi.2017.02.013 [DOI: 10.1016/j.cmi.2017.02.013]

Kalsi SS, Dargan PI, Waring WS, Wood DM (2011) A review of the evidence concerning hepatic glutathione depletion and susceptibility to hepatotoxicity after paracetamol overdose. Open Access Emerg Med 3:87–96. https://doi.org/10.2147/OAEM.S24963 [DOI: 10.2147/OAEM.S24963]

Lesna M, Watson AJ, Douglas AP, Hamlyn AN, James OFW (1976) Evaluation of paracetamol-induced damage in liver biopsies: acute changes and follow-up findings. Virchows Arch A Pathol Anat Histol 370(4):333–344. https://doi.org/10.1007/BF00445778 [DOI: 10.1007/BF00445778]

Dowman J, Arulraj R, Chesner I (2010) Recurrent acute hepatic dysfunction in severe anorexia nervosa. Int J Eat Disord 43(8):770–772. https://doi.org/10.1002/eat.20775 [DOI: 10.1002/eat.20775]

Sakada M, Tanaka A, Ohta D et al (2006) Severe steatosis resulted from anorexia nervosa leading to fatal hepatic failure [3]. J Gastroenterol 41(7):714–715. https://doi.org/10.1007/s00535-006-1845-7 [DOI: 10.1007/s00535-006-1845-7]

De Caprio C, Alfano A, Senatore I, Zarrella L, Pasanisi F, Contaldo F (2006) Severe acute liver damage in anorexia nervosa: two case reports. Nutrition 22(5):572–575. https://doi.org/10.1016/j.nut.2006.01.003 [DOI: 10.1016/j.nut.2006.01.003]

Henrion J, Schapira M, Luwaert R, Colin L, Delannoy A, Heller FR (2003) Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive cases. Medicine (Baltimore) 82(6):392–406. https://doi.org/10.1097/01.md.0000101573.54295.bd [DOI: 10.1097/01.md.0000101573.54295.bd]

Giordano F, Arnone S, Santeusanio F, Pampanelli S (2010) Brief elevation of hepatic enzymes due to liver ischemia in anorexia nervosa. Eat Weight Disord. https://doi.org/10.1007/BF03325312 [DOI: 10.1007/BF03325312]

Ramsoekh D, Taimr P, Vanwolleghem T (2014) Reversible severe hepatitis in anorexia nervosa: a case report and overview. Eur J Gastroenterol Hepatol 26(4):473–477. https://doi.org/10.1097/MEG.0000000000000030 [DOI: 10.1097/MEG.0000000000000030]

Fuhrmann V, Jäger B, Zubkova A, Drolz A (2010) Hypoxic hepatitis—Epidemiology, pathophysiology and clinical management. Wien Klin Wochenschr 122(5–6):129–139. https://doi.org/10.1007/s00508-010-1357-6 [DOI: 10.1007/s00508-010-1357-6]

Narayanan V, Gaudiani JL, Harris RH, Mehler PS (2010) Liver function test abnormalities in anorexia nervosa–cause or effect. Int J Eat Disord 43(4):378–381. https://doi.org/10.1002/eat.20690 [DOI: 10.1002/eat.20690]

Mehanna HM, Moledina J, Travis J (2008) Refeeding syndrome: what it is, and how to prevent and treat it. BMJ 336(7659):1495–1498. https://doi.org/10.1136/bmj.a301 [DOI: 10.1136/bmj.a301]

Crook MA, Hally V, Panteli JV (2001) The importance of the refeeding syndrome. Nutrition 17(7–8):632–637. https://doi.org/10.1016/S0899-9007(01)00542-1 [DOI: 10.1016/S0899-9007(01)00542-1]

Friedli N, Stanga Z, Sobotka L et al (2017) Revisiting the refeeding syndrome: results of a systematic review. Nutrition 35:151–160. https://doi.org/10.1016/j.nut.2016.05.016 [DOI: 10.1016/j.nut.2016.05.016]

de Pee S, Bloem MW (2009) Current and potential role of specially formulated foods and food supplements for preventing malnutrition among 6- to 23-month-old children and for treating moderate malnutrition among 6- to 59-month-old children. Food Nutr Bull 30(3 Suppl):S434–S463. https://doi.org/10.1177/15648265090303S305 [DOI: 10.1177/15648265090303S305]

Watanabe M, Risi R, De Giorgi F et al (2020) Obesity treatment within the Italian national healthcare system tertiary care centers: what can we learn? Eat Weight Disord. https://doi.org/10.1007/s40519-020-00936-1 [DOI: 10.1007/s40519-020-00936-1]

World Health Organization. Health topics. Obesity https://www.who.int/topics/obesity/en/ . https://www.who.int/topics/obesity/en/ . 2020:93. https://www.who.int/topics/obesity/en/ . https://www.who.int/topics/obesity/en/ . Accessed 1 Sept 2020

Farr OM, Tuccinardi D, Upadhyay J, Oussaada SM, Mantzoros CS (2018) Walnut consumption increases activation of the insula to highly desirable food cues: a randomized, double-blind, placebo-controlled, cross-over fMRI study. Diabetes Obes Metab 20(1):173–177. https://doi.org/10.1111/dom.13060 [DOI: 10.1111/dom.13060]

Watanabe M, Risi R, Masi D et al (2020) Current evidence to propose different food supplements for weight loss: a comprehensive review. Nutrients 12(9):1–43. https://doi.org/10.3390/nu12092873 [DOI: 10.3390/nu12092873]

Courcoulas AP, Yanovski SZ, Bonds D et al (2014) Long-term outcomes of bariatric surgery: a national institutes of health symposium. JAMA Surg 149(12):1323–1329. https://doi.org/10.1001/jamasurg.2014.2440 [DOI: 10.1001/jamasurg.2014.2440]

Watanabe M, Gangitano E, Francomano D et al (2018) Mangosteen extract shows a potent insulin sensitizing effect in obese female patients: a prospective randomized controlled pilot study. Nutrients. https://doi.org/10.3390/nu10050586 [DOI: 10.3390/nu10050586]

Basciani S, Camajani E, Contini S et al (2020) Very-low-calorie ketogenic diets with whey, vegetable, or animal protein in patients with obesity: a randomized pilot study. J Clin Endocrinol Metab. https://doi.org/10.1210/clinem/dgaa336 [DOI: 10.1210/clinem/dgaa336]

Basciani S, Costantini D, Contini S et al (2015) Safety and efficacy of a multiphase dietetic protocol with meal replacements including a step with very low calorie diet. Endocrine 48(3):863–870. https://doi.org/10.1007/s12020-014-0355-2 [DOI: 10.1007/s12020-014-0355-2]

Bruci A, Tuccinardi D, Tozzi R et al (2020) Very low-calorie ketogenic diet: a safe and effective tool for weight loss in patients with obesity and mild kidney failure. Nutrients. https://doi.org/10.3390/nu12020333 [DOI: 10.3390/nu12020333]

Gibson AA, Seimon RV, Lee CMY et al (2014) Do ketogenic diets really suppress appetite? A systematic review and meta-analysis. Obes Res Clin Pract 8:36. https://doi.org/10.1016/j.orcp.2014.10.066 [DOI: 10.1016/j.orcp.2014.10.066]

Low-Carbohydrate A (2006) Ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized controlled trial. Yearb Pediatr 2006:427–431. https://doi.org/10.1016/s0084-3954(07)70252-x [DOI: 10.1016/s0084-3954(07)70252-x]

Watanabe M, Tuccinardi D, Ernesti I et al (2020) Scientific evidence underlying contraindications to the ketogenic diet: an update. Obes Rev. https://doi.org/10.1111/obr.13053 [DOI: 10.1111/obr.13053]

EFSA (European Food Safety Authority) (2017) Dietary Reference Values for nutrients Summary report. EFSA Support Publ 14(12):e15121. https://doi.org/10.2903/sp.efsa.2017.e15121 [DOI: 10.2903/sp.efsa.2017.e15121]

Paoli A, Bianco A, Grimaldi KA, Lodi A, Bosco G (2013) Long term successful weight loss with a combination biphasic ketogenic Mediterranean diet and mediterranean diet maintenance protocol. Nutrients 5(12):5205–5217. https://doi.org/10.3390/nu5125205 [DOI: 10.3390/nu5125205]

Mardinoglu A, Wu H, Bjornson E et al (2018) An integrated understanding of the rapid metabolic benefits of a carbohydrate-restricted diet on hepatic steatosis in humans. Cell Metab 27(3):559-571.e5. https://doi.org/10.1016/j.cmet.2018.01.005 [DOI: 10.1016/j.cmet.2018.01.005]

Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV Jr, de Cabo R, Ulrich S, Akassoglou K, Verdin E (2013) Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 339(6116):211–214. https://doi.org/10.1126/science.1227166 [DOI: 10.1126/science.1227166]

Taggart AK, Kero J, Gan X, Cai TQ, Cheng K, Ippolito M, Ren N, Kaplan R, Wu K, Wu TJ, Jin L, Liaw C, Chen R, Richman J, Connolly D, Offermanns S, Wright SD, Waters MG (2005) (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem 280(29):26649–26652. https://doi.org/10.1074/jbc.C500213200 [DOI: 10.1074/jbc.C500213200]

Graff EC, Fang H, Wanders D, Judd RL (2016) Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. Metabolism 65(2):102–113. https://doi.org/10.1016/j.metabol.2015.10.001 [DOI: 10.1016/j.metabol.2015.10.001]

Youm YH, Nguyen KY, Grant RW et al (2015) The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 21(3):263–269. https://doi.org/10.1038/nm.3804 [DOI: 10.1038/nm.3804]

Wree A, Eguchi A, Mcgeough MD et al (2014) NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology 59(3):898–910. https://doi.org/10.1002/hep.26592 [DOI: 10.1002/hep.26592]

Vandanmagsar B, Youm YH, Ravussin A et al (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17(2):179–189. https://doi.org/10.1038/nm.2279 [DOI: 10.1038/nm.2279]

Alegre F, Pelegrin P, Feldstein AE (2017) Inflammasomes in liver fibrosis. Semin Liver Dis 37(2):119–127. https://doi.org/10.1055/s-0037-1601350 [DOI: 10.1055/s-0037-1601350]

Scolnick B (2017) Ketogenic diet and anorexia nervosa. Med Hypotheses 109:150–152. https://doi.org/10.1016/j.mehy.2017.10.011 [DOI: 10.1016/j.mehy.2017.10.011]

Chiurazzi C, Cioffi I, De Caprio C et al (2017) Adequacy of nutrient intake in women with restrictive anorexia nervosa. Nutrition 38:80–84. https://doi.org/10.1016/j.nut.2017.02.004 [DOI: 10.1016/j.nut.2017.02.004]

Hadigan CM, Anderson EJ, Miller KK et al (2000) Assessment of macronutrient and micronutrient intake in women with anorexia nervosa. Int J Eat Disord 28(3):284–292. https://doi.org/10.1002/1098-108X(200011)28:3%3c284::AID-EAT5%3e3.0.CO;2-G [DOI: 10.1002/1098-108X(200011)28]

Nova E, Varela P, López-Vidriero I et al (2001) A one-year follow-up study in anorexia nervosa. Dietary pattern and anthropometrical evolution. Eur J Clin Nutr. 55(7):547–554. https://doi.org/10.1038/sj.ejcn.1601181 [DOI: 10.1038/sj.ejcn.1601181]

Milos G, Kuenzli C, Soelch CM, Schumacher S, Moergeli H, Mueller-Pfeiffer C (2013) How much should I eat? Estimation of meal portions in anorexia nervosa. Appetite 63:42–47. https://doi.org/10.1016/j.appet.2012.12.016 [DOI: 10.1016/j.appet.2012.12.016]

Raatz SK, Jahns L, Johnson LAK et al (2015) Nutritional adequacy of dietary intake in women with anorexia nervosa. Nutrients 7(5):3652–3665. https://doi.org/10.3390/nu7053652 [DOI: 10.3390/nu7053652]

Fernstrom MH, Weltzin TE, Neuberger S, Srinivasagam N, Kaye WH (1994) Twenty-four-hour food intake in patients with anorexia nervosa and in healthy control subjects. Biol Psychiatry 36(10):696–702. https://doi.org/10.1016/0006-3223(94)91179-7 [DOI: 10.1016/0006-3223(94)91179-7]

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