920 Koop AH, et al. , 2018; 17 (6): 920-932 CONCISE REVIEW November-December, Vol. 17 No. 6, 2018: 920-932 The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver An Argument for Vitamin D, A, and Zinc Monitoring in Cirrhosis Andree H. Koop,*, Omar Y. Mousa,*, Ly Elaine Pham,** Juan E. Corral-Hurtado,* Surakit Pungpapong,*,*** Andrew P. Keaveny*,*** * Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA. ** Department of Internal Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA. *** Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA. Contributed equally. ©2018 Mayo Foundation for Medical Education and Research. ABSTRACT Malnutrition is prevalent in cirrhosis. Vitamin and mineral deficiencies, including vitamin D, vitamin A, and zinc, are common and have been shown to correlate with survival. Our aim was to review the mechanisms of vitamin D, vitamin A, and zinc deficiencies in cirrhosis and the clinical assessment of affected patients, their outcomes based on the current literature, and management. This is a narrative review including the relevant literature for cirrhosis and vitamin D, vitamin A, and zinc deficiencies. Vitamin D deficiency has important effects in cirrhosis, regardless of the cause of chronic liver disease.These effects include associations with fibrosis and outcomes such as infections, hepatocellular carcinoma, and mortality. Vitamin A deficiency is associated with liver disease pro- gression to cirrhosis and clinical decompensation, including occurrence of ascites or hepatic encephalopathy. Zinc deficiency can lead to hepatic encephalopathy and impaired immune function. Such deficiencies correlate with patient survival and disease severity. Caution should be applied when replacing vitamin D, vitamin A, and zinc to avoid toxicity. Identification and appropriate treatment of vitamin and mineral deficiencies in cirrhosis may reduce specific nutritional and cirrhosis-related adverse events. Routine monitoring of vitamin A, vitamin D and zinc levels in cirrhosis should be considered. Key words. Cirrhosis. Vitamin A deficiency. Vitamin D deficiency. Zinc deficiency. INTRODUCTION deficiencies individually in patients with cirrhosis.5-10 Vi- tamin D deficiency was associated with hepatic decom- Severe malnutrition has been associated with adverse pensation and higher mortality rates.6,8,10 Vitamin A outcomes among patients with cirrhosis and following liv- deficiency was frequent in patients with cirrhosis and may er transplantation.1-3 The prevalence of malnutrition in also have predicted a more severe disease course.11 Zinc cirrhosis is reported to be 50% to 90%, and the nutritional deficiency correlated with survival and the severity of dis- status predicts morbidity and mortality in this patient pop- ease.9 Although these micronutrients have been studied ulation. Multiple factors contribute to malnutrition, in- individually in cirrhosis, to our knowledge there has not cluding increased resting energy expenditure and been a comprehensive review of these deficiencies to date. hypermetabolism, fat maldigestion and malabsorption, al- Furthermore, specific recommendations regarding the tered macronutrient metabolism, anorexia and micronu- clinical assessment and treatment of these deficiencies in trient deficiencies. Fat malabsorption, use of diuretics, cirrhosis are poorly standardized. The current guidelines and anorexia contribute to micronutrient deficiencies.4 from the American Association for the Study of Liver Dis- Vitamin and mineral deficiencies are common in cir- eases (AASLD) regarding liver transplantation evaluation rhosis regardless of the etiology. Previous studies investi- recommend measuring vitamin D with no further recom- gated the effect of vitamin D, vitamin A, and zinc mendations on measurment of vitamin A and zinc levels.12 Manuscript received: September 12, 2018. Manuscript accepted:accepted: September 28, 2018. DOI:10.5604/01.3001.0012.7192 Vitamin D, A, and Zinc in Cirrhosis. , 2018; 17 (6): 920-932 921 In this narrative review, we disucss the mechanisms of vi- Patients with severe parenchymal disease or obstructive tamin D, vitamin A, and zinc deficiencies in cirrhosis and hepatic disease may have reduced synthesis of 25(OH)D. the clinical assessment of affected patients, their outcomes However, the majority of the liver must be dysfunctional based on the current literature, and appropriate further before synthesis is reduced.57 Other risk factors for vita- management. min D deficiency include high latitudes, seasonal varia- tion with decreased sun exposure, obesity, medications VITAMIN D DEFICIENCY IN CIRRHOSIS increasing vitamin D metabolism, and chronic medical conditions, such as chronic kidney disease, leading to de- Vitamin D deficiency occurrs in up to 1 billion people creased synthesis of 1,25(OH)D.58 Cirrhosis, non-white worldwide and approximately 25% to 50% of the adult pop- race, acute decompensation of cirrhosis, and triceps skin ulation in the United States.13,14 Vitamin D is an important fold thickness (a measurement for estimating body fat) are secosteroid most widely known for its role in calcium associated with lower vitamin D levels.59 homeostasis and bone mineralization, but has gained recog- nition for its extraskeletal effects, including the pathophysi- Clinical Assessment ology and treatment of chronic diseases, the immune and Laboratory Testing system, and cellular proliferation and differentiation.15-17 First reported in patients with cirrhosis in the 1970s, inade- The symptoms of vitamin D deficiency are nonspecific quate levels of vitamin D are common in cirrhosis, occur- and include fatigue, weakness, anxiety, depressed mood, and ring in up to 93% of patients, with severe vitamin D bone, muscle, or joint pain.The symptoms may overlap with deficiency being present in as many as one-third of other medical comorbidities, including cirrhosis, fibromyal- patients.15 Epidemiologic, clinical, and diagnostic infor- gia, myopathy, or chronic fatigue.60 Vitamin D is important mation regarding deficiency of vitamin D are listed in for bone mineralization, and severe deficiency is associated table 1.8,10,15,18-23 Vitamin D deficiency occurs in cirrhosis with rickets in children and osteomalacia in adults.16 of all etiologies, and is not limited to patients with chole- In the general population, optimal vitamin D levels static liver disease (Table 2).5,15,24-53 Prior to the year 2000, range from 30 to 50 ng/mL. Vitamin D deficiency is gener- the majority of studies on vitamin D deficiency in cirrho- ally defined as serum 25(OH)D levels < 20 ng/mL. Levels sis focused on bone demineralization and metabolism. of 25(OH)D < 30 ng/mL are associated with an increase Over the past 2 decades, there have been advances in the in parathyroid hormone, and 25(OH)D levels between 20 understanding of the pathophysiology of vitamin D to 32 ng/mL are associated with an increase in intestinal deficiency and its relation to chronic liver disease.25 calcium transport.61,62 As such, a vitamin D level of 21 to Vitamin D deficiency has important implications in 29 ng/mL is generally considered a relative deficiency.13 chronic liver disease, including associations with the There is no consensus definition regarding the optimal vi- degree of fibrosis and outcomes, such as infections, tamin D level for patients with chronic liver diseases, in- hepatocellular carcinoma, and mortality.8,10,37,54-56 cluding cirrhosis.25 Vitamin D Metabolism Cellular Changes and Clinical Outcomes The liver plays an important role in the metabolism of vitamin D, where it is hydroxylated into 25-hydroxyvita- Vitamin D deficiency correlates with the severity of min D (25[OH]D), the major circulating form, which is underlying chronic liver disease and is associated with generally tested to determine a patient’s vitamin D status. worse outcomes.20,50,63,64 In patients with cirrhosis and vi- 25(OH)D is transported to the kidneys where it under- tamin D deficiency, levels improve with oral vitamin D goes a second hydroxylation to the active form 1,25-dihy- supplementation and fall without supplementation.64 In a droxyvitamin D (1,25[OH]D).16 study of 75 cirrhotic patients in an outpatient liver clinic, vitamin D deficiency correlated with the Child-Pugh Mechanisms for Deficiency score and Model for End-Stage Liver Disease scores and was associated with hepatic decompensation and mortali- The etiology of vitamin D deficiency in liver disease is ty.8 In a prospective study of 65 patients with cirrhosis generally multifactorial, including decreased oral absorp- over a 24-month period, low vitamin D levels were asso- tion (eg, cholestatic liver disease or portal hypertensive ciated with increased mortality.10 In a study of 88 hospital- enteropathy) and decreased exposure to ultraviolet light. ized patients with cirrhosis, a severe deficiency (vitamin Patients with severe cholestasis have decreased absorption D < 10 ng/mL) occurred in 56.8% of patients, with low of vitamin D compared to patients with milder disease.23 levels of 25(OH)D being independently associated with 922 Koop AH, et al. , 2018; 17 (6): 920-932 Table 1. Epidemiology, Clinical Findings, and Diagnosis of Vitamin D, Vitamin A, and Zinc Deficiency in Cirrhosis. Epidemiologic, Vitamin D Vitamin A Zinc clinical, diagnostic information Prevalence 68%-86%8,10,15,19,20 - 28 -