ORIGINAL ARTICLE

High Prevalence of Vitamin A Deficiency andVitamin D Deficiency in Patients Evaluated forLiver TransplantationMukund Venu, Eric Martin, Kia Saeian, and Samer GawriehDivision of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI

Deficiencies in vitamins A, D, and E have been linked to night blindness, bone health, and post–liver transplant reperfusioninjury. The aim of this study was to determine the prevalence and predictive factors of fat-soluble vitamin deficiencies in livertransplant candidates. We reviewed the medical records of liver transplant candidates at our center from January 2008 toSeptember 2011. The etiology of cirrhosis, Model for End-Stage Liver Disease score, Child-Pugh class, body mass index(BMI), and vitamin A, vitamin E, and vitamin 25-OH-D levels were recorded. Patients were excluded for incomplete labora-tory data, short gut syndrome, celiac disease, pancreatic insufficiency, or prior liver transplantation. Sixty-three patientswere included. The most common etiologies of liver disease were alcohol (n 5 23), hepatitis C virus (n 5 19), and nonalco-holic steatohepatitis (n 5 5). Vitamin A and D deficiencies were noted in 69.8% and 81.0%, respectively. Only 3.2% of thepatients were vitamin E–deficient. There were no documented cases of night blindness. Twenty-five of the 55 patients withbone density measurements had osteopenia, and 10 had osteoporosis. Four patients had vertebral fractures. There was 1case of posttransplant reperfusion injury in a patient with vitamin E deficiency. In a multivariate analysis, there were no stat-istically significant predictors for vitamin D deficiency. The Child-Pugh class [odds ratio (OR) 5 6.84, 95% confidence interval(CI) 5 1.52-30.86, P 5 0.01], elevated total bilirubin level (OR 5 44.23, 95% CI 5 5.02-389.41, P< 0.001), and elevated BMI(OR 5 1.17, 95% CI 5 1.00-1.36, P 5 0.045) were found to be predictors of vitamin A deficiency. In conclusion, the majorityof liver disease patients evaluated for liver transplantation at our center had vitamin A and D deficiencies. The presence orabsence of cholestatic liver disease did not predict deficiencies, whereas Child-Pugh class, bilirubin level, and elevated BMIpredicted vitamin A deficiency. Liver Transpl 19:627–633, 2013. VC 2013 AASLD.

Received December 7, 2012; accepted March 11, 2013.

Malnutrition is commonly encountered in patientswith end-stage liver disease (ESLD) and has beenreported in up to 80% of all patients with cirrhosisand in up to 25% of patients with Child-Pugh class Acirrhosis.1,2 It has also been associated with highermorbidity and mortality.1,2 In fact, the original Child-Turcotte classification included nutritional status as aprognostic parameter.3 Cirrhosis is associated with ahypermetabolic state, increased protein catabolism,decreased glycogen storage and glucose oxidation,and increased lipid oxidation, all of which contributeto a poor nutritional status,4 but the precise etiology

of malnutrition in patients with cirrhosis is notestablished.

In patients with cirrhosis and chronic cholestasis,there is inadequate delivery of bile salts into the intes-tinal lumen. This can lead to insufficient absorptionand a fat-soluble vitamin deficiency.5 For example,vitamin A deficiency has been observed in patientswith primary biliary cirrhosis (PBC) and may be asso-ciated with night blindness.6,7 Several studies havealso shown vitamin D deficiency in both cholestaticand noncholestatic liver disorders.8-10 It is, however,not clear whether such vitamin deficiencies are due to

Abbreviations: AIH, autoimmune hepatitis; BMI, body mass index; CI, confidence interval; ESLD, end-stage liver disease; HCV,hepatitis C virus; MELD, Model for End-Stage Liver Disease; NASH, nonalcoholic steatohepatitis; OR, odds ratio; PBC, primarybiliary cirrhosis; PSC, primary sclerosing cholangitis; ROC, receiver operating characteristic.

This study was supported in part by grant 1UL1RR031973 from the Clinical and Translational Science Award program of theNational Center for Research Resources (National Institutes of Health).

Address reprint requests to Samer Gawrieh, M.D., Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI53226. Telephone: 414-955-6850; FAX: 414-955-6214; E-mail: sgawrieh@mcw.edu

DOI 10.1002/lt.23646View this article online at wileyonlinelibrary.com.LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

LIVER TRANSPLANTATION 19:627–633, 2013

VC 2013 American Association for the Study of Liver Diseases.

poor nutritional intake, hepatic dysfunction, malab-sorption, or a combination of these factors. There arefew data on the prevalence of fat-soluble vitamin defi-ciencies among patients with ESLD awaiting livertransplantation.11 The aims of this study were toassess the prevalence of fat-soluble vitamin deficien-cies in patients being evaluated for liver transplanta-tion and to elucidate the predictive factors for anysuch deficiencies.

PATIENTS AND METHODS

We retrospectively reviewed the charts of patients whopresented for an outpatient evaluation for liver trans-plantation at the Medical College of Wisconsin Hepa-tology Clinic from January 2008 to September 2011.The study protocol was reviewed and approved by theinstitutional review board of the Medical College ofWisconsin. The etiology of cirrhosis, Model for End-Stage Liver Disease (MELD) score, Child-Pugh score,body mass index (BMI), and vitamin A, vitamin E, andvitamin 25-OH-D levels were recorded. Patient demo-graphics, including age, sex, smoking history, alcoholuse, and drug use, were reviewed.

Serum vitamin A and E levels were determined viahigh-pressure liquid chromatography with ultravioletdetection (Agilent Technologies, Santa Clara, CA). Se-rum vitamin D 25-OH levels were determined with aradioimmunoassay (DiaSorin, Stillwater, MN). VitaminA, D, and E deficiencies were defined as levels<19lg/dL,<32 ng/mL, and<3 mg/L, respectively, andwere based on normal ranges used at our institution.A severe vitamin D deficiency was defined as a lev-el<10 ng/mL.

Patients were excluded if they had short gut syn-drome, celiac disease, pancreatic insufficiency, a pre-vious liver transplant, or an incomplete laboratoryanalysis.

Statistical Analysis

Univariate comparisons of patient characteristicsbetween vitamin-deficient and nondeficient subjectswere performed with the Student t test for continuousvariables (age, BMI, and MELD score), with the chi-square test for binary variables [sex; race; alaninetransaminase, aspartate transaminase, bilirubin, al-bumin, and alkaline phosphate levels; and contribu-tions of alcohol, nonalcoholic steatohepatitis (NASH),hepatitis C virus (HCV), and primary sclerosing chol-angitis (PSC) to the disease etiology], and with the Wil-coxon rank-sum test for ordinal variables (Child-Pughscore). The exact chi-square test was used when theexpected number of subjects in a category was 5 orfewer. Similar methods were used for the comparisonof excluded and included subjects.

Logistic regression was used for the multivariateanalysis of predictors of vitamin deficiencies. Due tothe large number of potential predictors, model build-ing was performed by forward stepwise selection witha 10% significance level for entry and a 5%

significance level for staying in the model. The predic-tive power of the final model for vitamin A deficiencywas evaluated with a receiver operating characteristic(ROC) analysis.

All analyses were performed with SAS 9.2 (SASInstitute, Cary, NC).

RESULTS

Sixty-three of the 211 patients referred for liver trans-plantation met the inclusion criteria. Incomplete labo-ratory data (139 patients) were the most commonreason for exclusion, and this was due to the varyingadherence of different providers in our practice toscreening and was not based on a clinical suspicionof vitamin deficiency. Subjects’ characteristics aresummarized in Table 1. There were no statisticallysignificant differences in age, race, sex, BMI, etiologyof liver disease, Child-Pugh class, MELD score, alco-hol use, or smoking history between the included andexcluded subjects. The most common etiologies ofchronic liver disease were alcohol abuse (n 5 23) andHCV (n 5 19; Table 2). The remaining patients hadHCV and alcohol (n 5 5), NASH (n 5 5), PSC (n 5 4),PBC (n 5 2), NASH and PBC (n 5 1), autoimmune hep-atitis (AIH; n 5 2), hepatic carcinoid tumor (n 5 1), orAIH and PSC (n 5 1). None of the included patientshad acute liver disease or failure. The majority of thepatients were deficient in vitamin A and vitamin D(69.8% and 81.0%, respectively); however, only 2 ofthe 63 patients (3.2%) were vitamin E–deficient, andboth had PSC. More than half of the patients were de-ficient in both vitamin A and vitamin D (36/63 or57.1%). A severe vitamin D deficiency (<10 ng/mL)was found in only 4 patients (6.3%). When 20 ng/mLwas used as the lower limit of normal for definingvitamin D deficiency, 47 of 63 patients (75%) were de-ficient. The one patient who was underweight but hadnormal fat-soluble vitamin levels had HCV cirrhosis.

There were no documented cases of night blindnessin our cohort. Vertebral fractures were documented in4 patients, all of whom were vitamin D–deficient.Bone density data, as measured by dual-energy X-rayabsorptiometry scanning, were available for 55patients. Osteopenia was noted in 25 patients, andosteoporosis was seen in 10 patients, whereas normalbone density was noted in 20 patients. In this groupwith bone density data, vitamin D deficiency wasnoted in 18 of the 25 patients (72%) with osteopenia,in 10 of the 10 patients (100%) with osteoporosis, andin 16 of the 20 patients (80%) with normal bone den-sity. Vertebral fractures were documented in 4patients, all of whom had vitamin D deficiency andosteopenia on a dual-energy X-ray absorptiometryscan. One of our patients who had vitamin E defi-ciency before transplantation had a reperfusion injurypostoperatively.

Most patients were not on any vitamin supplemen-tation (40/63 or 63.5%) before their assessment atthe hepatology clinic. Seventeen patients (27.0%) weretaking a multivitamin supplement. However, 13 of

628 VENU ET AL. LIVER TRANSPLANTATION, June 2013

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LIVER TRANSPLANTATION, Vol. 19, No. 6, 2013 VENU ET AL. 629

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630 VENU ET AL. LIVER TRANSPLANTATION, June 2013

these 17 patients (76.5%) were vitamin D–deficient,12 (70.6%) were vitamin A–deficient, and 3 (17.6%)had no vitamin deficiencies. The amounts of fat-solu-ble vitamins in the multivitamin pills and patients’compliance with taking them could not be determinedfrom the chart review. Only 6 patients were takingvitamin D (5 of whom were on >1000 IU/day dosing),and 2 patients were taking vitamin E supplementa-tion. Compliance with taking these supplements couldnot be verified. In the limited number of patients inthis cohort who had follow-up data, oral supplemen-tation with vitamins A and D resulted in the correc-tion of vitamin A and D deficiencies in 3 of 5 patients(60%) and 12 of 16 of patients (75%), respectively.

All patients with Child-Pugh class C cirrhosis(n 5 11) were deficient in vitamin A. In a multivariateanalysis, there were no statistically significant predic-tors for vitamin D deficiency. The Child-Pugh class[odds ratio (OR) 5 6.84, 95% confidence interval(CI) 5 1.52-30.86, P 5 0.01], an elevated total bilirubinlevel (OR 5 44.23, 95% CI 5 5.02-389.41, P<0.001),and an elevated BMI (OR 5 1.17, 95% CI 5 1.00-1.36,P 5 0.045) were found to be predictors of vitamin Adeficiency (Table 3). With the full model (including theChild-Pugh class, bilirubin level, and BMI), the areaunder the ROC curve for this model was 0.9139 (95%CI 5 0.84-0.98), and it was higher than the areas ofmodels including the Child-Pugh class and bilirubinlevel (0.8714, 95% CI 5 0.77-0.96) or the bilirubinlevel alone (0.7817, 95% CI 5 0.66-0.89; Fig. 1).

DISCUSSION

The majority of ESLD patients evaluated for livertransplantation at our center were deficient in vitaminA and vitamin D. The Child-Pugh class, the serum bil-irubin level, and an elevated BMI were predictors ofvitamin A deficiency. There were no predictors forvitamin D deficiency. Interestingly, the etiology of liverdisease was not predictive of a fat-soluble vitamindeficiency.

Malnutrition has been established as a negativeprognostic indicator in patients with ESLD.12-18 Previ-ous studies have evaluated fat-soluble vitamin defi-ciencies in patients with chronic cholestatic liverdisorders, in which impaired bile flow is the proposedunderlying mechanism leading to malabsorption offat-soluble vitamins. Few studies have evaluated this

in patients with noncholestatic liver diseases, andmost have focused on vitamin D deficiency.

Fisher and Fisher9 evaluated 100 consecutivepatients with noncholestatic liver disease for vitaminD deficiency. The most common etiologies of liver dis-ease were alcohol (n 5 40) and HCV (n 5 38). VitaminD deficiency was found in 68 patients and was moreprevalent in patients with Child-Pugh class C cirrho-sis. Malham et al.8 sought to compare vitamin D defi-ciency in patients with noncholestatic liver diseaseand patients with cholestatic liver disease. In thatstudy, 89 patients with alcoholic cirrhosis and 34patients with PBC were retrospectively evaluated forvitamin D deficiency. Vitamin D deficiency was moreprevalent in patients with alcoholic cirrhosis versuspatients with PBC (85% versus 60%). Arteh et al.10

evaluated vitamin D deficiency in 118 consecutivepatients with HCV. They found that 109 of the 118patients (92%) had vitamin D deficiency, with severevitamin deficiency (<7 ng/mL) more common inpatients with cirrhosis. A high incidence of vitamin Aand D deficiencies was also reported in a recent studyby Abbott-Johnson et al.11 In that study, 107 patientswith ESLD who were awaiting liver transplantationwere prospectively followed; 75% of the patients weredeficient in vitamin A, 66% were deficient in vitaminD, and only 3% were deficient in vitamin E. Similarlyto our findings, the severity of the underlying liver dis-ease, as reflected by the Child-Pugh class, was foundto be a predictor of fat-soluble vitamin deficiencies.

In agreement with prior studies, the majority of ourpatients with ESLD who were evaluated for livertransplantation were found to be deficient in bothvitamin A (69.8%) and vitamin D (81%), but the pro-portion of patients with vitamin E deficiency was low(3.2%). The MELD score and the presence or absenceof cholestatic liver disease were not found to be pre-dictive of vitamin deficiencies in our patients.

TABLE 3. Multivariate Analysis of Predictors

of Vitamin A Deficiency: Stepwise Logistic

Regression Results

Variable OR (95% CI) P Value

Child-Pugh class 6.84 (1.52-30.86) 0.01Total bilirubin level 44.23 (5.02-389.41) <0.001BMI 1.17 (1.00-1.36) 0.045

Figure 1. ROC graph for models predicting vitamin Adeficiency.

LIVER TRANSPLANTATION, Vol. 19, No. 6, 2013 VENU ET AL. 631

A fat-soluble vitamin deficiency may have significantclinical consequences. Osteoporosis is a potentialcomplication after liver transplantation. By causingsecondary hyperparathyroidism, vitamin D deficiencybefore liver transplantation may increase the risk forosteoporosis and fractures.19 There was a high rate ofosteoporosis and osteopenia in our patients, and 4subjects (6.3%) had vertebral fractures. In a recentstudy, Kaemmerer et al.20 evaluated the impact ofibandronate, vitamin D3, and calcium supplementsbefore and after liver transplantation on 31 patientswith osteopenia or osteoporosis before transplanta-tion. This regimen increased bone mineral density inthe lumbar spine up to 12 months after transplanta-tion, and after 24 months, there were only 2 reportedcases of fractures within this group. Although therewere no documented cases of night blindness in ourpatients with vitamin A deficiency, none of themunderwent a formal ophthalmological evaluation. Astudy by Abbott-Johnson et al.7 evaluated vitamin Adeficiency and night blindness in 8 patients with cir-rhosis awaiting liver transplantation. Interestingly, 6of the 8 patients were unaware of impairments intheir vision. All the patients showed improvementswith dark adaptation after intramuscular supplemen-tation with vitamin A. One of our 2 patients with vita-min E deficiency had a reperfusion injury after livertransplantation. Interestingly, Goode et al.21 demon-strated an increased risk of reperfusion injury afterliver transplantation in patients with vitamin E defi-ciency before transplantation. We found no predictorsfor vitamin D deficiency, and this was contrary to pre-vious studies that had identified cirrhosis, female sex,and African American race as predictors for vitamin Ddeficiency.10,22 Dietary insufficiency, malabsorption,impaired hepatic hydroxylation of vitamin D, and alack of sunlight exposure may contribute to vitamin Ddeficiency. Although no predictors for vitamin A defi-ciency were identified in prior reports, an advancedChild-Pugh class, the total bilirubin level, and an ele-vated BMI were associated with it in our cohort. It isunclear why Child-Pugh class C patients had a lowerfrequency of vitamin D deficiency and a higher fre-quency of vitamin A deficiency in comparison withChild-Pugh class A and B patients.

Our study has several limitations. We were unableto find data in the reviewed medical records concern-ing the adequacy of oral intake or other parametersfor assessing nutritional status such as pre-albumin,triceps skinfold thickness, and midarm muscle cir-cumference. Our patient population is located in Wis-consin (at a latitude of 43� N), and this may affect theprevalence of vitamin D deficiency because thereduced exposure to sunlight may contribute to lowervitamin D levels. Vitamin E deficiency was not evidentin our patient population. There are conflicting stud-ies on whether the serum measurement of a-tocoph-erol or the a-tocopherol/total lipid ratio is a moreaccurate measure of vitamin E in patients withchronic liver disease.23,24 Serum lipid panels from ourpatient population were not analyzed, and we did not

calculate this ratio to elucidate whether more patientshad vitamin E deficiency. Our study was designed notto evaluate the mechanism for these deficiencies butinstead to identify whether these patients had signifi-cant deficiencies in fat-soluble vitamins. Although anelevated BMI was identified as a predictor of vitaminA deficiency, our BMI calculation was not adjusted forfluid retention. Finally, the exact composition of eachpatient’s multivitamin was unknown; therefore, it isunclear how much impact, if any, these supplementsmay have had on serum values of fat-solublevitamins.

If our findings are validated in other studies, univer-sal screening for vitamins A and D in this populationof patients being evaluated for liver transplantationmay be reasonable because of the high prevalence ofthese deficiencies. Whether vitamin E deficiency islimited only to patients with PSC also needs to beexamined in order to make recommendations onappropriate screening. Whether using a daily multivi-tamin supplement will reduce these deficiencies hasnot been prospectively studied; however, it did notseem to affect vitamin A and D deficiencies in a sub-group of our patients.

In summary, our study confirms that deficiencies ofvitamins A and D in patients with ESLD awaiting livertransplantation are very common. The etiology of liverdisease did not predict vitamin deficiencies; however,the severity of liver disease affected vitamin A defi-ciency. The identification and correction of these com-mon deficiencies may be important elements in effortsto optimize this highly morbid patient populationbefore liver transplantation.

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