Nutritional Status of patients
undergoing Home Parenteral
Nutrition
Estado Nutricional de doentes sob
Nutrição Parentérica Domiciliária
Rita Bouça Soares Pereira
ORIENTADO POR: Mestre Alice Manuela Ribeiro Lopes
TRABALHO DE INVESTIGAÇÃO
1.º CICLO EM CIÊNCIAS DA NUTRIÇÃO | UNIDADE CURRICULAR ESTÁGIO
FACULDADE DE CIÊNCIAS DA NUTRIÇÃO E ALIMENTAÇÃO DA UNIVERSIDADE DO PORTO
TC
Abstract
Introduction: Home Parenteral Nutrition (HPN) is considered the primary and
life-saving therapy for chronic intestinal failure patients, enabling them to maintain an adequate nutrition status. However, proper delivery of HPN requires regular and continuous monitoring. Objectives: To know the nutritional status of patients undergoing HPN and to study its evolution. Methodology: An observational, retrospective study at Centro Hospitalar Universitário do Porto, analysed a sample of five patients undergoing HPN, throughout eight distinct moments. Sociodemographic, clinical, biochemical, anthropometric and body composition data were obtained. Results: There was an overall tendency for weight and body mass index to increase. Regarding phase-angle, in 81,3% (in men) and 95,8% (in women) of the assessments, patients were not at nutritional risk. Overall, there was an improvement in liver function, which was significant in women: aspartate aminotransferase (p=0,008), alanine aminotransferase (p=0,009), alkaline phosphatase (p=0,042) and gamma-glutamyl transferase (p=0,018) levels. A decrease in total cholesterol levels (p=0,011) was observed, with improvement in high density lipoprotein cholesterol and triglycerides levels. Albumin and electrolytes were mainly normal and an increase in vitamin D levels was observed (p=0,037), as well as in zinc for women (p=0,015). There was also a decrease in iron levels, but an improvement in transferrin, ferritin and haemoglobin levels.
Conclusion: Overall, the nutritional status of patients was adequate, with an
observed improvement in liver function, lipid and iron metabolism parameters, vitamin D and haemoglobin levels throughout assessments.
Introdução: A Nutrição Parentérica Domiciliária (NPD) é considerada a terapia de
primeira linha no tratamento de doentes com insuficiência intestinal crónica, permitindo-lhes manter um estado nutricional adequado. Contudo, uma administração eficaz de NPD requer uma monitorização regular e contínua.
Objetivos: Conhecer o estado nutricional de doentes sob NPD e estudar a sua
evolução. Metodologia: Foi realizado um estudo observacional, retrospetivo, no Centro Hospitalar Universitário do Porto, com uma amostra de cinco doentes sob NPD. Foram recolhidos dados sociodemográficos, clínicos, bioquímicos, antropométricos e de composição corporal, em oito momentos diferentes.
Resultados: Verificou-se uma tendência geral de aumento de peso e de índice de
massa corporal. Relativamente ao ângulo de fase, em 81,3% (em homens) e 95,8% (em mulheres) das avaliações, os doentes não se encontravam em risco nutricional. No geral, verificou-se melhoria da função hepática, sendo esta significativa em mulheres: aspartato aminotransferase (p=0,008), alanina aminotransferase (p=0,009), fosfatase alcalina (p=0,042) e gama glutamiltransferase (p=0,018). Observou-se diminuição nos níveis de colesterol total (p=0,011) e melhoria nos níveis de lipoproteínas de alta densidade e triglicerídeos. A maioria dos valores de albumina e de eletrólitos foram normais e houve aumento dos níveis de vitamina D (p=0,037) e de zinco nas mulheres (p=0,015). Verificou-se uma tendência de diminuição dos níveis de ferro, mas uma melhoria dos níveis de transferrina, ferritina e hemoglobina. Conclusão: De forma geral, o estado nutricional dos doentes era adequado, tendo-se verificado melhoria da função hepática, metabolismo lipídico e do ferro, níveis de vitamina D e hemoglobina, ao longo das avaliações.
Palavras-Chave: Nutrição Parentérica Domiciliária, Falência intestinal, Estado
nutricional
ALP: Alkaline phosphatase ALT: Alanine aminotransferase AST: Aspartate aminotransferase BIA: Bioelectrical impedance analysis BMI: Body mass index
CHUP: Centro Hospitalar Universitário do Porto CIF: Chronic intestinal failure
ESPEN: European Society for Clinical Nutrition and Metabolism FFM: Fat-free mass
FFMI: Fat-free mass index FM: Fat mass
FMI: Fat mass index
GGT: Gamma-glutamyl transferase HPN: Home parenteral nutrition IF: Intestinal failure
PhA: Phase angle
PN: Parenteral nutrition R: Resistance
RV: Reference values TG: Triglycerides TC: Total cholesterol
WHO: World Health Organization Xc: Reactance
Abstract ... i
Resumo ... iii
List of abbreviations, initials and acronyms ... v
Index ... vii Introduction ... 1 Aims ... 2 Methods ... 2 Results ... 5 Discussion ... 9 Conclusions ... 15 Acknowledgments ... 16 References ... 17 Appendices ... 21 List of appendices ... 22
Introduction
Parenteral Nutrition (PN) is a medical nutritional therapy(1), which involves the intravenous administration of fluids and nutrients, when an individual is not able to meet their nutritional requirements sufficiently, or not at all, via the oral or enteral route(2).
The European Society for Clinical Nutrition and Metabolism (ESPEN) defines Home Parenteral Nutrition (HPN) as PN administered outside the hospital(1, 3). It is an appropriate therapy for patients who are able to safely manage(3) and receive it outside an acute setting(4). The first described cases of HPN appear in the late 1960s and early 1970s(5), giving rise to the concept of “artificial gut” regarding the treatment of intestinal failure (IF)(5, 6), a condition characterized by a loss of the gut absorptive function to a level that intravenous supplementation is required for maintenance of health and growth(7).
Among all its purposes, HPN is often used in chronic IF (CIF)(1), being considered the primary and life-saving therapy for these patients(3, 7), enabling them to maintain an adequate nutrition status, maintain long term health(8) and to restore and improve the quality of life of the patients(4, 6). In this context, the intervention of multidisciplinary nutrition support teams is recommended(3, 9), proved to lead to better outcomes and possibly reduce costs of care. These teams are responsible for monitoring, reviewing indications(3), ensuring that the established treatment goals are being achieved(6), minimizing both short and long-term complications(10) and preventing hospital readmissions(11).
According to the updated ESPEN guidelines on HPN, for every three to six months, patients on long-term HPN should be monitoring body weight, hydration status,
energy and fluid balance, biochemistry and body composition. Vitamins and trace metals should be evaluated at least once per year(3).
Concerning body composition, its assessment is essential for determining the effectiveness of the current nutritional intervention(12). From the various existing methods, bioelectrical impedance analysis (BIA) is a safe, inexpensive(12, 13), practical, portable(13), quick and non-invasive method(1), with readily available and reproducible results(12). Additionally, it allows the calculation of phase angle (PhA), a raw measurement obtained from BIA’s resistance (R) and reactance (Xc)(12). PhA is considered an indicator of the nutritional status(14), associated with readmission rates and mortality(15) and identified as a strong prognostic value(1). This study incorporates the assessment of various parameters in a group of patients undergoing HPN in Portugal, allowing a deeper understanding of their evolution and nutritional status.
Aims
This study aims to know the nutritional status of a group of patients undergoing HPN and to study the evolution of their nutritional status.
Methods
Participants and Study Design: an observational, retrospective study was
conducted at Centro Hospitalar Universitário do Porto (CHUP). The analysed sample was a group of five patients, followed by Unit 1 of General Surgery, who enrolled in an HPN program, consecutively, from 1996, until the present moment.
Data collection: the collected variables included sociodemographic, clinical,
biochemical, anthropometric and body composition data (from BIA), all of them obtained from electronic patient records. The last three categories were gathered by consecutive assessment of patients in routine appointments, in a total of eight different moments, right after discharge from the hospital and until 2019. The chronogram of data collection is presented in Appendix A.
Sociodemographic and clinical data: age (years) and sex (male or female) were
recorded regarding sociodemographic data. Clinical data gathered comprised the diagnosis for HPN, time (years) undergoing the treatment, the characteristics of the current PN bag and HPN program (days of infusion/week). Basal metabolic rate was also calculated using Harris-Benedict equation (16, 17).
Biochemical blood analysis data: the following biochemical blood markers were
recorded: glucose (mg/dL), urea (mg/dL), creatinine (mg/dL), albumin (g/dL), total proteins (g/dL), total bilirubin (mg/dL), alkaline phosphatase (ALP) (U/L at 37º), gamma-glutamyl transferase (GGT) (U/L at 37º), aspartate aminotransferase (AST) (U/L at 37º), alanine aminotransferase (ALT) (U/L at 37º), total cholesterol (TC) (mg/dL), low density lipoprotein (LDL) cholesterol (mg/dL), high density lipoprotein (HDL) cholesterol (mg/dL), triglycerides (TG) (mg/dL), iron (μg/dL), transferrin (mg/dL), transferrin saturation (%), ferritin (ng/mL), sodium (mmol/L), potassium (mmol/L), chloride (mmol/L), phosphorus (mmol/L), magnesium (mmol/L), zinc (μmol/L), total calcium (mmol/L), vitamin D (nmol/L), vitamin B12 (pg/mL), folic acid (ng/mL), leukocytes (x10³/μL), erythrocytes
(x106/μL), haemoglobin (g/dL) and haematocrit (%). The reference values (RV) taken into account were the ones used by the Pathology Laboratory Department of the Clinical Chemistry Service of CHUP.
Anthropometrics: body weight (kg) and height (cm) values were obtained and body
mass index (BMI) (kg/m2) was then calculated using the standard formula weight (kg) / height2 (m). BMI classification was done according to the categories defined by the World Health Organization (WHO)(18).
Body composition evaluation: the values of R (ohms) and Xc (ohms) were collected
from BIA electronic patients’ records, with posterior calculation of PhA (º)(19), as well as fat-free mass (FFM) (kg), fat mass (FM) (kg)(20) (Appendix B) and respective indexes, dividing FFM and FM by the height squared (kg/m2)(21).
As proposed(22) and used (15, 23) previously, the PhA cut-off points in this study were 4,6º and 5º for women and men, respectively, grouping patients into nutritional risk (<4,6º and <5º) and not at nutritional risk (≥4,6ºand ≥5º). For FFM Index (FFMI) and FM Index (FMI), the ranges used by Pichard et al.(24) were applied.
Statistical Analysis: the statistical analysis made was descriptive, expressed as
the median and interquartile range. To understand the overall tendency of evolution of each variable over time, a regression line was calculated, with data from all the patients in the eight moments of assessment and a t-test p value was obtained to determine whether the mean slope was significantly different from 0. Statistical significance was defined for p<0.005. Variables with positive and negative slopes indicate an increasing and decreasing tendency of change over
time, respectively. When RV or cut-off points differed between men and women, two distinct linear regression equations were calculated, accordingly. All gathered data were structured and analysed into Software Package for Social Sciences (SPSS)® database, 26.0 version. Graphs were made using Microsoft Excel®.
Ethical Statement: this study was ethically conducted according to the principles
of the Declaration of Helsinki and approved by the ethics committee of CHUP. Written informed consent was obtained from participants.
Results
The five people study sample was composed of three females and two males, with a median age of 53,0 (47,5-61,0) years, a median weight of 59,9 (54,2-74,3) kg and a median BMI of 26,6 (19,6-28,2) kg/m2. The median of time undergoing HPN was 13,4 (8,1-20,5) years, with the most recent patient being on HPN for 4,9 years and the oldest for 23,5 years. The median number of hospital readmissions was 11,0 (3,5-24,5) and all diagnoses were CIF due to intestinal ischemia (n=5). A patient baseline overview is presented in Table 1.
Table 1. Baseline sociodemographic, anthropometric and clinical data of patients.
VARIABLE PATIENT 1 PATIENT 2 PATIENT 3 PATIENT 4 PATIENT 5 Sociodemographic data
Sex Female Female Female Male Male
Age (y) 44 64 53 58 51
Anthropometric data
Weight (kg) 53,7 59,9 68,3 54,6 80,2
Height (cm) 142,0 150,0 151,5 179,0 190,0 Body index mass (kg/m2) 26,6 26,6 29,8 17,0 22,2
Table 1. Baseline sociodemographic, anthropometric and clinical data of patients (continued).
VARIABLE PATIENT 1 PATIENT 2 PATIENT 3 PATIENT 4 PATIENT 5 Clinical data Diagnosis for HPN CIF due to intestinal ischemia CIF due to intestinal ischemia CIF due to intestinal ischemia CIF due to intestinal ischemia CIF due to intestinal ischemia Time undergoing HPN (y) 11,3 17,5 13,4 23,5 4,9 Total number of hospital readmissions 3 4 24 11 25 Basal metabolic rate (kcal/day) 1226 1206 1341 1314 1775 Characteristics of current PN bag 2 days/week 1500mL, 1710 kcal, 60g L, 66,4g AA, 210g G, 137 NPC/N 4 days/week 1000mL, 1140 kcal, 40g L, 44,3g AA, 140g G, 137 NPC/N 5 days/week 1000mL, 1140 kcal, 40g L, 44,3g AA, 140g G, 137 NPC/N 7 days/week 1500mL, 1050 kcal, 40g L, 44,3g AA, 140g G, 150 NPC/N 6 days/week 1500mL, 1710 kcal, 60g L, 66,4g AA, 210g G, 137 NPC/N 1 day/week 1000mL, 1140 kcal, 40g L, 44,3g AA, 140g G, 137 NPC/N 5 days/week 1000mL, 1140 kcal, 40g L, 44,3g AA, 140g G, 137 NPC/N
HPN, Home parenteral nutrition; CIF, Chronic intestinal failure; PN bag, Parenteral nutrition bag; L, Lipids; AA, amino acids; G, Glucose; NPC/N, Non Protein Calorie:Nitrogen Ratio
Results from linear regression analysis, as well as the proportion of values categorized according to cut-off values, when applicable, or proportion of measurements below, within and above the RV, are presented in Tables 2-5 for body composition, general biochemistry, lipid metabolism and electrolytes, trace elements and vitamin parameters.
Table 2. Results regarding body composition parameters.
Parameter Sex Classification (%) Slope (β) P value
Phase Angle (º)a
Nutritional risk Not-at-nutritional risk
M 18,8 81,3 -0,155 0,792
W 4,2 95,8 -0,264 0,705
Fat-free Mass Index
(kg/m2)b
Low Normal High
M 53,3 46,7 0,0 -0,090 0,670d
W 0,0 45,8 54,2 0,019 0,698
Fat Mass Index
(kg/m2)c
Low Normal High Very high
M 0,0 66,7 33,3 0,0 -0,186 0,066d
W 0,0 8,3 75,0 16,7 0,531 <0,001*
M, Men; W, Women
aNutritional risk (<4,6º and <5º for women and men, respectively) and not-at-nutritional risk (≥4,6º and ≥5º, for women and
men, respectively); bLow (<17,4 kg/m2 and <15,0 kg/m2), Normal (17,5-19,7 kg/m2 and 15,1-16,6 kg/m2), High (>19,8 kg/m2
and >16,7 kg/m2), with the first and second presented RV for men and women, respectively; cLow (<2,4 kg/m2 and <4,8
kg/m2), Normal (2,5-5,1 kg/m2 and 4,9-8,2 kg/m2), High (5,2-8,1 kg/m2 and 8,3-11,7 kg/m2), Very high (>8,2 kg/m2 and
>11,8 kg/m2), with the first and second presented RV for men and women, respectively; dOne missing value; *P value for a
Table 3. Results regarding general biochemistry parameters.
Parameter Sex values (RV) Reference % Below RV % Within RV % Above RV Slope (β) P value
Glucose (mg/dL) Both 70-105 10,0 77,5 12,5 -0,240 0,819 Creatinine (mg/dL) M 0,7-1,2 6,3 37,5 56,3 0,008 0,833 W 0,5-0,9 16,7 58,3 25,0 0,043 0,129 Urea (mg/dL) Both 10-50 0,0 72,5 27,5 1,767 0,057 Total bilirubin (mg/dL) Both 0,20-1,00 2,5 85,0 12,5 -0,031 0,212 Aspartate aminotransferase (U/L at 37º) M 10-34 0,0 81,3 18,8 -1,214 0,340 W 10-30 0,0 41,7 58,3 -7,734 0,008* Alanine aminotransferase (U/L at 37º) M 10-44 0,0 75,0 25,0 -3,101 0,215 W 10-36 0,0 37,5 62,5 -17,476 0,009* Alkaline phosphatase (U/L at 37º) M 40-129 0,0 6,3 93,8 3,435 0,236 W 35-104 0,0 12,5 87,5 -15,840 0,042* Gamma-glutamyl transferase (U/L at 37º) M 10-66 0,0 62,5 37,5 -6,240 0,116 W 6-39 0,0 41,7 58,3 -12,325 0,018*
M, Men; W, Women; Both, regression line includes data without differentiation between sex. *P value for a statistically significant result.
Table 4. Results regarding lipid metabolism parameters.
Parameter Sex Reference
values (RV) % Below RV % Within RV % Above RV Slope (β) P value Total cholesterol (mg/dL) Both 0-200 0,0 97,5 2,5 -6,126 0,011* HDL cholesterol (mg/dL) M 35-55 100,0 0,0 0,0 0,339 0,525a W 45-65 100,0 0,0 0,0 1,369 0,124b LDL cholesterol (mg/dL) Both 0-130 0,0 100,0 0,0 -1,658 0,263c Triglycerides (mg/dL) M 40-160 0,0 87,5 12,5 1,619 0,710 W 35-135 0,0 58,3 41,7 -5,472 0,335 M, Men; W, Women; Both, regression line includes data without differentiation between sex.
aTwo missing values; bThree missing values; cSix missing values; *P value for a statistically significant result.
Table 5. Results regarding electrolytes, trace elements and vitamins.
Parameter Sex values (RV) Reference % Below RV % Within RV % Above RV Slope (β) P value
Sodium (mmol/L) Both 135-145 2,5 95,0 2,5 -0,088 0,708
Potassium (mmol/L) Both 3,50-5,00 5,0 87,5 7,5 0,024 0,550
Chlorides (mmol/L) Both 95-105 0,0 95,0 5,0 -0,086 0,674
Phosphorus (mmol/L) Both 0,87-1,45 20,0 70,0 10,0 -0,029 0,348
Magnesium (mmol/L) Both 0,60-1,10 0,0 95,0 5,0 0,013 0,154
Total calcium (mmol/L) Both 2,15-2,50 15,0 62,5 22,5 -0,004 0,737
Zinc (μmol/L) M 10,7-23 40,0 60,0 0,0 0,379 0,446
a
W 9,1-18,3 0,0 86,4 13,6 0,736 0,015*b
Vitamin D (nmol/L) Both 50-150 86,1 13,9 0,0 2,505 0,037*c
Vitamin B12 (pg/mL) Both 191-663 0,0 66,7 33,3 -1,060 0,938a
Folic acid (ng/mL) Both 3,9-26,8 0,0 100,0 0,0 -0,019 0,915a
M, Men; W, Women; Both, regression line includes data without differentiation between sex.
Tables 6-9, in Appendix C, comprise the analysis for anthropometric, iron, protein and haemogram parameters.
Anthropometric results indicate a rise in weight and BMI with progression of HPN therapy. Normal weight (45,0%) and pre-obesity (45,0%) were the most frequent BMI classifications in the assessments. For body composition data, both FFMI and FMI values increased in women, with a significant positive slope for FMI (β=0,531; p=<0,001) whereas, in men, a slight decreasing propensity was observed, with a proportion of low FFMI of 53,3%. Concerning PhA, the negative slopes of the regression lines note a decreasing tendency with length of the therapy. However, in 81,3% and 95,8% of the assessments, in men and women, respectively, patients were not at nutritional risk.
With regards to liver function, not only was the tendency for total bilirubin to decrease, but also 85,0% of the values were within the reference range. Women had statistically negative slopes for AST (β=-7,734; p=0,008), ALT (β=-17,476; p=0,009), ALP (β=-15,840; p=0,042) and GGT (β=-12,325; p=0,018), with 58,3%, 62,5%, 87,5% and 58,3% of the results above the normal range, respectively. In lipid metabolism parameters, TC had a significant negative slope (β=-6,126; p=0,011), with 97,5% of normal values. With respect to iron metabolism (Appendix C, Table 7), 68,8% and 79,2% of iron values were within the RV, in men and women, respectively, with a decreasing tendency over time.
With the exception of one patient’s assessment low albumin level, all of the measurements were within the RV (97,5%) (Appendix C, Table 8). Regarding micronutrients, the majority of electrolytes levels were normal. Considering zinc, women had a significant increase (β=0,736; p=0,015) over time. Vitamin D values were mainly below the RV (86,1%), but a statistically significant increase (β=2,505;
p=0,037) was observed. Lastly, regarding the haemogram (Appendix C, Table 9), except for the haematocrit in men, all of the parameters had an increasing tendency throughout assessments, towards the RV.
The individual evolution of each patient for weight, BMI, FFMI, FMI and PhA is presented through graphs in Appendix D. Glucose, creatinine and urea are presented in Appendix E. Liver function parameters as well TC and TG can be found in Appendix F and Appendix G, respectively. Albumin can be found in Appendix H and Appendix I contains patients’ evolution for iron, transferrin and ferritin. Each electrolyte, zinc and vitamin D is in Appendix J. Haemoglobin patients’ evolution is presented in Appendix K.
Discussion
As far as we know, no portuguese studies were found on the subject of HPN, making the present article a pioneer on the nutritional status of HPN patients’ monitoring and the first one to ever describe the existence of patients undergoing the therapy in Portugal, with the oldest and the most recent one undergoing HPN for 23,5 and 4,9 years, respectively.
Until now, there are no available evidence-based guidelines for monitoring, reinforcing the need for reviewing indications, routes, risks, benefits and goals of nutrition support at regular intervals(3). In our sample, the frequency of monitoring of the various assessed parameters was done based on ESPEN guidelines(3, 4) and dependent on patients’ clinical stability.
The first parameters to be described were related to anthropometry and body composition. In one retrospective case series study(25), with a sample of 12 systemic sclerosis patients with IF on nocturnal HPN, a statistically significant
increase in mean weight and BMI was found, twelve months after the nutritional therapy initiation. In the present study, there was also an increase in weight and BMI over time, but without significant changes, possibly provided that this study comprises a longer period of HPN therapy length.
With regards to body composition using BIA, existing literature on the topic is still not consensual. BIA seems to be suitable in healthy subjects, with BMI ranging between 16–34 kg/m2(26) and without abnormal hydration(13, 26, 27), but according to the American Society for Parenteral and Enteral Nutrition Clinical Guidelines
on the Validity of Body Composition Assessment in Clinical Population(13), no recommendations can be made to support the use of BIA in the clinical setting. However, BIA can accurately estimate PhA, a direct measure, independent of predictive equations(28), and a current emerging area of research(13) because it is considered an indicator of cellular health integrity and function(12, 15). A recent systematic review of Rinald et al.(14) gathered various studies where PhA cut-off points were used to identify malnutrition in different clinical situations. Regarding HPN, specifically, there is still little information on the usefulness of the results(29).
On long-term HPN, oKøhler M. et al.(15) suggested the potential use of PhA as a prognostic marker and a tool for monitoring CIF patients in ambulatory context. With a sample of 77 clinically stable CIF patients, the authors observed that 29%, 64% and 10% of the patients had values of FMI, FFMI and PhA below RV, respectively, whereas, in our study, none of the patients had low FMI and, in both FFMI and PhA, low values were observed in 2 out of 5 patients (40%). Our PhA results indicate that throughout the majority of time undergoing HPN, patients
were not at nutritional risk. Even in assessments where PhA categorized patients at nutritional risk, improved values were observed posteriorly.
CIF patients not only seem to be at risk of altered muscle function(5), with body composition changes being mainly related to FFM(8, 29), but CIF has also been identified as an independent risk factor of sarcopenia(30). In the present study, to take into account differences in height between patients, FFMI and FMI were calculated. These indexes seem to allow a follow-up of the effects of illness, treatment or aging in individuals(31).
An opposite tendency of evolution regarding both FFMI and FMI between sexes was observed, which helps to draw the conclusion that the rise of BMI was due to the increasing women’s indexes values. According to a cross-sectional study(21) with 5635 apparently healthy adults in Switzerland, weight gain during aging is mainly due to increase in body fat, but is also linked to a slight rise in FFM. This could explain FFMI tendency to increase, along with a statistically significant increase of FMI, in women. Normal FFMI measures were observed in 46,7% and 45,8% of the assessments in men and women, respectively, and only men had low FFMI, with values mainly belonging to patient 4. Still, despite this patient irregular FFMI evolution, in comparison to the first available assessment, no lower FFMI values were observed. This may indicate that there was no deterioration of the initial clinical condition.
Hyperglycemia was reported in literature as the most common complication in PN, especially at the start of therapy(10). That was not verified in the current study, where in the majority of the assessments patients had normal blood glucose levels, with one happening right after initiation of HPN.
Regarding creatinine, the proportion above RV was mainly be due to patients 3 and 5 and, in fact, both these patients suffer from renal failure, which can explain their high creatinine levels due to impaired excretion. Moreover, risk factors for renal function in HPN CIF patients are dehydration, episodes of catheter-related blood stream infection, certain medication, renal stones and a pre-existing renal disease(32). These last two conditions apply to patient 3 and 5, respectively. About urea, values above the desired were mainly from patient 4. There are non-renal conditions contributing to the rise of urea levels, as ageing and dietary protein(33), but the reason that justifies these analytical values is unknown. Regarding liver function, intestinal failure-associated liver disease (IFALD) is one of the possible long-term metabolic complications of HPN(10, 34) and incidence of liver function test abnormalities has been reported to range between 25% to 100% in adults on long-term HPN(35). Indeed, all of our patients experienced elevated serum AST, ALT, ALP and GGT levels. In men, the majority of the parameters were within RV, except for their ALP high levels which tended to increase over time. Overall, there was an improvement in liver function parameters, especially in women, where the decreasing rate of all values was statistically significant. A possible explanation for the overtime reduction of liver enzyme levels, could be the maintenance of oral feeding in all patients, as lack of enteral/oral feeding is one the factors that can contribute to IFLAD(36, 37).
Concerning lipid metabolism, a decrease in TC was observed, along with a declining in LDL and rise in HDL levels. However, despite its proneness to increase towards the RV, all patients HDL levels were low. Apolipoprotein A-I accounts for about 70% of the HDL protein and is produced in both the liver and intestine(38), but patients with IF have reduced effective intestinal mucosal surface, decreasing
their synthesis(39). About TG, hypertriglyceridemia is a complication linked to some patients on PN, due to dextrose overfeeding or impaired lipid clearance(40). As men’s TG levels were mainly normal and women’s TG levels tended to decrease, along with the fact that TC and LDL levels were within the RV and HDL levels tendency was to rise, one can say that these HPN patients were able to improve and maintain their lipid profile.
Regarding albumin, inflammatory and infectious states can contribute to lower its serum levels(41). Yet, C-reactive protein patients’ levels were not considered, as all included data were from assessments outside hospital readmissions and patients were stable. Aside from the outlier value of albumin in patient 1, which might have resulted from an assessment near to a period of a complication or readmission, all other albumin values were normal.
As electrolytes are concerned, the majority of the measurements were within the RV. Electrolyte requirements are highly individualized(10), reinforcing the importance of regular monitoring and correction of irregularities, as these can be reversed by making adjustments in PN bag and in the added micronutrients. The 20% low phosphorous values were mainly due to patient 1, with its levels being posteriorly normalized. One possible explanation to the occurrence of hypophosphatemia, could be the contribution of vitamin D deficiency, also detected in this patient. Vitamin D deficiency prevalence in HPN patients varies from 60% to 70%(10). In fact, in our sample, all patients had low levels of this vitamin, with a total of 86,1% of measurements bellow the RV. However, there was a statistically significant tendency for improvement of vitamin D levels over time. Regarding zinc, levels in women were mostly consistently within the
reference range, with a statistically significant increase over time. In men, mainly due to patient 5, 40% of the assessments were low zinc levels. Btaiche I. et al.(42) concluded that higher zinc doses may be required to maintain normal serum concentrations in long term HPN patients.
Ultimately, a more thorough interpretation should be done regarding iron metabolism and haemogram results. In a Yi L Hwa et al. study(43), 60 out of 185
HPN patients were iron deficient and 47 developed iron deficient anemia during
HPN. In the present study, despite the decreasing tendency of iron, 68,8% and
79,2% of the total assessments in men and women, respectively, were normal values. When analysed individually, patient 4 stands out for having low iron and haemoglobin levels more frequently, as well as patients 1, 3 and 5 for the high levels of ferritin observed. Hyperferritinaemia without iron overload is commonly caused by inflammatory disorders, malignancy, chronic alcohol consumption, liver disease, metabolic abnormalities(44, 45) or renal failure(45), a condition present in patients 3 and 5. Moreover, in these cases, it is important to consider the levels of AST, ALT, ALP and GGT(46). In a study(47) with 16 CIF patients undergoing HPN, an association between liver disease in PN and high levels of ferritin was observed. This could not only be a plausible explanation for the encountered high levels of ferritin, considering the liver enzyme abnormalities observed, but also for the fact that, generally, there was an improvement in liver function parameters while ferritin levels decreased, throughout assessments. In fact, the overall propensity was for the improvement of haemogram parameters, the increase of transferrin and decrease of ferritin, both towards the RV.
Finally, it is to stand out that the previous results can be of greater interest, as these are patients, with a disabling condition, being compared against healthy individual reference measurements.
The present study has various limitations. The most outstanding one is the reduced size of the sample, which compromises external validity and extrapolation of the observed results. The second one is its retrospective nature, making it impossible not to have missing values. This not only leads to different sample sizes depending on the variable and moment of assessment, but also compromises results obtained in the regression analysis, where variables were assumed to have a normal distribution. Regarding the nutritional status of these patients, the eventual nutrient intestinal absorption was not measured, nor was the level of adhesion to the therapy known. Also, there is the influence of age(15, 48, 49), underlying disease(15, 49, 50) and cause of IF(15, 49), as well of certain medication(9) on clinical outcome, that were not considered in the statistical data analysis.
Conclusions
This retrospective study described the evolution of five patients on HPN throughout eight moments of assessment, regarding anthropometric, body composition and biochemistry parameters. PhA measurements indicated that, globally, patients were not at nutritional risk. Liver function and lipid metabolism parameters, as well as the levels of vitamin D, haemoglobin, transferrin and ferritin tented to improve as therapy progressed. These findings support the conclusion that these patients on HPN had an adequate nutritional status, with an observed improvement of some parameters throughout assessments.
Acknowledgments
To the authors of this article, Dr. Alice Lopes, Nurse Ana Ramalhão, Dr. Fernando Pichel and Dr. Anabela Rocha.
A special acknowledgment to Dr.Isabel Pereira and to the significance of all her work and legacy regarding patients in HPN.
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List of appendices
Appendix A - Chronogram of data collection ... 23 Appendix B – Equations used for body composition parameters calculation .. 24 Appendix C – Tables regarding anthropometric, iron, protein and haemogram parameters ... 25 Appendix D – Individual evolution of anthropometric and body composition parameters ... 26 Appendix E - Individual evolution of glucose, creatinine and urea levels ... 30 Appendix F - Individual evolution of liver function parameters ... 32 Appendix G - Individual evolution of lipid metabolism parameters ... 37 Appendix H – Individual evolution of albumin levels ... 39 Appendix I - Individual evolution of iron metabolism parameters ... 40 Appendix J - Individual evolution of electrolyte, zinc and vitamin D parameters ... 42 Appendix K - Individual evolution of haemoglobin levels ... 47
Appendix A - Chronogram of data collection
Appendix B – Equations used for body composition parameters calculation
1. Equation used for calculation of PhA (º)(19):
𝑎𝑟𝑐 𝑡𝑎𝑛𝑔𝑒𝑡 𝑋𝑐 𝑅 ×
180º 𝜋
R, resistance; Xc, reactance
2. Equation used for calculation of FFM (Kg)(20):
−4.104 +0.518 𝐻𝑡 2 𝑅50
+ 0.231 𝑤𝑒𝑖𝑔ℎ𝑡 + 0.130 𝑋𝑐 + 4.229 𝑠𝑒𝑥
R, resistance; Ht2, height2; R, resistance; Xc, reactance; sex: 1 for men, 0 for women
3. Equation used for calculation of FM (Kg): 𝑐𝑢𝑟𝑟𝑒𝑛𝑡 𝑤𝑒𝑖𝑔ℎ𝑡 − 𝐹𝐹𝑀
Appendix C – Tables regarding anthropometric, iron, protein and haemogram parameters
Table 6. Results regarding anthropometric parameters.
Parameter Sex Classification (%) Slope
(β) P value Weight (kg) Both - 0,490 0,539 Body mass index (kg/m2)a Both
Underweight Normal weight Pre-obesity Obesity
0,316 0,209
5,0 45,0 45,0 5,0
aClassification of BMI results according to the ranges defined by the WHO: Underweight (<18,5 kg/m2), Normal weight
(18,5-24,9 kg/m2), Pre-obesity (25,0-29,9 kg/m2) and Obesity (≥30,0 kg/m2)
Table 7. Results regarding iron metabolism biochemistry parameters.
Parameter Sex values (RV) Reference % Below RV % Within RV % Above RV Slope P value
Iron (μg/dL) M 53-167 25,0 68,8 6,3 -3,387 0,531 W 50-150 16,7 79,2 4,2 -5,687 0,110 Transferrin (mg/dL) Both 200-370 45,0 55,0 0,0 3,860 0,146 Transferrin saturation (%) Both 15-45 15,4 64,1 20,5 -2,463 0,056a Ferritin (ng/mL) M 12,80-454 0,0 12,5 87,5 -22,770 0,770 b W 2,20-178 0,0 27,3 72,7 -52,571 0,489 M, Men; W, Women; Both, regression line includes data without differentiation between sex.
aOne missing value; bTwo missing values
Table 8. Results regarding protein biochemistry parameters.
Parameter Sex values (RV) Reference % Below RV % Within RV % Above RV Slope P value
Albumin (g/dL) Both 3,5-5,0 2,5 97,5 0,0 0,046 0,128
Total proteins
(g/dL) Both 6,0-7,3 2,5 47,5 50,0 0,046 0,419 Both, regression line includes data without differentiation between sex.
Table 9. Results regarding haemogram parameters.
Parameter Sex Reference value (RV) % Below RV % Within RV % Above RV Slope value P Leukocytes (x10³/μL) Both 4,00-11,00 27,5 67,5 5,0 0,325 0,166 Erythrocytes (x106/μL) M 4,5-5,5 43,8 56,3 0,0 0,024 0,637 W 3,8-4,8 37,5 62,5 0,0 0,033 0,341 Haemoglobin (g/dL) M 13-17 31,3 68,8 0,0 0,017 0,921 W 12-15 33,3 66,7 0,0 0,085 0,364 Haematocrit (%) M 40,0-50,0 31,3 68,8 0,0 -0,012 0,978 W 36,0-46,0 37,5 62,5 0,0 0,195 0,428 M, Men; W, Women; Both, regression line includes data without differentiation between sex.
Appendix D – Individual evolution of anthropometric and body composition parameters
Figure 2. Weight evolution throughout assessments.
Figure 3. Body mass index evolution throughout assessments.
35,0 45,0 55,0 65,0 75,0 85,0 95,0 1 2 3 4 5 6 7 8 Wei gh t (k g) Assessment
Patient1 Patient2 Patient3 Patient4 Patient5
10,00 15,00 20,00 25,00 30,00 35,00 1 2 3 4 5 6 7 8 B M I (k g/ m ²) Assessment Patient1 Patient2 Patient3 Patient4
Figure 4. Men’s fat-free mass index evolution throughout assessments.
Figure 5. Women’s fat-free mass index evolution throughout assessments.
13,50 14,00 14,50 15,00 15,50 16,00 16,50 17,00 17,50 18,00 1 2 3 4 5 6 7 8 FFM I (k g/ m ²) Assessment
Normal FFMI (15,1-16,6 kg/m²) Patient1 Patient2 Patient3 0,00 5,00 10,00 15,00 20,00 25,00 1 2 3 4 5 6 7 8 FFM I (k g/ m 2) Assessment
Figure 6. Men’s fat mass index evolution throughout assessments.
Figure 7. Women’s fat mass index evolution throughout assessments.
Figure 8. Men’s phase angle evolution throughout assessments.
0,0 1,0 2,0 3,0 4,0 5,0 6,0 7,0 1 2 3 4 5 6 7 8 FM I (k g/ m ²) Assessment
Normal FMI (2,5-5,1 kg/m²) Patient4 Patient5
0 2 4 6 8 10 12 14 16 1 2 3 4 5 6 7 8 FM I (k g/ m ²) Assessment
Normal FMI (4,9-8,2 kg/m²) Patient1 Patient2 Patient3 FMI_RegressionLine
3,00 4,00 5,00 6,00 7,00 8,00 9,00 1 2 3 4 5 6 7 8 PhA (° ) Assessment
Patient4 Patient5 Not at nutritional risk (≥5◦)
Figure 9. Women’s phase angle evolution throughout assessments. 0,00 1,00 2,00 3,00 4,00 5,00 6,00 7,00 8,00 1 2 3 4 5 6 7 8 Ph A (° ) Assessment
Appendix E - Individual evolution of glucose, creatinine and urea levels
Figure 10. Glucose evolution throughout assessments.
Figure 11. Men’s creatinine evolution throughout assessments.
0 20 40 60 80 100 120 140 1 2 3 4 5 6 7 8 Gl u co se (m g/ d L) Assessment Patient1 Patient2 Patient3 Patient4 Patient5 Reference_Values (70-105mg/dL) 0,0 0,5 1,0 1,5 2,0 1 2 3 4 5 6 7 8 Cr e atinine ( m g/ d L) Assessment
Figure 12. Women’s creatinine evolution throughout assessments.
Figure 13. Urea evolution throughout assessments.
0,0 0,2 0,4 0,6 0,8 1,0 1,2 1,4 1,6 1,8 2,0 1 2 3 4 5 6 7 8 Cr e atinine ( m g/ d L) Assessment
Reference_Values (0,5-0,9mg/dL) Patient1 Patient2 Patient3
0 10 20 30 40 50 60 70 80 90 100 1 2 3 4 5 6 7 8 Ur e a ( m g/ d L) Assessment Reference_Values (10-50mg/dL) Patient1 Patient2 Patient3 Patient4 Patient5
Appendix F - Individual evolution of liver function parameters
Figure 14. Total bilirubin evolution throughout assessments.
Figure 15. Men’s aspartate aminotransferase evolution throughout assessments.
0,00 0,20 0,40 0,60 0,80 1,00 1,20 1,40 1,60 1,80 2,00 1 2 3 4 5 6 7 8 To tal B ili rr u b in ( m g/ d L) Assessment Reference_Values (0,20-1,00mg/dL) Patient1 Patient2 Patient3 Patient4 Patient5 0 10 20 30 40 50 60 1 2 3 4 5 6 7 8 A ST (10 -30 U/L at 37º ) Assessment
Figure 16. Women’s aspartate aminotransferase evolution throughout assessments.
Figure 17. Men’s alanine aminotransferase evolution throughout assessments.
0 20 40 60 80 100 120 140 160 180 1 2 3 4 5 6 7 8 A ST (10 -30 U/L at 37º ) Assessment
AST_RegressionLine_Women Reference_Values(10-30 U/L at 37º) Patient1 Patient2 Patient3 0 20 40 60 80 100 120 1 2 3 4 5 6 7 8 A LT (10 -30 U/L at 37º) Assessment
Reference_Values (10-44 U/L at 37º) Patient4 Patient5
Figure 18. Women’s alanine aminotransferase evolution throughout assessments.
Figure 19. Men’s alkaline phosphatase evolution throughout assessments.
0 50 100 150 200 250 1 2 3 4 5 6 7 8 A LP (U/L at 37º ) Assessment
Reference_Values (40-129 U/L at 37º) Patient4 Patient5 0 50 100 150 200 250 300 350 400 1 2 3 4 5 6 7 8 A LT (10 -30 U/L at 37º) Assessment
ALT_RegressionLine_Women Reference_Values (10-36 U/L at 37º) Patient1 Patient2
Patient3
Figure 20. Women’s alkaline phosphatase evolution throughout assessments.
Figure 21. Men’s gamma-glutamyl transferase evolution throughout assessments.
0,00 100,00 200,00 300,00 400,00 500,00 600,00 1 2 3 4 5 6 7 8 A LP (U/L at 37º ) Assessment
ALP_RegressionLine_Women Reference_Values (35-140 U/L at 37º) Patient1 Patient2 Patient3 0 20 40 60 80 100 120 140 160 180 200 1 2 3 4 5 6 7 8 G G T (U /L a t 37 º) Assessment
Reference_Values(10-66 U/L a 37º) Patient4 Patient5
Figure 22. Women’s gamma-glutamyl transferase evolution throughout assessments. 0,00 50,00 100,00 150,00 200,00 250,00 1 2 3 4 5 6 7 8 GG T (U/L at 37º ) Assessment
GGT_WomenRegressionLine Reference_Values(3-39 U/L a 37º) Patient1 Patient2
Patient3
Appendix G - Individual evolution of lipid metabolism parameters
Figure 23. Total cholesterol evolution throughout assessments.
Figure 24. Men’s triglycerides evolution throughout assessments.
0 50 100 150 200 250 300 1 2 3 4 5 6 7 8 To tal Ch o le ste ro l ( m g/ d L) Assessment TC_RegressionLine Reference_Values (0-200 mg/dL) Patient1 Patient2 Patient3 Patient5 Patient4 0 50 100 150 200 250 1 2 3 4 5 6 7 8 Tr ig ly ce ri d e s (m g/ d L) Assessment
Reference_Values (40-160mg/dL) Patient4 Patient5
Figure 25. Women’s triglycerides evolution throughout assessments. 0 50 100 150 200 250 300 350 400 1 2 3 4 5 6 7 8 Tr ig ly ce ri d e s (m g/ d L) Assessment
Appendix H – Individual evolution of albumin levels
Figure 26. Albumin evolution throughout assessments.
2,00 2,50 3,00 3,50 4,00 4,50 5,00 5,50 1 2 3 4 5 6 7 8 A lb u m in ( m g/ d L) Assessment Patient1 Patient2 Patient3 Patient4 Patient5 Reference_Values(3,5-5,0mg/dL)
Appendix I - Individual evolution of iron metabolism parameters
Figure 27. Men’s iron evolution throughout assessments.
Figure 29. Women’s iron evolution throughout assessments.
Figure 30. Transferrin evolution throughout assessments.
0 50 100 150 200 250 1 2 3 4 5 6 7 8 Ir o n ( μ g/ d L) Assessment
Reference_Values (50-167 μg/dL) Patient4 Patient5
0 50 100 150 200 250 1 2 3 4 5 6 7 8 Ir o n ( μ g/ d L) Assessment
Reference_Values (50-150 μg/dL) Patient1 Patient2 Patient3
0 100 200 300 400 1 2 3 4 5 6 7 8 Tr an sf e rr in ( m g/ d L) Assessment Reference_Values (200-370mg/dL) Patient1 Patient2 Patient3 Patient4 Patient5
Figure 31. Men’s ferritin evolution throughout assessments.
Figure 32. Women’s ferritin evolution throughout assessments.
0 500 1000 1500 2000 2500 1 2 3 4 5 6 7 8 Fer ri tin (μ g/ d L) Assessment
Reference_Values (12,80-454 μg/mL) Patient4 Patient5
0 500 1000 1500 2000 2500 3000 1 2 3 4 5 6 7 8 Fer ri tin (μ g/ d L) Assessment
Appendix J - Individual evolution of electrolyte, zinc and vitamin D parameters
Figure 33. Sodium evolution throughout assessments.
Figure 34. Chloride evolution throughout assessments.
125 130 135 140 145 150 1 2 3 4 5 6 7 8 So d iu m ( m m o l/ L) Assessment
Reference_Values (135-145mmol/L) Patient1 Patient2 Patient3 Patient4 Patient5 85 90 95 100 105 110 1 2 3 4 5 6 7 8 Ch lo ri d e ( m m o l/ L) Assessment
Reference_Values (95-105mmol/L) Patient1 Patient2 Patient3 Patient4 Patient5
Figure 35. Potassium evolution throughout assessments.
Figure 36. Magnesium evolution throughout assessments.
0 1 2 3 4 5 6 7 1 2 3 4 5 6 7 8 Pot assi u m ( m m o l/ L) Assessment
Reference_Value (3,5-5mmol/L) Patient1 Patient2 Patient3 Patient4 Patient5 0 0,2 0,4 0,6 0,8 1 1,2 1,4 1 2 3 4 5 6 7 8 M ag n e si u m ( m m o l/ L) Assessment
Reference_Values (0,6-1,1mmol/L) Patient1 Patient2 Patient3 Patient4 Patient5
Figure 37. Phosphorous evolution throughout assessments.
Figure 38. Total calcium evolution throughout assessments.
0 0,5 1 1,5 2 2,5 3 3,5 4 1 2 3 4 5 6 7 8 Ph o sp h o ro u s (m m o l/ L) Assessment
Reference_Values (0,87-1,45mmol/L) Patient1 Patient2 Patient3 Patient4 Patient5 1,5 1,7 1,9 2,1 2,3 2,5 2,7 2,9 1 2 3 4 5 6 7 8 Total Cal cium (m m ol/L) Assessment
Reference_Values (2,15-2,5mmol/L) Patient1 Patient2 Patient3 Patient4 Patient5
Figure 39. Men’s zinc evolution throughout assessments.
Figure 40. Women’s zinc evolution throughout assessments.
0,00 5,00 10,00 15,00 20,00 25,00 1 2 3 4 5 6 7 8 Zi n c ( μ m o l/ L) Assessment
Reference_Values (10,7-23 μmol/L) Patient4 Patient5
0,00 5,00 10,00 15,00 20,00 25,00 30,00 1 2 3 4 5 6 7 8 Zi n c ( μ m o l/ L) Assessment
Zn_RegressionLine_Women Reference_Values (9,1-18,3 μmol/L) Patient1 Patient2
Patient3
Figure 41. Vitamin D evolution throughout assessments. 0,00 20,00 40,00 60,00 80,00 100,00 120,00 140,00 160,00 1 2 3 4 5 6 7 8 Vi tam in D ( n m o l/ L) Assessment
VitD_RegressionLine Reference_Values (50-150 nmol/L) Patient1 Patient2
Patient3 Patient4 Patient5
Appendix K - Individual evolution of haemoglobin levels
Figure 42: Men’s haemoglobin evolution throughout assessments.
Figure 43. Women’s haemoglobin evolution throughout assessments.
0,00 2,00 4,00 6,00 8,00 10,00 12,00 14,00 16,00 18,00 1 2 3 4 5 6 7 8 H ae m o gl o b in (g/d L) Assessment
Reference_Values (13-17g/dL) Patient4 Patient5
0 2 4 6 8 10 12 14 16 1 2 3 4 5 6 7 8 H ae m o gl o b in (g/d L) Assessment
