Can A 15 Lb Weight Loss Due To Clean Eating Make A Difference In Your Liver Enzyme Levels

Br J Clin Pharmacol. 2004 Feb; 57(2): 199–208.

The influence of diet upon liver function tests and serum lipids in healthy male person volunteers resident in a Phase I unit of measurement

E R Beloved

¹Pfizer Research Clinic, Canterbury, Kent, UK

Grand D Eve

¹Pfizer Research Clinic, Canterbury, Kent, Great britain

C Fifty Wooldridge

ⁱPfizer Research Clinic, Canterbury, Kent, UK

W K Rapeport

²Middle of Excellence in Drug Discovery, Glaxo Smith Kline Ltd, Stevenage, Herts, UK

Received 2003 January 23; Accepted 2003 Jul 24.

Abstract

Aim

To investigate the event of diet upon liver office tests and serum lipids within the restricted environment of a Phase I unit.

Methods

An open randomized three-style crossover study was designed with subjects consuming three types of diet. The diets comprised, a balanced normal calorie nutrition, a high-saccharide high-calorie diet and a high-fat high-calorie diet. Each diet was consumed in a randomized sequence over eight days with a recovery catamenia of xiv days between periods. The blood concentrations of various laboratory parameters were measured at intervals throughout each dietary catamenia and during the recovery periods.

Results

Claret transaminase activity and triglyceride concentrations increased significantly whilst subjects consumed a loftier-sugar loftier-calorie diet but non when fed either a high-fat high-calorie diet or a counterbalanced normal calorie diet.

Conclusions

The rises in transaminases and triglycerides were caused by the carbohydrate content of the nutrition rather than its calorific value. Sucrose rather than starch was the carbohydrate which caused the ascension in transaminases and triglycerides. The importance of controlling diet in Phase I studies is stressed.

Keywords: diet, liver office tests, lipids, Phase I

Introduction

The liver is the site at which many drugs are removed from the circulation and after metabolized and excreted. By virtue of its position astride the portal circulation the liver is exposed to greater concentrations of orally administered drugs than any other organ apart from the intestine itself. It is not surprising therefore that many drugs can produce hepatic injury including hepatocellular damage, cholestasis and even tumour production [1]. Consequently a major safe concern in any clinical report of a new chemical entity (NCE) volition be the effect of the drug upon the liver. Such effects are monitored by changes in the so-chosen liver office tests (LFTs). These tests include the transaminases [alanine transaminase (ALT) and aspartate transaminase (AST)], alkaline phosphatase (ALP), bilirubin, total protein and albumin with, in addition, gamma glutamyl transferase (γGT), a usually measured sensitive marking of cholestasis.

In early clinical studies of NCEs in healthy volunteers (Stage I trials) it is important to provide an environs in which any potential effects of nondrug factors upon LFTs are minimized. The reason for this is that nondrug-related changes in LFTs might (incorrectly) be attributed to an effect of the drug itself resulting in the delay, or even termination, of the evolution of a potentially useful compound. Changes in LFTs of obscure origin take been noted during prolonged periods of residence at the Pfizer Stage I units (unpublished data) and have also been reported in Phase I studies at other centres. Such findings have been attributed to several factors including excess calorie intake due to lack of practise [2] or to prestudy factors, namely ALT>AST, a high obesity index and/or a loftier γGT activity [iii]. The prestudy activities of ALT and AST/ALT ratios have been proposed to exist useful discriminators betwixt 'ALT-susceptible' and 'ALT-nonsusceptible' volunteers in a retrospective meta-analysis of 13 studies of volunteers taking placebo [4]. Alternatively, Rosenzweig, Brohier and Zipfel [v] tentatively attributed transaminase changes in healthy volunteers taking placebo to 'dietary factors and rest', and a more detailed newspaper from the aforementioned group, over again studying healthy volunteers taking placebo, came to a like determination [6]. Indeed, at that place is testify in the literature that diet can have an result upon hepatic enzymes both in animals [7–9] and in healthy humans [2, 10, xi]. However, in patients receiving enteral nutrition, the observed changes in LFTs were considered more probable to be associated with clinical complications rather than with the enteral nutritional back up itself [12].

Many of the salubrious volunteers in Phase I studies are manual workers who retain large appetites despite much reduced levels of concrete activity, compounded by boredom, during long periods of residence within the Phase I environment. Unless advisedly monitored these volunteers volition eat far in excess of their calorific requirements and they take been noted to consume large amounts of sugariness high-sugar foods. We have also observed that restriction of these sweet foods appeared to decrease the incidence of spurious LFTs. With these empirical observations in listen and on the footing of the testify outlined to a higher place, it was decided to investigate formally the effect of diet upon laboratory parameters.

A report was designed to test the effects of 3 types of nutrition [high carbohydrate, loftier calorie (HCHC); high fat, loftier calorie (HFHC); and balanced normal calorie diets] upon LFTs and also upon antipyrine clearance (equally a measure of hepatic microsomal metabolizing capacity). In addition, since height of transaminase activities, specially AST, in the claret can upshot from musculus impairment, the enzyme creatinine kinase (CK), a relatively specific and sensitive marker of muscle impairment, was also measured to discriminate betwixt possible effects of diet upon musculus and liver. The calorific values of the high-calorie diets used were excessive but this was done deliberately to maximize the furnishings of excess calorie intake on the one paw and dietary limerick on the other.

It was postulated over 40 years ago that dietary composition, particularly carbohydrate content, could affect blood lipid profiles [13], but there have been conflicting reports in the literature on whether or not this is so [14]. Therefore, as a secondary objective, the effects of the three types of nutrition upon serum cholesterol and triglyceride levels were besides investigated.

Methods

The report

This was an open up, randomized, three-way crossover written report which involved 12 healthy male subjects aged 20–41 years eating each of 3 diets in a randomized society to avoid sequence furnishings. Subjects spent 8 days (9 nights) at the Pfizer Research Clinic eating the randomly selected nutrition with a recovery menstruation of 14 nonresident days betwixt each dietary menstruum. The 8-day dietary period was selected mainly on personal experience from previous Phase I studies, although there is likewise show in the literature indicating that eight days is a sufficient period to produce enzyme changes [11]. Similarly the fourteen-twenty-four hour period recovery menstruation was based empirically upon in-firm feel, although Porikos and Van Itallie discovered that raised transaminase activities returned to baseline 12 days after switching from a sucrose to an aspartame-containing diet [11]. Whilst nonresident, the subjects consumed their usual diets without restriction. All aspects of the report were conducted in accord with Good Clinical Do (GCP) following a advisedly designed protocol together with a volunteer information canvass and consent class, all of which had been approved by the Kent and Canterbury Local Hospital Research Ethics Committee. Volunteers were given a full explanation of the study and time for consideration prior to signing the consent form.

Earlier entry into the study, each field of study had a medical screen including a full medical history and physical examination with routine biochemical (including LFTs) and haematological profiles, a hepatitis B screen and a urinary drugs of abuse screen. Fully informed consent for the written report was obtained at that time. Subjects were immune to enter the report only if their medical screen was adequate, including laboratory profiles which were inside the appropriate reference ranges. They were also required to fulfil a number of other criteria which included a body weight which was within the range of eighteen–28 past Quetelet's alphabetize [(weight (kg)/height (m)^two], smoking less than v cigarettes/twenty-four hour period and drinking less than 21 units of alcohol/calendar week. In improver, the subjects had to remain gratis of any medication (excluding ibuprofen for minor ailments) for at least 3 weeks prior to the showtime of and throughout the study. The subjects were not immune to consume booze or caffeine, or undertake any unaccustomed exercise for a minimum of 2 days prior to each admission to the unit. Unaccustomed practice is defined as any practise which the subject does non routinely take as part of his normal week. Apart from this, during periods of nonresidency, diet and do were unrestricted. A dietary history was taken from each subject to ensure that their usual diet was satisfactory and that they were non malnourished.

On the evening of each admission the subjects had a physical test, were screened for drugs of abuse (urine) and breathalysed for alcohol. Routine urinalysis was also performed at that fourth dimension. The post-obit morn, prior to commencing the nutrition, the subjects were weighed, fasting blood samples (baseline) were taken and 600 mg of antipyrine were administered orally for the measurement of antipyrine clearance (see beneath). Antipyrine was also administered on day viii of each dietary menstruation.

The diets used in this study with the relative amounts of fat, carbohydrate and protein and the split of carbohydrate between unproblematic sugars and starch are shown in Table 1. The HFHC diet was approximately isocaloric to the HCHC diet, both diets providing more than twice the calories provided by the standard diet. The diets were devised using readily available everyday food and no special dietary supplements were used. The diets were given as 3 primary meals a day together with a light supper. Whilst subjects were on the high-calorie diets they were too given supplementary snacks (eastward.thousand. crisps for fat, biscuits for sugar) at appropriate times during the day. The eating of meals/snacks was advisedly supervised to ensure that all food and drink was consumed. Subjects received each diet for 8 days. On days 3, 5, vii and 9 (day of discharge) of each dietary period, fasting morning claret samples were collected, centrifuged and the serum saved for subsequent biochemical analysis. Similarly treated additional fasting blood samples were taken on the mornings of days half dozen and eight. These samples were analysed retrospectively just if the results from the other days were of involvement. In addition to this, subjects were asked to return to the Clinic following discharge 12 and 16 days after commencing each diet when farther fasting claret samples were taken for biochemical assay. A follow-up examination was conducted on day xvi afterwards the starting time of the terminal dietary regimen. This included a physical examination and collection of blood and urine samples for assay.

Table one

Composition of diets

Diet	Daily kCal	Fat	Poly peptide	Total	Carbohydrate Sucrose	Starch
Standard	1900	798 (42%)	228 (12%)	874 (46%)	266 (fourteen%)	608 (32%)
HFHC	4500	2610 (58%)	585 (thirteen%)	1305 (29%)	180 (4%)	1125 (25%)
HCHC	4400	1320 (30%)	484 (11%)	2596 (59%)	1408 (32%)	1188 (27%)

Laboratory analyses

Blood samples for routine biochemical and haematological assessment were collected at the prestudy medical screen, prior to the start of each dietary regimen and at follow-upwardly. These tests included routine urea and electrolytes, LFTs (including γGT), creatinine, calcium, CK, full cholesterol and triglycerides together with a full claret count (FBC) with white cell differential. Boosted tests, performed at the prestudy screening examination but, were a hepatitis B screen, a fasting glucose and a reticulocyte count. All examination results were reviewed past a dr. prior to inclusion of the volunteer in the study.

On fixed days afterward the start of each dietary regimen (see earlier), the LFTs, CK, total cholesterol and triglycerides were measured on serum from fasting forenoon claret samples. The biochemical analyses were performed using a Kodak Ektachem automated analyser (Kodak Ltd Britain Supplers, Orthochnical Diagnostics, Amersham, UK) and haematological tests with a Coulter counter (Beckman Coulter UK Ltd., High Wycombe, UK). Standard urinalysis (pH, protein, glucose, ketones and blood) was performed with a stix examination (BM-Examination-5 50; Boehringer, Mannheim, Federal republic of germany). Urine was analysed for drugs of abuse (cocaine, barbiturate, methadone, benzodiazepines, opiates, cannabinoids and amphetamines) on each admission with a Triage 8® kit (Biosite® Diagnostics, Biosite Inc., San Diego, CA, Usa).

Antipyrine clearance was measured by the simplified method described by Dossing et al.[15]. This involved collecting one sample of saliva for antipyrine analysis 24 h subsequently administering an oral antipyrine dose (i.e. on solar day 2 and 24-hour interval 9 of each report period). Antipyrine was assayed in the saliva using loftier-performance liquid chromatography with UV detection at a wavelength of 254 nm. The overall inaccuracy (bias%) for QC samples within each analytical batch ranged from eight.fourscore to nine.67% and overall imprecision (CV%) varied from one.47 to 2.52%; the coefficients of variation (CV%) for calibration standards within each belittling batch ranged from 2.13 to 4.40%.

Statistical analysis

All analyses were performed using a statistical software plan (SAS, version 6.09; SAS Institute Inc., Cary, NC, USA).

For all parameters (except antipyrine clearance), the natural logarithm (ln) of the value which deviated the most from baseline in each study period (day 1 to 24-hour interval 16) was analysed using analysis of variance (anova). This was the maximum observed value for each subject area on each diet for all parameters except bilirubin, which used the minimum observed value. The anova model included terms for discipline, diet and period. Differences between diets were estimated using pairwise contrasts. Antipyrine clearance values from mean solar day two and mean solar day 9 of each study flow were logged (ln) and analysed using anova every bit above, only included an additional term for day and a solar day by diet interaction.

The mean, difference between means and standard error (of the divergence) values were back transformed (exponentiated) to requite geometric ways and approximate 95% confidence intervals (CIs). To confirm model specification, besprinkle plots of residuals and absolute residuals confronting fitted values were checked.

Results

Subjects remained well and there were no changes of note in any of the physical examinations performed throughout the study. All drugs of abuse screens performed on each admission were negative and there was naught of notation in whatsoever of the routine urinalyses.

Trunk mass, recorded on day 1 and twenty-four hour period ix of each period, is summarized in Tabular array 2. Comparison twenty-four hours 1 with day 9 values, both the HFHC and HCHC diets acquired significant rises in body mass (P < 0.001), with hateful increases of two.5 kg (95% CI 1.9, iii.2) and 2.ane kg (95% CI 1.five, two.8) for the HFHC and HCHC diets, respectively.

Table 2

Effect of the diets on body mass (kg) (values hateful ± SD).

Day of diet	Standard	HFHC	HCHC
1	76.half-dozen ± x.five	76.4 ± ten.2	76.6 ± 10.0
ix	75.8 ± 9.9	78.nine ± ix.7	78.7 ± 10.5
Difference	−0.8*	two.5**	two.i**

In dissimilarity, the standard (normal calorie) regimen resulted in a small simply significant (P < 0.05) mean fall in torso mass of 0.8 kg (95% CI −ane.five, −0.2).

Antipyrine clearance

Antipyrine clearance values are shown in Tabular array iii. Hateful values fell consistently for each nutrition from day two to day 9 by about 12% (95% CI −17, −6; P < 0.001), although there was no testify of a day by nutrition interaction (P = 0.801) indicating that antipyrine clearance was not affected by diet.

Table three

Antipyrine clearance (values mean ± SD)

24-hour interval of diet	Standard	HFHC	HCHC
2 (ml min−i)	56.4 ± 12.i	58.iii ± 8.4	55.nine ± x.three
9 (ml min−1)	48.0 ± vii.3	52.iv ± 5.five	49.seven ± ix.iii

Liver office tests (LFTs)

Total protein and albumin in serum were not affected by nutrition (P = 0.264 and P = 0.705, respectively).

The HCHC diet had a modest just statistically meaning event on ALP action (P = 0.007) with values 6% (95% CI 1, 11; P = 0.017) higher compared with the standard diet, and 8% (95% CI 3, 13; P = 0.003) college compared with the HFHC diet. Still, all activities remained inside the reference range for ALP.

Bilirubin concentrations fell during all dietary periods (meet Figure one). The magnitude of fall was significantly greater for the HCHC (95% CI −35%, −12%) and HFHC (95% CI −38%, −18%) diets compared with the standard nutrition (P < 0.001) only at that place was no departure between the HCHC and HFHC diets (95% CI −8%, 23%; P = 0.395). When the subjects reverted to their usual diet (day 9 onwards) bilirubin concentrations rose again to baseline levels.

Effect of diet upon bilirubin. [Graphs (Figures 1–6) stand for various laboratory parameters for the three diets (Standard (▾), HFHC (○) and HCHC (•)). Data points are determined from blood samples taken on days 1, 3, 5, half dozen, vii, 8, 9, 12 and 16 (mean ± SEM). Shaded blocks represent fourth dimension spent resident at the Research Dispensary. Horizontal line(s) denote upper and lower reference limits (ULN and LLN, respectively) where they fall within the scale on the ordinates.]

There was powerful show for the influence of dietary regimen on transaminase activities. ALT activeness remained stable up to day 3 for all diets but subsequently began to ascent for both the HFHC and HCHC diets (come across Figure 2). Compared with the standard nutrition, by day ix and twenty-four hours 12, values had risen significantly to, on average, 38% (95% CI two, 89; P = 0.040) college on the HFHC nutrition and 143% (95% CI 79, 231; P < 0.001) higher on the HCHC nutrition. The high ALT activities achieved on the HCHC diet were also 76% (95% CI 29, 139; P < 0.001) higher than those on the HFHC diet. This large increase in hateful ALT activity on the HCHC diet reflects the fact that eight out of the 12 subjects had ALT values that exceeded the upper limit of the reference range (56 U l⁻¹).

Effect of diet upon alanine transaminase. ULN (—), Standard (▾), HFHC (○) and HCHC (•).

AST activity was too markedly influenced by nutrition (P < 0.001) merely, in contrast to the findings for ALT, no departure was found between the standard and HFHC diets (95% CI −6, 56; P = 0.130). However a similar finding to that for ALT was observed for the HCHC diet compared with the standard diet (Effigy iii) with AST activities ninety% (95% CI 48, 145) higher. Furthermore, AST activities were 57% (95% CI 22, 103; P < 0.001) higher on the HCHC diet compared with the HFHC diet. 9 out of the 12 subjects on the HCHC diet had AST activities that exceeded the upper limit of the reference range (40 U fifty⁻¹).

Effect of diet upon aspartate transaminase. ULN (—), Standard (▾), HFHC (○) and HCHC (•).

Although the pattern of modify was less dramatic, nutrition also had an outcome on γGT activities (P < 0.001). Initially the γGT remained stable, but by solar day half dozen of the HCHC diet had started to rise (see Effigy 4). The maximum change from baseline was 45% (95% CI 26, 70) higher than on the standard diet and 32% (95% CI fifteen, 51) higher than on the HFHC nutrition (P < 0.001). However, merely one of the 12 subjects on the HCHC nutrition had a γGT activeness (lxxx U 50⁻¹) that exceeded the upper limit of the reference range (78 U l^−one). No significant difference was found betwixt the HFHC and standard nutrition, with activities in the one-time group being slightly higher (95% CI −4%, 27%; P = 0.157).

Effect of nutrition upon gamma glutamyl transferase. Standard (▾), HFHC (○) and HCHC (•).

CK activities did not change significantly amongst any of the diets (P = 0.276).

Fasting lipids

Diet had a pocket-size but statistically significant influence on fasting serum cholesterol (P = 0.001). Cholesterol levels remained relatively stable for all diets until day 7, when levels began to rise slowly for the high-calorie diets. The rises in cholesterol were 15% (95% CI seven, 22; P < 0.001) and 7% (95% CI 1, fifteen; P = 0.032) higher than the standard diet for the HCHC and HFHC diets, respectively. There was no pregnant difference between the HCHC and HFHC diets, although it tin can exist seen from the lower limit of the 95% CI (95% CI 0%, 14%; P = 0.057) that college values accomplished for the HCHC diet nearly achieved statistical significance. None of the mean values rose above the desirable range for cholesterol of <v.2 mmol l⁻¹(Table 4).

Table iv

Maximum divergence of laboratory parameters from baseline.

Test	Normal range	Standard	HFHC	HCHC
Albumin (g l−1)	39–fifty	46.1 ± 3.two	46.3 ± 2.4	45.vii ± 2.2
ALP (U l−ane)	38–126	79.9 ± 24.3	78.0 ± 22.ii	84.3 ± 25.5
ALT (U l−1)	7–56	36.8 ± 6.4	51.8 ± 13.0	103.8 ± 63.3
AST (U fifty−1)	five–40	27.iv ± iv.vi	33.3 ± six.7	56.8 ± 30.ii
Bilirubin (µmol l−1)	3–22	8.47 ± 2.44	vi.01 ± 1.66	6.46 ± 2.00
Cholesterol (mmol l−i)	0.0–half dozen.5	iv.fifty ± 0.96	4.79 ± 0.81	5.11 ± 0.84
CK (U l−1)	57–374	170 ± 100	252 ± 215	400 ± 794
γGT (U l−1)	8–78	26.v ± vii.0	28.7 ± iv.0	39.8 ± xv.viii
Full protein (yard l−1)	63–82	77.1 ± iv.vii	78.9 ± 4.3	78.6 ± 2.6
Triglycerides (mmol fifty−1)	0.45–i.82	1.77 ± 0.75	1.56 ± 0.45	3.xxx ± 1.fifty

In contrast to cholesterol, diet was constitute to strongly influence fasting triglycerides (P < 0.001), but only when the subjects were on the HCHC diet. Triglyceride levels on the HCHC diet started to rising markedly from day 1 of the diet and continued rising throughout the dietary menses (Figure 5). Fasting triglycerides were 80% (95% CI 42, 131) higher on the HCHC diet than on the standard diet and 99% (95% CI 56, 153) higher than on the HFHC diet (P < 0.001). These high values reflect the fact that 10 out of the 12 subjects on the HCHC nutrition had values that exceeded the upper limit of the reference range (1.82 mmol l⁻ⁱ).

Event of diet upon triglycerides. LLN (—), ULN (—), Standard (▾), HFHC (○) and HCHC (•).

The means of the highest observed values (at any fourth dimension betoken) for each parameter (lowest observed value for bilirubin) are shown in Table 4. It tin can be seen that in general the standard deviation of the mean increases with the value of the mean, and this is the bones supposition that has been made in the model used for the statistical analyses. The just hateful values lying exterior the reference range are for ALT, AST, CK and triglycerides on the HCHC diet. The highest (and highly variable) activities for CK were achieved following belch from the clinic (Figure half-dozen), whilst for ALT, AST and triglycerides rises commenced during residency (Figures 2, ​ three and ​ 5).

Issue of diet upon creatinine kinase. LLN (—), ULN (—), Standard (▾), HFHC (○) and HCHC (•).

Discussion

This study was designed primarily to investigate the effect of diet on LFTs and to distinguish between the result of high-calorie intake compared with the result of dietary composition (high fat or high carbohydrate) upon these laboratory parameters. In addition, the issue of the diets upon serum full cholesterol and triglycerides has been investigated.

The report was performed upon good for you young men in the environment of a Stage I unit under the full general conditions that apply to Phase I studies with new chemical entities (i.e. GCP). Since GCP will exist observed past all Phase I units, the results obtained are relevant to studies performed at whatever unit of measurement.

Antipyrine clearance

Previous work on animals and on isolated tissue suggested that dietary limerick could have marked effects upon cytochrome P450 mixed function oxidases and conjugation enzymes [7, 16]. Information technology is difficult to extrapolate these findings to humans, but such effects might exist indicated by any changes establish in antipyrine clearance which reflects metabolism by the cytochrome P450 systems.

The lack of effect of any of the diets upon antipyrine clearance (Table 3) suggests that these diets had no direct effect upon the overall oxidative capacity of the liver. Such a finding concurs with earlier work in humans with regard to carbohydrates and lipids, although other dietary factors, such as high protein content, were found to affect both antipyrine and theophylline clearance [17]. The antipyrine clearance values reported in that study compare well with those currently obtained despite the unlike written report conditions.

Creatinine kinase (CK) and transaminases (AST and ALT)

CK is a sensitive marker of muscle damage. Comparing of Figures 2, ​ 3 and ​ 6 indicate that the rises in transaminase activity in resident subjects on the HCHC diet were non of muscular origin. Although clinically there are other potential causes of raised activities of transaminases in the blood (east.g. tissue hypoxia, haemolysis and pancreatitis) these are very unlikely to be pertinent to the healthy subjects in this study. The liver therefore remains by far the near likely source of the big increases in transaminase activities recorded during the HCHC dietary regimen.

The highly variable rises in CK activity following belch (Figure 6) are likely to exist due to a sharp increment in muscular do in reaction to the period of inactivity during residency at the Clinic. Many of the subjects commonly took regular exercise and missed this whilst resident in the restrictive environment of the Phase I unit.

Liver office tests and diet

The outcome of varying the composition of sugar in the diet upon various enzymes (including transaminases) in the claret of healthy humans has been studied previously [10, 11]. However, to our knowledge a directly comparison of the effect of isocaloric high-saccharide and high-fat diets (allowing discrimination betwixt calorific value and composition) has not been made.

There is a clear human relationship between the marked rises in transaminases and the number of days on the HCHC nutrition (Figures ii and ​ 3). Such a powerful relationship was not found with the isocaloric HFHC diet and demonstrates the importance of carbohydrate rather than calories as the prime cistron in the changes found. However, some small changes were credible in ALT when subjects ate the HFHC diet. These effects may be due to the fact that subjects were eating virtually 50% more than calories as carbohydrate daily whilst on the HFHC diet compared with the standard diet (Table i) and are entirely consistent with the primary role of carbohydrate in the recorded changes. This contrasts somewhat with the findings of Porikos and Van Itallie [11], who concluded that both surplus calories and high sucrose intake contributed significantly to the observed rises in transaminase activities. Indeed, surplus calories were attributed to be the sole crusade of elevated transaminases found in healthy volunteers afterward 7 days of residence in a Stage I unit in Japan [2]. Nevertheless, this study was not directly comparable to the present work since the calorific value of the diet used was not loftier and remained constant, whereas the level of physical activity of the volunteers was changed. Surplus calories were judged as the difference betwixt calorie intake and their consumption by exercise. We consider that physical exercise during residency in Stage I studies is best avoided since it introduces some other variable with the potential of causing changes in laboratory parameters (encounter earlier).

A much higher proportion of the calories in the carbohydrate fraction of the HCHC diet was due to sucrose than in the other diets. In contrast, the amount of starch in each of the high-calorie diets was near the same and about double that in the balanced normal calorie diet (Table 1). This implies that it is the amount of sucrose in the high-carbohydrate diet which mainly underlies the marked rises in transaminases. Such a conclusion concurs with before findings [10, 11].

It has been suggested previously that a ascent in transaminase activity may be due to the fructose moiety of the sucrose in the diet causing harm to hepatocytes [11] or to lipid deposition in the liver [2]. The antipyrine results suggest that diet does not affect hepatic oxidative office (Table 3) then that although minor hepatic impairment cannot be excluded, information technology seems more plausible that the transaminases are induced past the increased flux of carbohydrate through glycolysis and related pathways. The greater effect upon ALT compared with AST (Figures 2 and ​ 3) might be explained past the fact that the erstwhile enzyme is involved directly with pyruvate metabolism whereas AST is more indirectly related to carbohydrate metabolism. Hepatic enzyme induction by increased availability of substrate, such as when certain drugs, e.g. barbiturates, phenytoin, ethanol, etc. are taken regularly, is a well-recognized phenomenon.

The HCHC nutrition likewise produced small-scale just meaning rises in ALP and γGT activities as suggested previously [ten, 18, 19]. In contrast, bilirubin levels fell significantly (Effigy 1). These results appear contradictory, since increased ALP and γGT activities commonly indicate biliary stasis (which would be expected to issue in a rise in bilirubin). However, the high calorie intake may decrease serum bilirubin by stimulating biliary flow, as indicated indirectly by the finding that fasting increases bilirubin levels by decreasing biliary flow [20]. Therefore the current findings are not inconsistent with previous published data and emphasize the complex nature of the effect of nutrition upon tests which are generally accepted to reflect liver role. However, such tests are not ideal, being afflicted by many factors [21]. The results should be interpreted with caution, probably reflecting normal adaptive changes in hepatic function in healthy individuals.

Lipids and diet

The finding that the high-sugar nutrition caused an increase in fasting serum triglycerides is past no means new [thirteen, 22–27], although more recent piece of work has been equivocal [11, 14]. However, the unequivocal and highly statistically significant ascent in triglycerides to well above the reference range acquired by the HCHC diet compared with the isocaloric HFHC nutrition cogently supports the hypothesis that carbohydrate rather than calories is the chief crusade. It is impossible to define from the results whether the increment in triglycerides is due to an increase in endogenous synthesis by the liver from backlog sugar or to a subtract in clearance from the apportionment. Nor is the literature clear on this matter [22–25, 27]. Whatsoever the machinery, information technology seems that the sucrose moiety of the diet is responsible since sucrose is the major correspondent to full calories in the HCHC diet (Table 1). This finding is in agreement with the results of other groups [23, 26, 28], although this is not undisputed [29]. In dissimilarity, the lack of a substantial effect upon cholesterol levels which are more stable than triglycerides may be considering the diets were not maintained for long enough. Reiser et al.[28] constitute that cholesterol levels increased significantly when sucrose was substituted for starch in the nutrition, but merely later on the fifth calendar week.

Determination

The marked effect of excess carbohydrate upon the transaminases and as well upon triglycerides underlines the importance of diet as a consideration in all Stage I studies. It is strongly recommended that a well-balanced diet with just sufficient calories to maintain body weight be used at all times, peculiarly in studies where volunteers are resident for any length of time. In that location are many other nondrug factors that can bear upon laboratory parameters, east.g. practise, circadian rhythm, stress, posture, time of taking sample, etc. [21, 30] and Stage I units should take these into consideration when planning studies and interpreting results. This volition reduce the chance of erroneously attributing changes in laboratory parameters to a drug effect with all of the consequences which might follow from this.

Acknowledgments

The authors give thanks the staff at the Pfizer Research Clinic, Canterbury, for their hard work during this study.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884438/

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