Health Implications of Whey Protein Consumption

Health Implications of Whey Protein Consumption: Comparison

Please note this is a comparison between Version 1 by Mauro Lombardo and Version 3 by Fanny Huang.

Whey protein (WP), commonly consumed for muscle building and weight loss, has been associated with various health concerns. Significant findings were revealed, such as WP’s potential link to liver and kidney damage, alterations in gut microbiota, increased acne incidence, impacts on bone mass, and emotional and behavioural changes. These findings underscore the complexity of WP’s effects on human health, indicating both beneficial and detrimental outcomes in relation to different posologies in a variety of settings. Be cautious for protein intaking in situations of hepatic and renal compromised functions, as well as in acne susceptibility, while possible beneficial effects can be achieved for the intestinal microbiota, humoral and behavioural level, and finally bone and muscle mass in elderly. The importance of balanced WP consumption and call for more in-depth research to understand its long-term health effects were emphasized. Health professionals and individuals considering WP supplementation should be aware of these potential risks and approach its use with informed caution.

whey protein
health risks
protein supplement
side effects
kidney function
acne

1. Introduction

Whey protein (WP), a key component of milk proteins [1], has gained widespread popularity for its purported benefits in muscle building and weight management. However, its increasing consumption has raised concerns about potential health implications. WP characteristics can vary based on multiple factors such as method of casein precipitation, storage conditions, heat treatment, and other variables [2]. WP are commonly subjected to various processing methods, including ultra and/or microfiltration or ion exchange, resulting in the creation of WP isolate (containing 90–95% protein, minimal fat, lactose, and mineral content), WP hydrolyzed to achieve more readily absorption and less antigenic reactions, as well as WP concentrate (with protein content ranging from 20% to 85%, along with varying amounts of fat, lactose, and minerals) [3]. Table 1 provides a comprehensive overview of types and concentrations of WP. WP provides a rich essential amino acids (AAs) source being rich in both sulphur-containing and branched-chain AAs. Table 2 provides a detailed breakdown of the key constituents found in WP, including Beta-Lactoglobulin, Alpha-Lactoalbumin, and various Immunoglobulins, highlighting their concentration percentages.

Table 1.

Types and Concentrations of Whey Protein Supplements.

WHEY PROTEIN (WP) Type	Concentration
WP Isolate	90–95%
WP Concentrated

Table 2.

Composition and Concentration of Whey Protein Constituents.

WHEY PROTEIN Constituents	% Concentration
25–99%
Hydrolysed WP	Variable
Undenatured WP	Variable, common range 25–99%
Beta Lactoglobulin (β-LG)	50–55
Alfa-Lactoalbumin (α-LA)	15–20
Immunoglobulin A (IgA)	<15
Immunoglobulin G1 (IgG1)
Immunoglobulin G2 (IgG2)
Immunoglobulin M (IgM)
Bovin Serum Albumin (BSA)	5–10
LActoferrin (Lf)	<1–2%
Lysozyme (Ly)	<1%
Lactoperoxidase (Lp)	<1%
Casein Macropeptides	<10%
Sulphydryl oxidase	<1%
Superoxide Dysmutase	<1%

WP supplementation has gained considerable attention in the field of health and sports. Athletes often use WP seeking to improve muscle mass, strength or body composition [4]. Nutritional and physiological properties of WP supplementation and its effects on body composition and performance are widely studied, but the results are not always consistent due to the lack of study standardization in terms of samples, tests used, duration, amount or types of protein supplements and more [5].

Numerous studies have extensively explored the effects of WP supplementation in sports. These investigations have led to the formation of broadly accepted recommendations regarding WP use in athletic contexts. The meta-analysis of Davies et al., showed that WP supplementation has a small to medium ergogenic effect on the recovery of muscle function after endurance training, however, less than half of the included studies reported an overall beneficial effect [6]. Notably, the timing and dosage of WP intake play a critical role in maximizing its benefits for athletes. Pre- and post-training supplementation has been shown to significantly impact muscle recovery and growth. For instance, Kim et al. [7] demonstrated that whey protein consumed immediately before or after an exercise session significantly enhances muscle protein synthesis (MPS). Moreover, the amount of WP intake is crucial, with studies suggesting an optimal dosage range to maximize muscle recovery and growth without adverse effects. Naclerio and Seijo [8] provides insights into the ideal quantity of WP intake for athletes to facilitate muscle repair and growth post-exercise. Other studies report improvements in muscle mass [9], also due to an increase in the recruitment of satellite cells [10], strength [9], performance [5] and improvement in recovery times and in body composition [5], particularly if the oral intake is combined with resistance training [11], while other results are not in agreement [12]. The key amino acid in stimulating MPS is leucine, and its presence in WP is likely a major factor contributing to WP’s effectiveness in stimulating MPS when compared to other protein supplements, such as soy or casein [13].

Little is known about the side effects and possible long-term detrimental consequences of WP supplementation. Doubts have been raised especially regarding the effects of chronic use, at high doses by sedentary subjects, on liver and kidney function ^[3][14][3,14]. However, these doubts are not shared by all the researchers, who have refuted the previous conclusions [15]. Other concerns have been raised about whether WP may elicit allergic responses [16] or symptoms of lactose intolerance. Over-supplementation with WP may contribute to the excess of animal protein in the diet, increasing the potential risk of health-related conditions such as type 2 diabetes (T2DM) [17]. The intake of WP, especially in excessive amounts, may influence the onset of T2DM through several physiological mechanisms. Firstly, the high content of branched-chain amino acids (BCAAs) in WP may lead to insulin resistance, a key factor in the development of T2DM. This is because BCAAs, especially leucine, can activate the mammalian target of rapamycin (mTOR) pathway, which plays a crucial role in insulin signaling and glucose homeostasis ^[18][19][18,19]. Chronic activation of this pathway is associated with impaired insulin signaling and reduced glucose uptake into muscle cells, contributing to hyperglycaemia. Furthermore, excessive protein intake can increase the pancreas’ demand for insulin, potentially leading to beta-cell dysfunction over time ^[20][21][20,21].

Furthermore, the rapid digestion and absorption of WP leads to a rapid and significant increase in blood amino acid and insulin levels, potentially desensitising insulin receptors and contributing to insulin resistance [22]. Moreover, during the COVID-19 pandemic, significant changes occurred in physical activity [23] and dietary habits, especially in the types of protein sources consumed [24].

This table outlines the various types of Whey Protein (WP) supplements, highlighting their respective protein concentrations. It also details the main protein components found in whey, along with their relative concentration percentages. The main proteins in whey and their concentration (relative to the total whey proteins) are β-lactoglobulin (~55%), αlactalbumin (~20%), blood serum albumin (~7%), immunoglobulins (~13%) and minor proteins (~5%).

This table provides a detailed breakdown of the key constituents found in Whey Protein (WP), along with their respective concentration percentages. The table covers a range of components from major proteins like Beta-Lactoglobulin and Alpha-Lactoalbumin, to less abundant but significant elements such as various Immunoglobulins, Lactoferrin, and enzymes.

2. Health Implications of Whey Protein Consumption

Details of studies on health and side effects from WP supplementation are presented in Table 3 for human studies and Table 4 for preclinical studies.

Table 3.

Human Health and Side Effects from Whey Supplementation: A Summary.

First Author	Year	Study Design	Participants	N. of Patients	Age	Dose (per day)	Follow-Up Period	Outcomes	Ref.
Chitapanarux	2009	open labeled pilot study	Male and female with NASH

Table 4.

Preclinical Studies on Health and Side Effects from Whey Supplementation.

First Author	Year	Model	WP Dose	Follow-Up Period	Outcome	Ref.
38	15–60	20 g WP	12 weeks	↓ Hepatic steatosis		↓ Oxidative stress		↑ GSH
Amanzadeh	2003	Male Sprague Dawley rats, (8 weeks old, Weight 232 g)	3.34 g/kg/day:	59 days	↓ urinary pH, ↑ ammonia and calcium concentration in urine in the ↑ protein group ↓ bone density at the femur level in the ↑ protein group	^[37][38]	^[	²⁵	^][26]
Zhu	2011	RCT	Healthy menopausal women	210	70–80	30 g of WP vs. 2.1 g of protein	2 years	↔ hip BMD
Orosco	2004	Male Wistar rats (Weight 200–250 g)	190 g/Kg alpha-lactalbumin	6 days	↑ Serotonin production ↓ Anxiety after alpha-lactalbumin consumption	^[38][39]		↔ femoral neck strength ↑ IGF-1 in WP group	^[26][27]
Santos	2011	Cross-sectional study	Male bodybuilders	127	17–44	Not specified, but included regular diet and supplements
Aparicio	N/A	2011	↑ Anger scores and anger expression above average		↓ Anger management and inward anger below average		Association between ↑ weekly protein intake and ↑ anger expression	^[	Albino male Wistar rats (Young, Weight 150 g) undergoing endurance training²⁷	Not specified^]	3 months	↑ Renal volume; ↑ Calcium excretion with high protein intake ↓ Effects of high protein with endurance exercise	^[39][28]
[	40	]	Simonart	2012	Case series	Healthy male adult bodybuilders	5	19–35
Delamaire	2012	Male Sprague Dawley Rats	8.7–13 g/dL	15 days	Not specified	↔ Presence of mesenteric fat	6 months	↓ Low neonatal weight ↑ Weight gain in puberty/adulthood ↑ Food intake ↑ Serum insulin, leptin, triglycerides ↑ Pancreatic β-cell number; ↑ Adipocyte size↑ Development of moderate to severe acne after whey protein consumption ↑ Acne severity according to GAGS	^[40] ↔ No change with standard acne treatments for some; complete clearance for one after discontinuing whey protein and initiating topical treatment ↔ Partial regression with topical treatments for others	[^[28][29]
41	]	Silverberg	2012	Case series	Athletes and adolescents	5	14–18	Not specified	N/A	↑ cystic acne, papules, pustules, and a few comedones on bilateral cheeks WP discontinuation led to acne improvement	^[29][
Nunes	2013	Sedentary Wistar rats (250 to 300 g; 90 days old) undergoing endurance training	30	]
1.8 g/kg post-training	8 weeks	↑ Plasma ALT/AST; ↑ Liver/kidney toxicity with protein supplements, no training		↓ Liver/kidney toxicity with protein + resistance training	^[	^41][42]	Pontes	2013	prospective observational study	Men and women	30	18–30	Not specified	60 days	↑ Comedones, papules, pustules counts over time ↔ No significant change in scar count ↑ Severity of acne according to Leeds Acne Grading System over time ↔ No influence of sex or family history on lesion increase	^[30][31]
Cengiz
Deminice	2015	Wistar rats (weight 120 g)	Not specified	4 weeks	↑ Hepatic oxidative stress markers in protein-supplemented vs. control	^[42][43]	2017	Retrospective analysis of case series	Male adolescent users of protein-calorie supplements	6	16–18	Not specified	3 months	↑ Acne lesions post protein supplement initiation Acne localization to the trunk, sparing the face ↓ Acne severity with discontinuation of supplements and treatment ↔ No other health anomalies detected in blood tests	^[31][32]
Gürgen	2015	Young male Wistar albino rats (Weight 170 g) Untrained mice	Not specified	5 days and 4 weeks	↑ Inflammatory interleukins/TNF-alpha with 4 weeks protein supplementation ↑ Liver toxicity; ↑ Apoptotic signals	^[43][44]	Hattori	2017	Interventional study	Men and women
Sanchez-Moya	2017	In vitro (donor faeces)	18	Variable	21–38	27 g WP vs. Albumin	24 h	↑ Bifidobacterium and Lactobacillus with whey supplementation. ↑ Production of short-chain fatty acids.	^[44][3 days with a 1-week washout period between supplements	45]↑ mean protein equivalent of nitrogen appearance ↔ in lithogenic parameters ↑ Urinary calcium in 39% of subjects ↓ Urinary pH in 44% of subjects ↔ other urinary elements	^[32][33]
Moreno- Pérez	2018	Randomized pilot study	Cross-country runners	24	18–45	1.8–3 g/kg
Zhou	2022	Female Kunming mice (age 6 weeks, weight 25–30 g)	Variable	7 weeks	↑ SOD concentrations; ↓ Oxidative stress with protein supplementation. ↑ Lactobacillus; ↓ Helicobacter; positive intestinal effects.	^[	Ten weeks.	^45][46]↔ Fecal pH ↔ Fecal water content ↔ Fecal ammonia ↔ Fecal SCFA concentrations ↔ Plasma malondialdehyde levels ↑ Bacteroidetes phylum ↓ Roseburia ↓ Blautia ↓ Bifidobacterium longu	^[33][34]
Bauer	2020	RCT	Sarcopenic older adults	380	>65	21 g protein, 3 g leucine, 10 µg vitD and 500 mg calcium per serving	26 weeks in total (13-week RCT followed by 13-week OLE)	↑ eGFR in test group during RCT; no change during OLE Plateau of serum calcidiol and calcium levels after 13 weeks ↓ PTH levels in the test group during RCT and in former control groups during OLE Overall good tolerability of the WP-MND over the 6-month intervention period	^[34][35]
Schlickmann	2021	Cross-sectional study	Gym users	594	37	Not specified	N/A	↑ Slight alterations in AST ↑ Slight alterations in urea levels	^[35][36]
Nhean	2023	prospective, cross-sectional survey with retrospective, observational cohorts	High- risk HIV subjects consuming APES while under PrEP	50	>18 (median 32)	survey on regular usage	34	↑ grade 3–4 ALT/AST elevations ↑ serum creatinine	^[36][37]

This table summarizes key findings from human studies on health and side effects resulting from whey protein supplementation. Details include first author, year, study design, participant characteristics, number of patients, age range, dosage, follow-up period, outcomes, and references. Abbreviations: 1,25D: 1,25-dihydroxyvitamin D, APES: Appearance- and performance-enhancing supplements, BMD: Bone Mineral Density, eGFR: Estimated Glomerular Filtration Rate, GAGS: Global Acne Grading System, GSH: Glutathione, Hepatic steatosis: Fatty liver condition, IGF-1: Insulin-like Growth Factor 1, Lithogenic parameters: Factors affecting stone formation in the urinary system, NASH: Non-alcoholic steatohepatitis, OLE: Open-Label Extension, PrEP: HIV pre-exposure prophylaxis, PTH: Parathyroid Hormone, RCT: Randomized Controlled Trial, SCFAs: Short-Chain Fatty Acids, WP: Whey Protein, WP-MND: Whey Protein Medical Nutrition Drink, ↑: Increase, ↓: Decrease, ↔: No change.

This table presents a summary of preclinical studies investigating the health impacts and side effects of whey protein supplementation. It includes information about the first author, publication year, model used in the study, whey protein dose, follow-up period, observed outcomes, and references. Abbreviations: ↑: Increased, ↓: Decreased, ↔: No change/Stable, ALT: Alanine Aminotransferase, AST: Aspartate Aminotransferase, SOD: Superoxide Dismutase, TNF-alpha: Tumor Necrosis Factor-alpha.

2.1. Liver Function

The impact of WP on liver function appears to vary across studies. In human research, Chitapanarux et al. ^[25][26] observed beneficial effects, including a decrease in hepatic steatosis and oxidative stress in NASH patients. Meanwhile, Schlickmann et al. ^[35][36] reported slight alterations in liver function markers, such as aspartate aminotransferase (AST) and urea levels, in gym users. Thus, Nhean et al. ^[36][37] demonstrated that 8% of patients using appearance- and performance-enhancing supplements (APES), mainly represented by WP, experienced grade 3–4 ALT/AST elevations. In preclinical studies, Deminice et al. ^[42][43] found increased hepatic oxidative stress markers in rats supplemented with WP, and Gürgen et al. ^[43][44] reported liver toxicity and increased inflammatory markers in untrained mice following WP supplementation. Similarly, Nunes et al. ^[41][42] found elevated liver/kidney toxicity markers in sedentary WP mice, but noted that combining supplements with resistance training mitigated these effects.

2.2. Kidney Function

Studies on kidney function following WP consumption have mixed results. In human studies, Bauer et al. ^[34][35] observed an improvement in estimated glomerular filtration rate among sarcopenic older adults consuming WP-micronutrient drinks. Hattori et al. ^[32][33] identified increased urinary calcium and decreased urinary pH in individuals consuming WP and Nhean et al. ^[36][37] found elevated serum creatinine levels in 12% users of APES who were under a concurrent chronic antiviral therapy. Aparicio et al. ^[39][40] in a study with sedentary mice, reported increased renal volume and calcium excretion with high protein intake, though these effects were less pronounced with endurance exercise. Confirming the data of the already cited study by Nunes et al. ^[41][42], Amanzadeh et al. ^[37][38] demonstrated that increased WP intake led to decreased urinary pH, and increased ammonia and calcium concentrations in the urine of murine models.

2.3. Acne

Research has highlighted a notable link exploring the connection between WP consumption and acne development. In human studies, Simonart et al. ^[28][29], Silverberg et al. ^[29][30], Pontes et al. ^[30][31], and Cengiz et al. ^[31][32] consistently found an increase in acne severity and the development of lesions among individuals consuming WP supplements. Improvements were experienced after discontinuation of WP supplements. The consistency in findings across these studies indicates a strong link between WP supplementation and increased acne severity, particularly pronounced in specific groups such as male bodybuilders and adolescents.

2.4. Gut Function and Microbiota

Several papers suggest that WP can influence gut microbiota composition and function, although the effects may vary depending on individual gut microbiomes and the specific context of consumption. In human research, Moreno-pérez et al. ^[33][34] observed changes in the intestinal microbiota of cross-country runners, including an increase in the Bacteroidetes phylum and a decrease in beneficial bacteria such as Roseburia and Blautia. Thus Zhou et al. ^[45][46], found that donkey WP and hydrolysate improved gut microbiota and physiological functions in aging mice, enhancing weight gain and liver health, and reducing oxidative stress markers. Additionally, Sanchez-Moya et al. ^[44][45], in their in vitro study, reported an increase in beneficial bacteria like Bifidobacterium and Lactobacillus, as well as an enhanced production of short-chain fatty acids, which are crucial for gut health.

2.5. Emotional and Behavioural Influences

Emerging evidence suggests that WP may affect emotional and behavioral responses. In a human study, Santos et al. ^[27][28] identified a correlation between higher protein intake and increased expression of anger among male bodybuilders. Orosco et al. ^[38][39] studied murine models and noted increased serotonin production and reduced anxiety after the consumption of alpha-lactalbumin, a component of WP. The plasma ratio of tryptophan over the sum of its competitor large neutral amino acids (Trp/LNAAs) that may represents a non-pharmacologic measure of reward accounting for the hedonic state of the animals and may produce behavioural effects known by involving enhanced serotonin synthesis and transmission, with antidepressant-like action.

2.6. Bone Metabolism

Studies investigating the impact of WP on bone metabolism have produced diverse results. In a pre-clinical study, Amanzadeh et al. ^[37][38] found that high protein intake in murine models led to decreased bone density along with changes in urinary pH and calcium concentration. In human research, Hattori et al. ^[32][33] observed increased urinary calcium excretion and decreased urinary pH in individuals consuming WP. Bauer et al. ^[34][35] investigated the impact of WP consumption in older adults. Their study reported modifications in serum calcidiol and calcium levels, along with a decrease in parathyroid hormone levels. However, contrasting these findings, Zhu et al. ^[26][27] reported no significant impact on bone mineral density from WP consumption on menopausal women. These varied findings in bone metabolism studies underscore the complex nature of WP’s effects, suggesting that individual factors may significantly influence outcomes.

2.7. Other Health Effects

In a pre-clinical setting, Delamaire et al. ^[40][41] observed in rats significant increase in weight gain, food intake, and several metabolic parameters including serum insulin, leptin, and triglycerides. Additionally, this study noted changes in pancreatic β-cell number and adipocyte size, suggesting broad metabolic effects of WP in animal models. Overall, the collected data from these studies presents a multifaceted view of WP’s health effects, highlighting both potential risks and areas where further research is required to draw definitive conclusions.