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Preface

This risk-benefit analysis (RBA) is part of Forever Healthy's "Rejuvenation Now" initiative that seeks to continuously identify new rejuvenation therapies and systematically evaluate them on their risks, benefits, procedures, and potential application.

Special thanks are extended to the whole Rejuvenation Now team at Forever Healthy for their friendly contributions.

Section 1: Overview 

Motivation

Phospholipids are an important structural component of cell and organelle membranes and play a role in many cell signaling pathways. Membranes incur oxidative damage over time and in several disease conditions. Oral and/or i.v. supplementation of phospholipids (particularly phosphatidylcholine) is hypothesized to repair this damage through the replacement of oxidized membrane phospholipids with "healthy" phospholipids, thus restoring or maintaining membrane integrity and function. 

Key questions 

This analysis seeks to answer the following questions:

• Which benefits result from phospholipid therapy (PLT)? 

• Which risks are involved in PLT (general and method-specific)?

• What are the potential risk mitigation strategies?

• Which method or combination of methods is the most effective for PLT?

• Which of the available methods are safe for use? 

• What is the best therapeutic protocol available at the moment?

• What is the best monitoring protocol currently available?

Impatient readers may choose to skip directly to Section 6 for the Presentation of Results and tips on practical application. 

Recommended reading/viewing

General introduction

The following sites offer information on PLT at a consumer level and are useful as an introduction to the topic:

• Mitochondria and the Anti-Aging Role Of Lipid Replacement Therapies - clinicaleducation.org

• Phosphatidylcholine (PPC/EPL) - heartfixer.com
  
  
  

Scientific overview 

The following scientific review provides a more detailed overview of the topic of PLT:

• Lipid Replacement Therapy: A natural medicine approach to replacing damaged lipids in cellular membranes and organelles and restoring function

Section 2: Methods

Analytic model

This RBA has been prepared based on the principles outlined in A Comprehensive Approach to Benefit-Risk Assessment in Drug Development (Sarac et al., 2012). 

Literature search

A literature search was conducted on Pubmed using the search terms shown in Table 1 and included articles available as of August 31, 2021. Titles and abstracts of the resulting studies were screened and relevant articles downloaded in full text. The references of the full-text articles were manually searched in order to identify additional trials that may have been missed by the search terms. Results reported in the book, Essential Phospholipids as a Membrane Therapeutic (Gundermann, 1993) were included as it summarized several clinical papers only available in other languages (see Table 3).

Many studies were published using brand names so we also included the brand names in our literature search. Please see Table 6 for a list of the brands we identified.

Inclusion criteria: Any clinical trial that used PLT, orally, or by i.v. was included. Meta-analyses that reported results from trials either in other languages or papers that were not available online were also included.

Exclusion criteria: We excluded animal and in vitro studies from the analysis because of an abundance of clinical trials as well as trials that used phospholipid s.c. injections for cosmetic purposes. 

Table 1: Literature search 

Abbreviation list

Section 3: Existing Evidence

Summary of results

Our search terms identified 3,665 studies of which 107 were relevant to this analysis (see Table 2). We also included the clinical studies summarized in Gundermann's book in our analysis following a discussion with the author, despite being unable to locate the majority of the original papers (see Table 3). Although PLT has long been used in medical practice, the quality of the evidence is quite low overall. For many papers, only the abstracts are available (in English) and many of the trials are observational. Most of the compounds administered for PLT contained several vitamins and minerals in addition to phospholipids, leading to difficulties in determining whether the benefits/risks occurred due to the phospholipid content or other components of the supplements and much of the research has been funded by producers of phospholipid supplements. Moreover, almost all of the trials were performed in subjects with preexisting health conditions making it difficult to determine the extent of the benefits in a healthy population.

Table 2: Clinical trials

Table 3: Gundermann summary

Section 4: Risk-Benefit Analysis

Decision model

Risk and benefit criteria

The decision profile is made up of risk and benefit criteria extracted from the outcomes of the above-mentioned papers. The benefit criteria are organized by category and type and are assessed according to magnitude, likelihood, duration, and perceived importance. The risk criteria are organized by category and type and are assessed according to severity, frequency of occurrence, and difficulty in detection and mitigation. Each criterion is assigned a numerical value for each assessment category:

1 = low 

2 = moderate

3 = high

The numerical values for the criterion are then summarized, serving as the justification for the weighting in the following column.

Weight

The criteria are weighted on a value scale to enable comparison (based on the relative importance of a difference). The value in the summary column is divided by 4 to result in a weight between 1 → 3.

Score

Each criterion is assessed according to the performance of PLT against the comparator (physiological aging) whereby a numerical value is assigned for each criterion -1 (inferior), 0 (equivalent or non-inferior), and +1 (superior) to the comparator.

Uncertainty

Uncertainty is determined according to the amount and quality of the evidence, availability of full text articles & supplementary data, number of participants and whether methodological flaws, conflicting studies, or conflicts of interest (i.e. funding) are present. Evidence that is based on RCTs is initially upgraded by 1 point, evidence from open-label trials is considered neutral, and evidence that is based on observational studies is downgraded by 1 point. The uncertainty is then further valued using the above-mentioned criteria to result in an uncertainty score. 

Weighted score

The weights and scores are multiplied to produce weighted scores that enable direct comparison (-3 → +3) and then adjusted according to the uncertainty score. Weighted scores are upgraded where the uncertainty score is low (positive) or downgraded where the uncertainty score is high (negative).

Benefit assessment 

We identified a total of 58 benefits associated with PLT. The benefits extended across several organ systems, were mostly of small magnitude and largely dependent on continued supplementation. Almost all benefits occurred in the context of pre-existing disease. There is limited evidence that the benefits would occur in healthy individuals. 

Table 4: Benefit assessment 

Blood

Reduction in platelet aggregation & blood coagulability

In two studies on patients with ischemic heart disease (n=24, 25), 14 days of i.v. EPL led to a substantial decrease (60%) in platelet aggregation (Gundermann, 1993). Microscopic examination showed both reduced numbers of aggregates and reduced platelet conglomerates within the aggregates.

An open-label trial that administered i.v. EPL for 10 days followed by oral supplementation for 30 days found a clear reduction in the sensitivity of platelets to ADP that remained during a 3-month follow-up period. This was attributed to an inhibitory effect on the ADP-induced rise in calcium in the platelets (Gundermann, 1993). Another open-label trial (n=11) demonstrated a decrease in the thromboxane/6-keto-PGF1 ratio (aggregatory/anti-aggregatory factors) following oral administration of EPL for 16 weeks (Gundermann, 1993). 

A study of elderly patients with cerebral vascular insufficiency that received i.v. injections of EPL for one month reported a significant decrease in blood coagulation and an increase in fibrinolytic activity (Gundermann, 1993). Another open-label trial also reported a significant decrease of platelet aggregability following 8 weeks of EPL, though the number of platelets remained unchanged and no alteration of coagulation parameters of fibrinolysis was found (Schneider et al., 1976).

An increased linolenic acid content in platelet phospholipids and a reduction in lipid and cholesterol content were observed in a small study (n=7) following oral intake of EPL for 6 weeks (Gundermann, 1993). The increased linolenic acid content indicates uptake of the supplemental phospholipids by cell membranes and could account for the improved platelet function seen in the previously mentioned studies.

In contrast, a DB-RCT (n=60) that compared the effects of taking soy lecithin (which contains 65-75% phospholipids) vs. control or fish oil for two weeks, reported an increase in platelet adhesiveness in response to stimulation with ADP (23.2% vs. 18.7%). This was attributed to the stimulatory effect of omega-6 fatty acids (i.e. linoleic acid) found in soy lecithin (Andrioli et al., 1999).

Improved composition & function of RBC cell membranes

Several studies reported improvements in the composition and function of erythrocyte membranes such as lowering of the cholesterol content and increase of linoleic acid in the membranes, improved deformability, increased osmotic resistance, and reduced blood viscosity (Gundermann, 1993).

An open-label study reported improved filtration of red blood cells through a capillary membrane in terms of rate and total number of RBCs following a single injection of EPL (Gundermann, 1993). The benefit occurred within 15-45 min after the injection in healthy volunteers and after 60 min in patients with chronic occlusive arterial disease. However, the values returned almost to baseline within 30 min.

A second study of longer duration (i.v. injection 500 mg followed by 1.8 g/day of oral EPL for 3 months) also reported improved passage of RBCs through a capillary membrane as well as a reduction in RBC aggregation (Gundermann, 1993). Cholesterol/phospholipid indexes in the RBC membranes dropped by 28% and there was a normalization of hematocrit and blood viscosity. All of these benefits also correlated with an improved clinical picture that persisted for up to 12 months after completion of the therapy. An open-label trial (n=30) also reported an increase in relative erythrocyte phospholipid levels and in erythrocyte phosphatidylcholine following 6 months of treatment with lipostabil-forte (Bobkova et al., 1989).

An RCT (n=23) in patients with hepatitis B reported a greater recovery of lipid metabolism in RBC membranes after treatment with Lipostabil (Tsyrkunov, 1992).

A case series in patients with psoriatic arthritis treated with Phosphogliv for 3 months also reported a considerable decrease in RBC aggregability (Ipatova et al., 2003). Another case-control study in patients with liver disease (cirrhosis or cholestasis) showed that a single i.v. infusion of EPL resulted in a regression of changes of RBCs due to hemolytic anemia (Salvioli et al., 1977).

Improved antioxidant properties of the blood

An RCT (n=23) reported improvements in the antioxidant properties of the blood following treatment with Lipostabil in patients with hepatitis B (Tsyrkunov, 1992).

Cardiovascular system

Stagnation/regression of atherosclerotic plaques

In a small study (n=15) of patients with asymptomatic atherosclerosis in which EPL was administered orally for one year, the majority of plaques tended to stagnate after an initial increase in growth. Larger initial volumes stagnated or showed a downward trend after a 12 month observation period. The tendency to regression was clearer in the femoral artery than in the carotid (Gundermann, 1993). 

Decreased ECG abnormalities

Twelve studies reported an improvement in ECG findings following various doses of EPL (Gundermann, 1993). There was a dose-related reversal of pathological findings including the disappearance of negative T-waves (Gundermann, 1993).

Decreased anginal attacks

Several studies reported a decrease in anginal attacks (Gundermann, 1993). In an open-label trial (n=34), patients with moderate-severe angina pectoris received i.v. EPL for 14 days and 59% (20/34) reported an absence of anginal attacks by the end of the first/beginning of the second week of treatment. The remaining 14 patients also experienced a significant reduction in the frequency and severity of angina attacks and daily nitro-consumption was decreased (Gundermann, 1993). A second open-label trial (n=42) also reported a 50% reduction in the nitro-consumption of the patients and a multicentre trial (n=507) showed similar results (Gundermann, 1993). 

In an open-label study (n=100) that compared Lipostabil (2 ampoules of 5 mL (500 mg) i.v. per day for 2 weeks followed by 1800 mg orally for 5.5 months) to nicotinic acid for treatment of angina, both groups experienced a reduction in the intensity (1.5 down to 0.5) and number (3.8 per week down to 0.9) of anginal attacks, with the Lipostabil group exhibiting a superior side effect profile (Klimov et al., 1995).

Increased exercise tolerance

Substantial increases in walking distance were reported by several studies in Gundermann's book following treatment with EPL. In one study, the walking distance in patients with angina pectoris rose from 30-50m to 3000m following treatment with EPL (Gundermann, 1993). A second, 20-month study (n=200) in which patients received both i.v. and oral EPL, reported improvements in walking distance in 35/200 patients, from 0-200m to 1500m (Gundermann, 1993). The subsequent withdrawal of EPL treatment resulted in a decreased walking distance. 

A large trial on patients with peripheral arterial disease (n=808) reported that after 6 weeks of treatment with EPL, 198 patients with intermittent claudication and 505 patients with pain at rest, had complete relief. The mean pain-free walking time was increased from 9.8 to 21.3 minutes (Gundermann, 1993). 

In an open-label study (n=100) that used Lipostabil (2 ampules of 5 mL i.v. per day for 2 weeks and 1800 mg orally for 5.5 months) in patients with hyperlipidemia and ischemic heart disease, an increase in exercise tolerance was also reported (Klimov et al., 1995).

Increased vitality

In a controlled trial (n=94) of geriatric patients with atherosclerosis, 94% (88/94) of patients reported a decrease in complaints (fatigue, disturbed sleep, retrosternal pain, palpitations) and increased vitality that was more pronounced after two months of EPL therapy than after one month (Gundermann, 1993). 

Increased blood flow 

An increase in blood flow to the lower extremities was measured in patients with peripheral arterial disease following a 30-day treatment with oral EPL (Gundermann, 1993). The increase occurred both at rest and with reactive hyperemia, and flow velocity was also raised. A longer (20-month) study (n=200) in which patients received both i.v. and oral EPL, reported improved patency of major vessels in 17% (35/200) of patients, as measured by the oscillometric index (Gundermann, 1993). Another study found there was a dose-related increase in the oscillometric index following EPL treatment, indicating increased blood flow (Gundermann, 1993). 

An observational study (n=34) reported that treatment with Essentiale had a normalizing effect on blood flow and vascular tone in the lower extremity of patients with chronic ischemic heart disease (Kukes et al., 1978). 

Improved survival after fat embolism

In an open-label study of patients that suffered a fat embolism (n=221), 91% (202/221) survived with EPL treatment vs. a retrospective control group who had not received EPL in which 70% (58/83) of the patients died (Gundermann, 1993). 

Decreased blood pressure & cardio-ankle vascular index

A DB-RCT (n=96) that administered soy lecithin tablets (PC 24%, PE 20%, and PI 12%) at 1200 mg/day for 8 weeks found that diastolic blood pressure and cardio-ankle vascular index decreased significantly (-4 mmHg, -0.4) (Hirose et al., 2018). 

Central nervous system

Improved memory 

In a DB-RCT (n=328) of patients with mild cognitive impairment or Alzheimer's disease who were fed phospholipids (derived from scallops) for 24 weeks, memory improved significantly in some subgroups of AD patients (female patients and those under 77 years of age) (Fujino et al., 2017). There was, however, no statistically significant difference in the phospholipid content of erythrocyte or plasma phosphatidylethanolamine, or in cognitive function between the placebo and treatment groups in this trial.

A DB-RCT (n=66) in adults with mild forgetfulness who received phospholipids for 12 weeks in the form of ascidian plasmalogen oil soft capsules, reported that the intervention group improved significantly in the composite memory score (visual & verbal memory) as well as visual memory alone (Watanabe et al., 2020). Another DB-RCT (n=75) in healthy adults with mild cognitive problems reported significant improvements in the MMSE after 12-weeks of therapy with plasmalogens. In the between-group analysis, the intervention group showed improvements in more than half of the individual test items as well (Najima et al., 2016). However, both of these trials were sponsored by the manufacturer of the supplements. 

A DB-RCT (n=75) in subjects with chronic stress (n=75), reported that 42 days of treatment with PL-supplemented milk resulted in participants from the high-dose treatment group showing a significantly better memory performance on the Trier Social Stress Test as compared with participants from the placebo and low–PL dosage groups (Schubert et al., 2011).

In contrast, another DB-RCT (n=46) that used PL-supplemented milk, did not report a significant improvement in memory of healthy participants (Hellhammer et al., 2010).

Improved cerebral blood flow

Several open-label studies summarized in Gundermann's book reported improvements in cerebral blood flow and oxygen consumption. The studies used a variety of forms/doses ranging from 250 mg i.v. to 3 g orally, and from a single dose up to 2-14 years of treatment (Gundermann, 1993).

Decreased symptoms in multiple sclerosis

Four studies (3 open-label and 1 DB-RCT) have shown positive effects of EPL supplementation on the disease course of multiple sclerosis (Gundermann, 1993). Doses in these studies ranged from 500 mg i.v. + 800 mg orally to 6-8 g orally per day and treatment duration varied from 5.7 up to 23.8 years. More recently, research has shown the importance of phosphatidylcholine in MS with oxidized phosphatidylcholine serving as a marker for neuroinflammation in MS (Qin et al., 2007). IgM antibodies to PC have also been measured in the serum of MS patients (Sadaba et al., 2020).

Improved cognitive function in hepatic encephalopathy

An open-label trial (n=97) reported improved cognitive test dynamics in 82% of patients with hepatic encephalopathy that received Phospholipovit vs. 43% of patients that received standard therapy (Kudinov et al., 2016).

Decision-making latency improved on EEG in an open-label trial on patients with hepatic encephalopathy that received Essentiale i.v. daily for two weeks (Bruha & Marecek, 2000).

Increased availability of free cortisol in chronic stress

In a DB-RCT on patients with chronic stress (n=75), the group that received milk-based PL showed a delayed decline from peak levels in morning salivary cortisol suggesting a prolonged availability of free cortisol (Schubert et al., 2011).

Decreased risk of dementia

An observational study (n=2497), found that participants in the highest compared with the lowest phosphatidylcholine intake quartile had a 28% lower risk of incident dementia (Ylilauri et al., 2019). Total choline intake had no association with the risk of incident dementia. However, both total choline and phosphatidylcholine intakes were associated with better performance in cognitive tests assessing frontal and temporal lobe functioning.

Metabolism

Reduction in total cholesterol

Several trials have reported a significant lowering of total cholesterol (TC) following treatment with EPL. However, of the studies we identified, only 10 reported the percentage decrease which ranged from no effect to -42% as seen in the table below. In general, the higher the initial cholesterol levels, the greater was the effect. A summary of studies published before 1993 (participants n=3836) reported an average reduction in serum TC between 12-19% across studies (Gundermann, 1993). In some studies, there was an initial slight rise in TC.

Oral and i.v. administration show similar efficacy at lowering TC with oral EPL at 1.8 g/day leading to mean reductions of 12.7% and i.v. EPL to a reduction of approximately 13% within about 2 weeks (Gundermann, 1993). 

PC has shown positive effects on lowering TC when used in conjunction with fibrates or diet modifications. A DB-RCT (crossover) (n=67) in patients with hyperlipidemia that received PC and clofibrate or clofibrate alone for 4 weeks, reported that the addition of PC negated the LDL-raising effect of clofibrate while lowering TC an additional 5 mg/dL (Schneider et al., 1979). 

Two studies on oral lecithin reported 33 and 42% decreases in TC (Wojicki et al., 1995; Mourad et al., 2009). 

On the other hand, a few studies reported no significant effect on TC levels. An RCT (n=8) in patients with renal failure treated with Essentiale forte 900 mg/day reported no significant difference in TC after 8 weeks (Chan et al., 1991). An open-label trial (n=29) found that although there was a trend towards the reduction of TC in patients with alcoholic fatty acid liver disease treated with Essentiale (oral 6 capsules for 3 months), there was no statistically significant effect (Turecky et al., 2003). Another open-label trial reported that 8 weeks of oral Lipostabil (1.8 g/day) treatment had no effect on blood lipid content (Ozerova et al., 2005).

A systematic review of 24 studies that analyzed the effect of oral lecithin on serum cholesterol concluded that only the early studies reported marked reductions in serum cholesterol. Most investigators noted only small changes or none at all (Knuiman et al., 1989).

Table of studies that reported a change in total cholesterol levels:

Reduction in LDL-C, LDL-P, ApoB

An extensive summary of studies up to 1993 (n=1160) reported that EPL treatment results in an LDL-C reduction of 10-31% with the exact extent being influenced by the type of hyperlipoproteinemia, as well the dosage and duration of treatment (Gundermann, 1993). Of these studies, DB-RCTs using oral doses between 1.8 and 2.7 g/day showed reductions of 12% and 20% after 14 and 21 days, respectively and a controlled cross-over study, reported a reduction of 25.8% within two months. Other studies in the summary reported a 25% reduction after 218 days of treatment, a 27.9% reduction after 120 days of treatment and a 34.1% reduction after 42 days (Gundermann, 1993).

Several other trials showed similar results. A DB-RCT (n=30) in patients with Type II DM and hyperlipidemia found that LDL-C decreased by 17% (191 to 159 mg/dl) with 2.7 g daily oral EPL over a 2 month period (Kirsten et al., 1994). A DB-RCT (n=20) in dialysis patients with hyperlipidemia reported that treatment with PC (oral 2.7 g/day for 6 weeks) led to a significant decrease (-32 mg/dL) in LDL-C two weeks after beginning treatment began that remained constant for the duration of the study (Kirsten et al., 1989).

In an open-label study (n=100) that compared Lipostabil (2 ampules of 5 ml of Lipostabil N i.v. per day (= 0.5 g/day EPL) for 2 weeks followed by 1800 mg/day orally for 5.5 months) to treatment with nicotinic acid, both groups showed a reductions LDL-C (Klimov et al., 1995). Baseline LDL-C was 200.3 mg/dl which decreased to 172.4 mg/dl and then to 170 mg/dl after 5.5 months of oral Lipostabil. Another open-label trial (n=121) in patients with diabetes type II who received oral Lipostabil (900 mg/day) for 52 weeks reported that LDL-P levels were reduced from 5.54 to 4.04 mmol/L (Mel'chinskaia et al., 2000). Similarly, an open-label trial (n=8) in healthy volunteers that consumed 10 g PPC/day in the form of a paste reported a decrease from 62 mg/dL to 45 mg/dL in the apoB content of LDL after 21 days (Spann et al., 1987).

An open-label trial (n=32) in patients with primary hyperlipidemia treated with lecithin for 30 days reported a mean LDL-C decrease of 38% (Wojicki et al., 1995) and a DB-RCT (n=30) reported that soy lecithin at 500 mg/day resulted in a 42% lowering of LDL after one month and a 56% lowering after two months (Mourad et al., 2009).

In contrast, a few trials did not show significant decreases in ApoB with EPL treatment. An RCT (n=8) in patients with renal failure treated with Essentiale forte 900 mg/day reported no significant difference in ApoB after 8 weeks (Chan et al., 1991) and a DB-RCT (n=27) reported that while LDL-C was significantly lowered in patients receiving oral PC, apoB showed only a downward trend that didn't reach significance (Noseda et al., 1985). 

Decreased LDL/HDL ratio

A summary of studies up to 1993 reported a lowering of the LDL/HDL ratio in several trials (Gundermann, 1993). One RCT (n=30) reported a 24% reduction in the LDL/HDL ratio while another DB-RCT also reported a 34% decrease (from 5.6 to 3.7). A DB-RCT (n=27) reported that the change in the LDL/HDL ratio due to LDL decreasing as HDL was unchanged (Noseda et al., 1985). 

The LDL/HDL ratio was also found to decrease by 35% (from 4.3 to 2.8) in an open-label trial (n=14) in which patients received a 4-week course of treatment with i.v. EPL 0.5-1g/day. In another study, patients with coronary artery disease showed a drop in the LDL/HDL ratio to normal values and patients with hypercholesterolemia also approached normal values.

The reductions followed a clear dose-response with the greatest effect occurring at 1.5 to 2.25 g of EPL/day (Gundermann, 1993).

Increased HDL-C, ApoA-I, LCAT activity

10 trials and one meta-analysis (of 15 studies) reported increases in HDL-C and/or ApoA-I, the magnitude of which varied according to dose and duration of the studies. In a meta-analysis of studies published before 1993, HDL showed increases of 10-45% across trials with the greatest changes occurring in patients with the lowest initial levels (Gundermann, 1993). In the additional studies we identified, the increase in HDL-C varied from 5% to 46% with most studies reporting values between 10-20% as seen in the table below. Subgroup analysis in one trial showed that the increase was due to a shift towards the most antiatherogenic subtype (HDL-2b) (Klimov et al., 1995).

Some studies reported that the elevation in HDL persisted for at least 3 months after the end of treatment (Gundermann, 1993). In one study, the significant increase in HDL extended only to the group that received phospholipids with food (Burgess et al., 2005).

3 studies reported no change in HDL-C following treatment. An RCT (n=8) in patients with renal failure treated with Essentiale forte 900 mg/day reported no significant difference in HDL-C after 8 weeks (Chan et al., 1991). A DB-RCT (n=27) reported that HDL-C was not significantly raised in patients receiving oral PPC (Noseda et al., 1985). An open-label trial (n=10) with oral lecithin (20-30g per day for 8 weeks-11 months) also reported no change in HDL-C (Simons et al., 1977). 

Table of studies that reported a change in HDL levels:

Improved composition of HDL

A case-control study (n=24) in patients with liver disease reported that one infusion with EPL resulted in an increased content of linoleic acid in HDL proteins as well as increased LCAT activity. The polyunsaturated fatty acid component of the membranes was significantly lower at baseline in diseased patients compared with controls (Salvioli et al., 1977).

Reduction of TG

11 trials reported a significant lowering of TG following treatment with EPL as seen in the table below. Five trials only reported that the change was "significant" while another 6 reported changes between 9-36%. A summary of all trials up until 1993 reported that reductions of 25% were the most common (Gundermann, 1993).

The reduction in TG was lost three months after EPL therapy discontinuation in at least one trial (Dobiásová et al., 1988). Another study found that the reduction of TG extended only to a subgroup of patients that received EPL with food (Burgess et al., 2005).

Several trials reported no significant decrease or even an increase in TG levels. An RCT (n=8) in patients with renal failure treated with Essentiale forte 900 mg/day reported no significant difference in TG after 8 weeks (Chan et al., 1991). A DB-RCT (n=30) reported that soy lecithin (500 mg/day) also had no effect on TG levels after two months (Mourad et al., 2009). A third DB-RCT (n=27) reported that TG was not significantly lowered in patients receiving oral PC (Noseda et al., 1985). An open-label trial (n=57) reported no significant change in TG levels with two weeks of i.v. EPL therapy (Blaton et al., 1972).

Additionally, one DB-RCT (n=26) reported significantly higher TG concentrations following two weeks of PC treatment (Olthof et al., 2005) and a second DB-RCT (n=67) in patients with hyperlipidemia that received PPC and clofibrate for 4 weeks, reported that the administration of PPC lessened the decrease of TG compared to clofibrate alone (Schneider et al., 1979).

An open-label trial found there was no significant reduction of TGs in patients with alcoholic fatty acid liver disease (Turecky et al., 2003). An open-label trial (n=10) with oral lecithin (20-30g per day for 8 weeks-11 months) reported a statistically significant reduction in TG in only 1 subject (Simons et al., 1977). 

Table of studies that reported a change in TG levels:

Reversal of hyperinsulinemia/improvement in glucose levels

An open-label trial (n=30) reported that patients showed a reversal of hyperinsulinemia within 6 months of treatment with Lipostabil-forte (Bobkova et al., 1989). A second open-label trial in patients with cirrhosis showed improvements in the capacity of RBCs to process insulin receptors that continued to increase up to the end of treatment (i.v. 3 days) and then declined over the following 3 days (Cantafora et al., 1992). A meta-analysis (n=3384) reported a median reduction of 0.33% in HbA1C and a reduction in fasting glucose of 0.3 mmol/L from baseline in a treatment adherent group of NAFLD patients taking 1800 mg/day of Essentiale for at least 12 weeks (Ivashkin et al., 2021).

However, a DB-RCT reported that blood glucose, immunoreactive insulin, and non-esterified fatty acid concentrations didn't change significantly following 3 months of treatment with Lipostabil-forte (Zeman & Stolba, 1995). An open-label trial (n=12) in patients with chronic hepatitis also reported that Lipostabil administration for 2 weeks failed to exert any significant effect on carbohydrate intolerance and disturbances in insulin secretion (Kuska & Kokot, 1975).

Reduction in homocysteine levels

A DB-RCT crossover trial (n=26) found that in healthy men with mildly elevated homocysteine levels, supplementation with PhosChol for 2 weeks led to an 18% decrease in fasting plasma homocysteine compared to placebo. In response to methionine loading, the treated had a 15% lower homocysteine level than the placebo group on the first day and a 29% lower homocysteine level at the end of two weeks (Olthof et al., 2005).

A retrospective analysis (n=35) also reported a significant decrease in homocysteine levels (-31.8%) in patients with chronic fatigue taking an NT factor & vitamin mix for 6 months (Ellithorpe et al., 2015).

Reduction in CRP levels

A case series in patients with psoriatic arthritis treated with Phosphogliv (0.6 g/day for 3 months) reported a considerable decrease in CRP, hypothesized to occur either via a direct effect on RBC membranes or an indirect effect on liver function (Ipatova et al., 2003).

Increased lipoprotein lipase

A summary reported that lipoprotein lipase activity was increased in several trials (Gundermann, 1993). During a 6 week treatment with oral EPL in patients with hyperlipoproteinemia (n=80) an increase in activity of 25% was seen. In another trial (n=45) patients received 1.8 g/day EPL orally and exhibited a 40% increase after 3 weeks of treatment while no change was observed in the control group.

Endocrine

Improved thyroid function

An open-label trial (n=30) reported that all patients showed improvements in thyroid function within 6 months (usually within 1 month) under treatment with lipostabil-forte (Bobkova et al., 1989).

Energy/mitochondrial function

Fatigue

A DB-RCT (n=96) on females between the ages of 40-60 that administered soy lecithin tablets (PC 24%, PE 20%, and PI 12%) at 600 or 1200 mg/day for 8 weeks found that fatigue decreased significantly in all groups (including placebo) while vigor increased significantly in the high-dose group (Hirose et al., 2018).

An open-label trial (n=20) that administered NT Factor (3 tablets, twice/day for 12 weeks) to aged subjects with fatigue reported improvements in patients with moderate fatigue as measured by the Piper fatigue scale (PFS). The initial PFS group score was 5.75 and after 4 weeks of treatment, this improved to 4.59, a 20.2% reduction in fatigue. After 8 weeks of treatment, the PFS improved to 3.8 (33% reduction) and at 12 weeks to 3.71 (35.5%). Men showed a greater improvement than women (42.9% vs. 32.3%) after 12 weeks of treatment (Agadjanyan et al., 2003). Patients with mild fatigue did not show significant improvements (5.6% reduction). When the treatment was stopped, fatigue scores increased. Twelve weeks after stopping the average score was 4.53 (21% reduction from baseline).

Several studies reported reduced fatigue using phospholipids in combination with a multivitamin/mineral supplement (Ellithorpe et al., 2003; Colodny et al., 2000; Nicolson et al., 2010; Nicolson et al., 2009). An open-label trial (n=34) reported a 33% reduction in fatigue after 8 weeks of treatment with Propax (a multivitamin/mineral supplement) & NT factor (Ellithorpe et al., 2003). A study reported on two trials (open-label (n=16) and DB-RCT (n=22)) in patients that took Propax & NT factor in an attempt to reduce the adverse effects of chemotherapy. In the open-label study, patients received the supplement 5-7 days in advance and continued through the 12 weeks of the chemotherapy treatment and reported significant improvements in fatigue. Patients in the DB-RCT crossover trial who began with Propax & NT factor also reported improvements in fatigue during the study period (Colodny et al., 2000).

Another open-label trial (n=67) in patients with fatigue who received NTFactor Advanced Physician's Formula with B-Vitamin Complex reported a 36.8% reduction in fatigue according to the Piper Fatigue Scale. All subcategories improved by between 34.6-40.6% at the end of the one-week trial (Nicolson et al., 2010).

An open-label trial (n=30) in patients with chronic fatigue syndrome given a combination of white kidney bean extract and NTFactor before each meal reported a 23% decrease in overall fatigue (Nicolson et al., 2009).

Increased mitochondrial function

The staining of mitochondria using a rhodamine-123 assay (a dye for assessing mitochondrial function) changed significantly in an open-label trial (n=20) of aged patients with mild-moderate fatigue that were administered NT Factor for 12 weeks (Agadjanyan et al., 2003). At the end of the treatment, the rhodamine-123 assay yielded results similar to those found in young adults (Agadjanyan et al., 2003). The increase in mitochondrial function was approximately 23.7% after 12 weeks of treatment in moderately fatigued subjects. Following discontinuation of the treatment, mitochondrial function returned to intermediate values.

Increased sense of well-being

An open-label control trial (n=29) in patients with alcoholic fatty liver disease treated with Essentiale forte (1800 mg/day for 3 months) reported that sense of well-being was assessed as "good" in 76% (23/29) of patients treated patients (Turecky et al., 2003). Another open-label trial (n=30) on women with fatty liver disease that received oral Essentiale forte capsules over 6 months reported that all patients were subjectively better (Horejsova & Urban, 1994). An RCT (n=30) on patients treated with Essentiale reported an improved sense of wellbeing in 8/15 patients in the treatment group vs. 1/14 in the placebo group (Gonciarz et al., 1988). 

Gallbladder

Decreases postcholecystectomy syndrome

A case series (n=58) reported that administration of EPL has hepatoprotective effects, eliminates pain and dyspeptic symptoms, and normalizes biochemical parameters after gall bladder removal (Nichitaĭlo & Bulik, 2012).

Improved bile composition

A case series (n=6) that analyzed bile composition found an increase in fatty acid unsaturation following 3 weeks of treatment with 4.5 g EPL/day orally (Holan et al., 1979). Two open-label trials (n=100, 50) also reported beneficial changes in the physicochemical properties of bile that would decrease bile lithogenicity (Vakhrushev & Suchkova, 2005; Vakhrushev et al., 2002).

Another open-label trial found that administration of EPL corrects the linoleic acid deficiency that is found in patients with gallstones (Gundermann, 1993) and a DB-RCT (n=8) on patients after gall bladder surgery reported that the cholesterol content of the bile decreased in relation to the dose of EPL (Gundermann, 1993). 

Lipostabil reduced cholestasis in patients with viral hepatitis in an RCT (n=23) (Tsyrkunov, 1992).

In contrast, a case series (n=6) failed to show a therapeutic response on gallstone dissolution with EPL therapy (4.5 g/day for 3 weeks) (Holan et al., 1979).

Gastrointestinal system

Decrease in NSAID-induced damage to GI mucosa

A summary of several trials reported less damage to GI mucosa when NSAIDs were combined with EPL. In one of these studies (n=20), 90% (18/20) of patients reported an improvement in symptoms such as pain, nausea, and bowel evacuation within a few days of starting the combined therapy (Gundermann, 1993).

Another open-label trial (n=20) on patients with rheumatoid arthritis & drug-induced gastric complaints found that complaints were reduced by an average of 65% following 14 days of EPL treatment (2.7 g/day) (Gundermann, 1993). Pre-and-post-treatment gastroscopies were performed in 13/20 patients and in 80%, an improvement or even complete healing was seen (Gundermann, 1993).

A third open-label trial (n=19) on patients with NSAID-induced GI complaints, reported that 79% (15/19) of patients' symptoms disappeared almost completely after a few days. An open-label trial that assessed the effect of various doses of EPL on NSAID-induced GI complaints found complete relief of all symptoms in 42% (5/12) of patients at the low EPL dose, 50% (4/8) at the medium dose, and in 80% (8/10) at the high dose (Gundermann, 1993).

A case-control study (n=41) of children with duodenal ulcers reported that pain, dyspeptic and astenovegetative symptoms disappeared in the treated group. The concentration of pepsin in the gastric juice fell significantly, and the activity of lipid peroxidation was normalized to the levels found in healthy children. The rate of relapse was lowered by a factor of 1.7 compared to the control group (Gundermann, 1993). 

A DB-RCT (n=125) found that in patients with osteoarthritis that were treated with NSAIDs + PC (2400 mg/day for 6 weeks) there was a reduction in gastrointestinal erosions and ulcers (Lanza et al., 2008). In the sub-group of patients >55 years old, the risk of lesions/ulcers was 270% higher than in the PC-treated patients.

A SB-RCT (n=204) in healthy patients that were administered aspirin or aspirin/PC, found that 42.2% of the aspirin-treated subjects developed multiple erosions and/or ulcers vs. 22.2% of the PC treated group (Cryer et al., 2010). Gastroduodenal ulcers were observed in 17.6% of aspirin-treated patients, compared with 5.1% of PC-treated patients. 

The EPL treatment does not result in a reduction of the effectiveness of the NSAID (Gundermann, 1993; Lanza et al., 2008) although it has been shown to slightly slow down the absorption of indomethacin (Gundermann, 1993).

Improved bowel evacuation

In an open-label trial (n=19) on patients with piroxicam-induced GI complaints, 4 patients reported improvement in bowel evacuation with EPL treatment (2.7 g/day) (Gundermann, 1993).

Improved mucosal healing in ulcerative colitis

A DB-RCT (n=156) that used a modified-release form of PC in patients with ulcerative colitis reported a remission rate of 31.4% compared with 15% in the placebo group. Mucosal healing was seen in 32.5% of the placebo group compared with 47.4% of the treated group. Symptom resolution occurred 2 weeks earlier and twice as often in the treated group. Additionally, patients in the treated group maintained longer remissions (Karner et al., 2014).

Reproductive system

Improved sexual function

An open-label study (n=23) reported substantial improvements in sexual dysfunction following 60 days of EPL (1.8 g/day). There was a significant decrease in the number of patients with erectile dysfunction (8 vs. 18) and loss of libido (6 vs. 19), and an abnormality of ejaculation (11 vs. 18). Treatment with EPL also increased the sperm count but not to a level of statistical significance. The motility of the sperm was, however, significantly improved (Kiriakova et al., 1998).

Reduction of vomiting in pregnancy

Two studies (n=47,7) reported the disappearance of pregnancy-associated vomiting after 1 to 4 injections of EPL (Gundermann, 1993). However, a third study was unable to confirm the effect despite increasing the dose (Gundermann, 1993). 

Reduction of symptoms of preeclampsia

A summary of 20 trials (n=1057) of EPL in preeclamptic patients reported positive effects, particularly in combination with vitamin E (Gundermann, 1993). For example, a case series reported that in 52 patients with preeclampsia, symptoms of edema disappeared, liver and kidney function and diuresis normalized after an average of 7 days of treatment with EPL 500 mg/day i.v. (Gundermann, 1993). A second case series (n=42) reported that perinatal mortality and jaundice were reduced in preeclamptic patients treated with 2 ampules (500 mg) or 6 capsules (1800 mg) of Essentiale daily for 10-15 days (Gundermann, 1993). A third case series reported increases in protein and albumin and decreases in transaminases with oral EPL treatment for 7 days (Gundermann, 1993) as well as improvements in subjective well-being.

Another study reported normalization of pathological lipid values and increased utilization of lipids by the fetus following EPL treatment (Gundermann, 1993). Lipid peroxidation was found to be inhibited with EPL therapy, with values almost reaching the levels of healthy controls (Gundermann, 1993). These results were confirmed in a large study (n=549) that used Essentiale and reported antioxidative effects and diminished fetal hypoxia (Gundermann, 1993).

A case-control study (n=100) that compared EPL therapy with glutathione, vitamin B12, and UDP-glucose reported 46 patients were symptom-free after 10 days of EPL treatment (the remaining 4 patients after 15 days), compared to the control group in which 40 patients were free of symptoms after 10 days and the remaining 10 after 22 days (Gundermann, 1993).

A study (n=163) in which patients received i.v. and oral EPL for 10 days, followed by oral-only therapy, and newborns received i.v. EPL for 7 days, reported no perinatal deaths and higher birthweights compared to the control group, where the death rate was 5.1% and low birthweights occurred in 8.5% (Gundermann, 2017).

EPL was shown to positively affect pregnant patients with nephropathy (7/8 patients with mild, 13/18 patients with moderate, and 6/7 patients with severe nephropathy showed positive changes). However, discontinuation of EPL led to a relapse within 2-6 days (Gundermann, 2017). EPL treatment was also shown to reduce the likelihood of developing preeclampsia in patients with preexisting liver pathology (Gundermann, 2017).

Antenatal prevention of respiratory disorders in premature infants

In patients showing a high risk of surfactant deficiency (due to reduced phosphatidylcholine levels), Essentiale was found to increase phospholipid values in both mother and fetus as well as to positively influence hormones that favor surfactant production in the fetus (Gundermann, 1993).

Decreased miscarriages in antiphospholipid syndrome

One open-label study (n=43) reported improved lab values and decreased miscarriages in women diagnosed with antiphospholipid syndrome treated with Essentiale forte in addition to conventional treatment (Manizova et al., 2016).

Reduced risk of breast cancer

An epidemiological study (n=3101 breast cancer and n=3471 controls) reported a 23% reduced risk of breast cancer in subjects that had ever-used lecithin supplements (odds ratio = 0.77) (Anderson et al., 2011).

Lung

Normalization of surfactant composition in pneumonia

An open-label trial (n=27) reported normalization of surfactant composition, improved oxygen uptake, and a shorter disease duration in 27 children with acute pneumonia who were treated with a combination of Essentiale and a vasodilator (Gundermann, 1993).

Further studies reported that treatment with EPL is able to reduce lipid peroxidation and phospholipase activities with a simultaneous increase of the PC/lysoPC ratio. These changes were associated with an improvement of the clinical picture and a shortened duration of disease (Gundermann, 1993). 

Improvement in chronic lung disease

A summary reported on two trials in patients with chronic lung disease (Gundermann, 1993). In the first trial (n=54), after 4 weeks of Essentiale therapy,the cholesterol/phospholipid ratio was found to have decreased and erythrocyte flexibility increased. In the other study (n=104), treatment with EPL resulted in reduced azotemia and increased effects of antibiotics.

Decreases radiation-induced tissue injury in lung cancer

A retrospective analysis of patients with NSCLC receiving a complete course of PC treatment reported a significantly lower risk of developing symptomatic radiation pneumonitis (27.6%) than those patients without PC supplementation (43.5%). The hazard ratio (HR) of the PC treatment group was 0.55 for ≥ grade 2 radiation pneumonitis compared to the untreated patients (Zhang et al., 2019). 

Liver

Reduced mortality in liver failure/hepatic coma

A phase III clinical trial reported a faster recovery from encephalopathy and ascites as well as a lower overall mortality rate in patients with acute liver failure that were given PC by i.v. 350 mg 3x/day for 6-8 weeks (Singh & Prasad, 1998).

Mean survival time was increased from 34.7 days to 50.3 days in an open-label trial (n=12) on patients with severe hepatic encephalopathy treated with Essentiale. Corresponding improvements in EEG latency and ammonia levels were also seen (Bruha & Marecek, 2000). Ammonia levels decreased from 95 umul/L to 49.7 umol/L while values in the control group did not change significantly (Bruha & Marecek, 2000).

A summary of studies on the use of i.v. EPL for the treatment of hepatic coma reported good results, with reductions in ammonia levels, AST, and AP. In one report, 51% (18/35) of patients awoke from the coma as compared to 35% (7/20) in the control group. In cases of severe liver insufficiency, 3 g EPL by i.v. over 8-16 days resulted in improvements in 70% (7/10) of patients and after 4 weeks, 90% (9/10) patients were alive and recompensated. An open-label trial (n=50) reported also reported a significantly improved survival rate and time with EPL treatment (500-1000 mg/day over 14 days) in fulminant hepatitis (Gundermann, 1993).

Improved liver enzymes & function

We identified two summaries and 20 clinical studies that reported significant changes in liver function enzymes following EPL treatments of various durations. A summary of studies up to 1993 found many studies in which patients with cirrhosis that were treated with Essentiale for periods between 3-8 months reported the return of nearly all biochemical parameters to normal, decreased IgA, and an improved clinical picture (Gundermann, 1993).

17 studies reported on AST levels, 5 of which reported no significant change. In the other 12 studies, significant decreases were reported. In the studies that provided numbers, the decreases ranged from 32% to 72% as seen in the table below.

20 trials reported ALT levels, 5 of which reported no significant change. The remaining trials reported decreases, mainly between 25 and 55%.

12 trials reported GGT levels, 2 of which reported no significant change. Two studies reported a decrease to the normal range. The remaining studies reported 28 to 61% decreases.

Only 6 trials reported decreases in AP levels, none of which provided a percentage decrease or change from baseline. One trial reported that AP was not significantly changed. 7 trials reported on bilirubin levels, 4 of which reported no significant change while the remaining studies reported decreases. 

Of note, some studies found that benefits were maximal at 3-4 months despite continued treatment (Gundermann et al., 2016; Gonciarz et al., 1988). For example, an RCT (n=30) reported significantly decreased serum GGT after 1,3, and 6 months of therapy with Essentiale forte in patients with NAFLD, with the best results achieved after 3 months, despite continued administration for 6 months (Gonciarz et al., 1988). Transient rises in transaminases occurred following dose reductions (Dajani et al., 2015).

Table of studies reporting changes in liver enzymes:

Decreased drug/poison-related liver dysfunction

A summary of studies up to 1993 on chronic intoxication (organophosphates, CCl4, anti-epileptic drugs, etc.) reported many beneficial effects on liver function including improved uptake and secretory functions (Gundermann, 1993). This included a summary of 47 case reports on mushroom poisoning that found lower mortality (3/24) when treatment with Essentiale was initiated within 2 days vs. when treatment was initiated 3-4 days after disease onset (7/10) (Gundermann, 1993). Liver abnormalities were also of shorter duration.

An open-label trial (n=38) reported that treatment with EPL in conjunction with anti-epileptic drugs for an average of 5.9 months resulted in an impressive decrease in previously elevated GGT levels while not affecting the serum drug level (Hisanaga et al., 1980). 

An open-label trial (n=79) in patients on highly active anti-retroviral therapy (HAART) reported that ALT only increased an average of 1.73 iu/L in the Livolin supplemented group (3 capsules/day) vs. 7.73 iu/L in the control group (Otegbayo et al., 2012). 

Gundermann's summary reported that 8 open-label trials using EPL in addition to regular antitubercular treatment showed hepatoprotective effects including (Gundermann, 1993):

• An open-label controlled trial (n=380) reported that concomitant administration of EPL with anti-tuberculosis drugs delayed the onset of hepatic injury to 60 days as compared to 30 days in the control group. The number of patients suffering from elevated ALT/AST was also less and the clinical symptoms were milder. 

• Another study reported that only 5/42 participants developed liver dysfunction when administered EPL in conjunction with anti-tubercular drugs, a far-lower than expected number.

• An open-label trial found that all treated subjects (n=17) maintained normal AST/ALT values under anti-TB treatment while 63% (n=150) of the non-EPL treated group experienced elevations.

• Another study reported that only 16% of the treated group developed elevated AST vs. 38.5% of the control group and only 8.2% of the treated group developed elevated ALT compared with 25% of the controls. GGT also decreased in the treatment group.

• A study reported that even when anti-TB drugs had to be stopped due to liver dysfunction, the addition of Essentiale prevented further liver deterioration and allowed the treatment to resume

Additionally, another study (n=199) reported that the inclusion of essentiale (and/or tocopherol acetate, astragalus) in addition to usual antitubercular treatment exerted pronounced hepatoprotective effects and antioxidant effects (Skakun & Blikhar, 1986).

Improved liver elasticity/decreased fat infiltration/fibrosis

Three RCTs and a systematic review on patients with hepatic steatosis reported improvements in liver ultrasound findings following treatment with EPL. One DB-RCT (n=30) found a significant difference in the size of the liver by ultrasound examination following 6 months of therapy with Essentiale forte (1.8 g/day) (Gonciarz et al., 1988). Biopsies with marked histological improvements were seen in 4 patients in the treated group and 4 more patients showed some improvement compared with the placebo group in which only 4 patients exhibited an improvement (Gonciarz et al., 1988).

The second DB-RCT (n=215) with a follow-up of 7 years reported a significant improvement in the hepatic structure on ultrasound in 66.4% (101/152) diabetic patients with non-alcoholic steatohepatitis (NASH) that were treated with oral Essentiale forte (Sas et al., 2013). In the patients that were followed up long-term, signs of fatty liver decreased in 81.6% (93/114). Hepatic fibrosis was also significantly reduced in the long-term treated group compared with the control group.

The third RCT found that Essentiale-treated alcoholic patients (n=64) showed greater improvements in liver damage than controls (Khodzhaeva, 1990). 

The systematic review (of 10 trials published mainly in Chinese) reported that the addition of EPL to standard antidiabetic therapy resulted in a 50% improvement of non-alcoholic fatty liver disease (NAFLD) (Dajani & Popovic, 2020).

Several open-label trials also reported decreased fatty infiltration of the liver following treatment with EPL. In a randomized open-label trial (n=324), 20-30% of patients with NAFLD/DMII/hyperlipidemia showed an improvement in the fatty infiltration of the liver. The patients had a regression of at least one "grade" of the fatty infiltration, some even to normal (Dajani et al., 2015). 15-26% of patients in various subgroups also experienced a change in the liver stiffness measurement with a mean drop of 3.1-3.4 kilopascal per patient (Dajani et al., 2015). 

Another open-label trial (n=30) reported that following 6 months of oral Essentiale forte treatment, 25% of patients were completely free of ultrasonographic signs of steatosis (Horejsova & Urban, 1994). In the same trial, 25% of patients showed no improvement. The study also reported a decrease in average liver size from 12.9 cm to 11.4 cm.

A third open-label trial (n=40) reported that 74% (14/19) patients treated with EPL (1.8 g/day for 3 months) showed improvements on ultrasonography compared to 15% (3/20) in the group that was instructed about diet only (Cairella et al., 1989).

3 more open-label trials also reported significant decreases in liver fat as measured by CT or ultrasound (Gundermann et al., 2017; Babak & Bashkirova, 2019; Huang et al., 2016) and another open-label trial reported that EPL reduced the morphological severity of inflammatory and degenerative changes in the liver as well as improved the clinical status and laboratory status of patients (Butov et al., 2014).

A large case series (n=51) in patients with fatty liver disease of various causes also reported that liver ultrasound findings improved or normalized in 51% of subjects. A subanalysis showed that when alcohol-related liver disease cases were excluded, all patients improved. No further benefits occurred after 16 weeks of treatment (Gundermann et al., 2016).

In contrast, a large DB-RCT (n=789) reported that a biopsy taken after 2 years of oral PC treatment (4.5 g/day) did not differ significantly from placebo in patients with alcoholic liver disease (Lieber et al., 2003). It was not shown to affect the progression of liver fibrosis.

Reduced postoperative complications

In a retrospective analysis (n=117) of patients that underwent surgical treatment for liver echinococciasis, postoperative complications were reduced from 34.83% to 17.2% by the use of Essentiale and T-activin (Akhmedov et al., 2003). 

Faster recovery/better outcomes in hepatitis

A summary of 9 clinical trials (Gundermann et al., 1993) reported earlier improvement of symptoms such as dyspepsia, pressure, tension, fullness, nausea, and epigastric pain as well as of liver function parameters and liver histology. One of the included trials was an RCT (n=60) that reported that in 50% (15/30) of treated patients, the HBsAg was not detectable after 30 days vs. 23% (7/30) in the control group. A second study reported that the HBsAg disappeared after 3 months of EPL treatment in 62% (5/8) of patients compared with 14% (1/7) controls (Gundermann, 1993).

A summary of 67 studies of EPL treatment in chronic hepatitis (n= 2245) reported several benefits including improvements in liver biopsy, normalization of LCAT activity, decreased transaminases, increased albumin, improved clinical symptoms, improved biochemical values, decreased inflammatory activity, and less liver cell necrosis (Gundermann, 1993).

An open-label (n=23) found that Lipostabil shortened the time of jaundice in hepatitis B patients (Tsyrkunov, 1992).

Comparison of baseline and post-treatment biopsies revealed a significant reduction in the disease activity of chronic active hepatitis patients in a DB-RCT (n=30) (Jenkins et al., 1982).

PC therapy increased the response rate of patients with hepatitis C to antiviral (interferon) therapy in a DB-RCT (n=176) (Niederau et al., 1998). 71% of patients responded in the PC group compared to only 51% of patients in the placebo group. Additionally, prolonging the therapy tended to reduce the relapse rate in hepatitis C patients (41% vs 15% in the control group remained in remission). The benefit did not extend to patients with hepatitis B.

Another RCT (n=46) reported that EPL therapy (6 weeks) hastened recovery in patients with acute non-B hepatitis. However, it showed no advantage in patients with hepatitis that was due to septicemia (Atoba & Olubuyide, 1989).

An open-label trial (n=40) reported the advantage of 2 months of treatment with Phosphogliv in combination with regular treatment in children with hepatitis C. It resulted in a stable remission rate of 36.3% of patients for 9 months (Mukhamedov et al., 2003).

Hepatocyte regeneration

A summary of 18 trials (n=714) reported increases in the regenerative activity of hepatocytes (Gundermann, 1993).

Renal system

Improved kidney function

Most of the information about improvements in kidney function comes from Gundermann's summary.

In 19 patients with renal insufficiency, 5 days i.v. EPL 1000 mg plus 750 mg orally followed by 1500 mg/day orally for 10 days led to a significant rise in creatinine clearance, urea clearance, and sodium clearance. Five patients had a complete clinical remission while 3 showed clear improvements, only two remained unchanged (Gundermann, 1993). Another study reported decreased nitrogen and BP in 2 nephrosclerotic patients.

In healthy subjects (n=12), administration of i.v. EPL 250 mg was shown to increase GFR, renal plasma flow, and renal blood flow 30 min after administration (Gundermann, 1993). Another study (n=22) also reported improved GFR and creatinine clearance and a decrease in creatinine after a single dose of oral EPL (2 g) (Gundermann, 1993). Another study showed that a 3-days of i.v. EPL 3.5 mg/kg led to an increase in renal plasma flow, GFR, and sodium and water excretion. This increase was reversible by the simultaneous administration of aspirin (Gundermann, 1993).

Phospholipids in combination with diuretics were shown to lead to a further increase in sodium diuresis and potassium retention (Gundermann, 1993). A study (n=20) reported that phosphate and potassium excretion decreased and magnesium levels fell following a 10 mL EPL infusion (Gundermann, 1993). Another study found that sodium and chloride excretion increased in patients with fatty liver as well as healthy controls when treated with oral Essentiale 1050mg/day (Gundermann, 1993). The use of Essentiale in patients (n=41) with persistent hepatitis and cirrhosis of the liver was shown to increase sodium excretion due to an increase of natriuretic hormone (Gapon, 1990).

An open-label trial (n=180) on patients with kidney stones reported that treatment with Lipostabil moderately improved kidney function one month after lithotripsy (Neimark et al., 1998).

Two studies that used EPL in addition to chronic peritoneal dialysis found that it restored or increased ultrafiltration whether given orally or by i.v.. However, a third study that used oral EPL did not confirm these results (Gundermann, 1993) and an RCT (n=8) in patients with renal failure treated with Essentiale forte 900 mg/day also reported no significant difference in ultrafiltration after 8 weeks (Chan et al., 1991).

Nephrotic/nephritis syndrome

A study (n=9) reported that 330-700 mg daily EPL improved the symptoms of nephrotic syndrome including, edema reduction, increased diuresis (64%), increased albumin, and reductions in serum lipids (Gundermann, 1993). 

A controlled study (n=49) of children with glomerulonephritis that received Essentiale by i.v. for 10 days and oral EPL for 20 days reported earlier recovery of both renal and extrarenal manifestations of the disease, including reduction of blood pressure, hepatomegaly, hematuria, proteinuria, hypoalbuminemia, leukocytosis and stabilization of the excretion of renal phospholipids (Gundermann, 1993). 

A second study (n=11) reported that 67% (6/9) of patients with glomerulonephritis showed a reduction of edema and that serum albumin increased by 35% and TC and lipids fell by 13.7% and 17.2% respectively (Gundermann, 1993).

Musculoskeletal system

Decreased risk of fat emboli after fractures

In patients with large bone fractures, high doses of EPL resulted in fewer fat particles in the urine, indicating a decreased risk of fat emboli (Gundermann, 1993).

Improved motor function in Duchenne's muscular dystrophy

An open-label trial in patients with Duchenne's muscular dystrophy reported beneficial effects on motor function that were most pronounced at the initial stages of the disease (Islamova & Grinio, 1989).

Skin

Improvements in psoriasis

A summary reported on several studies that showed improvements in the clinical picture of psoriasis following EPL treatment (Gundermann, 1993). Oral EPL administration for 1-5 months in 4 patients resulted in an improvement in 3 patients 2-3 weeks after beginning the therapy. After 4 months, the skin manifestations disappeared completely in 2 subjects. Other papers reported that repeat episodes of psoriasis and neurodermatitis were limited and not severe in patients who received 2.3-4 g EPL/day. Another study also reported marked healing of lesions within 2-3 months of initiating treatment. It is hypothesized that deficiency of linoleic and linolenic acid might be the root cause of psoriasis due to disturbed synthesis of arachidonic acid from linoleic acid. Oxidized phospholipids have also been linked to the inflammatory processes of psoriasis (Sorokin et al., 2020).

Risk assessment 

We identified 9 risks that have occurred in clinical trials of EPL, most of which were mild and mitigable.

According to Gundermann's analysis, based on the existing reports of adverse drug reactions up to 1993, the incidence rate is 0.77% (27/3499) for i.v. injections. Of the 27 cases, only 5 resulted in the discontinuation of the medication. All others could be mitigated by dose reduction or slowing the injections (Gundermann, 1993). The incidence of side effects reported by doctors between the years of 1979-1989 was between 0.00056%-0.0018% per ampule (Gundermann, 1993). 

Because EPL corresponds to membrane-located phospholipids in its chemical configuration, toxic reactions are not expected, and side effects are uncommon and slight. In all clinical studies we identified, EPL was well tolerated. Serious adverse drug reactions were not observed either in the inpatients or during long-term treatment of the outpatients. The intravenous form of EPL contains deoxycholate as a solvent and was not used for longer than 2–4 weeks in the trials.

There are, however, an additional 4 risks that are much more serious in nature though "indirect" as they are largely based on data from observational trials that found elevated levels of choline or phosphatidylcholine were associated with a higher level of risk for CVD, lethal prostate cancer, and all-cause mortality.

Table 5: Risk assessment 

Risks

Increase in all-cause mortality

A large retrospective analysis (n= 80,978 women and 39,434 men) found that dietary phosphatidylcholine intake was associated with a higher risk of all-cause mortality. Each 100 mg/d higher phosphatidylcholine intake was associated with an 8% increment in all-cause mortality that remained despite adjustments for the 3 major food sources of phosphatidylcholine (red meat, eggs, and fish). Even when participants who took lecithin (phosphatidylcholine) supplements were excluded, the results did not change significantly. Diabetic participants in the top quintile of phosphatidylcholine intake had a 24% increased risk of all-cause mortality and a 67% increased CVD-mortality risk, whereas the nondiabetic participants in the top quintile had a 9% increased all-cause mortality risk and a 19% increased CVD-specific mortality risk versus those in the bottom quintile in each population (Zheng et al., 2016).

Increased risk of lethal prostate cancer

A large analysis (n=47,896) reported that men in the highest quintile of choline intake had a 70% increased risk of lethal prostate cancer compared with men in the lowest quintile and that the relationship was not appreciably changed after adjustment for important food contributors to choline intake (eg. whole eggs, skim milk, beef or lamb as a main dish, and chicken or turkey without skin) (Richman et al., 2012).

Increased risk of acute myocardial infarction & CVD

An observational study (n=1981) reported an increased risk for acute myocardial infarction per 50 mg/d increment of total choline (HR 1.1) and PC (1.24) intake (Van Parys et al., 2019). It is hypothesized that choline may exert negative effects through the conversion to triethylamine (TMA) by the intestinal microbiota, which is then absorbed and transformed in the liver to trimethylamine N-oxide (TMAO) by flavin-containing monooxygenase 3 (FMO3). Plasma TMAO might advance atherosclerosis by reduction of reverse cholesterol transport, increased macrophage cholesterol accumulation, upregulation of macrophage scavenger receptors, and augmented foam cell formation, resulting in increased inflammation and low-density lipoprotein cholesterol oxidation (Van Parys et al., 2019).

A systematic review (6 studies) funded by the Egg Nutrition Center found no significant association between dietary choline intake and CVD (Meter & Shea, 2017).

Increase in TMAO

Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after a phosphatidylcholine challenge in an open-label trial (n=40). Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics supporting the mechanism of gut microbiome involvement (Tang et al., 2013).

The observational arm of the same study reported a 2.54 HR for particants in the highest quintile of TMAO vs. the lowest, for the risk of a major adverse cardiovascular event (Tang et al., 2013).

Another study found that compared to phosphatidylcholine and control, choline bitartrate yielded three-times higher plasma TMAO and a 4.4-times higher plasma TMAO maximum increase from baseline. Gut microbiota composition differed between high-TMAO producers (with ≥40% increase in urinary TMAO response to choline bitartrate) and low-TMAO producers (with <40% increase in TMAO response). High-TMAO producers had more abundant lineages of Clostridiumfrom Ruminococcaceae and Lachnospiraceae compared to low-TMAO producers (Cho et al., 2020). An RCT (n= 82) reported increased TMAO after consumption of choline biartrate but not eggs or phospholipids indicating that the form and source of choline may play a role in determining TMAO production (Wilcox et al., 2021).

Another study found that patients with coronary artery disease consume more precursors of TMAO and have have higher blood TMAO concentrations compared to healthy volunteers. Fecal microflora of patients with CAD was shown to contain a greater number of gut bacteria related to trimethylamine producers compared with those of healthy volunteers (Ivashkin & Kashukh, 2019).

Increased gastrointestinal symptoms

In 39 clinical trials (n=1705) at doses ranging from 700-2700 mg/day, the only undesired drug reactions were those affecting the GI system. The incidence of side-effects was 1.3% (20/1504) with complaints such as slight, unspecific gastric disorders, soft stool, and diarrhea (Gundermann, 1993). Diarrhea and abdominal complaints were reported by 7/3499 patients with fatty liver disease after receiving i.v. EPL (Gundermann, 1993). Increased "intestinal movement" was noted in 3/30 patients with cirrhosis. One patient reported nausea on the initiation of 1000 mg EPL/day i.v. which disappeared when the infusion was given as a slow drip (Gundermann, 1993). 

Some later studies also reported GI side effects. A DB-RCT (n=26) found that although PC was well tolerated, dyspepsia was reported more frequently in the treated group (Olthof et al., 2005).

Another DB-RCT (n=125) reported dyspepsia in 14.8% of the PC-treated group and diarrhea in 9.8%. These adverse events were transient and self-resolved with a median duration of 4.5 and 8 days respectively (Lanza et al., 2008).

Increased oxidation

One risk that has been proposed regarding phospholipids, is the possibility that they are oxidized during storage, leading to detrimental effects. However, it has been shown that 1 Mol of tocopherol is enough to protect 2,000-20,000 Mol linoleic acid from oxidation with atmospheric oxygen. As tocopherol is added during manufacturing, this risk is negligible (Gundermann, 1993). 

Allergic reactions

Two reports of allergic reactions were made in Germany between the years of 1978-1989 (Gundermann, 1993). The usage instructions for the injectable form of Lipostabil contain a warning of possible allergic reaction due to the benzyl alcohol content.

Fever/chills

One patient with cirrhosis reported fever following EPL (Gundermann, 1993). A patient with chronic hepatitis reported fever on the initiation of 1000 mg EPL/day i.v. which disappeared when the infusion was given as a slow drip (Gundermann, 1993). A patient with chronic hepatitis reported chills after receiving i.v. EPL therapy (Gundermann, 1993).

Weakness

One patient reported general weakness on the initiation of 1000 mg EPL/day i.v. which disappeared when the infusion was given as a slow drip (Gundermann, 1993). 

Arrhythmias

There are 3 reports about arrhythmias from the time before 1988 when the formulation of Lipostabil still contained etophylline. A fourth patient reported tachycardia on the initiation of 1000 mg EPL/day i.v. which disappeared when the infusion was given as a slow drip (Gundermann, 1993). 

Hypersensitivity of the skin

A patient reported reddening of the skin on the initiation of 1000 mg EPL/day i.v. which disappeared when the infusion was given as a slow drip (Gundermann, 1993). Four patients with liver disease reported hypersensitivity reactions of the skin (Gundermann, 1993).

Headache

A patient with chronic hepatitis reported headache after receiving i.v. EPL therapy (Gundermann, 1993). 

Pain

In one study, 6/17 patients reported temporary pain following i.v. injection of EPL (Gundermann, 1993). In a study of patients with chronic hepatitis, 3/75 exhibited a slight exacerbation of pain in the right hypochondrium (Gundermann, 1993).

Gingivitis 

A patient with cirrhosis reported an aggravation of gingivitis that required the discontinuation of EPL therapy (Gundermann, 1993). 

Weight gain

In an open-label trial (n=10), lecithin resulted in an initial 1kg weight gain that rapidly stabilized in all but one subject who gained 6 kg over the treatment period (Simons et al., 1977).

Increased LDL-C/apoB

An open-label trial (n=8) in healthy volunteers reported that LDL-C increased significantly in the subjects that received i.v. Intralipid (from 590 to 700 mg/L) or egg phospholipids (from 730 to 810 mg/L). In contrast, the subjects that ingested the compounds orally did not exhibit an increase in LDL-C (Thompson et al., 1976).

A DB-RCT (n=30) reported that administration of PC to patients with hyperlipoproteinemia type IIB and hypoalfacholesterolemia led to a slight rise of apoB in comparison with the group treated with placebo (Zeman & Stolba, 1995). 

Hypertension

A DB-RCT (n=125) in patients with osteoarthritis treated with ibuprofen-PC reported an increased risk of hypertension (3.3%) as compared with patients treated with ibuprofen only (1.6%) (Lanza et al., 2008).

Section 5: Pharmacodynamics & Pharmacokinetics

Mechanism of action

Phospholipids (particularly phosphatidylcholine) are indispensable for cellular differentiation, proliferation, and regeneration, as well as for the transport of molecules through membranes. They control membrane-dependent metabolic processes between the intracellular and intercellular space, maintain and promote the activity and activation of membrane-bound proteins such as enzymes (e.g. Na -K -ATPase, lipoprotein lipase, lecithincholesterol acyltransferase (LCAT) and cytochrome oxidase) and receptors (e.g. insulin), and contain bound polyunsaturated fatty acids to be released on demand as precursors of cytoprotective prostaglandins and other eicosanoids. They are a source of second messengers in cell signaling (e.g. diacylglycerol), contain phosphate for cellular processes including ATP formation, participate in fat emulsification in the gastrointestinal tract and bile, are a determinant of erythrocyte and platelet aggregation, and influence immunological processes at the cellular level (Gundermann et al., 2011).

EPL have been to shown to be primarily incorporated into the liver, with minor incorporation into other organs such as the gastrointestinal tract, spleen, lung, muscles, kidneys and brain. Analytic examinations of the incorporated EPL showed that radioactivity was primarily localized in the membrane-containing fractions, with the distribution being ubiquitous in all liver cell fractions (Gundermann et al., 2011).

Dietary phospholipids have been shown not only to block the absorption of cholesterol but to "extract" cholesterol from the intestinal mucosa, resulting in negative absorption values (Cohn et al., 2010).

Type, composition, and dose

Phospholipids extracted from food products (e.g. soybeans, egg yolk, milk, or marine organisms like fish, roe or krill) are defined as "dietary phospholipids" and can be ingested either in the normal diet or as supplements. Naturally occurring PLs, predominantly contain an unsaturated FA (such as oleic, linoleic or linolenic acid) in the sn-2 position, or the pro-inflammatory arachidonic acid (usually from animal origin) or the anti-inflammatory eicosapentaenoic acid (usually from marine origin), while the sn-1 position predominantly carries a saturated FA, such as stearic acid or palmitic acid (Küllenberg et al., 2012).

EPL are similar to endogenous phospholipids and differ only by in its polyunsaturated fatty acids in the 1-position of the phosphatidylcholine molecules (Gundermann, 1993). Most of the EPL research has been conducted using a supplement brand known as "Essentiale". It was marketed for the first time in 1952 and since then has been further purified and registered in 54 countries (Gundermann, 1993).

A comparative analysis of 5 commercially available EPL preparations (Essentiale forte, Esentin forte, Fortifikat, Fortifikat forte, and Hepatoprotect Regenerator) found considerable differences between the compositions of the preparations in terms of the levels of PC and PE but found that the fatty acid compositions were relatively similar (Lüchtenborg et al., 2020). The analysis concluded that Essentiale forte was superior to the others because it contained the most PC. However, it was coauthored and funded by Sanofi, the company that manufactures it.

Plasmalogen is a commonly used term for a subclass of phospholipids that have an ether bond in position sn1 to an alkenyl group. In mammals, the sn1 position is typically derived from C16:0, C18:0, or C18:1 fatty alcohols while the sn2 position is most commonly occupied by polyunsaturated fatty acids (PUFAs). The most common head groups present in mammalian plasmalogens are ethanolamine (designated plasmenylethalomines) and choline (designated plasmenylcholines).

We were able to find out the composition of 15 of the supplements used in the studies included in our analysis (see table below). Most of the supplements contained additional vitamins/minerals so it is difficult to compare to the various formulas.

As seen in Tables 2 & 3, an extremely wide variety of doses have been used, ranging from 500 mg/day up to >40 g/day (Gundermann et al., 2011). Many of the studies on oral EPL used a dose of 1-2 capsules, 3x/day up to 1800 mg/day. The i.v. dose is 1-4 ampoules for injection or infusion up to 4 g/day (Gundermann, 1993). 

An intravenous-delivered mixture can deliver high phospholipid concentrations without the need for inhibiting intestinal disruption. However, the product is still susceptible to enzymatic and oxidative damage, and daily intravenous delivery comes with some risk for adverse events, such as infection, blood vessel damage, thrombosis, pruritus, dyspnoea, urticaria, among other potential problems (Nicolson, 2016). 

Table 6: Product composition