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Gilbert's Syndrome Successfully Treated with the Paleolithic Ketogenic Diet

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Csaba Csiba-Tóth at Nutrition intervention foundation
Csaba Csiba-Tóth
  • Nutrition intervention foundation
Zsofia Clemens at International Center for Medical Nutritional Intervention
Zsofia Clemens
  • International Center for Medical Nutritional Intervention
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Gilbert’s syndrome (GS) is a common hyperbilirubinaemia syndrome caused by reduced conjugation of serum bilirubin by the liver. Although it is considered as a common and harmless condition not requiring treatment symptoms associated with GS may be unfavorable. Here we present a case of GS where high level of total and direct bilirubin, yellowish discoloration of the sclera as well as associated symptoms including migraine, fatigue and granulomatosus dermatitis were reversed following a shift toward the popular paleolithic and then toward the paleolithic ketogenic diet.
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American Journal of Medical Case Reports, 2015, Vol. 3, No. 4, 117-120
Available online at http://pubs.sciepub.com/ajmcr/3/4/9
© Science and Education Publishing
DOI:10.12691/ajmcr-3-4-9
Gilbert’s Syndrome Successfully Treated with the
Paleolithic Ketogenic Diet
Csaba Tóth1, Zsófia Clemens1,2,*
1Paleomedicina Hungary Ltd., Evolutionary Medicine Working Group, Budapest, H-1026 Hidász u. 3/A, Hungary
2Neurological Department, University of Pécs, Pécs, H-7623, Rét u. 2, Hungary
*Corresponding author: clemenszsofia@gmail.com
Received March 17, 2015; Revised April 03, 2015; Accepted April 12, 2015
Abstract Gilbert’s syndrome (GS) is a common hyperbilirubinaemia syndrome caused by reduced conjugation of
serum bilirubin by the liver. Although it is considered as a common and harmless condition not requiring treatment
symptoms associated with GS may be unfavorable. Here we present a case of GS where high level of total and direct
bilirubin, yellowish discoloration of the sclera as well as associated symptoms including migraine, fatigue and
granulomatosus dermatitis were reversed following a shift toward the popular paleolithic and then toward the
paleolithic ketogenic diet.
Keywords: Gilbert’s syndrome, Paleolithic ketogenic diet, hyperbilirubinaemia, liver function
Cite This Article: Csaba Tóth, and Zsófia Clemens, “Gilbert’s Syndrome Successfully Treated with the
Paleolithic Ketogenic Diet.” American Journal of Medical Case Reports, vol. 3, no. 4 (2015): 117-120. doi:
10.12691/ajmcr-3-4-9.
1. Introduction
Gilbert’s syndrome (GS) is a hereditary
hyperbilirubinaemia syndrome affecting 5-10% of the
population [1]. It is primarily attributed to impaired
conjugation of bilirubin in the liver due to decreased
bilirubin glucuronyltransferase activity. Impaired activity
of this enzyme is attributed to mutations of the UGT1A1
gene. Beside this failure other alterations of the hepatic
bilirubin metabolism have been suggested in GS including
impaired hepatic uptake of bilirubin [2] and a positive
feedback of bilirubin through its mild haemolytic effect
[3].
GS is regarded as a common and harmless condition. In
population studies GS is associated with decreased
cardiovascular risk and all-cause mortality [4,5] which
may also be due to to the low BMI of those with GS [3].
Nevertheless GS is also known to be associated with a set
of unfavorable symptoms including fatigue, itching,
gastrointestinal symptoms [2], increased risk for
gallstones [6] as well as several unspecific symptoms
including neurologic ones.
Given that GS is regarded as a chronic condition not
requiring treatment symptoms are persisting life-long after
onset of the disease. Herein we present a case of a patient
with GS in whom both laboratory parameters and
associated symptoms have been reversed following a shift
toward the popular paleolithic and then toward the
paleolithic ketogenic diet. Previously we have published
successful treatment of epilepsy [7], type 1 diabetes [8]
and metabolic syndrome [9] with the paleolithic ketogenic
diet. This diet is close to the meat-fat based diet originally
proposed by gastroenterologist Voegtlin as being the
evolutionary adapted diet in humans [10].
2. Case Report
In 2006 GS was accidentally discovered in the female
patient aged 30 due to a routine laboratory test. This
showed elevations in both serum total bilirubin (31 µmol/l)
and directbilirubin (9.16 µmol) levels. Liver function tests
as well as other laboratory parameters were normal except
for low serum iron concentration (Table 1). Sclera of the
eyes showed persistent yellowish discolouration but no
signs of liver disease were present. Based on the
proportion of direct bilirubin to total bilirubin and clinical
features the hyperbilirubinaemia was classified as
Gilberts’s syndrome [11]. At this time the patient had a
10-year history of migrain episodes with an average
frequency of ~3/month. Her additional symptoms included
fatigue, constipation and unclassified granulomatosus
dermatitison both legs. Dermatitis was present for 10
years. No biopsy was taken to specify histology. She had
not been taking any medicines, vitamins or other
supplements. She reported no smoking and alcohol
abstinence. She was weak with a BMI of 17,9 (weight: 50
kg, height: 167 cm).
2.1. Popular Paleolithic Diet
On 09 November 2010 the patient decided to initiate
the paleolithic diet. Laboratory blood test performed at
diet onset showed a further eleveation in total bilirubin but
other laboratory parameters were normal (Figure 1 and
Table 1). Direct bilirubin was not tested at this time. The
popular form of the paleolithic diet she initiated restricted
118 American Journal of Medical Case Reports
milk, dairy, refined carbohydrates, cereals, legumes,
maize, rice and most vegetable oils. Thus the diet was
based on vegetables, fruits, meat, eggs but also contained
oilseeds, coconut oil, sugar alcohols and coconut. This
diet was however low in animal fat, red meats and offal.
Amount of fat, protein and carbohydrates were not
predefined in the popular paleolithic diet. She had been
following the diet for 20 months between Nov 2010 and
Jul 2012.
A laboratory test on 09 Nov 2011, a year after diet
onset, indicated a decrease in the level of both total and
direct bilirubin. Iron level was now in the normal range
and other parameters were normal too (Table 1).
Yellowish decoloration of the sclera disappeared. There
was a decrease in the number of migraine episodes (~6
episodes/year) and constipation resolved too. However
there was no change in feeling fatigue and in the presence
of granulomatosus dermatitis. Another concern was
weight loss. While on the popular paleolithic diet she lost
5 kilograms and so her BMI at this time was only 16.1.
2.2. Paleolithic Ketogenic Diet
In July 2012 we adviced a shift toward the paleolithic
ketogenic diet. This diet is based on animal fat, meat, eggs
and offal and to a lesser extent (less than 30%) vegetables
and fruits. Fat to protein ratio was at least 2:1 (in gram).
Fat and red meats derived from pork and cattle were
encouraged over lean meats from poultry. She consumed
offal from pork and cattle (predominantly liver, brain and
marrow) at least two times a week. She was avoiding
foods with additives including nitrites and/or nitrates.
Foods that are allowed or even encouraged in the popular
paleolithic diet such as artificial sweeteners, coconut oil,
oilseeds, oilseed flours and cocoa were excluded. She used
small amounts of honey. Ketosis was checked regularly by
urinary keton strips which showed sustained ketosis. The
four laboratory tests taken five months, 12 months, 19
months and 31 months after the onset of the paleolithic
ketogenic diet showed total bilirubin and direct bilirubin
levels below the upper reference limit (Figure 1). In these
measurements cholesterol and LDL cholesterol were
elevated but other laboratory measures were normal.
Testing for folic acid, vitamin B12 and vitamin D
(25(OH)D) in years 2014 and 2015 showed adequate
levels of these vitamins (Table 1).
Figure 1. Time course of total bilirubin levels through the normal, the
popular paleolithic and the paleolithic ketogenic diet. Note that with a
shift toward the popular paleolithic and then toward the paleolithic
ketogenic diet bilirubin levels fall below the upper reference limit
While on the paleolithic ketogenic diet her fatigue
disappeared and she experienced increased fittness both
physically and mentally. Her migraine episodes further
decreased (to ~2/year). Granulomatosus dermatitis
disappeared on both legs. Her weight was increased by 4
kilograms. Currently her BMI is 17.6. She reports no side
effects of the diet.
3. Discussion
GS is regarded as a lifelong condition of altered
bilirubin metabolism [11]. In our patient, however, clinical
features designating this condition have been reversed by
shifting first toward the paleolithic then toward the
paleolithic ketogenic diet. During this time serum level of
both total and directbilirubin declined below the upper
limit of the normal range. Although bilirubin levels
decreased and yellowish decoloration of the sclera
disappeared while on the popular paleolithic diet,
weakness, fatigue, migraine and granulomatosus
dermatitis improved considerably only after the shift
toward the paleolithic ketogenic diet.
While on the paleolithic ketogenic diet a laboratory
assessement indicated low level of inflammatory markers
(CRP, fibrinogen), normal level of triglicerides, uric acid,
glucose, ions, normal liver and kidney function. Total
cholesterol as well as LDL cholesterol were elevated.
Such a laboratory profile corresponds to that seen in our
previous patients with epilepsy [7], type 1 diabetes [8] and
metabolic syndrome [9] on the paleolithic ketogenic diet.
Supplementing vitamins on the classical ketogenic diet is
generally recommended. In the present case, however,
despite the absence of supplementing, vitamin D, folic
acid and vitamin B12, as assessed by laboratory
measurements in 2014 and 2015, were in the normal range.
Physicians generally opine that a metabolic condition
with a perceived genetic predisposition such as the GS
cannot be influenced by diet. We are not aware of studies
using dietary intervention is GS. However fasting and
glucose administration both orally and intravenously are
known to elevate bilirubin levels in GS patients [12,13].
Interestingly in a study carried out 40 years ago both
phenomena could be reversed by the addition of lipids
[14]. Then it was concluded that both phenomena are due
to the withdrawal of lipids.
Current dietary guidelines recommend the reduction of
fat and especially saturated fat in the diet [15]. However
there is growing evidence that the recommendation on
high carbohydrate/low fat diet may not be supported with
sufficient evidence [16] while carbohydrate-restricted
ketogenic diets have been shown to confer several health
benefits [17]. This was also the case in our patient with
GS and in the three other cases on the paleolithic
ketogenic diet [7,8,9].
It is of important to emphasize that unlike the classical
ketogenic diet which is known to be associated with
several adverse effects the paleolithic ketogenic diet does
not have any side effects as also examplified our present
and previous patients [7,8,9]. A second important point is
that although in this case there were some improvements
onthe popular paleolithic diet, the remaining symptoms
were only resolved with the paleolithic ketogenic diet.
American Journal of Medical Case Reports 119
We believe that the beneficial effects of the paleolithic
ketogenic effect are due tothe shift from carbohydrate-
based to fat-based metabolism, adequate intake and
bioavailability of vitamins and minerals as well as the
restriction of ”antinutrients” found in non-paleolithic [18]
and in the popular paleolithic foods.
In the literature there are a few short-term studies
[19,20,21] and a long-term intervention study [22] with
the paleolithic diet in healthy people and in patients with
metabolic syndrome. The present case strenghtens our
experience that the paleolithic diet in its widely used
popular form is limited in effectiveness in diseases with
components other than glucose metabolism alterations.
The paleolithic ketogenic diet, however, may be remedial
in these cases [7,8,9,23].
Table 1. Laboratory data while on the normal, the popular paleolithic and the paleolithic ketogenic diet. Dashes indicate that the given
parameter was not measured
Normal diet
Popular paleolithic diet
Paleolithic ketogenic diet
26 Apr 2006
09 Nov 2011
04 Dec 2012
18 Jul 2013
11 Feb 2014
12 Feb 2015
Total bilirubin
31
21.6
17.4
20.5
20.5
17.7
µmol/l
Direct bilirubin
9.16
< 5
-
-
3
3
µmol/l
WBC
8.6
6.3
6.06
6.1
6.4
6.4
G/l
RBC
5.07
4.78
4.44
4.82
4.8
4.6
T/l
Hgb
143
139
136
141
144
136
g/l
Ht
45
43
41
42
0.44
0.42
%
Thrombocyte
277
285
284
249
253
252
G/l
Natrium
136.3
138
132
133
136
138
mmol/l
Kalium
3.8
4.3
4.1
4.4
4.2
4.1
mmol/l
Glucose
4.7
5.1
5.1
5.5
5.4
4.7
mmol/l
GGT
10
13
16
19
14
13
U/l
GOT
19
16
12
15
20
22
U/l
GPT
26
26
23
33
15
12
U/l
ALP
70
70
62
66
-
-
U/l
Total cholesterol
4.03
4.8
5.8
5
7.7
6.8
mmol/l
HDL cholesterol
1.95
2.25
2.23
2.36
-
2.21
mmol/l
LDL cholesterol
1.81
2.39
-
-
-
4.49
mmol/l
Triglycerides
0.59
0.35
0.48
0.24
0.71
0.99
mmol/l
Uric acid
189
-
188
175
201
266
µmol/l
Total protein
79.3
70
72
71
73
72
g/l
Albumin
50
49
40
40
47.8
48.2
g/l
Carbamide
3.8
4.1
5
4.7
5.7
5.7
mmol/l
Creatinine
72
68
58
79
63
75
µmol/l
CRP
<3
1
1
<3
0.27
0.28
mg/l
ESR
-
3
7
3
3
4
mm/h
Iron
8.2
17.6
14.9
24.9
22.1
19.7
µmol/l
Magnesium
-
-
-
0.64
0.87
0.84
mmol/l
Vitamin B12
-
-
-
-
371.6
429
pmol/l
Folic acid
-
-
-
-
51.2
31.8
nmol/l
25(OH)D
-
-
-
-
163
124.1
nmol/l
Abbreviations: WBC – white blood cell, RBC – red blood cell, Hgb – hemoglobin, Ht – hematocrit, GOT – glutamate-oxaloacetate transaminase, GPT –
glutamate-pyruvate transaminase, GGT – gamma-glutamyl transferase, ALP – alkaline phosphatase, CRP – C reactive protein, ESR – erythrocyte
sedimantation rate.
Funding
None
Statement of Competing Interests
The authors have no competing interests.
References
[1] Owens D, Evans J. Population studies on Gilbert's syndrome. J
Med Genet 1975; 12: 152-6.
[2] Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-
Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor
syndrome). Best Pract Res Clin Gastroenterol 2010; 24: 555-71.
[3] Wallner M, Bulmer AC, Mölzer C, Müllner E, Marculescu R,
Doberer D, et al. Haem catabolism: a novel modulator of
inflammation in Gilbert's syndrome. Eur J Clin Invest 2013; 43:
912-9.
[4] Vítek L, Jirsa M, Brodanová M, Kalab M, Marecek Z, Danzig V,
et al. Gilbert syndrome and ischemic heart disease: a protective
effect of elevated bilirubin levels. Atherosclerosis 2002; 160: 449-
56.
[5] Horsfall LJ, Nazareth I, Pereira SP, Petersen I. Gilbert's syndrome
and the risk of death: a population-based cohort study. J
Gastroenterol Hepatol 2013; 28: 1643-7.
[6] Tsezou A, Tzetis M, Giannatou E, Spanos I, Roma E, Fretzayas A,
et al. Gilbert syndrome as a predisposing factor for cholelithiasis
risk in the Greek adult population. Genet Test Mol Biomarkers
2009; 13: 143-6.
[7] Clemens Z, Kelemen A, Fogarasi A, Tóth C. Childhood Absence
Epilepsy Successfully Treated with the Paleolithic Ketogenic Diet.
Neurology and Therapy 2013; 2: 71-6.
[8] Tóth C, Clemens Z. Type 1 diabetes mellitus successfully
managed with the paleolithic ketogenic diet. Int J Case Rep
Images 2014; 5: 699-703.
[9] Tóth C, Clemens Z. Successful treatment of a patient with obesity,
type 2 diabetes and hypertension with the paleolithic ketogenic
diet. 2015 Int J Case Rep Images (accepted for publication).
[10] Voegtlin WL. The stone age diet: based on in-depth studies of
human ecology and the diet of man. New York: Vantage Press;
1975.
[11] Fevery J. Bilirubin in clinical practice: a review. Liver Int 2008;
28: 592-605.
[12] Barrett PV. Effects of caloric and noncaloric materials in fasting
hyperbilirubinemia. Gastroenterology 1975; 68: 361-9.
[13] Felsher BF, Carpio NM. Caloric intake and unconjugated
hyperbilirubinemia. Gastroenterology 1975; 69: 42-7.
[14] Gollan JL, Bateman C, Billing BH. Effect of dietary composition
on the unconjugated hyperbilirubinaemia of Gilbert's syndrome.
Gut 1976; 17: 335-40.
120 American Journal of Medical Case Reports
[15] Nicklas T, Johnson R; American Dietetic Association. Position of
the American Dietetic Association: Dietary guidance for healthy
children ages 2 to 11 years. J Am Diet Assoc 2004; 104: 660-77.
[16] Harcombe Z, Baker JS, Cooper SM, et al. Evidence from
randomised controlled trials did not support the introduction of
dietary fat guidelines in 1977 and 1983: a systematic review and
meta-analysis. Open Heart 2015; 2: e000196.
[17] Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a
review of the therapeutic uses of very-low-carbohydrate
(ketogenic) diets. Eur J Clin Nutr 2013; 67: 789-96.
[18] Cordain L. The paleo diet: lose weight and get healthy by eating
the food you were designed to eat. New York: Wiley; 2002.
[19] Österdahl M, Kocturk T, Koochek A, Wändell PE. Effects of a
short-term intervention with a paleolithic diet in healthy
volunteers. Eur J Clin Nutr 2008; 62: 682-5.
[20] Jönsson T, Granfeldt Y, Ahrén B, Branell UC, Pålsson G, Hansson
A, Söderström M, Lindeberg S. Beneficial effects of a Paleolithic
diet on cardiovascular risk factors in type 2 diabetes: a randomized
cross-over pilot study. Cardiovasc Diabetol 2009; 8: 35.
[21] Frassetto LA, Schloetter M, Mietus-Synder M, Morris RC Jr,
Sebastian A. Metabolic and physiologic improvements from
consuming a paleolithic, hunter-gatherer type diet. Eur J Clin Nutr
2009; 63: 947-55.
[22] Mellberg C, Sandberg S, Ryberg M, Eriksson M, Brage S, Larsson
C, Olsson T, Lindahl B. Long-term effects of a Palaeolithic-type
diet in obese postmenopausal women: a 2-year randomized trial.
Eur J Clin Nutr 2014; 68: 350-7.
[23] Tóth C. Paleolithic medicine (Paleolit orvoslás). Budapest: Jaffa;
2012.
... This is an animal fat-meat based diet similar to that originally proposed and used by gastroenterologist Voegtlin (13). To date we have published eight cases including patients with epilepsy (14,15), type 1 diabetes (16,17), metabolic syndrome (18), Gilbert's syndrome (19), Crohn's disease (20) and soft palate cancer (21) successfully treated with the paleolithic ketogenic diet. Importantly, the classic version of the ketogenic diet is known to be associated with low magnesium levels (22) one of the most well-known side-effects of the classic ketogenic diet. ...
... Importantly, the classic version of the ketogenic diet is known to be associated with low magnesium levels (22) one of the most well-known side-effects of the classic ketogenic diet. Our published cases (14)(15)(16)(17)(18)(19)(20)(21), along with our general experience, however, indicate that magnesium levels are normal on the paleolithic ketogenic diet. In order to quantify this clinical observation we performed a study in which we retrospectively assessed magnesium levels in relation to glycemic parameters in 45 patients with various diseases and five healthy subjects on the paleolithic ketogenic diet. ...
... were low. A similar pattern of laboratory parameters was seen in our previous case studies with the paleolithic ketogenic diet (14)(15)(16)(17)(18)(19)(20)(21) and may be regarded as indicating adequate dietary adherence. ...
The paleolithic ketogenic diet may ensure adequate serum magnesium levels
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Magnesium plays an essential role in several enzymatic reactions. Its deficiency is known to be widespread and has been associated with a variety of pathological conditions characterized by chronic inflammation and/or oxidative stress. The connection between the metabolism of glucose and magnesium at the cell level is wellestablished. We hypothesize that magnesium deficiency in chronic conditions is primarily due to Western type carbohydrate based metabolism. In previous case studies we have shown that magnesium levels are normal on the paleolithic ketogenic diet. Here we assessed magnesium levels in a larger sample (n=50) to address whether the paleolithic ketogenic diet is able to ensure normal blood magnesium levels. Materials and Methods To assess magnesium levels in patients and healthy controls on the paleolithic ketogenic diet in a larger sample, we retrospectively analysed laboratory data obtained from 50 patients/subjects who were following the diet and were also not taking magnesium or other supplements. Correlation calculation was performed between magnesium and glucose levels. Results We found magnesium levels to be in the normal range in all but one patient/subject. There was a significant inverse correlation between glucose and magnesium levels. Discussion Our results indicate that the paleolithic ketogenic diet ensures normal magnesium levels in various pathological conditions as well as in healthy subjects. We believe that the high prevelance of magnesium deficiency reported earlier for a variety of chronic conditions is correlated with carbohydrate-based Western type nutrition rather than that of the chronic condition itself. We discuss underlying mechanisms. Keywords magnesium, paleolithic, ketogenic, glucose, glycated hemoglobin, diabetesn
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... An increasing number of studies, as also reviewed by a recent metaanalysis [15], indicate metabolic benefits of the human evolutionary diet also known as the stone age diet [16] or paleolithic diet [17]. In recent years we have published a series of case studies where type 1 diabetes [18,19], type 2 diabetes [20], epilepsy [21,22], Gilbert's syndrome [23] and Crohn's disease [24] where was successfully treated by the paleolithic ketogenic diet, an animal fat-meat based diet. In our most recent case study we reported on halted progression of soft palate cancer for 20 months in a patient on the paleolithic ketogenic diet [25]. ...
... It is known that plant oils, grains and dairy, among their other possible negative effects, may promote inflammation [17]. On the contrary, the paleolithic ketogenic diet, which is based on animal fat, meat and offal, seems to have an anti-inflammatory effect, as also seen in our other patients on the same diet [18][19][20][21][22][23][24][25]. In addition, while the classical ketogenic diet is known to induce nutrient deficiencies [29], the paleolithic ketogenic diet seems to supply optimal amounts of micronutrients as shown by the absence of deficiency symptoms and the normalization of laboratory parameters including iron, magnesium and vitamin levels, and normal function of the liver, kidney and thyroid gland. ...
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... Помимо риска нарушения биотрансформации ксенобиотиков, практически нет оснований называть людей с синдромом Жильбера «пациентами», рекомендовать им диетические ограничения или снизить физическую активность [25]. Напротив, синдром Жильбера чаще встречается среди элитных спортсменов, которые обычно имеют более высокие концентрации билирубина в сыворотке крови по сравнению с населением в целом [26], что предрасполагает их к лучшей физической работоспособности [27]. ...
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... Thus far, we have published several case reports of patients successfully treated with the PKD. These include: type 2 (Tóth and Clemens, 2015a) and type 1 diabetes (Tóth and Clemens, 2014;2015b), Crohn's disease , Gilbert's syndrome (Tóth and Clemens, 2015c), epilepsy (Clemens et al., 2013(Clemens et al., , 2015; complete reversal of cervical intraepithelial neoplasia ; halted progression of soft palate cancer , regression of rectal cancer (Tóth and Clemens, 2017) and unexpectedly long survival with glioblastoma (Tóth et al., 2019). In 2017, we published a study with 50 patients on the PKD with 98% showing magnesium levels in the normal range, which is unexpected for a population with chronic diseases. ...
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Full-text available
  • Dec 2023
C-peptide is used as a measure of endogenous insulin production. Given that insulin and C-peptide are produced in equal amounts, C-peptide is typically used to differentiate between external and endogenously produced insulin in insulin-treated type 1 diabetes mellitus (T1DM). In a clinical setting, a decline in C-peptide is regarded as a loss of beta cell function. However, physiological conditions may also be associated with low C-peptide levels. The authors of this paper use a low-carbohydrate diet, the so-called paleolithic ketogenic diet (PKD), in the treatment of various conditions and observed that C-peptide is typically low on this diet. In order to characterize C-peptide levels on this diet, we designed a study to retrospectively assess C-peptide levels in 100 non-T1DM subjects. We found that 55% of the subjects had a C-peptide level below the standard reference range. C-peptide levels correlated with glucose levels. A significant correlation was found between C-peptide and age, with younger subjects having lower C-peptide levels. Males also showed lower C-peptide levels than females. Given the increasing number of patients using low-carbohydrate diets worldwide, physicians should be aware of laboratory correlates of low-carbohydrate diets, including low C-peptide levels, most importantly to prevent incorrect T1DM diagnosis.
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... The bilirubin concentration reduction observed in our study is also an interesting finding, since its value dropped below the lower limit of normal. It is known from the literature that even in such conditions as Gilbert's syndrome, a ketogenic diet is able to decrease bilirubin concentration [44]. A wider context of ketogenic diet and liver function was described in the publication by Watanabe et al. [45]. ...
Keto Menu–Effect of Ketogenic Menu and Intermittent Fasting on the Biochemical Markers and Body Composition in a Physically Active Man—A Controlled Case Study
Article
Full-text available
  • Aug 2023
The combination of ketogenic diet (KD) with intermittent fasting (IF) has, for years, aroused a great interest in the scientific world and among healthy lifestyle enthusiasts. Its importance is even greater when the study subjects are physically active individuals. The aim of the study was a determination of the effect of strict calculated ketogenic menu combined with IF and with caloric deficit on the selected biochemical markers and body composition in a 23-year-old man performing strength training. At the same time, we decided to conduct the first so-deeply investigated and controlled case study in this respect. The study protocol included a 13-week-long ketogenic diet with intermittent fasting (of delayed time-restricted eating 16:8 type) and caloric deficit. A detailed menu was designed and was used by the man throughout the whole study duration. A number of blood tests were performed before and after the implemented dietary intervention. Additionally, body composition was determined weekly and the concentrations of glucose and ketone bodies, as well as pulse rate and arterial pressure, were measured daily. The most important changes noted included a significant increase in testosterone and vitamin D concentrations and significant reduction in the HOMA-IR index and concentrations of hepatic enzymes, insulin, glucose, iron, urea, and free triiodothyronine (FT3). Moreover, a significant improvement of body composition occurred (the ratio of total body mass to the adipose and muscular tissue and water mass improved). Favourable changes were also noted in heart rate and arterial pressure values. In view of that, the KD with IF and caloric deficit exerted favourable effects on most biochemical parameters and on body composition and caused an almost twofold increase in serum testosterone concentration.
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... As we previously reported, recovery from Crohn's disease using the paleolithic ketogenic diet may be hindered by eating components of the popular paleolithic diet [22]. In another case study we reported that the popular paleolithic diet did not confer all the benefits that were provided by the paleolithic ketogenic diet in Gilbert's syndrome [23]. Previously we have published a case of soft palate cancer halted by the paleolithic ketogenic diet for 20 months [10]. ...
Complete Cessation of Recurrent Cervical Intraepithelial Neoplasia (CIN) by the Paleolithic Ketogenic Diet: A Case Report
Article
Full-text available
  • Jan 2018
Background: Ketogenic diets have repeatedly been suggested for the treatment of cancer. To date, only a few case studies reporting long term benefits associated with such diets have been published. Case report: Here we present a case where recurrent cervical intraepithelial neoplasia (CIN), a premalignant condition of cervical cancer, was successfully treated with the paleolithic ketogenic diet. The patient had a history of high grade CIN in 2011, which was successfully treated with cervical conization and fractional curettage. In October 2015 she was found to have a recurrence of high grade CIN (HSIL: High Grade Squamous Intraepithelial Lesion). The patient was then commenced on the paleolithic ketogenic diet and her repeat Pap (Papanicolaou) smear three months later was found to have reverted to normal. The patient has remained on the paleolithic ketogenic diet for 26 months, her repeat smears have stayed normal, and she is free of symptoms and side effects. Conclusion: We conclude that the diet was effective and safe in this patient. As a major benefit the patient was able to avoid a hysterectomy, which is the standard treatment for recurrent high-grade CIN. We believe that the paleolithic ketogenic diet combines benefits of both paleolithic and classical ketogenic diets, while excluding their disadvantages.
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... Erickson et al. [1] recently published a review on the use of the ketogenic diet in cancer. The authors of this reply are clinicians who bring into play an evolutionary approach in the practice of medicine and specifically have been using the paleolithic ketogenic diet in the treatment of chronic diseases since 2011 [2][3][4][5][6][7][8][9]. We have instituted the paleolithic ketogenic diet in approximately 4000 patients, of whom several hundred have been followed up for at least one year, and 60 cancer patients who have been followed up for at least 6 months. ...
Comment on " Systematic Review: Isocaloric Ketogenic Dietary Regimes for Cancer Patients " by Erickson et al
Article
Full-text available
  • Jul 2017
Erickson et al. recently published a review on the use of the ketogenic diet in cancer. The authors of this reply are clinicians who bring into play an evolutionary approach in the practice of medicine and specifically have been using the paleolithic ketogenic diet in the treatment of chronic diseases since 2011. We have instituted the paleolithic ketogenic diet in approximately 4000 patients, of whom several hundred have been followed up for at least one year, and 60 cancer patients who have been followed up for at least 6 months. Previously (prior to 2011) we had been using the classic paleolithic diet, which was useful in the treatment of certain diseases but proved to be ineffective in the treatment of autoimmune diseases and cancer.
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Gilbert’s syndrome - bright and dark sides of the disease - literature review
Article
Full-text available
  • Feb 2024
Gilbert’s syndrome is the most common inherited jaundice worldwide. It affects 5-10% of the population. It is caused by a mutation of the UGT1A1 gene, which results in impaired bilirubin metabolism. It is a benign disease and does not affect the life expectancy of patients. Patients with Gilbert’s syndrome should be alert to factors that exacerbate the course of the disease, interactions with medications taken and possible comorbidities such as hemolytic anemia, cholelithiasis or schizophrenia. However, it is the responsibility of physicians with such patients under their care to properly educate patients. Gilbert’s syndrome carries not only the consequences associated with the mutation, but also has many benefits that patients may not be fully aware of. Mildly elevated bilirubin levels have an antioxidant and anti-inflammatory effect, which prevents the development of lifestyle diseases and cancer. Ongoing clinical trials suggest that this could be a great step toward new treatments for diseases affecting the entire human population. PURPOSE OF THE WORK: This review paper aims to show Gilbert’s syndrome as a multifaceted disease and to sensitize doctors' attention to patients with the described mutation. MATERIALS AND METHODS: An analysis of papers available in PubMed and Google Scholar was performed using the following key words: Gilbert’s syndrome, bilirubin, UDP-glucuronosyltransferase, Gilbert’s syndrome harmful and protective aspects, iatrogenic Gilbert’s syndrome RESULTS: The result of the work is to present Gilbert’s syndrome as a disease that carries medical problems directly related to the mutation, but also, in some cases, has a protective effect on affected individuals. The work highlights the complexity of the problem.
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Gilbert´s syndrome revisited
Article
  • Jun 2023
Gilbert´s syndrome, also known as benign hyperbilirubinemia, was described more than 100 years ago. It has usually been considered a physiological abnormality characterized by a mild elevation of the systemic level of unconjugated bilirubin, in the absence of any underlying liver or overt hemolytic disease. However, since the re-discovery of the potent antioxidant effects of bilirubin in the late 1980s, as well as multiple intracellular signaling pathways affected by bilirubin, an ever-increasing body of evidence suggests that subjects with Gilbert´s syndrome may benefit from the mild hyperbilirubinemia and are virtually protected from the development of a wide variety of "diseases of civilization" such as cardiovascular diseases, certain cancers, autoimmune or neurodegenerative diseases. This review analyzes the current state of medical knowledge given recent discoveries in this rapidly developing field, as well as their possible clinical significance, and gives a new perspective to this condition.
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Physiological changes in the albumin-bound non-esterified free fatty acids critically influence heme/bilirubin binding properties of the protein: A comparative, in vitro, spectroscopic study using the endogenous biomolecules
Article
  • Mar 2020
  • SPECTROCHIM ACTA A
Heme and bilirubin (BR), as by-products of red blood cells (and hemoglobin) degradation, show increased plasma concentrations in some diseases. These two toxic hydrophobic molecules are mainly transported in the blood-stream by human serum albumin (HSA) that carries a wide variety of ligands. Under normal physiological conditions, ~3 fatty acid (FA) molecules are bound to each HSA; and its possible effect on BR/heme binding remains to be more clarified. In the present study, to provide deeper insight on this issue, we purified albumin from healthy individuals (as purified non-defatted albumin or PA) with normal plasma levels of FA, then defatted some of the purified protein (as defatted-HSA; or DA). In the next step, using various spectroscopic methods, their interactions with heme and BR were investigated. By 1: 1 binding of the ligands, quenching and thermodynamic analysis of parameters indicated that binding constants (Kb) values of bilirubin and heme for PA and DA are different. It could be perceived that the presence of FAs in high-affinity FA binding sites (FABSs) exerted considerable conformational changes in the structure followed by an improved BR binding while hindered heme interaction. The data was confirmed by determining surface hydrophobicity of the purified albumin (PA) and DA, and then supported by bioinformatics analyses. The physiological and clinical relevance of the observed dynamic interactions is also discussed. This study, also, re-confirmed that the primary BR binding site is subdomain IIA not subdomain IB.
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Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: A systematic review and meta-analysis
Article
Full-text available
  • Feb 2015
Objectives National dietary guidelines were introduced in 1977 and 1983, by the US and UK governments, respectively, with the ambition of reducing coronary heart disease (CHD) by reducing fat intake. To date, no analysis of the evidence base for these recommendations has been undertaken. The present study examines the evidence from randomised controlled trials (RCTs) available to the US and UK regulatory committees at their respective points of implementation. Methods A systematic review and meta-analysis were undertaken of RCTs, published prior to 1983, which examined the relationship between dietary fat, serum cholesterol and the development of CHD. Results 2467 males participated in six dietary trials: five secondary prevention studies and one including healthy participants. There were 370 deaths from all-cause mortality in the intervention and control groups. The risk ratio (RR) from meta-analysis was 0.996 (95% CI 0.865 to 1.147). There were 207 and 216 deaths from CHD in the intervention and control groups, respectively. The RR was 0.989 (95% CI 0.784 to 1.247). There were no differences in all-cause mortality and non-significant differences in CHD mortality, resulting from the dietary interventions. The reductions in mean serum cholesterol levels were significantly higher in the intervention groups; this did not result in significant differences in CHD or all-cause mortality. Government dietary fat recommendations were untested in any trial prior to being introduced. Conclusions Dietary recommendations were introduced for 220 million US and 56 million UK citizens by 1983, in the absence of supporting evidence from RCTs.
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Successful treatment of a patient with obesity, type 2 diabetes and hypertension with the paleolithic ketogenic diet
Article
Full-text available
  • Mar 2015
Introduction: Metabolic syndrome is a major public health problem affecting at least 20% of the world’s adult population. Components of the metabolic syndrome include obesity, impaired glucose metabolism, hypertension and altered lipid profile. Currently, medical treatment relies on drugs. A major problem is that patients with long-standing disease are excessively medicated because of an increase in the number of symptoms over time. A few clinical studies indicate that low-carbohydrate diets, including the paleolithic as well as the ketogenic diet, may be beneficial in the treatment of conditions associated with the metabolic syndrome. Case Report: Herein, we present a case of patient with metabolic syndrome successfully treated with the paleolithic ketogenic diet. While on the diet the patient was able to discontinue eight medicines, lost weight, showed a continuous improvement in glucose parameters and her blood pressure normalized. Currently, the patient is on the paleolithic ketogenic diet for 22 months, free of symptoms and side effects. Conclusion: We conclude that the paleolithic ketogenic diet was safe, feasible and effective in the treatment of this patient with metabolic syndrome.
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Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review and meta-analysis
Article
Full-text available
  • Feb 2015
Objectives: National dietary guidelines were introduced in 1977 and 1983, by the US and UK governments, respectively, with the ambition of reducing coronary heart disease (CHD) by reducing fat intake. To date, no analysis of the evidence base for these recommendations has been undertaken. The present study examines the evidence from randomized controlled trials (RCTs) available to the US and UK regulatory committees at their respective points of implementation. Methods: A systematic review and meta-analysis were undertaken of RCTs, published prior to 1983, which examined the relationship between dietary fat, serum cholesterol and the development of CHD. Results: 2467 males participated in six dietary trials: five secondary prevention studies and one including healthy participants. There were 370 deaths from all-cause mortality in the intervention and control groups. The risk ratio (RR) from meta-analysis was 0.996 (95% CI 0.865 to 1.147). There were 207 and 216 deaths from CHD in the intervention and control groups, respectively. The RR was 0.989 (95% CI 0.784to 1.247). There were no differences in all-cause mortality and non-significant differences in CHD mortality, resulting from the dietary interventions. The reductions in mean serum cholesterol levels were significantly higher in the intervention groups; this did not result in significant differences in CHD or all-cause mortality. Government dietary fat recommendations were untested in any trial prior to being introduced. Conclusions: Dietary recommendations were introduced for 220 million US and 56 million UK citizens by 1983, in the absence of supporting evidence from RCTs.
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Type 1 diabetes mellitus successfully managed with the paleolithic ketogenic diet
Article
Full-text available
  • Oct 2014
Introduction: Type 1 diabetes mellitus (T1DM) patients are usually instructed to follow a low fat/high carbohydrate diet. A few studies in literature, however, reported metabolic benefits and sustainability of carbohydrate restricted diets. Case Report: Herein, we present a case of a 19-year-old male with newly diagnosed T1DM. The patient was first put on an insulin regime. Twenty days later, he shifted towards the paleolithic ketogenic diet and was able to discontinue insulin. Strict adherence to the diet resulted in normal glucose levels and a more than three-fold elevation of C-peptide level indicating restored insulin production. Currently, the patient is on the paleolithic ketogenic diet for 6.5 months. He is free of complaints, and no side effects emerged. Conclusion: We conclude that the paleolithic ketogenic diet was effective and safe in the management of this case of newly diagnosed T1DM. Marked increase in C peptide level within two months indicates that the paleolithic ketogenic diet may halt or reverse autoimmune processes destructing pancreatic beta cell function in T1DM.
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Long-term effects of a Palaeolithic-type diet in obese postmenopausal women: A 2-year randomized trial
Article
Full-text available
  • Jan 2014
Background/objectives: Short-term studies have suggested beneficial effects of a Palaeolithic-type diet (PD) on body weight and metabolic balance. We now report the long-term effects of a PD on anthropometric measurements and metabolic balance in obese postmenopausal women, in comparison with a diet according to the Nordic Nutrition Recommendations (NNR). Subjects/methods: Seventy obese postmenopausal women (mean age 60 years, body mass index 33 kg/m(2)) were assigned to an ad libitum PD or NNR diet in a 2-year randomized controlled trial. The primary outcome was change in fat mass as measured by dual-energy X-ray absorptiometry. Results: Both groups significantly decreased total fat mass at 6 months (-6.5 and-2.6 kg) and 24 months (-4.6 and-2.9 kg), with a more pronounced fat loss in the PD group at 6 months (P<0.001) but not at 24 months (P=0.095). Waist circumference and sagittal diameter also decreased in both the groups, with a more pronounced decrease in the PD group at 6 months (-11.1 vs-5.8 cm, P=0.001 and-3.7 vs-2.0 cm, P<0.001, respectively). Triglyceride levels decreased significantly more at 6 and 24 months in the PD group than in the NNR group (P<0.001 and P=0.004). Nitrogen excretion did not differ between the groups. Conclusions: A PD has greater beneficial effects vs an NNR diet regarding fat mass, abdominal obesity and triglyceride levels in obese postmenopausal women; effects not sustained for anthropometric measurements at 24 months. Adherence to protein intake was poor in the PD group. The long-term consequences of these changes remain to be studied.
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Childhood Absence Epilepsy Successfully Treated with the Paleolithic Ketogenic Diet
Article
Full-text available
  • Sep 2013
Introduction Childhood absence epilepsy is an epilepsy syndrome responding relatively well to the ketogenic diet with one-third of patients becoming seizure-free. Less restrictive variants of the classical ketogenic diet, however, have been shown to confer similar benefits. Beneficial effects of high fat, low-carbohydrate diets are often explained in evolutionary terms. However, the paleolithic diet itself which advocates a return to the human evolutionary diet has not yet been studied in epilepsy. Results Here, we present a case of a 7-year-old child with absence epilepsy successfully treated with the paleolithic ketogenic diet alone. In addition to seizure freedom achieved within 6 weeks, developmental and behavioral improvements were noted. The child remained seizure-free when subsequently shifted toward a paleolithic diet. Conclusion It is concluded that the paleolithic ketogenic diet was effective, safe and feasible in the treatment of this case of childhood absence epilepsy.
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Beyond weight loss: A review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets
Article
Full-text available
  • Jun 2013
Very-low-carbohydrate diets or ketogenic diets have been in use since the 1920s as a therapy for epilepsy and can, in some cases, completely remove the need for medication. From the 1960s onwards they have become widely known as one of the most common methods for obesity treatment. Recent work over the last decade or so has provided evidence of the therapeutic potential of ketogenic diets in many pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors. The possibility that modifying food intake can be useful for reducing or eliminating pharmaceutical methods of treatment, which are often lifelong with significant side effects, calls for serious investigation. This review revisits the meaning of physiological ketosis in the light of this evidence and considers possible mechanisms for the therapeutic actions of the ketogenic diet on different diseases. The present review also questions whether there are still some preconceived ideas about ketogenic diets, which may be presenting unnecessary barriers to their use as therapeutic tools in the physician's hand.European Journal of Clinical Nutrition advance online publication, 26 June 2013; doi:10.1038/ejcn.2013.116.
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Haem catabolism: A novel modulator of inflammation in Gilbert's syndrome
Article
  • May 2013
  • EUR J CLIN INVEST
Moderately elevated unconjugated bilirubin concentrations protect against inflammatory diseases and are present in individuals with Gilbert's syndrome. This study examined the relationship between circulating haem oxygenase catabolites, unconjugated bilirubin, carboxy haemoglobin, iron and inflammatory parameters. Seventy-six matched individuals were allocated to Gilbert's syndrome (GS) or control group (unconjugated bilirubin ≥ or < 17·1 μM). Iron, carboxy haemoglobin and high-sensitivity C-reactive protein were analysed using routine diagnostic tests. Unconjugated bilirubin and haem were analysed using high-performance liquid chromatography. The cytokines IL-1β, TNF-α and IL-6 were assessed using high-sensitivity enzyme-linked immunosorbent assays. Gilbert's syndrome subjects had significantly greater levels of unconjugated bilirubin (P < 0·05), carboxy haemoglobin (P < 0·05), iron (P < 0·05), IL-1β (P < 0·05), a significantly lower body mass index (P < 0·05) and IL-6 concentrations (P < 0·05) vs. controls. Regression analysis revealed that unconjugated bilirubin mainly explained IL-1β results (16%), and body mass index+IL-6 predicted 26% of the variance in C-reactive protein concentrations. A positive relationship between unconjugated bilirubin and free plasma haem, iron and carboxy haemoglobin indicated a positive feedback loop of haem oxygenase induction possibly mediated by unconjugated bilirubin. Furthermore, reduced body mass index in Gilbert's syndrome individuals was linked to reduced inflammation status, which could be influenced by circulating haem oxygenase catabolites and contribute to reduced risk of noncommunicable diseases in this population.
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