Question: Question--How do I get diagnosed with the proper diagnosis--a special type of hepatic encephalopathy?

Please read my case very carefully, and please render your opinion on whether it is likely and appropriate for a diagnosis of hepatic encephalopathy to be made.

. . . . . . . . .

"HEPATIC ENCEPHALOPATHY



(A) INDICATORS OF AND SYMPTOMS OF THE CONDITION? AMMONIA.



(1) From the study 'Ammonia Levels and Hepatic Encephalopathy in Patients with Known Chronic Liver Disease', “Grundling et al. determined the sensitivity … of venous ammonia levels >= 55 μmol/L to diagnose [hepatic encephalopathy] to be [close to 50] percent.”



I have close to double the concentration of this, at 105, tested just a few days ago; this drastically increases the respective sensitivity measure, at this level, to well above the 50% mark, thus suggesting heavily that it is much more likely that I have HE, than not.



This is supported by the study 'Ammonia as a cause for hepatic encephalopathy', where it states “A serum ammonia level of 54 micrograms/liter … supported the diagnose [of hepatic encephalopathy]”; 54 micrograms/liter equals about 42 μmol/L.



(2) From the study 'Arterial and venous ammonia concentrations in the diagnosis of canine hepato-encephalopathy.', “A significant positive correlation was demonstrated between arterial or venous concentrations and the degree of hepato-encephalopathy. … Elevated ammonia values confirm the diagnosis of hepato-encephalopathy, but normal levels do not exclude it.”



Furthermore, two additional relationships are found in the literature between the respective relevant variables:


Firstly, that arterial ammonia is almost always generally higher in the arterial blood than it is in the venous blood (the reason being that a large portion of arterial blood ammonia is metabolized by the cells of the body before the remainder is found in blood now circulating in the veins); and,

secondly, that arterial ammonia concentrations (this is also supported by assessing all data, where arterial levels of ammonia are either equal or higher at all levels of severity of condition and non-condition), for this reason listed above, arterial ammonia has an even higher degree of correlation with the degree of hepatic encephalopathy than venous ammonia does.



From the same study, “In patients with liver disease ammonia values were significantly higher in arterial blood than in venous blood, therefore arterial measurements are preferable for clinical diagnosis.”



This is supported by the finding of the study 'Blood Ammonia Determination in Cirrhosis: Still Confusing After All These Years? ', in which it is noted that “Each of the four measures of ammonia [tested] increased with the degree of hepatic encephalopathy.” It goes on to note that the correlations with degree of hepatic encephalopathy are, “[for] arterial ammonia, r=0.61, and [for] venous ammonia, r=0.56)”; both of these correlations are high and are noted to carry strong statistical significance.



Therefore, we can reasonably conclude:



—If my venous ammonia was tested at 105, that the expected value of ammonia within my arterial blood at the time of the blood draw, was likely (expected value) significantly higher than 105.



BUT WHAT ARE THE AVERAGE LEVELS OF AMMONIA IN THOSE PATIENTS WITH ALREADY-DIAGNOSED HEPATIC ENCEPHALOPATHY, AND HOW TO THEY RELATE TO THOSE LEVELS TESTED IN CONTROLS?



In the same study listed above, venous ammonia averaged at a level of 83.1±12.5 in those already diagnosed with the highest grade of hepatic encephalopathy, grade IV! Arterial concentrations of Grade I, Grade II, Grade III and Grade IV averaged at 71, 84, 98, and 106, respectively.



Furthermore, in the study 'Hyperammonemia Is Associated with Increasing Severity of Both Liver Cirrhosis and Hepatic Encephalopathy', it is stated that “Normal blood ammonia concentration is less than 35 μmol/L"



The study goes on to reveal, “The results of ANOVA showed that serum ammonia level was higher in patients with high-grade HE, that is, grades 3 and 4 … than in the patients with low-grade HE, that is, grades 1 and 2… Patients with no evidence of HE had the lowest levels of blood ammonia … Thus one-way ANOVA showed a statistically significant difference between the groups with regard to serum ammonia level; … Hence, it can be postulated, that the higher the grade of hepatic coma, the higher the blood ammonia level will be.”



What were those levels of venous ammonia found in this study?


Patients with no evidence of H.E:     29.91 ± 3.32 μmol/L

Grade I …:                    35.17 ± 4.72 “

Grade II …:                    37.61 ± 4.22 “

Grade III …:                    51.98 ± 8.01 “

Grade IV …:                    76.28 ± 10.70 “



This further supports my tested level as meeting the diagnostic threshold for H.E. To further elaborate, my tested ammonia level of 105 is many, many standard deviations above the non-H.E. control group, thus effectively ruling out the possibility that I would belong to the non-H.E. population; this virtually guarantees an appropriate diagnosis.



FASTING VERSUS NON-FASTING SAMPLES: THE EXAMPLE OF ORAL GLUTAMINE CHALLENGE



Is there any significant difference between ammonia levels between fasting and non-fasting samples taken, amongst the population?



This depends on whether the patient is a healthy control or a sufferer of H.E.



According to multiple studies, regular controls do not experience an increase in ammonia levels after consumption of large amounts of the ammonia acid glutamine, as their levels do not change or elevate in a statistically significant way. However, in patients with liver disease, it is found that ammonia levels do increase much more, post-glutamine, than in healthy control groups.



From the study 'Oral glutamine challenge improves the performance of psychometric tests for the diagnosis of minimal hepatic encephalopathy in patients with liver cirrhosis.', it is shown that “Baseline arterial ammonia levels significantly raised post-glutamine in cirrhotics (85.2+/-20.8μg/dL versus 159.82 +/- 66.01μg/dL, p<0.0001), while in controls they remained unchanged [47.15±17.3μg/dL versus 52.15±18.07]”



Converted to the proper units (μmol/L), we see that even after consuming 20 grams of glutamine, a potent ammonia inducer in those with liver dysfunction, the average ammonia levels in those with healthy livers only increases from about 28±10 μmol/L to about 31±11 μmol/L. The average absolute increase in concentration caused by the glutamine load was merely +3 μmol/L for healthy people.



(At level of 105 μmol/L in venous blood, which imply significantly higher levels in arterial blood, we would be more than six standard deviations above the mean for the non-HE group; thus, we would effectively rule out a patient with such a result from belonging to the non-HE population, regardless of fasting or non-fasting conditions.)



However, with those who had liver dysfunction, average ammonia levels went up from about 50±12 μmol/L to about 94±39 μmol/L—the average absolute increase in concentration here was +44 μmol/L for patients with pre-diagnosed liver disease/H.E.



...



WHAT’S THE CAUSE OF HEPATIC ENCEPHALOPATHY IN MY CASE?



Beyond just ammonia levels, appropriate clinical history must be considered in making a diagnosis.



Does my clinical history support the occurrence of such a hepatic condition?



According to the study 'The GABA hypothesis of the pathogenesis of hepatic encephalopathy: current status', we learn that:

“Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter of the mammalian brain, can induce coma. … GABA and its agonists, as well as benzodiazepines and barbiturates [and other GABA drugs such as PHENIBUT], induce neural inhibition as a consequence of their interaction with specific binding sites for each of these classes of neuroactive substances on the GABA receptor complex of postsynaptic neurons. In a rabbit model of acute liver failure: 

(i) the pattern of postsynaptic neuronal activity in hepatic coma, as assessed by visual evoked potentials, is identical to that associated with coma induced by drugs [that] activate the GABA neurotransmitter system (benzodiazepines, barbiturates, and GABA agonists); 

(ii) the levels of GABA-like activity in peripheral blood plasma increase appreciably before the onset of hepatic encephalopathy, due at least in part to impaired hepatic extraction of gut-derived GABA [or of recirculating GABA agonists/drugs] from portal venous blood; 

(iii) the blood-brain barrier becomes abnormally permeable to an isomer of GABA, alpha-amino-isobutyric acid, before the onset of hepatic encephalopathy; and 

(iv) hepatic coma is associated with an increase in the density of receptors for GABA and benzodiazepines in the brain [such as that which is caused by FASORACETAM aka NS-105]”



We see, therefore, that excessive GABAergic tone, caused by either excessive GABAergic agonism, increased GABA receptor density, is associated with hepatic encephalopathy.



To highlight—what is known to cause drastically-increased GABA receptor density? The drug Fasoracetam, which I took along with Phenibut in 2016 and ended up in a coma (a first of its kind case in medical history, involving this exact specific combination of GABA-ergic drugs).



From this case study report done on me in 2016 shortly after it happened, which is entitled 'Phenibut Overdose in Combination with Fasoracetam: Emerging Drugs of Abuse' it states about me that, “In contrast to previously reported cases, our patient was [in addition to Phenibut] also taking fasoracetam which … up-regulates GABAB receptors. … Fasoracetam could potentially enhance the response to phenibut through the up-regulation of GABAB receptors and decrease the threshold for tolerance [in our patient], … and can produce unique toxidromes especially with co-administration of multiple supplements.”



Therefore, it is no coincidence that the symptoms of hepatic encephalopathy, and the apparent inhibition of liver microsomes, started once I was poisoned with the combination of Phenibut and Fasoracetam, as detailed in this study. I have been consistently reporting liver dysfunction since immediately following this poisoning in 2016. For over three years, I have been ignored and ridiculed.



One of those effects would obviously be GABA-induced or CNS-suppression-induced microsomal inhibition—which is exactly what I have been saying is going on.

 This is supported by saliva drug tests that would stay positive for 12 days after most recent use, where all studies indicate that it becomes undetectable in the saliva of a normal, healthy person within 48 hours.


It is well known that overdoses of barbiturates acutely cause inhibition of drug-metabolizing microsomal activity of the liver. Barbiturates are known GABA agonists with a very powerful CNS-lowering action—so much so, that they have largely as an entire class been replaced by the more common modern use of benzodiazepines, which act more safely on the nervous systems of users than barbiturates had. It, thus, is clear: excessive GABAergic tone results in a central nervous system activity level that is so low, that microsomes of the liver as disabled and what is essentially hepatic encephalopathy results.



—Additionally, have there been any other signs of symptoms consistent with an apparent long-term, chronic decrease of the CNS activity level?



Yes. For three years, I have lived with undiagnosed bradypnea, which is a respiratory rate that, for me, reaches as low as 3 - 5 breaths per minute. This has been clearly reported to doctors and emergency rooms over the years; however, despite it being a clear phenomenon to observe and diagnose, and despite my consistent reporting, no doctor to date has diagnosed me with this low respiratory rate resulting from lowered CNS levels.



If doctors had paid attention to and treated seriously the very clear and outwardly-manifest symptoms of bradypnea, they would have been able to draw conclusions regarding my CNS state that would have led clinicians to a much quicker likely realization and diagnosis of the underlying CNS suppression / drug effects / hepatic encephalopathy / microsomal dysfunction that I have been consistently and aggressively telling to doctors over three years. The delay in doing so has thus reasonably contributed to the delay of my treatment.

I

conclude, that the poisoning of the GABA agonist Phenibut combined with the GABA modulator Fasoracetam produced neurological effects inducing hepatic coma, including the cessation of drug-metabolizing action and process by the liver's microsomes. This is supported by that fact that up to 6 - 7 days after most recent alcohol use, family members tell me that I still smell of live, fresh alcohol constantly coming from my skin for days.

This condition has gone undiagnosed until now.



Both the ammonia levels tested and the relevant patient history each individually, as well as especially collectively together, support the conclusion and diagnosis of hepatic encephalopathy; they do this to such a high degree that it is impossible to clinically refute or ignore anymore.

Question--How do I get diagnosed with the proper diagnosis--a special type of hepatic encephalopathy?

Please read my case very carefully, and please render your opinion on whether it is likely and appropriate for a diagnosis of hepatic encephalopathy to be made.

. . . . . . . . .

"HEPATIC ENCEPHALOPATHY



(A) INDICATORS OF AND SYMPTOMS OF THE CONDITION? AMMONIA.



(1) From the study 'Ammonia Levels and Hepatic Encephalopathy in Patients with Known Chronic Liver Disease', “Grundling et al. determined the sensitivity … of venous ammonia levels >= 55 μmol/L to diagnose [hepatic encephalopathy] to be [close to 50] percent.”



I have close to double the concentration of this, at 105, tested just a few days ago; this drastically increases the respective sensitivity measure, at this level, to well above the 50% mark, thus suggesting heavily that it is much more likely that I have HE, than not.



This is supported by the study 'Ammonia as a cause for hepatic encephalopathy', where it states “A serum ammonia level of 54 micrograms/liter … supported the diagnose [of hepatic encephalopathy]”; 54 micrograms/liter equals about 42 μmol/L.



(2) From the study 'Arterial and venous ammonia concentrations in the diagnosis of canine hepato-encephalopathy.', “A significant positive correlation was demonstrated between arterial or venous concentrations and the degree of hepato-encephalopathy. … Elevated ammonia values confirm the diagnosis of hepato-encephalopathy, but normal levels do not exclude it.”



Furthermore, two additional relationships are found in the literature between the respective relevant variables:


Firstly, that arterial ammonia is almost always generally higher in the arterial blood than it is in the venous blood (the reason being that a large portion of arterial blood ammonia is metabolized by the cells of the body before the remainder is found in blood now circulating in the veins); and,

secondly, that arterial ammonia concentrations (this is also supported by assessing all data, where arterial levels of ammonia are either equal or higher at all levels of severity of condition and non-condition), for this reason listed above, arterial ammonia has an even higher degree of correlation with the degree of hepatic encephalopathy than venous ammonia does.



From the same study, “In patients with liver disease ammonia values were significantly higher in arterial blood than in venous blood, therefore arterial measurements are preferable for clinical diagnosis.”



This is supported by the finding of the study 'Blood Ammonia Determination in Cirrhosis: Still Confusing After All These Years? ', in which it is noted that “Each of the four measures of ammonia [tested] increased with the degree of hepatic encephalopathy.” It goes on to note that the correlations with degree of hepatic encephalopathy are, “[for] arterial ammonia, r=0.61, and [for] venous ammonia, r=0.56)”; both of these correlations are high and are noted to carry strong statistical significance.



Therefore, we can reasonably conclude:



—If my venous ammonia was tested at 105, that the expected value of ammonia within my arterial blood at the time of the blood draw, was likely (expected value) significantly higher than 105.



BUT WHAT ARE THE AVERAGE LEVELS OF AMMONIA IN THOSE PATIENTS WITH ALREADY-DIAGNOSED HEPATIC ENCEPHALOPATHY, AND HOW TO THEY RELATE TO THOSE LEVELS TESTED IN CONTROLS?



In the same study listed above, venous ammonia averaged at a level of 83.1±12.5 in those already diagnosed with the highest grade of hepatic encephalopathy, grade IV! Arterial concentrations of Grade I, Grade II, Grade III and Grade IV averaged at 71, 84, 98, and 106, respectively.



Furthermore, in the study 'Hyperammonemia Is Associated with Increasing Severity of Both Liver Cirrhosis and Hepatic Encephalopathy', it is stated that “Normal blood ammonia concentration is less than 35 μmol/L"



The study goes on to reveal, “The results of ANOVA showed that serum ammonia level was higher in patients with high-grade HE, that is, grades 3 and 4 … than in the patients with low-grade HE, that is, grades 1 and 2… Patients with no evidence of HE had the lowest levels of blood ammonia … Thus one-way ANOVA showed a statistically significant difference between the groups with regard to serum ammonia level; … Hence, it can be postulated, that the higher the grade of hepatic coma, the higher the blood ammonia level will be.”



What were those levels of venous ammonia found in this study?


Patients with no evidence of H.E:     29.91 ± 3.32 μmol/L

Grade I …:                    35.17 ± 4.72 “

Grade II …:                    37.61 ± 4.22 “

Grade III …:                    51.98 ± 8.01 “

Grade IV …:                    76.28 ± 10.70 “



This further supports my tested level as meeting the diagnostic threshold for H.E. To further elaborate, my tested ammonia level of 105 is many, many standard deviations above the non-H.E. control group, thus effectively ruling out the possibility that I would belong to the non-H.E. population; this virtually guarantees an appropriate diagnosis.



FASTING VERSUS NON-FASTING SAMPLES: THE EXAMPLE OF ORAL GLUTAMINE CHALLENGE



Is there any significant difference between ammonia levels between fasting and non-fasting samples taken, amongst the population?



This depends on whether the patient is a healthy control or a sufferer of H.E.



According to multiple studies, regular controls do not experience an increase in ammonia levels after consumption of large amounts of the ammonia acid glutamine, as their levels do not change or elevate in a statistically significant way. However, in patients with liver disease, it is found that ammonia levels do increase much more, post-glutamine, than in healthy control groups.



From the study 'Oral glutamine challenge improves the performance of psychometric tests for the diagnosis of minimal hepatic encephalopathy in patients with liver cirrhosis.', it is shown that “Baseline arterial ammonia levels significantly raised post-glutamine in cirrhotics (85.2+/-20.8μg/dL versus 159.82 +/- 66.01μg/dL, p<0.0001), while in controls they remained unchanged [47.15±17.3μg/dL versus 52.15±18.07]”



Converted to the proper units (μmol/L), we see that even after consuming 20 grams of glutamine, a potent ammonia inducer in those with liver dysfunction, the average ammonia levels in those with healthy livers only increases from about 28±10 μmol/L to about 31±11 μmol/L. The average absolute increase in concentration caused by the glutamine load was merely +3 μmol/L for healthy people.



(At level of 105 μmol/L in venous blood, which imply significantly higher levels in arterial blood, we would be more than six standard deviations above the mean for the non-HE group; thus, we would effectively rule out a patient with such a result from belonging to the non-HE population, regardless of fasting or non-fasting conditions.)



However, with those who had liver dysfunction, average ammonia levels went up from about 50±12 μmol/L to about 94±39 μmol/L—the average absolute increase in concentration here was +44 μmol/L for patients with pre-diagnosed liver disease/H.E.



...



WHAT’S THE CAUSE OF HEPATIC ENCEPHALOPATHY IN MY CASE?



Beyond just ammonia levels, appropriate clinical history must be considered in making a diagnosis.



Does my clinical history support the occurrence of such a hepatic condition?



According to the study 'The GABA hypothesis of the pathogenesis of hepatic encephalopathy: current status', we learn that:

“Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter of the mammalian brain, can induce coma. … GABA and its agonists, as well as benzodiazepines and barbiturates [and other GABA drugs such as PHENIBUT], induce neural inhibition as a consequence of their interaction with specific binding sites for each of these classes of neuroactive substances on the GABA receptor complex of postsynaptic neurons. In a rabbit model of acute liver failure: 

(i) the pattern of postsynaptic neuronal activity in hepatic coma, as assessed by visual evoked potentials, is identical to that associated with coma induced by drugs [that] activate the GABA neurotransmitter system (benzodiazepines, barbiturates, and GABA agonists); 

(ii) the levels of GABA-like activity in peripheral blood plasma increase appreciably before the onset of hepatic encephalopathy, due at least in part to impaired hepatic extraction of gut-derived GABA [or of recirculating GABA agonists/drugs] from portal venous blood; 

(iii) the blood-brain barrier becomes abnormally permeable to an isomer of GABA, alpha-amino-isobutyric acid, before the onset of hepatic encephalopathy; and 

(iv) hepatic coma is associated with an increase in the density of receptors for GABA and benzodiazepines in the brain [such as that which is caused by FASORACETAM aka NS-105]”



We see, therefore, that excessive GABAergic tone, caused by either excessive GABAergic agonism, increased GABA receptor density, is associated with hepatic encephalopathy.



To highlight—what is known to cause drastically-increased GABA receptor density? The drug Fasoracetam, which I took along with Phenibut in 2016 and ended up in a coma (a first of its kind case in medical history, involving this exact specific combination of GABA-ergic drugs).



From this case study report done on me in 2016 shortly after it happened, which is entitled 'Phenibut Overdose in Combination with Fasoracetam: Emerging Drugs of Abuse' it states about me that, “In contrast to previously reported cases, our patient was [in addition to Phenibut] also taking fasoracetam which … up-regulates GABAB receptors. … Fasoracetam could potentially enhance the response to phenibut through the up-regulation of GABAB receptors and decrease the threshold for tolerance [in our patient], … and can produce unique toxidromes especially with co-administration of multiple supplements.”



Therefore, it is no coincidence that the symptoms of hepatic encephalopathy, and the apparent inhibition of liver microsomes, started once I was poisoned with the combination of Phenibut and Fasoracetam, as detailed in this study. I have been consistently reporting liver dysfunction since immediately following this poisoning in 2016. For over three years, I have been ignored and ridiculed.



One of those effects would obviously be GABA-induced or CNS-suppression-induced microsomal inhibition—which is exactly what I have been saying is going on.

 This is supported by saliva drug tests that would stay positive for 12 days after most recent use, where all studies indicate that it becomes undetectable in the saliva of a normal, healthy person within 48 hours.


It is well known that overdoses of barbiturates acutely cause inhibition of drug-metabolizing microsomal activity of the liver. Barbiturates are known GABA agonists with a very powerful CNS-lowering action—so much so, that they have largely as an entire class been replaced by the more common modern use of benzodiazepines, which act more safely on the nervous systems of users than barbiturates had. It, thus, is clear: excessive GABAergic tone results in a central nervous system activity level that is so low, that microsomes of the liver as disabled and what is essentially hepatic encephalopathy results.



—Additionally, have there been any other signs of symptoms consistent with an apparent long-term, chronic decrease of the CNS activity level?



Yes. For three years, I have lived with undiagnosed bradypnea, which is a respiratory rate that, for me, reaches as low as 3 - 5 breaths per minute. This has been clearly reported to doctors and emergency rooms over the years; however, despite it being a clear phenomenon to observe and diagnose, and despite my consistent reporting, no doctor to date has diagnosed me with this low respiratory rate resulting from lowered CNS levels.



If doctors had paid attention to and treated seriously the very clear and outwardly-manifest symptoms of bradypnea, they would have been able to draw conclusions regarding my CNS state that would have led clinicians to a much quicker likely realization and diagnosis of the underlying CNS suppression / drug effects / hepatic encephalopathy / microsomal dysfunction that I have been consistently and aggressively telling to doctors over three years. The delay in doing so has thus reasonably contributed to the delay of my treatment.

I

conclude, that the poisoning of the GABA agonist Phenibut combined with the GABA modulator Fasoracetam produced neurological effects inducing hepatic coma, including the cessation of drug-metabolizing action and process by the liver's microsomes. This is supported by that fact that up to 6 - 7 days after most recent alcohol use, family members tell me that I still smell of live, fresh alcohol constantly coming from my skin for days.

This condition has gone undiagnosed until now.



Both the ammonia levels tested and the relevant patient history each individually, as well as especially collectively together, support the conclusion and diagnosis of hepatic encephalopathy; they do this to such a high degree that it is impossible to clinically refute or ignore anymore.

Hi Doctor,

I am preparing a detailed and comprehensive reply to you, which will be prepared and ready within the next day or two, most likely.

I am already aware of at least one study refuting the apparent utility of ammonia--I do invite you to please followup on your offer and provide all additional studies and quotations that provide the basis for your position.

I will likely include these within my upcoming response. Thank you

Hi Doctor,

I am preparing a detailed and comprehensive reply to you, which will be prepared and ready within the next day or two, most likely.

I am already aware of at least one study refuting the apparent utility of ammonia--I do invite you to please followup on your offer and provide all additional studies and quotations that provide the basis for your position.

I will likely include these within my upcoming response. Thank you

Hi,

Yes, as indicated I shall have a full response for you, which will be ready in a day or two.

I may send it through here or through email.

In the mean time, you had mentioned that you have additional sources or studies to support your position. If so, would you please be able to kindly provide these as well, so that I may have analyzed them by the time my response is prepared, so that I can discuss conclusions regarding these? Thank you.

Otherwise, will send you what I will have ready based on your initial reply. Thank you for your time

Hi,

Yes, as indicated I shall have a full response for you, which will be ready in a day or two.

I may send it through here or through email.

In the mean time, you had mentioned that you have additional sources or studies to support your position. If so, would you please be able to kindly provide these as well, so that I may have analyzed them by the time my response is prepared, so that I can discuss conclusions regarding these? Thank you.

Otherwise, will send you what I will have ready based on your initial reply. Thank you for your time

Sending two attachments now to attachments email

Sending two attachments now to attachments email

Note--the first of the two documents contains, in part, what you have already read. However, extensive additions were made to this original document. Now, new additions to the material include:

(1) the entire second half of the first document; and,
(2) the entirety of the second document.

Thank you

Note--the first of the two documents contains, in part, what you have already read. However, extensive additions were made to this original document. Now, new additions to the material include:

(1) the entire second half of the first document; and,
(2) the entirety of the second document.

Thank you

Additionally, one point I forgot to include more clearly in my content. This will be a part III to my current set of responses...:

With respect to your assertion that "it's not ammonia which causes HE"--

It is from one study, 'Ammonia as a cause for hepatic encephalopathy', where it is reported: "A serum ammonia level of 54 ... puzzled the medical staff regarding the possibility that ammonia may directly induce the [HE-related] confusion. ... It is widely accepted that the ammonia level is a marker that usually parallels the amount of toxins and metabolites that bypasses the liver, ... Since ammonia may directly hinder the metabolism of neuro-transmitters,...it is assumed that ammonia by itself had a role in bringing about the encephalopathy manifestations in our patients and other patients with cirrhosis of the liver."

From the clevelandclinicmeded.com article on the subject matter, it states "In addition, ammonia is the best characterized neurotoxin that precipitates HE."

From the study 'Pathophysiological Mechanisms of Hepatic Encephalopathy', it states "Ammonia has long been regarded as the key metabolic factor underpinning the development of HE,"

From 'Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation', we see that "...in another canine study with surgical portocaval fistulas, it was discovered that the urinary concentration of ammonia salts was elevated, leading to the logical first suggestion that ammonia may be key in the development of this neurobehavioural syndrome [of HE]."

And, lastly, from 'Pathogenesis of Hepatic Encephalopathy', we are told that, "Ammonia is a neurotoxin responsible for HE development via a direct effect on the metabolism and functions of the CNS..."

...

To address your claim that "If it were true [that ammonia has a relation to HE] then just by bringing ammonia levels to normal we can cure every patient of HE.

I have a two-part reply:

Firstly, the lowering of ammonia seems to directly reduce symptoms and severity of HE--
From one source, "Ammonia scavengers have been used in HE patients, leading to improvements in symptoms,"; From another, "Because ammonia plays such a major role in the pathogenesis of HE, ammonia-lowering strategies remain a focus for HE treatments."

Secondly--based on the material I have included and referenced in the documents, we can see that it isn't strictly the removal of ammonia, per se, that causes a reversal of HE; rather, it is the overall lowering of GABAergic tone in the CNS altogether, that drastically and immediately produces reversals of HE (as in the case of GABA inhibitors). TO come around full circle, ammonia, too, is a GABA agent in itself; hence removal of ammonia lowers the excessive GABAergic tone within the body that causes the H.E. This is key to the whole situation: it is excessive GABAergic tone that has precipitated by heretofore undiagnosed HE for the last three years, as I have discussed earlier.

From the well-named study 'Does ammonia contribute to increased GABA-ergic neurotransmission in liver failure?' they ultimately conclude:
"Thus, the modestly elevated concentrations of ammonia that commonly occur in liver failure may contribute to the manifestations of HE by enhancing GABAergic inhibitory neurotransmission. This concept appears to unify the ammonia and GABAergic neurotransmission hypotheses."

Lastly, regarding the relationship between ammonia and H.E.--I have found an excellent statement reflecting the real truth of this unnecessarily controversial relationship:

From 'Ammonia-Lowering Strategies for the Treatment of Hepatic Encephalopathy':

"Although there is overwhelming evidence of the central role of ammonia in the pathogenesis of HE, and data show that 80% of patients with cirrhosis present some degree of hyperammonemia, it is important to note that many studies have reported an imperfect correlation between hyperammonemia and the severity of HE in chronic liver disease. This suggests that pathogenic factors besides ammonia are involved in the pathogenesis of HE."

This is the most accurate statement I have seen on the subject matter! They say the truth so well--that the relationship and correlation between those two is "imperfect"--NOT that it is "no relation at all." It then goes on to state not that ammonia is not a pathogenic factor--but instead, that it is not the ONLY factor, and other causes contribute as well. Brilliant! Careful and accurate reporting.

. . .

Thank you for reading. Please let me know what you think of this rather fascinating subject matter, after having reviewed all of the information presented.

Additionally, one point I forgot to include more clearly in my content. This will be a part III to my current set of responses...:

With respect to your assertion that "it's not ammonia which causes HE"--

It is from one study, 'Ammonia as a cause for hepatic encephalopathy', where it is reported: "A serum ammonia level of 54 ... puzzled the medical staff regarding the possibility that ammonia may directly induce the [HE-related] confusion. ... It is widely accepted that the ammonia level is a marker that usually parallels the amount of toxins and metabolites that bypasses the liver, ... Since ammonia may directly hinder the metabolism of neuro-transmitters,...it is assumed that ammonia by itself had a role in bringing about the encephalopathy manifestations in our patients and other patients with cirrhosis of the liver."

From the clevelandclinicmeded.com article on the subject matter, it states "In addition, ammonia is the best characterized neurotoxin that precipitates HE."

From the study 'Pathophysiological Mechanisms of Hepatic Encephalopathy', it states "Ammonia has long been regarded as the key metabolic factor underpinning the development of HE,"

From 'Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation', we see that "...in another canine study with surgical portocaval fistulas, it was discovered that the urinary concentration of ammonia salts was elevated, leading to the logical first suggestion that ammonia may be key in the development of this neurobehavioural syndrome [of HE]."

And, lastly, from 'Pathogenesis of Hepatic Encephalopathy', we are told that, "Ammonia is a neurotoxin responsible for HE development via a direct effect on the metabolism and functions of the CNS..."

...

To address your claim that "If it were true [that ammonia has a relation to HE] then just by bringing ammonia levels to normal we can cure every patient of HE.

I have a two-part reply:

Firstly, the lowering of ammonia seems to directly reduce symptoms and severity of HE--
From one source, "Ammonia scavengers have been used in HE patients, leading to improvements in symptoms,"; From another, "Because ammonia plays such a major role in the pathogenesis of HE, ammonia-lowering strategies remain a focus for HE treatments."

Secondly--based on the material I have included and referenced in the documents, we can see that it isn't strictly the removal of ammonia, per se, that causes a reversal of HE; rather, it is the overall lowering of GABAergic tone in the CNS altogether, that drastically and immediately produces reversals of HE (as in the case of GABA inhibitors). TO come around full circle, ammonia, too, is a GABA agent in itself; hence removal of ammonia lowers the excessive GABAergic tone within the body that causes the H.E. This is key to the whole situation: it is excessive GABAergic tone that has precipitated by heretofore undiagnosed HE for the last three years, as I have discussed earlier.

From the well-named study 'Does ammonia contribute to increased GABA-ergic neurotransmission in liver failure?' they ultimately conclude:
"Thus, the modestly elevated concentrations of ammonia that commonly occur in liver failure may contribute to the manifestations of HE by enhancing GABAergic inhibitory neurotransmission. This concept appears to unify the ammonia and GABAergic neurotransmission hypotheses."

Lastly, regarding the relationship between ammonia and H.E.--I have found an excellent statement reflecting the real truth of this unnecessarily controversial relationship:

From 'Ammonia-Lowering Strategies for the Treatment of Hepatic Encephalopathy':

"Although there is overwhelming evidence of the central role of ammonia in the pathogenesis of HE, and data show that 80% of patients with cirrhosis present some degree of hyperammonemia, it is important to note that many studies have reported an imperfect correlation between hyperammonemia and the severity of HE in chronic liver disease. This suggests that pathogenic factors besides ammonia are involved in the pathogenesis of HE."

This is the most accurate statement I have seen on the subject matter! They say the truth so well--that the relationship and correlation between those two is "imperfect"--NOT that it is "no relation at all." It then goes on to state not that ammonia is not a pathogenic factor--but instead, that it is not the ONLY factor, and other causes contribute as well. Brilliant! Careful and accurate reporting.

. . .

Thank you for reading. Please let me know what you think of this rather fascinating subject matter, after having reviewed all of the information presented.

--Yes doctor, thank you for your reply. I have just seen it now.

For now, the only question that comes up for me, is--

(1) Do you believe, based on all of the evidence and information presented, that this patient (in this case, myself) may be likely to have an underlying disorder consistent with that of H.E./ALF?

Thank you for your deep and thoughtful consideration.

--Yes doctor, thank you for your reply. I have just seen it now.

For now, the only question that comes up for me, is--

(1) Do you believe, based on all of the evidence and information presented, that this patient (in this case, myself) may be likely to have an underlying disorder consistent with that of H.E./ALF?

Thank you for your deep and thoughtful consideration.

(In other words--I have an appointment with. gastroenterologist here in my own country this Saturday.

During the appointment, it is very difficult to get someone like this to sit and read extensive typed papers, outside of a hospital setting or for research/academic purposes. The doctors here have a short attention span and are generally extremely busy, thus leaving all patients feel somewhat rushed.

I need to make an effective presentation as to why and how it is that I may have H.E. However, he may not be inclined to read through my material, and without doing so, he is also inclined to disregard my claims altogether, since "he is the doctor--not me."

However, if I can state that "one doctor--a gastroenterology specialist himself from another country/medical system--has also reviewed the deeper details of my writing and research, and based on my symptoms and extensive history and numerous supportive test results, does himself conclude that he would support towards to favorable diagnosis for HE/ALF/related condition in my case--

--This would be a game-changer, and a true blessing for me. This would get his attention more seriously, and allow him to be that much more likely to agree to review the material more deeply--and then to agree with the original opinion that you give.

A favorable diagnosis from my own doctor will, in turn, XXXXXXX me two important things:

- Access to proper GABA inhibitors/antagonists (not just coffee, chocolate and tryptophan), as I have discussed; and,

- The ability to bring suit against an entity that essentially called me crazy for believing what I believe, diagnosing me falsely with mental illness and forcing me into a hold under false pretense. If I can support that the basis of my concerns was valid and based on a real medical concern, I will have the right to be compensated legally for the wrongful treatment and dismissal of my case earlier.

These are valuable things.

And, if after carefully reviewing the entirety of what I present, you do find it to honestly be the case that it truly may be "more likely than not" that this is a real manifestation of H.E., then by indicating a favorable opinion on this matter, you may be able to help me push the first domino to get the series of favorable impressions, events and effects to start.

Thank you so much, Doctor)

(In other words--I have an appointment with. gastroenterologist here in my own country this Saturday.

During the appointment, it is very difficult to get someone like this to sit and read extensive typed papers, outside of a hospital setting or for research/academic purposes. The doctors here have a short attention span and are generally extremely busy, thus leaving all patients feel somewhat rushed.

I need to make an effective presentation as to why and how it is that I may have H.E. However, he may not be inclined to read through my material, and without doing so, he is also inclined to disregard my claims altogether, since "he is the doctor--not me."

However, if I can state that "one doctor--a gastroenterology specialist himself from another country/medical system--has also reviewed the deeper details of my writing and research, and based on my symptoms and extensive history and numerous supportive test results, does himself conclude that he would support towards to favorable diagnosis for HE/ALF/related condition in my case--

--This would be a game-changer, and a true blessing for me. This would get his attention more seriously, and allow him to be that much more likely to agree to review the material more deeply--and then to agree with the original opinion that you give.

A favorable diagnosis from my own doctor will, in turn, XXXXXXX me two important things:

- Access to proper GABA inhibitors/antagonists (not just coffee, chocolate and tryptophan), as I have discussed; and,

- The ability to bring suit against an entity that essentially called me crazy for believing what I believe, diagnosing me falsely with mental illness and forcing me into a hold under false pretense. If I can support that the basis of my concerns was valid and based on a real medical concern, I will have the right to be compensated legally for the wrongful treatment and dismissal of my case earlier.

These are valuable things.

And, if after carefully reviewing the entirety of what I present, you do find it to honestly be the case that it truly may be "more likely than not" that this is a real manifestation of H.E., then by indicating a favorable opinion on this matter, you may be able to help me push the first domino to get the series of favorable impressions, events and effects to start.

Thank you so much, Doctor)

Hi Doctor,

--Just to confirm, you were able to read both documents carefully that I had snt vita the YYYY@YYYY service, which are entitled

(1) '01 - ammonia and HE part 1 (v2.pdf)', and
(2) '02 - ammonia HE part 2.pdf'--

in addition to (3) the written "Part III" direct message I sent through the messaging field via the website itself?

If so, then I thank you once again for your time and consideration. Regarding your questions, with respect to what I have presented:

(A) Regarding the question of where my biopsy results are--

- I indicated in my second document, in direct response to your previous inquiry into biopsy reports, that "No [biopsies have been] performed, as the source of my not-yet-diagnosed HE is not cirrhotic or inflammatory- or damage-based in nature or origin"

To elaborate on this--from the first document, it is stated from a source, "Classification and types of hepatic encephalopathy. Based on the underlying cause, hepatic encephalopathy (HE) is divided into three forms:
(1) type A, associated with acute liver failure;
(2) type B, arising because of portal-systemic shunting in the absence of any intrinsic liver disease; and
(3) type C, which develops in patients with cirrhosis.”

Given this, it is understood that a biopsy would only be indicated for Type C HE--that HE which is secondary to cirrhosis.

For those other causes, particularly the first one, Type A (in my case, an apparent form of ALF, manifesting as (and/or caused by) neurologically-induced chronic, long-lasting microsomal inhibition and impairment of drug metabolism, as a result of excessive GABAergic tone, which was caused by the poisoning of a combination of Fasoracetam and Phenibut in 2016, which placed me into a coma and then left me with an inability to metabolize things properly ever since.

A biopsy, therefore, on a neurologically-induced form of HE, rooted in neurological failure of the liver (not based on inflammatory and phsyical damage) would not be indicated, as a biopsy would not reveal the excessive GABAergic tone present within the entire central nervous system.

To support the fact that GABAergic overwhelm is indicated solely with Type A of HE, and not Type C--

--Quoted from my earlier documents, "HE could be precipitated by [GABAergic drugs] in a similar manner to benzodiazepine hypnotics. Caution should be taken with the use of [any such GABAergic drug] … because its half life could be severely prolonged with liver [function] failure [associated with HE]”;

"[Prothrombin time and its derivates] are sensitive markers of hepatic synthetic failure and are usually abnormal in the setting of fulminant hepatic failure”

"These findings suggest that in hepatic encephalopathy due to fulminant hepatic failure
(a) there is increased GABAergic tone, 
(b) an amelioration of encephalopathy can be induced by blockade of GABA ... receptors [such as by any GABA inhibitor including Flumazenil, or to a lesser extent, natural ones like caffeine and theobromine],..."

(B) Regarding the symptoms I have n a normal basis, whether "right now" at this moment, or just generally when indications of HE and/or Phenibut/Fasoracetam activity are high--

--This is listed and explained in greater detail in my first document. To quote from it, in short, the list is:

" (1) Drastic bradypnea, with respiratory rate often down to 2 - 5 breaths per minute (a clear sign of CNS suppression consistent with GABAergic drug poisoning, which in turn is consistent with Type A of HE);

 (2) Drastically diminished reflexes (sign of both GABAergic poisoning and HE);

 (3) Drastically sharpened and enhanced peripheral vision (visual receptors are GABA-based; sign of prolonged/chronic exposure to the nootropic GABAergic drug last taken three years ago, which possesses this specific ability);

 (4) Drastically diminished/disabled pain perception (consistent with drug poisoning);

 (5) Drastically diminished/disabled inflammation (consistent with GABAergic drug poisoning--please look up studies to confirm this if you'd like, but it is true.);

(6) Drastically diminished/disabled immune function/response (already confirmed by tests; studies show that active GABAergic drug toxicity causes acutely lowered immune response; I have not been sick in 3 years despite multiple serious lab-confirmed infections);

 (7) No fear or anxiety; it is chemically-suppressed;
(8) Enhanced senses of hearing, taste, smell, sight, etc. (GABA underlies acuity of the psychical senses of an organism; these are the effects of prolonged drug toxicity of this type);

 (9) Prolonged effects from alcohol (drunk and smell of alcohol to others for days from a couple of drinks), drugs (feel them and taste/smell them for up to a very long time--***AS INDICATED IN MORE DETAIL IN ORIGINAL DOCUMENT***), among others...

I have more fully gone into these issues in the first document.

(C) Regarding what treatments I am on--

I indicated in the second document, in response to your orginal inquiry into my treatments, that "- Unfortunately, no treatments were given, as there has not been a diagnosis yet made!
"

(D) Regarding your statement that "AMMONIA, ...is just an indicator of failing liver. Even in acute liver failure, it's level would increase"--

--I agree, and I have been trying to put forward strongly that I am experiencing a chronic/long-lasting liver failue consistent with specifically the Type A version of H.E (and not types B or C);

(E) Regarding "...A liver biopsy [being] done to be sure if the liver has stopped functioning or not.--

As I indicated above, this may only be indicated in Type C HE, as a biopsy most clearly reveals macroscopic manifestations of inflammation and damaged tissue; it does not reveal as clearly the signs of a neurological imbalance.

(F) As for your assertion that "Treatment would be given as per current recommendations,"--

Indeed so--and the most effective and recommended forms of treatment, according to multiple studies, include the administration of GABA-inhibiting drugs.

From studies and quotes already mentioned:

"[The inhibitory-neurotransmitter-imbalance theory] can be confirmed by the fact that use of flumazenil-competitive antagonist of the…GABA receptor significantly improves the clinical status of patients [with HE]."

"“The approach to HE [treatment] comprises
... [1] ...exclusion of other causes of encephalopathy,
... [2]... identification of the precipitating cause and
... [3]... a trial of empiric treatment for HE.

A rapid response to this empiric treatment confirms a diagnosis of HE, whereas lack of response within 72 hours indicates that further diagnostic options should be considered.”

Therefore, observed improvements as a result of the appropriate treatment does confirm a diagnosis of HE!

And what is the indicated form of treatment for Type A HE?

(i) According to the clevelandclinicmeded.com article you linked to, "Flumazenil [and by extension, any GABA-inhibiting compounds] may be used in selected cases of suspected benzodiazepine use [or any use of or poisoning from any GABAergic drugs]"

(ii) From xyz, "In a controlled trial by Hojer et al., 0.5mg/h infusion of flumazenil used empirically prevented relapse into coma in severe [GABA drug] overdose."

(Coma Glasgow Grade 3 was what I went into, following my GABA drug overdose.)

(iii) According to the study 'Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure.' it is found that, "an amelioration of encephalopathy can be induced by blockade of GABA or benzodiazepine receptors,"

(iv) --and it is confirmed in the study 'Benzodiazepine antagonist in the treatment of human hepatic encephalopathy' that, "[the] findings indicate that flumazenil may be valuable in treatment of acute HE occurring in fulminant hepatic failure [Type A HE] or in decompensated cirrhosis [Type C HE]."

Now, how does treatments with GABA inhibitors compare to the "standard" treatments that you mentioned, which focus only on lowering the symptoms of ammonia? Let's see...

(G) Regarding the assertion that "If you have HE, you need lactose and Rifaxamin"--

From the study 'Flumazenil in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double blind randomized placebo controlled study.', it is described, "The aim of this study was to evaluate the effects of flumazenil on hepatic encephalopathy ... In the double blind randomized, placebo controlled study, 54 patients with hepatic encephalopathy grade III-IV were randomly assigned to receive either flumazenil 2 mg iv (group A) or placebo (group B); conventional treatment with branched-chain amino acid, saline, glucose, and lactulose was administered in both groups. ... [The findings:] Clinical improvement was obtained in 22/28 patients in group A and in 14/26 in group B (p<0.05); improvement was observed within the first six hours in 21/22 patients in group A and only in 3/14 in group B."

It seems, therefore, that GABA-inhibitors such as Flumazenil offer a tremendous benefit beyond that which standard treatments alone can offer.

(H) Regarding "All these trials related to ammonia [having] been done before the year 2018 and [thus having] no role in current guidelines."

--"Although there is overwhelming evidence of the central role of ammonia in the pathogenesis of HE, and data show that 80% of patients with cirrhosis present some degree of hyperammonemia, it is important to note that many studies have reported an imperfect correlation between hyperammonemia and the severity of HE in chronic liver disease. This suggests that pathogenic factors besides ammonia are involved in the pathogenesis of HE."

Biological mechanism underlying these dynamics do not change from 1990 to 2005 to 2018. They are consistent with evolution.

It is only our understanding of these dynamics which shifts. However, truth is absolute, and the closer our understanding comes to the truth, the more immovable and certain it will therefore be.

What I have been presenting is the strongest understanding of the truth regarding these matters that I believe exists. Any person may obvserve the dialogue and read both sides, until they come to their own educated conclusion.

...

We must also understand this:

Ammonia is only one symptom; in most cases, it may be a central pillar and chief element accounting for the increased GABAergic tone within the patient--however, in my case, it is not. I have strongly put forward that it is the ongoing presence and effects of the combination of Phenibut and especially Fasoracetam, which is a potent upregulator of GABA. The only key to their removal? (1) hemoperfusion, or (2) re-enabling of the function of the liver's microsomes--and thus, re-enabling of the drug-metabolizing function of the liver.

***THIS IS WHY THE USE OF GABA-INHIBITING DRUGS AND COMPOUNDS IS SO KEY! It is excessive GABAergic tone which neurologically inhibits the liver's microsomes (and concomitantly the CNS as a whole) to such a strong degree that they no longer metabolize toxins. (This is why it is stated by one source cited earlier in my document, that "It is widely accepted that the ammonia level is a marker that usually parallels the amount of toxins and metabolites that bypasses the liver"; furthemore, from another source, healthline.com, "In [HE], your liver can’t adequately remove toxins [or drugs] from your blood. This causes a buildup of toxins [and drugs] in your bloodstream." It is thus WHEN WE APPLY GABA-INHIBITORS, THAT THE NERVOUS SYSTEM IS (AT LEAST TEMPORARILY) RELEASED FROM THE EXCESSIVE NEURAL INHIBITION, CAUSING A METABOLIZATION AND BREAK-DOWN OF THE SOURCE TOXINS, DRUGS OR COMPOUNDS WITHIN THE BLOODSTREAM THAT WERE RESPONSIBLE FOR THE EXCESSIVE GABAERGIC TONE IN THE FIRST PLACE!***

Ammonia-lowering agents and other standard treatments alone cannot do this.

So what about our understanding of the dynamics of the disease, and of the most effective treatments?

(I) You state for me to "Try to undestand that coffee chocolate etc are not going to help."

According to all the information above and the information within the previous documents, GABA inhibitors are key in producing drastic improvements.

Let us recall from the first document, how is it that I have found coffee and chocolate to be extremely effective?

Caffeine from coffee: According to the study cited in document 1--
“Inhibitory effect of caffeine on GABA-activated current [occured] in acutely isolated rat ... neurons"


Theobromine from chocolate: According to the study cited in document 2--
“…Theobromine … inhibited [GABA response] in a competitive manner…"

Thus, why and how are there effects from caffeine and chocolate?

Because they are NATURAL ANALOGUES OF FLUMAZENIL, IN THAT THEY ARE NATURALLY-OCCURING GABA INHIBITORS JUST AS FLUMAZENIL IS A GABA INHIBITOR! CAFFEINE AND CHOCOLATE IN HIGH DOSES PRODUCE EFFECTS COMPARABLE TO LOW DOSES OF THE SYNTHETIC AND POTENT GABA-INHIBITING DRUGS.

I clearly stated that after months and years of a lack of progress that I had had with symptoms, a sudden increase in caffeine and chocolate showed immediate and profoundly unimaginable improvements in condition--within minutes. Just like suggested here: "The onset of reversal is usually evident within 1-2 minutes after the injection [of GABA inhibiting agent] is completed as was observed with the trial dose in our patient. Eighty percent response will be reached within 3 minutes, with the peak effect occurring at 6-10 minutes."

...

Finally, in response to the assertion that "A Doctor will follow only what's written in the current volume of standard book and that I had already answered..."

A doctor is entitled, by his capacity, to exercise a level of reasoning and diagnostic flexibility that goes beyond the rigid methodologies of the standard books. As I described, this is his power to utilize "presumptive diagnoses," in the face of symptoms that are clear and consistent with an underlying dysfunction or illness that IS apparent, but does not yet have proper standardized results.

And, in response to "In short when gold standard tests are available to diagnose HE, why would a Doctor follow such trialed literature."--

--Because if the doctor believed that he may be dealing with a covert yet logically aparent case of HE, withholding a diagnosis is an effective sentence and condemnation for the ill person to continue to suffer.

Addiionally, whether psychometric tests are a fully sensitive test among all people that actually have covert or minimal HE, is debatable. To the extent that the tests have obvious limitaitons, and in practicality will never be met and tried by all patients currently suffering from those dysfunctions, a flexible approach must be taken via presumptive diagnosis.

...

Let's take one additional look at the table from my document, to differentiate myself from the normal, non-HE/LF population.

This table is attached as a picture file to my case, here on this site.

I ask you to please do the following two things--

(1) Carefully read through the two .pdf documents I have sent (I will re-send again if necessary, as the email service had not confirmed that you received it, which is atypical); and,

(2) please examine the table I have included and uploaded here.

After doing these thing, please then tell me whether a doctor can morally justify sending a patient home who has the symptoms and signs shown in the table, who also bears the complete backstory discussed in the documents.

Thank you.

Hi Doctor,

--Just to confirm, you were able to read both documents carefully that I had snt vita the YYYY@YYYY service, which are entitled

(1) '01 - ammonia and HE part 1 (v2.pdf)', and
(2) '02 - ammonia HE part 2.pdf'--

in addition to (3) the written "Part III" direct message I sent through the messaging field via the website itself?

If so, then I thank you once again for your time and consideration. Regarding your questions, with respect to what I have presented:

(A) Regarding the question of where my biopsy results are--

- I indicated in my second document, in direct response to your previous inquiry into biopsy reports, that "No [biopsies have been] performed, as the source of my not-yet-diagnosed HE is not cirrhotic or inflammatory- or damage-based in nature or origin"

To elaborate on this--from the first document, it is stated from a source, "Classification and types of hepatic encephalopathy. Based on the underlying cause, hepatic encephalopathy (HE) is divided into three forms:
(1) type A, associated with acute liver failure;
(2) type B, arising because of portal-systemic shunting in the absence of any intrinsic liver disease; and
(3) type C, which develops in patients with cirrhosis.”

Given this, it is understood that a biopsy would only be indicated for Type C HE--that HE which is secondary to cirrhosis.

For those other causes, particularly the first one, Type A (in my case, an apparent form of ALF, manifesting as (and/or caused by) neurologically-induced chronic, long-lasting microsomal inhibition and impairment of drug metabolism, as a result of excessive GABAergic tone, which was caused by the poisoning of a combination of Fasoracetam and Phenibut in 2016, which placed me into a coma and then left me with an inability to metabolize things properly ever since.

A biopsy, therefore, on a neurologically-induced form of HE, rooted in neurological failure of the liver (not based on inflammatory and phsyical damage) would not be indicated, as a biopsy would not reveal the excessive GABAergic tone present within the entire central nervous system.

To support the fact that GABAergic overwhelm is indicated solely with Type A of HE, and not Type C--

--Quoted from my earlier documents, "HE could be precipitated by [GABAergic drugs] in a similar manner to benzodiazepine hypnotics. Caution should be taken with the use of [any such GABAergic drug] … because its half life could be severely prolonged with liver [function] failure [associated with HE]”;

"[Prothrombin time and its derivates] are sensitive markers of hepatic synthetic failure and are usually abnormal in the setting of fulminant hepatic failure”

"These findings suggest that in hepatic encephalopathy due to fulminant hepatic failure
(a) there is increased GABAergic tone, 
(b) an amelioration of encephalopathy can be induced by blockade of GABA ... receptors [such as by any GABA inhibitor including Flumazenil, or to a lesser extent, natural ones like caffeine and theobromine],..."

(B) Regarding the symptoms I have n a normal basis, whether "right now" at this moment, or just generally when indications of HE and/or Phenibut/Fasoracetam activity are high--

--This is listed and explained in greater detail in my first document. To quote from it, in short, the list is:

" (1) Drastic bradypnea, with respiratory rate often down to 2 - 5 breaths per minute (a clear sign of CNS suppression consistent with GABAergic drug poisoning, which in turn is consistent with Type A of HE);

 (2) Drastically diminished reflexes (sign of both GABAergic poisoning and HE);

 (3) Drastically sharpened and enhanced peripheral vision (visual receptors are GABA-based; sign of prolonged/chronic exposure to the nootropic GABAergic drug last taken three years ago, which possesses this specific ability);

 (4) Drastically diminished/disabled pain perception (consistent with drug poisoning);

 (5) Drastically diminished/disabled inflammation (consistent with GABAergic drug poisoning--please look up studies to confirm this if you'd like, but it is true.);

(6) Drastically diminished/disabled immune function/response (already confirmed by tests; studies show that active GABAergic drug toxicity causes acutely lowered immune response; I have not been sick in 3 years despite multiple serious lab-confirmed infections);

 (7) No fear or anxiety; it is chemically-suppressed;
(8) Enhanced senses of hearing, taste, smell, sight, etc. (GABA underlies acuity of the psychical senses of an organism; these are the effects of prolonged drug toxicity of this type);

 (9) Prolonged effects from alcohol (drunk and smell of alcohol to others for days from a couple of drinks), drugs (feel them and taste/smell them for up to a very long time--***AS INDICATED IN MORE DETAIL IN ORIGINAL DOCUMENT***), among others...

I have more fully gone into these issues in the first document.

(C) Regarding what treatments I am on--

I indicated in the second document, in response to your orginal inquiry into my treatments, that "- Unfortunately, no treatments were given, as there has not been a diagnosis yet made!
"

(D) Regarding your statement that "AMMONIA, ...is just an indicator of failing liver. Even in acute liver failure, it's level would increase"--

--I agree, and I have been trying to put forward strongly that I am experiencing a chronic/long-lasting liver failue consistent with specifically the Type A version of H.E (and not types B or C);

(E) Regarding "...A liver biopsy [being] done to be sure if the liver has stopped functioning or not.--

As I indicated above, this may only be indicated in Type C HE, as a biopsy most clearly reveals macroscopic manifestations of inflammation and damaged tissue; it does not reveal as clearly the signs of a neurological imbalance.

(F) As for your assertion that "Treatment would be given as per current recommendations,"--

Indeed so--and the most effective and recommended forms of treatment, according to multiple studies, include the administration of GABA-inhibiting drugs.

From studies and quotes already mentioned:

"[The inhibitory-neurotransmitter-imbalance theory] can be confirmed by the fact that use of flumazenil-competitive antagonist of the…GABA receptor significantly improves the clinical status of patients [with HE]."

"“The approach to HE [treatment] comprises
... [1] ...exclusion of other causes of encephalopathy,
... [2]... identification of the precipitating cause and
... [3]... a trial of empiric treatment for HE.

A rapid response to this empiric treatment confirms a diagnosis of HE, whereas lack of response within 72 hours indicates that further diagnostic options should be considered.”

Therefore, observed improvements as a result of the appropriate treatment does confirm a diagnosis of HE!

And what is the indicated form of treatment for Type A HE?

(i) According to the clevelandclinicmeded.com article you linked to, "Flumazenil [and by extension, any GABA-inhibiting compounds] may be used in selected cases of suspected benzodiazepine use [or any use of or poisoning from any GABAergic drugs]"

(ii) From xyz, "In a controlled trial by Hojer et al., 0.5mg/h infusion of flumazenil used empirically prevented relapse into coma in severe [GABA drug] overdose."

(Coma Glasgow Grade 3 was what I went into, following my GABA drug overdose.)

(iii) According to the study 'Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure.' it is found that, "an amelioration of encephalopathy can be induced by blockade of GABA or benzodiazepine receptors,"

(iv) --and it is confirmed in the study 'Benzodiazepine antagonist in the treatment of human hepatic encephalopathy' that, "[the] findings indicate that flumazenil may be valuable in treatment of acute HE occurring in fulminant hepatic failure [Type A HE] or in decompensated cirrhosis [Type C HE]."

Now, how does treatments with GABA inhibitors compare to the "standard" treatments that you mentioned, which focus only on lowering the symptoms of ammonia? Let's see...

(G) Regarding the assertion that "If you have HE, you need lactose and Rifaxamin"--

From the study 'Flumazenil in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double blind randomized placebo controlled study.', it is described, "The aim of this study was to evaluate the effects of flumazenil on hepatic encephalopathy ... In the double blind randomized, placebo controlled study, 54 patients with hepatic encephalopathy grade III-IV were randomly assigned to receive either flumazenil 2 mg iv (group A) or placebo (group B); conventional treatment with branched-chain amino acid, saline, glucose, and lactulose was administered in both groups. ... [The findings:] Clinical improvement was obtained in 22/28 patients in group A and in 14/26 in group B (p<0.05); improvement was observed within the first six hours in 21/22 patients in group A and only in 3/14 in group B."

It seems, therefore, that GABA-inhibitors such as Flumazenil offer a tremendous benefit beyond that which standard treatments alone can offer.

(H) Regarding "All these trials related to ammonia [having] been done before the year 2018 and [thus having] no role in current guidelines."

--"Although there is overwhelming evidence of the central role of ammonia in the pathogenesis of HE, and data show that 80% of patients with cirrhosis present some degree of hyperammonemia, it is important to note that many studies have reported an imperfect correlation between hyperammonemia and the severity of HE in chronic liver disease. This suggests that pathogenic factors besides ammonia are involved in the pathogenesis of HE."

Biological mechanism underlying these dynamics do not change from 1990 to 2005 to 2018. They are consistent with evolution.

It is only our understanding of these dynamics which shifts. However, truth is absolute, and the closer our understanding comes to the truth, the more immovable and certain it will therefore be.

What I have been presenting is the strongest understanding of the truth regarding these matters that I believe exists. Any person may obvserve the dialogue and read both sides, until they come to their own educated conclusion.

...

We must also understand this:

Ammonia is only one symptom; in most cases, it may be a central pillar and chief element accounting for the increased GABAergic tone within the patient--however, in my case, it is not. I have strongly put forward that it is the ongoing presence and effects of the combination of Phenibut and especially Fasoracetam, which is a potent upregulator of GABA. The only key to their removal? (1) hemoperfusion, or (2) re-enabling of the function of the liver's microsomes--and thus, re-enabling of the drug-metabolizing function of the liver.

***THIS IS WHY THE USE OF GABA-INHIBITING DRUGS AND COMPOUNDS IS SO KEY! It is excessive GABAergic tone which neurologically inhibits the liver's microsomes (and concomitantly the CNS as a whole) to such a strong degree that they no longer metabolize toxins. (This is why it is stated by one source cited earlier in my document, that "It is widely accepted that the ammonia level is a marker that usually parallels the amount of toxins and metabolites that bypasses the liver"; furthemore, from another source, healthline.com, "In [HE], your liver can’t adequately remove toxins [or drugs] from your blood. This causes a buildup of toxins [and drugs] in your bloodstream." It is thus WHEN WE APPLY GABA-INHIBITORS, THAT THE NERVOUS SYSTEM IS (AT LEAST TEMPORARILY) RELEASED FROM THE EXCESSIVE NEURAL INHIBITION, CAUSING A METABOLIZATION AND BREAK-DOWN OF THE SOURCE TOXINS, DRUGS OR COMPOUNDS WITHIN THE BLOODSTREAM THAT WERE RESPONSIBLE FOR THE EXCESSIVE GABAERGIC TONE IN THE FIRST PLACE!***

Ammonia-lowering agents and other standard treatments alone cannot do this.

So what about our understanding of the dynamics of the disease, and of the most effective treatments?

(I) You state for me to "Try to undestand that coffee chocolate etc are not going to help."

According to all the information above and the information within the previous documents, GABA inhibitors are key in producing drastic improvements.

Let us recall from the first document, how is it that I have found coffee and chocolate to be extremely effective?

Caffeine from coffee: According to the study cited in document 1--
“Inhibitory effect of caffeine on GABA-activated current [occured] in acutely isolated rat ... neurons"


Theobromine from chocolate: According to the study cited in document 2--
“…Theobromine … inhibited [GABA response] in a competitive manner…"

Thus, why and how are there effects from caffeine and chocolate?

Because they are NATURAL ANALOGUES OF FLUMAZENIL, IN THAT THEY ARE NATURALLY-OCCURING GABA INHIBITORS JUST AS FLUMAZENIL IS A GABA INHIBITOR! CAFFEINE AND CHOCOLATE IN HIGH DOSES PRODUCE EFFECTS COMPARABLE TO LOW DOSES OF THE SYNTHETIC AND POTENT GABA-INHIBITING DRUGS.

I clearly stated that after months and years of a lack of progress that I had had with symptoms, a sudden increase in caffeine and chocolate showed immediate and profoundly unimaginable improvements in condition--within minutes. Just like suggested here: "The onset of reversal is usually evident within 1-2 minutes after the injection [of GABA inhibiting agent] is completed as was observed with the trial dose in our patient. Eighty percent response will be reached within 3 minutes, with the peak effect occurring at 6-10 minutes."

...

Finally, in response to the assertion that "A Doctor will follow only what's written in the current volume of standard book and that I had already answered..."

A doctor is entitled, by his capacity, to exercise a level of reasoning and diagnostic flexibility that goes beyond the rigid methodologies of the standard books. As I described, this is his power to utilize "presumptive diagnoses," in the face of symptoms that are clear and consistent with an underlying dysfunction or illness that IS apparent, but does not yet have proper standardized results.

And, in response to "In short when gold standard tests are available to diagnose HE, why would a Doctor follow such trialed literature."--

--Because if the doctor believed that he may be dealing with a covert yet logically aparent case of HE, withholding a diagnosis is an effective sentence and condemnation for the ill person to continue to suffer.

Addiionally, whether psychometric tests are a fully sensitive test among all people that actually have covert or minimal HE, is debatable. To the extent that the tests have obvious limitaitons, and in practicality will never be met and tried by all patients currently suffering from those dysfunctions, a flexible approach must be taken via presumptive diagnosis.

...

Let's take one additional look at the table from my document, to differentiate myself from the normal, non-HE/LF population.

This table is attached as a picture file to my case, here on this site.

I ask you to please do the following two things--

(1) Carefully read through the two .pdf documents I have sent (I will re-send again if necessary, as the email service had not confirmed that you received it, which is atypical); and,

(2) please examine the table I have included and uploaded here.

After doing these thing, please then tell me whether a doctor can morally justify sending a patient home who has the symptoms and signs shown in the table, who also bears the complete backstory discussed in the documents.

Thank you.

P.S.

In response to "--When gold standard tests are available to diagnose HE, why would a Doctor follow such trialed literature."

--Because in addition to the fact that the findings from trialed literature form the basis of all scientific and medical understanding of the dynamics underlying these diseases, it is simply because the trialed literature reveals the true underlying dynamics and associations of disease and confers incredibly valuable insight into the pathology, best modes of identification of disease, and best forms of treatment--

--While the supposed "gold standard" tests (psychometrics) are, according to one source ('Hepatic encephalopathy: what the multidisciplinary team can do'), "...limited by their time-intensive nature and lack of standardization [and thus not of full practical value]"

The same source mentions, too, that "The diagnosis for MHE is challenging."

However if it were true that the gold standard tests were truly golden, there would be no challenge in diagnosing HE. Resultingly, a challenging diagnosis means more people suffer; therefore, to prevent excess patient suffering via excessive false-negatives with diagnoses, clinicians are therefore encouraged to (1) "better understand the pathophysiology" (as per quoted study from our previous dialogue) and also (2) to utilize the method and tool of presumptive diagnosis to identify cases that are intuitively apparent (as mine seems to be, given the multiple intersectioning factors consistent with HE).

From same study, "--While there has been an increased effort to create fast and reliable methods for the detection of MHE, screening is still underperformed due to the lack of standardization and efficient methods of diagnosis. The management of HE requires consultation from various disciplines, including hepatology, primary care physicians, neurology, psychiatry, dietician/nutritionist, social workers, and other medical and surgical subspecialties based on clinical presentation and clear communication among these disciplines to best manage patients with HE throughout their course."

There are clear shortcomings. They are obvious. Thus, doctors take the bad moral karma for being overly dismissive of the patient that others in the general community can clearly see. (I have had multiple people review the facts of my case who are not doctors, and have said offered their personal opinions that "It is incredibly, stupefyingly obvious that your issues are 100% consistent with a non-working liver and consistent with HE")

Since HE is still officially technically considered to be a diagnosis of "exclusion," therefore, the burden is on the clinician to explain for the apparent sources and causes of the symptoms presented.

When examining the features presented in my table, how can you explain the perfect intersectionality of all symptoms and factors there?

***Critical Question: Are you able to rule out H.E?

If so (which I would think would be nearly impossible given my presentation), then how do each of the 10 or 11 factors get explained individually as to their respective causes? And, after reviewing each of the factors, do you as a clinician truly believe that I am better off "going back home and not doing anything" with regards to this?

Thank you.

P.S.

In response to "--When gold standard tests are available to diagnose HE, why would a Doctor follow such trialed literature."

--Because in addition to the fact that the findings from trialed literature form the basis of all scientific and medical understanding of the dynamics underlying these diseases, it is simply because the trialed literature reveals the true underlying dynamics and associations of disease and confers incredibly valuable insight into the pathology, best modes of identification of disease, and best forms of treatment--

--While the supposed "gold standard" tests (psychometrics) are, according to one source ('Hepatic encephalopathy: what the multidisciplinary team can do'), "...limited by their time-intensive nature and lack of standardization [and thus not of full practical value]"

The same source mentions, too, that "The diagnosis for MHE is challenging."

However if it were true that the gold standard tests were truly golden, there would be no challenge in diagnosing HE. Resultingly, a challenging diagnosis means more people suffer; therefore, to prevent excess patient suffering via excessive false-negatives with diagnoses, clinicians are therefore encouraged to (1) "better understand the pathophysiology" (as per quoted study from our previous dialogue) and also (2) to utilize the method and tool of presumptive diagnosis to identify cases that are intuitively apparent (as mine seems to be, given the multiple intersectioning factors consistent with HE).

From same study, "--While there has been an increased effort to create fast and reliable methods for the detection of MHE, screening is still underperformed due to the lack of standardization and efficient methods of diagnosis. The management of HE requires consultation from various disciplines, including hepatology, primary care physicians, neurology, psychiatry, dietician/nutritionist, social workers, and other medical and surgical subspecialties based on clinical presentation and clear communication among these disciplines to best manage patients with HE throughout their course."

There are clear shortcomings. They are obvious. Thus, doctors take the bad moral karma for being overly dismissive of the patient that others in the general community can clearly see. (I have had multiple people review the facts of my case who are not doctors, and have said offered their personal opinions that "It is incredibly, stupefyingly obvious that your issues are 100% consistent with a non-working liver and consistent with HE")

Since HE is still officially technically considered to be a diagnosis of "exclusion," therefore, the burden is on the clinician to explain for the apparent sources and causes of the symptoms presented.

When examining the features presented in my table, how can you explain the perfect intersectionality of all symptoms and factors there?

***Critical Question: Are you able to rule out H.E?

If so (which I would think would be nearly impossible given my presentation), then how do each of the 10 or 11 factors get explained individually as to their respective causes? And, after reviewing each of the factors, do you as a clinician truly believe that I am better off "going back home and not doing anything" with regards to this?

Thank you.

Hello,

Sending response document to you via YYYY@YYYY .

Thank you.

Hello,

Sending response document to you via YYYY@YYYY .

Thank you.