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The build up of uric acid causing high amount of uric acid in blood, is a condition called hyperuricemia. Long-standing hyperuricemia can cause deposition of monosodium urate crystals in or around joints, resulting in a arthritic condition called [[gout]].<ref>{{Cite journal|last=Bardin|first=Thomas|last2=Richette|first2=Pascal|date=2014|title=Definition of hyperuricemia and gouty conditions|url=https://pubmed.ncbi.nlm.nih.gov/24419750|journal=Current Opinion in Rheumatology|volume=26|issue=2|pages=186–191|doi=10.1097/BOR.0000000000000028|issn=1531-6963|pmid=24419750}}</ref>
The build up of uric acid causing high amount of uric acid in blood, is a condition called hyperuricemia. Long-standing hyperuricemia can cause deposition of monosodium urate crystals in or around joints, resulting in a arthritic condition called [[gout]].<ref>{{Cite journal|last=Bardin|first=Thomas|last2=Richette|first2=Pascal|date=2014|title=Definition of hyperuricemia and gouty conditions|url=https://pubmed.ncbi.nlm.nih.gov/24419750|journal=Current Opinion in Rheumatology|volume=26|issue=2|pages=186–191|doi=10.1097/BOR.0000000000000028|issn=1531-6963|pmid=24419750}}</ref>


When the body is unable to process or eliminate ammonia, such as in protein toxicity, will lead to the build up of ammonia in the bloodstream. Symptoms of elevated blood ammonia include muscle weakness, fatigue, and left untreated, ammonia can cross the blood brain barrier and affect brain tissues. Causing encephalopathy, confusion, delirium.<ref>{{Cite web|title=Ammonia Levels: MedlinePlus Medical Test|url=https://medlineplus.gov/lab-tests/ammonia-levels/|access-date=2021-08-01|website=medlineplus.gov|language=en}}</ref>
When the body is unable to process or eliminate ammonia, such as in protein toxicity, will lead to the build up of ammonia in the bloodstream, causing a condition called hyperammonemia. Symptoms of elevated blood ammonia include muscle weakness and fatigue. If left untreated, ammonia can cross the blood brain barrier and affect brain tissues, leading to a spectrum of neuropsychiatric and neurological symptoms including impaired memory, seizure, confusion, delirium, excessive sleepiness, disorientation, brain edema, intracranial hypertension, coma, and even death. <ref>{{Cite web|title=Ammonia Levels: MedlinePlus Medical Test|url=https://medlineplus.gov/lab-tests/ammonia-levels/|access-date=2021-08-01|website=medlineplus.gov|language=en}}</ref><ref>{{Cite journal|last=Bosoi|first=Cristina R.|last2=Rose|first2=Christopher F.|date=2009|title=Identifying the direct effects of ammonia on the brain|url=https://pubmed.ncbi.nlm.nih.gov/19104924|journal=Metabolic Brain Disease|volume=24|issue=1|pages=95–102|doi=10.1007/s11011-008-9112-7|issn=0885-7490|pmid=19104924}}</ref><ref>{{Cite journal|last=Walker|first=Valerie|date=2014|title=Ammonia metabolism and hyperammonemic disorders|url=https://pubmed.ncbi.nlm.nih.gov/25735860|journal=Advances in Clinical Chemistry|volume=67|pages=73–150|doi=10.1016/bs.acc.2014.09.002|issn=0065-2423|pmid=25735860}}</ref>


== Epidemiology ==
== Epidemiology ==

Revision as of 22:57, 1 August 2021

Not to be confused with protein poisoning.

Protein toxicity is the effect of the buildup of protein metabolic waste compounds, like urea, uric acid, ammonia, and creatinine. Protein toxicity has many causes, including urea cycle disorders, genetic mutations, excessive protein intake, and insufficient kidney function, such as chronic kidney disease and acute kidney injury.[1][2][3][4] Symptoms of protein toxicity include unexplained vomiting and loss of appetite, and untreated protein toxicity can lead to serious complications such as seizures, encephalopathy, further kidney damage, and even death.[1][5][6]

Definition

Protein toxicity occurs when protein metabolic wastes build up in the body. During protein metabolism, nitrogenous wastes such as urea, uric acid, ammonia, and creatinine are produced. These compounds are not utilized by the human body and are usually excreted by the kidney.[7] However, due to conditions such as renal insufficiency, the under-functioning kidney is unable to excrete these metabolic wastes, causing them to accumulate in the body and lead to toxicity.[8] Although there are many causes of protein toxicity, this condition is most prevalent in people with chronic kidney disease who consumes a protein-rich diet, specifically, proteins from animal sources that are rapidly digested and metabolized, causing the release of a high concentration of protein metabolic wastes in the blood stream rapidly.[9][10]

Causes and pathophysiology

Protein toxicity has a significant role in neurodegenerative diseases. Whether it is due to high protein intake, pathological disorders lead to the accumulation of protein waste products, the no efficient metabolism of the proteins, or oligomerization of the amino acids from proteolysis. The mechanism by which protein can lead to well known neurodegenerative diseases includes transcriptions dysfunction, propagation, pathological cytoplasmic inclusions, mitochondrial and stress granule dysfunction.[11]

Ammonia, one of the waste products of protein metabolism, is very harmful, especially to the brain, where it crosses the blood brain barrier leading to a whole range of neurological dysfunctions from cognitive impairment to death. The brain has a mechanism to counteract the presence of this waste metabolite. One of the mechanisms involved in the impairment of the brain is the compromise of astrocyte potassium buffering, where astrocytes play a key role. However, as more ammonia crosses, the system gets saturated, leading to astrocyte swelling and brain edema.[12]

Effects of a high protein diet

A high-protein diet is a health concern for those suffering from kidney disease. The main concern is that a high protein intake may promote further renal damage that can lead to protein toxicity. The physiological changes induced by an increased protein intake, such as an increased glomerular pressure and hyperfiltration, place further strain on already damaged kidneys. This strain can lead to proteins being inadequately metabolized and subsequently causing toxicity. A high-protein diet can lead to complications for those with renal disease and has been linked to further progression of the disease. The well-known Nurse’s Health Study found a correlation between the loss of kidney function and an increased dietary intake of animal protein by patients who had already been diagnosed with renal disease.[13] This association suggests that a total protein intake that exceeds the recommendations may accelerate renal disease and lead to risk of protein toxicity within a diseased individual. For this reason, dietary protein restriction is a common treatment for patients with renal disease in which proteinuria is present. Protein restricted patients have been shown to have slower rates of progression of their renal diseases.[14]

Several studies, however, have found no evidence of protein toxicity due to high protein intakes on kidney function in healthy people. Diets that regularly exceed the recommendations for protein intake have been found to lead to an increased glomerular filtration rate in the kidneys and also have an effect on the hormone systems in the body. It is well established that these physiological effects are harmful to individuals with renal disease, but research has not found these responses to be detrimental to those who are healthy and demonstrate adequate renal activity. In people with healthy kidney function, the kidneys work continuously to excrete the by-products of protein metabolism which prevents protein toxicity from occurring. In response to an increased consumption of dietary protein, the kidneys maintain homeostasis within the body by operating at an increased capacity, producing a higher amount of urea and subsequently excreting it from the body. Although some have proposed that this increase in waste production and excretion will cause increased strain on the kidneys, other research has not supported this.[13] Currently, evidence suggests that changes in renal function that occur in response to an increased dietary protein intake are part of the normal adaptive system employed by the body to sustain homeostasis. In a healthy individual with well-functioning kidneys, there is no need for concern that an increased dietary protein intake will lead to protein toxicity and decreased renal function.

Protein toxicity and other metabolic disorders associated with chronic kidney failure have been shown to related to more systemic complications such as atherosclerosis, anemia, malnutrition, and hyperparathyroidism [15]

Symptoms

Unexplained vomiting and a loss of appetite are indicators of protein toxicity. If those two symptoms are accompanied by an ammonia quality on the breath, the onset of kidney failure is a likely culprit. People with kidney disease who are not on dialysis are advised to avoid consumption of protein if possible, as consuming too much accelerates the condition and can lead to death. Most of the problems stem from the accumulation of unfiltered toxins and wastes from protein metabolism.

Kidney function naturally declines with age due to the gradual loss of nephrons (filters) in the kidney. Therefore, a 90-year-old cannot safely consume the same amount of protein as a 20-year-old.[citation needed]

Common causes of chronic kidney disease include diabetes, heart disease, long term untreated high blood pressure,[16] as well as abuse of analgesics like ibuprofen, aspirin, and paracetamol.[17] Kidney disease like the polycystic kidney disease can be genetic in nature and progress as the patient ages.[18]

Diagnosis

A confirmation of kidney disease or kidney failure is often obtained by performing a blood test which measures the concentration of creatinine and urea (blood urea nitrogen).[19]

Complications

Accumulation of protein metabolic waste products in the body can cause diseases and serious complications such as gout, uremia, acute renal failure, seizure, encephalopathy, and death. These products of protein metabolism, including urea, uric acid, ammonia, and creatinine, are compounds that the human body must eliminate in order for the body to function properly.

The build up of uric acid causing high amount of uric acid in blood, is a condition called hyperuricemia. Long-standing hyperuricemia can cause deposition of monosodium urate crystals in or around joints, resulting in a arthritic condition called gout.[20]

When the body is unable to process or eliminate ammonia, such as in protein toxicity, will lead to the build up of ammonia in the bloodstream, causing a condition called hyperammonemia. Symptoms of elevated blood ammonia include muscle weakness and fatigue. If left untreated, ammonia can cross the blood brain barrier and affect brain tissues, leading to a spectrum of neuropsychiatric and neurological symptoms including impaired memory, seizure, confusion, delirium, excessive sleepiness, disorientation, brain edema, intracranial hypertension, coma, and even death. [21][22][23]

Epidemiology

The prevalence of protein toxicity cannot be accurately quantified as there are numerous etiologies from which protein toxicity can arise.

Many people have protein toxicity as a result of chronic kidney disease (CKD) or end-stage renal disease (ESRD). The prevalence of CKD (all stages) from 1988 to 2016 in the U.S. has remained relatively consistent at about 14.2% annually.[24] The prevalence of people who have received treatment for ESRD has increased to about 2,284 people per 1 million in 2018, up from 1927 people per 1 million in 2007. Prevalence of treated ESRD increases with age, is more prevalent in males than in females, and is higher in Native Hawaiians and Pacific Islanders over any other racial group.[25] However, the prevalence of protein toxicity specifically is difficult to quantify as people who have diseases that cause protein metabolites to accumulate typically initiate hemodialysis before they become symptomatic.[26]

Urea cycle disorders also cause toxic buildup of protein metabolites, namely ammonia. As of 2013, in the U.S., the incidence of urea cycle disorders has been estimated to be 1 case in every 31,000 births, resulting in about 113 new cases annually.[27]

Special Populations

Neonates

Protein toxicity, specifically ammonia buildup, can affect preterm newborns that have serious defects in the urea cycle enzymes with almost no physical manifestations at birth. Clinical symptoms can manifest within a few days of birth, causing extreme illness and intellectual disability or death, if left untreated.[28] Hyperammonemia in newborns can be diagnosed with visual cues like sepsis-like presentation, hyperventilation, fluctuating body temperature, and respiratory distress; blood panels can also be used to form differential diagnoses between hyperammonemia caused by urea cycle disorders and other disorders.[29]

Neurodegenerative diseases

People who have neurodegenerative diseases like Huntington's disease, dementia, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), also often show symptoms of protein toxicity.[30] Cellular deficits and genetic mutations caused by these neurodegenerative diseases can pathologically alter gene transcription, negatively affecting protein metabolism.[31]

See also

References

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  2. ^ Dubin RF, Rhee EP (March 2020). "Proteomics and Metabolomics in Kidney Disease, including Insights into Etiology, Treatment, and Prevention". Clinical Journal of the American Society of Nephrology. 15 (3): 404–411. doi:10.2215/CJN.07420619. PMC 7057308. PMID 31636087.
  3. ^ Kölker S, Häberle J, Walker V (2016). "Urea Cycle Disorders". Oxford Medicine Online. doi:10.1093/med/9780199972135.003.0017.
  4. ^ Chung CG, Lee H, Lee SB (September 2018). "Mechanisms of protein toxicity in neurodegenerative diseases". Cellular and Molecular Life Sciences. 75 (17): 3159–3180. doi:10.1007/s00018-018-2854-4. PMC 6063327. PMID 29947927.
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  7. ^ Fowler S, Roush R, Wise J (2013). Concepts of biology. Houston, Texas. ISBN 978-1-947172-03-6. OCLC 896436135. {{cite book}}: |work= ignored (help)CS1 maint: location missing publisher (link)
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  10. ^ Ko, Gang-Jee; Rhee, Connie M.; Kalantar-Zadeh, Kamyar; Joshi, Shivam (2020). "The Effects of High-Protein Diets on Kidney Health and Longevity". Journal of the American Society of Nephrology: JASN. 31 (8): 1667–1679. doi:10.1681/ASN.2020010028. ISSN 1533-3450. PMC 7460905. PMID 32669325.
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  17. ^ Hörl WH (July 2010). "Nonsteroidal Anti-Inflammatory Drugs and the Kidney". Pharmaceuticals. 3 (7): 2291–2321. doi:10.3390/ph3072291. PMC 4036662. PMID 27713354.
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  20. ^ Bardin, Thomas; Richette, Pascal (2014). "Definition of hyperuricemia and gouty conditions". Current Opinion in Rheumatology. 26 (2): 186–191. doi:10.1097/BOR.0000000000000028. ISSN 1531-6963. PMID 24419750.
  21. ^ "Ammonia Levels: MedlinePlus Medical Test". medlineplus.gov. Retrieved 2021-08-01.
  22. ^ Bosoi, Cristina R.; Rose, Christopher F. (2009). "Identifying the direct effects of ammonia on the brain". Metabolic Brain Disease. 24 (1): 95–102. doi:10.1007/s11011-008-9112-7. ISSN 0885-7490. PMID 19104924.
  23. ^ Walker, Valerie (2014). "Ammonia metabolism and hyperammonemic disorders". Advances in Clinical Chemistry. 67: 73–150. doi:10.1016/bs.acc.2014.09.002. ISSN 0065-2423. PMID 25735860.
  24. ^ "218 Understanding and Making the Most of the Centers for Disease Control and Prevention's (CDC) Chronic Kidney Disease (CKD) Surveillance System". American Journal of Kidney Diseases. 77 (4): 636. 2021. doi:10.1053/j.ajkd.2021.02.223. ISSN 0272-6386.
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  28. ^ Kölker S, Häberle J, Walker V. Urea Cycle Disorders. Oxford University Press. doi:10.1093/med/9780199972135.003.0017. ISBN 978-0-19-046308-3.
  29. ^ Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, et al. (November 2019). "Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision". Journal of Inherited Metabolic Disease. 42 (6): 1192–1230. doi:10.1002/jimd.12100. PMID 30982989.
  30. ^ Taylor JP, Hardy J, Fischbeck KH (June 2002). "Toxic proteins in neurodegenerative disease". Science. 296 (5575): 1991–5. doi:10.1126/science.1067122. PMID 12065827.
  31. ^ Chung CG, Lee H, Lee SB (September 2018). "Mechanisms of protein toxicity in neurodegenerative diseases". Cellular and Molecular Life Sciences. 75 (17): 3159–3180. doi:10.1007/s00018-018-2854-4. PMC 6063327. PMID 29947927.

Further reading

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