Protein toxicity/ja

タンパク質毒性とは、尿素、尿酸、アンモニア、クレアチニンなどの蛋白代謝性老廃物化合物の蓄積による影響である。タンパク質中毒には、尿素サイクル障害、遺伝子変異、タンパク質の過剰摂取、慢性腎臓病や急性腎障害などの腎機能不全など、多くの原因がある。タンパク質中毒の症状には、原因不明の嘔吐や食欲不振がある。未治療のタンパク質中毒は、痙攣、脳症、さらなる腎障害、さらには死亡などの重篤な合併症を引き起こす可能性がある。

定義

タンパク質中毒は、タンパク質の代謝老廃物が体内に蓄積することで起こる。タンパク質の代謝中に、尿素、尿酸、アンモニア、クレアチニンなどの窒素性老廃物が産生される。これらの化合物は人体では利用されず、通常は腎臓から排泄される。しかし、腎不全などの状態により、機能低下した腎臓はこれらの代謝老廃物を排泄することができず、体内に蓄積して毒性を引き起こす。タンパク質中毒の原因はたくさんあるが、この状態は、タンパク質が豊富な食事、具体的には、消化・代謝が速い動物性由来のタンパク質を摂取している慢性腎臓病の人に最も多く、血液中に高濃度のタンパク質代謝老廃物が急速に放出される。

原因と病態生理学

蛋白質毒性は 変性変性疾患において生ずる蛋白質毒性は生ずる蛋白質毒性は生ずる蛋白質毒性は生す。タンパク質の大量摂取が原因であれ、病理学的障害はタンパク質の老廃物の蓄積、タンパク質の効率的な代謝の欠如、タンパク質分解によるアミノ酸のオリゴマー化につながる。タンパク質が神経変性疾患を引き起こすメカニズムとしては、転写産物の機能不全、増殖、病的な細胞質封入体、ミトコンドリアおよびストレス顆粒の機能不全などがよく知られている。

アンモニアはタンパク質代謝の老廃物のひとつで、特に脳にとって非常に有害で、血液脳関門を通過し、認知障害から死に至るまで、さまざまな神経機能障害を引き起こす。脳はこの老廃物の存在に対抗するメカニズムを持っている。脳の機能障害に関与するメカニズムのひとつは、アストロサイトのカリウム緩衝作用の低下であり、アストロサイトが重要な役割を果たしている。しかし、より多くのアンモニアが交差すると、システムは飽和状態になり、アストロサイトの腫脹と脳浮腫を引き起こす。

尿素もまた、人間のタンパク質代謝に由来する廃棄物である。しかし、尿素は成長や生命維持に不可欠な窒素源として体内で利用される。尿素サイクルに最も関連する障害は遺伝的なもので、酵素または輸送体の欠陥によって尿酸塩の再吸収が阻害され、それに伴って有毒なアンモニア濃度が上昇する。

高タンパク質摂取は高タンパク質廃棄につながる可能性があり、これは廃棄代謝産物の高レベルに関する問題であるため、タンパク質中毒とは異なる。通常、タンパク質の摂取量が食事量の3分の1を超えると、このような状況になる。肝臓の能力には限界があり、タンパク質を脱アミノ化しないため、体内の窒素が増加する。尿素が排泄される速度は、尿素が生成される速度に追いつかない。アミノ酸の異化は、有毒レベルのアンモニアにつながる可能性がある。さらに、消化管がタンパク質からアミノ酸を吸収できる速度には限りがある。

尿酸はタンパク質代謝から生じる廃棄物代謝物ではないが、多くの高タンパク食は相対的に核酸の割合が高い。核酸には2つのタイプがあり、ピリミジン（問題を引き起こさないもの）と並んで、プリンは過剰なときに人間の体内で尿酸に代謝され、これが主に痛風などの問題を引き起こす可能性がある。

腎臓は尿酸の再吸収と排泄において重要な役割を果たしている。腎の先端面と基底側面にある特定のトランスポーターが、尿酸の血清濃度を調節している。尿酸は他の窒素誘導体ほど毒性は強くない。尿酸は、低レベルでは血液中で抗酸化作用を発揮する。腎臓の機能が低下している人は、尿酸の排泄が低下し、さらなる腎障害、心血管疾患、糖尿病、痛風など、いくつかの病気を引き起こす。

クレアチニンは、タンパク質毒性の直接的な指標ではないかもしれない。しかし、クレアチニンは、高レベルのタンパク質廃棄物にさらされた腎臓の過労により増加する可能性があることは重要である。また、血清クレアチニン値が高い場合は、腎臓病による腎濾過率の低下、筋肉分解の結果としての副産物の増加、または高タンパク質摂取を示す可能性がある。

高タンパク食の効果

高タンパク食は、腎臓病を患っている人にとって健康上の懸念事項である。主な懸念は、高タンパク質摂取がさらなる腎障害を促進し、タンパク質中毒を引き起こす可能性があることである。糸球体圧の上昇や糸球体過濾過など、タンパク質摂取量の増加によって引き起こされる生理学的変化は、すでに損傷を受けている腎臓にさらなる負担をかける。この負担は、タンパク質が十分に代謝されず、毒性を引き起こすことにつながる。高タンパク食は腎臓病患者の合併症を引き起こし、病気のさらなる進行に関係している。よく知られているNurse's Health Studyでは、すでに腎臓病と診断されている人の腎機能の低下と動物性タンパク質の食事からの摂取量の増加との間に相関関係があることがわかった。この関連性から、推奨量を超える総タンパク質摂取は腎臓病を促進し、病人におけるタンパク質中毒のリスクにつながることが示唆される。このため、食事による蛋白質制限は、蛋白尿のある腎疾患患者に対する一般的な治療法である。蛋白質制限を受けた人は、腎疾患の進行速度が遅いことが示されている。

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 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. 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.

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.

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

Diagnosis

Under normal conditions in the body, ammonia, urea, uric acid, and creatinine are produced by protein metabolism and excreted through the kidney as urine. When these by-products cannot be excreted properly from the body they will accumulate and become highly toxic. Protein consumption is a major source of these waste products. An accumulation of these waste products can occur in people with kidney insufficiency who eat a diet rich in protein and therefore can not excrete the waste properly.

Blood urea nitrogen (BUN) test measures the amount of urea nitrogen in the blood. Increased levels of urea in the blood (uremia) is an indicator for poor elimination of urea from the body usually due to kidney damage. Increased BUN levels can be caused by kidney diseases, kidney stones, congestive heart failure, fever, and gastrointestinal bleedings. BUN levels can also be elevated in pregnant people and people whose diet consists mainly of protein.

Increased creatinine levels in the blood can also be a sign of kidney damage and inability to excrete protein waste by-products properly.

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). A creatinine blood test and BUN test are usually performed together along with other blood panels for diagnosis.

Treatment

Treatment options for protein toxicity can include renal replacement therapies like hemodialysis and hemofiltration.

Lifestyle modifications like a diet low in protein, decreased sodium intake, and exercise can also be in incorporated as part of a treatment plan.

Medications may also be prescribed depending on symptoms. Common medications prescribed for kidney diseases include hypertension medications like angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) as they have been found to be kidney protective. Diuretics may also be prescribed to facilitate with waste excretion as well as any fluid retention.

A kidney transplant surgery is another treatment option where a healthy kidney is donated from a living or deceased donor to the recipient.

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 an arthritic condition called gout.

When the body is unable to eliminate urea, it can cause a serious medical condition called uremia, which is a high level of urea in blood. Symptoms of uremia include nausea, vomiting, fatigue, anorexia, weight loss, and change in mental status. If left untreated, uremia can lead to seizure, coma, cardiac arrest, and death.

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.

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. 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. 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.

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.

特別な集団

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. 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.

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. Cellular deficits and genetic mutations caused by these neurodegenerative diseases can pathologically alter gene transcription, negatively affecting protein metabolism.

こちらも参照

• タンパク質中毒 – 十分なタンパク質と脂肪の不足による栄養失調
• Proteopathy/ja – ミスフォールドしたタンパク質によるダメージ

さらに読む

• Noli D, Avery G (1988). "Protein poisoning and coastal subsistence". Journal of Archaeological Science. 15 (4): 395–401. doi:10.1016/0305-4403(88)90037-4.
• Skov AR, Toubro S, Bülow J, Krabbe K, Parving HH, Astrup A (November 1999). "Changes in renal function during weight loss induced by high vs low-protein low-fat diets in overweight subjects". International Journal of Obesity and Related Metabolic Disorders. 23 (11): 1170–7. doi:10.1038/sj.ijo.0801048. PMID 10578207.
• Michaelsen KF (November 2000). "Are there negative effects of an excessive protein intake?". Pediatrics. 106 (5): 1293. doi:10.1542/peds.106.S4.1293. PMID 11061839. S2CID 45080721.
• Educational resource for renal protein toxicity