Carbamoyl Phosphate Synthetase I (CPS1) Deficiency Disease

Carbamoyl Phosphate Synthetase I (CPS1) deficiency is a rare, inherited problem of the urea cycle. The urea cycle is the liver’s “nitrogen-cleaning” system. It turns extra nitrogen (from protein breakdown) into urea, which the body sends out in urine. In CPS1 deficiency, the first step of this cycle does not work well because the CPS1 enzyme is missing or weak. As a result, ammonia (a toxic waste) builds up in the blood (hyperammonemia). High ammonia is dangerous for the brain and can cause sleepiness, vomiting, seizures, coma, or even death if not treated quickly. The condition is autosomal recessive, which means a child gets one faulty CPS1 gene from each parent. Some babies get very sick in the first days of life. Others have milder, later symptoms that appear in childhood or adulthood during illness, heavy exercise, high-protein intake, fasting, or stress. MedlinePlus+2Orpha+2

CPS1 deficiency is a rare, inherited metabolic disease where the liver enzyme carbamoyl phosphate synthetase I does not work properly. This enzyme starts the urea cycle, the body’s main path to turn toxic ammonia (from protein breakdown) into urea so it can be safely removed in urine. When CPS1 is weak or absent, ammonia builds up in the blood (hyperammonemia). High ammonia can quickly injure the brain and cause sleepiness, vomiting, seizures, coma, or death without fast treatment. Some babies become sick in the first days of life; others have later-onset episodes during stress, infection, heavy exercise, high protein intake, or fasting. CPS1 deficiency is autosomal recessive (both gene copies have to be affected). Diagnosis uses blood ammonia, amino acids (very low citrulline is typical), and CPS1 gene testing. Lifelong care aims to prevent ammonia spikes with low-protein diet, special amino acid supplements, and nitrogen-scavenger medicines; liver transplant can provide a permanent liver source of the missing enzyme. NCBI+2Orpha+2

CPS1 sits inside liver cell mitochondria and needs a natural activator called N-acetylglutamate (NAG). If CPS1 is low or inactive, the cycle stalls at the beginning, and ammonia rises. Low citrulline levels in blood and normal/low orotic acid in urine often point to a proximal urea-cycle defect like CPS1 deficiency rather than OTC deficiency. Genetic testing confirms the diagnosis. MedlinePlus+2BioMed Central+2

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Other names

• CPS1 deficiency; CPS1D; CPSID

• Carbamoyl-phosphate synthetase I deficiency

• Congenital hyperammonemia, type I

• Urea cycle disorder due to CPS1 deficiency NCBI+1

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Types

1) Neonatal-onset (severe):
Symptoms start in the first 24–72 hours after birth. Babies feed poorly, vomit, are very sleepy, breathe fast, and may have low body temperature or seizures. Without rapid treatment, coma can occur. Orpha+1

2) Late-onset (partial):
Symptoms appear later (childhood to adulthood). People may be well between episodes, but ammonia spikes during triggers such as infection or high-protein intake. Typical signs are confusion, headache, vomiting, ataxia (unsteady walk), and lethargy. NCBI

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Causes

CPS1 deficiency itself is caused by pathogenic variants in the CPS1 gene. Many of the items below are triggers that make ammonia rise in people who already have CPS1 deficiency.

1. Pathogenic CPS1 gene variants (autosomal recessive) – the root cause; leads to absent or reduced CPS1 enzyme. MedlinePlus

2. High-protein meals – extra nitrogen increases ammonia load. BioMed Central

3. Fasting or prolonged starvation – increases tissue breakdown (catabolism) → more ammonia. BioMed Central

4. Intercurrent infections (fever, sepsis) – catabolic stress raises ammonia. BioMed Central

5. Major surgery or trauma – stress hormones and tissue breakdown increase ammonia. BioMed Central

6. Post-partum state – sudden metabolic shifts can unmask late-onset UCDs. BioMed Central

7. Intense or prolonged exercise – protein catabolism may trigger episodes. MDPI

8. Dehydration – lowers renal clearance; worsens catabolism. BioMed Central

9. Gastrointestinal bleeding – digested blood acts like high-protein intake. BioMed Central

10. Total parenteral nutrition (TPN) with high protein – excessive nitrogen load. BioMed Central

11. Certain medicines: valproate – can raise ammonia and precipitate encephalopathy. BioMed Central

12. Topiramate (with valproate) – higher risk for hyperammonemia. BioMed Central

13. Glucocorticoids – promote catabolism in some settings. BioMed Central

14. Chemotherapy (e.g., L-asparaginase) – catabolism and liver effects. BioMed Central

15. High fever – accelerates protein breakdown. BioMed Central

16. Poor caloric intake (dieting, illness) – catabolism during low energy intake. BioMed Central

17. Late weaning with high-protein formula – increased nitrogen load in infants. newbornscreening.hrsa.gov

18. Liver stress or dysfunction – reduces urea cycle capacity. BioMed Central

19. N-acetylglutamate synthase (NAGS) inhibitor states – reduce CPS1 activation (important in differential; similar presentation). BioMed Central

20. Lack of timely treatment during minor illnesses – small triggers can escalate quickly without early rescue. BioMed Central

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Symptoms

1. Poor feeding in babies. rarediseases.info.nih.gov

2. Vomiting, especially after protein. rarediseases.info.nih.gov

3. Lethargy / extreme sleepiness. MedlinePlus

4. Confusion or disorientation (older children/adults). NCBI

5. Irritability or behavior change. MedlinePlus

6. Headache. NCBI

7. Ataxia (unsteady walking). NCBI

8. Hypotonia (weak muscle tone). rarediseases.info.nih.gov

9. Rapid breathing (respiratory alkalosis). newenglandconsortium.org

10. Low body temperature in neonates. rarediseases.info.nih.gov

11. Seizures. rarediseases.info.nih.gov

12. Poor school performance / attention problems between crises. Rare Diseases Clinical Research Network

13. Coma in severe episodes. rarediseases.info.nih.gov

14. Nausea / loss of appetite. MedlinePlus

15. Failure to thrive or slow growth in infants. Rare Diseases Clinical Research Network

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Diagnostic tests

A) Physical examination

1. General state and vitals
   Doctors check temperature, heart rate, blood pressure, and breathing. Fast breathing with lethargy can suggest high ammonia and early brain stress. newenglandconsortium.org

2. Neurologic exam
   Looks for sleepiness, confusion, abnormal reflexes, tremor, asterixis (flapping hands), or seizures—signs of encephalopathy due to ammonia. Rare Diseases Clinical Research Network

3. Hydration status
   Dry mouth, poor urine output, and weight change can show dehydration, which worsens catabolism and hyperammonemia. BioMed Central

4. Growth and development review
   Measures weight/length/head size and checks milestones. Slow growth or delays may reflect repeated ammonia spikes. Rare Diseases Clinical Research Network

B) “Manual” bedside tests / structured assessments

5. Glasgow Coma Scale (GCS)
   Scores eye, verbal, and motor responses to track mental status during an episode. Falling scores suggest worsening encephalopathy. Rare Diseases Clinical Research Network

6. Asterixis test
   Patient extends arms and hands; a flap-like tremor points to metabolic encephalopathy like hyperammonemia. Rare Diseases Clinical Research Network

7. Bedside orientation and memory checks
   Simple questions (name, place, time) detect confusion during late-onset attacks. NCBI

8. Serial neurologic checks
   Regular, repeated exams help detect early decline and need for urgent ammonia removal. BioMed Central

C) Laboratory and pathological tests

9. Plasma ammonia
   The key test. Very high levels confirm hyperammonemia and guide urgent treatment. Blood must be handled on ice and analyzed quickly for accuracy. BioMed Central

10. Plasma amino acids
    Often show low citrulline and low arginine in CPS1 deficiency (a proximal urea-cycle block). Glutamine may be high. Patterns help with differential. SpringerLink

11. Urine orotic acid
    Usually normal or low in CPS1 deficiency (helps distinguish from OTC deficiency, where orotic acid is high). BioMed Central

12. Genetic testing (CPS1 gene sequencing/panels)
    Confirms diagnosis by finding pathogenic variants; useful for family counseling and newborn testing. BioMed Central

13. Liver CPS1 enzyme assay
    Directly measures enzyme activity in liver tissue; used when genetic results are unclear. Less common today but still definitive. SpringerLink

14. Arterial/venous blood gas (ABG/VBG)
    May show respiratory alkalosis from rapid breathing and help track severity. newenglandconsortium.org

15. Basic metabolic panel
    Looks for low bicarbonate (from alkalosis/therapy), glucose status, and electrolytes important in care. BioMed Central

16. Liver function tests and INR
    Check for liver stress and clotting. They help manage safety during treatment and rule out other causes. BioMed Central

17. Plasma carnitine and acylcarnitines / urine organic acids
    Often non-specific in CPS1 deficiency but used to exclude other inborn errors. BioMed Central

18. Newborn screening (where available)
    Some programs flag urea-cycle disorders early, prompting ammonia testing and genetic confirmation. newbornscreening.hrsa.gov+1

D) Electrodiagnostic test

19. Electroencephalogram (EEG)
    Assesses seizures and diffuse brain dysfunction from hyperammonemia; helps monitor recovery. Rare Diseases Clinical Research Network

E) Imaging tests

20. Brain MRI or CT
    Used when neurologic signs are severe or prolonged. May show brain swelling or changes from ammonia injury; supports prognosis and excludes other causes. Rare Diseases Clinical Research Network

Non-pharmacological treatments (therapies & “others”)

1. Low-protein, individualized diet. Purpose: lower nitrogen load while meeting growth/energy needs. Mechanism: limits ammonia generation from protein catabolism. Managed by metabolic dietitian; protein targets change with age and growth. ScienceDirect+1

2. Adequate calories (high-carb ± lipids). Purpose: stop body protein breakdown. Mechanism: carbohydrate/lipid calories suppress catabolism and ammonia production. PMC

3. Essential amino acid (EAA) or special formulas. Purpose: supply required amino acids without excess nitrogen. Mechanism: balances intake to support growth with minimal ammonia burden. ScienceDirect

4. Citrulline supplementation (dietary amino acid). Purpose: restore downstream urea-cycle flow in proximal defects (CPS1/OTC). Mechanism: citrulline → arginine to help detoxify nitrogen via alternative handling. PMC

5. Arginine supplementation. Purpose: support urea cycle and nitric-oxide pathways when indicated. Mechanism: provides substrate for cycle steps; selection of arginine vs citrulline depends on defect; in CPS1, citrulline is typically preferred. PMC

6. Emergency “sick-day” regimen. Purpose: a written plan for first hours of illness. Mechanism: immediate high-glucose intake, protein stop, and early medical contact prevent catabolism. PMC+1

7. Rapid IV dextrose during crises. Purpose: halt protein breakdown. Mechanism: 10% dextrose or higher to maintain anabolism while definitive care begins. PMC

8. Hemodialysis / CRRT for severe hyperammonemia. Purpose: remove ammonia fast when levels are high or patient is encephalopathic. Mechanism: extracorporeal clearance; CRRT can be used continuously in unstable infants. AJKD+1

9. Avoidance of ammonia-raising drugs. Purpose: prevent iatrogenic spikes. Mechanism: avoid/monitor agents like valproate (and combinations with topiramate). NCBI+1

10. Hydration & antiemetics. Purpose: prevent dehydration-induced catabolism and maintain intake. Mechanism: fluids and nausea control sustain energy delivery. BIMDG

11. Fever/infection control. Purpose: reduce catabolic drive. Mechanism: early treatment and temporary protein reduction under a plan. Çocuk Metabolizma

12. Nutrition education & label literacy. Purpose: help families spot hidden protein and manage holidays/travel. Mechanism: practical skills reduce accidental protein overload. Metabolic

13. School/workplace accommodations. Purpose: ensure access to emergency drinks, meds, and rest. Mechanism: plans reduce crisis delays. Metabolic

14. Enteral access (gastrostomy) when needed. Purpose: reliable delivery of formulas/medicines. Mechanism: ensures intake during illness or feeding difficulty. FDA Access Data

15. Psychological support & neurocognitive follow-up. Purpose: address ADHD, learning, anxiety common in UCDs. Mechanism: routine screening and therapy improve function. NCBI

16. Exercise pacing. Purpose: avoid prolonged high-intensity exertion that increases ammonia. Mechanism: moderate activity with breaks reduces nitrogen production. SpringerLink

17. Pregnancy/Peri-operative protocols. Purpose: prevent decompensation during high-stress periods. Mechanism: pre-planned calories, IV glucose, and close monitoring. AWMF Leitlinienregister

18. Home ammonia monitoring (select centers). Purpose: earlier detection of rising levels. Mechanism: point-of-care or lab strategies trigger sick-day steps sooner. BIMDG

19. Genetic counseling. Purpose: inform family planning and carrier testing. Mechanism: explains autosomal recessive risk and newborn planning. NCBI

20. Timely referral for transplant evaluation in unstable disease. Purpose: consider definitive enzyme source. Mechanism: liver transplant removes dietary/medication constraints in many patients. Frontiers

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Drug treatments

Important reality check: Only a small number of FDA-approved drugs directly treat UCDs by removing nitrogen; there are not 20 distinct approved drugs for CPS1 deficiency. Below are the key, label-supported agents and how they are used—plus honest notes on adjuncts. (Label PDFs are from accessdata.fda.gov.)

1. Glycerol phenylbutyrate (RAVICTI®) – oral nitrogen scavenger.
   Class & purpose: Nitrogen-binding agent for chronic management of UCDs (≥2 years), used with protein restriction and supplements. Mechanism: Converted to phenylacetic acid, which binds glutamine to make phenylacetylglutamine (carries 2 nitrogens) excreted in urine—an alternate pathway to urea. Dose/timing: Label-titrated to control ammonia; lower starting doses in hepatic impairment. Key safety: Watch for phenylacetic acid neurotoxicity if overdosed; not for acute crises. Common issues: GI effects; requires adherence with diet. FDA Access Data+2FDA Access Data+2

2. Sodium phenylbutyrate (BUPHENYL® / PHEBURANE® pellets) – oral nitrogen scavenger.
   Class & purpose: Chronic UCD management adjunct to diet; Pheburane improves palatability. Mechanism: Phenylbutyrate → phenylacetate → binds glutamine → urinary excretion as phenylacetylglutamine. Dose/timing: Label-based by body surface area/weight; max daily limits. Key safety: Taste/odor (BUPHENYL) and GI intolerance may limit dosing; electrolyte shifts possible. Not for acute crisis. FDA Access Data+1

3. Sodium phenylacetate + sodium benzoate injection (AMMONUL®) – acute IV therapy.
   Class & purpose: Emergency ammonia-lowering when oral agents and diet cannot control or patient is encephalopathic. Mechanism: Phenylacetate binds glutamine; benzoate binds glycine—both carry nitrogen out via urine. Dose/timing: Weight-based IV loading + maintenance; must be diluted and prefer central line; often given with IV dextrose and arginine. Key safety: Line-related risks; electrolyte shifts; label compatibility limits. Not a substitute for dialysis when ammonia is very high—often used with dialysis. FDA Access Data+3FDA Access Data+3FDA Access Data+3

4. Arginine hydrochloride (R-Gene® 10) IV – acute adjunct (selected defects).
   Class & purpose: Amino acid given during hyperammonemic crises to supply urea-cycle substrate; in proximal defects such as CPS1, citrulline is generally preferred chronically, but arginine may be used acutely per protocol. Mechanism: Supports cycle flux and nitrogen disposal; also corrects low arginine. Safety: Hyperkalemia risk; must be dosed/monitored carefully. FDA Access Data+1

5. Citrulline (oral supplement grade) – chronic adjunct in CPS1/OTC.
   Class & purpose: Medical-nutrition amino acid (dietary supplement, not an FDA-approved drug for UCDs). Mechanism: Bypasses the proximal block; preferred over arginine for raising plasma arginine in UCDs according to observational data. Use: Dietitian/physician determines dosing; continue with protein restriction and scavengers. PMC

6. Intravenous dextrose ± lipids – acute metabolic support.
   Class & purpose: Not a “drug for UCD,” but essential therapy in crises. Mechanism: Provides non-protein calories to stop catabolism while scavengers work. Often the first step in ER protocols. PMC

7. Carglumic acid (Carbaglu®) – not routinely effective in CPS1 deficiency.
   Label note: FDA-approved for N-acetylglutamate synthase (NAGS) deficiency and some organic acidemias, not for CPS1. A few reports suggest potential benefit in select CPS1 variants, but evidence is limited; most guidelines do not recommend it for CPS1D. Use should be expert-guided if ever considered. NCBI

Other agents sometimes discussed (e.g., lactulose, rifaximin) are for liver-failure (porto-systemic) hyperammonemia, not primary UCDs, and are not standard in CPS1D. Always follow a metabolic specialist’s protocol. NCBI

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Dietary molecular supplements

1. Citrulline (preferred in CPS1/OTC): typically divided daily dosing to maintain arginine; mechanism above. PMC

2. Arginine (use varies by defect; often less preferred than citrulline for CPS1 long-term): substrate support. PMC

3. Essential amino acids mix: ensure growth with minimal nitrogen excess. ScienceDirect

4. Branched-chain amino acid–balanced formulas: tailored to reduce nitrogen burden while supporting muscle. ScienceDirect

5. Glucose polymers (e.g., maltodextrin drinks) in sick-day plans for fast calories. e-imd.org

6. Medium-chain triglyceride (MCT) or standard lipids: extra non-protein calories to suppress catabolism. PMC

7. Micronutrients (zinc, selenium, vitamins): replace deficits from restricted diets under dietitian guidance. ScienceDirect

8. Calcium/vitamin D: support bone health with long-term protein restriction/limited dairy. ScienceDirect

9. Fiber/constipation plan: maintain gut regularity to avoid stress/dehydration (adjunctive). mdda.org.au

10. Electrolyte oral rehydration during illness: maintain intake, prevent catabolic dehydration. e-imd.org

(Doses are individualized by weight, labs, and clinical response—set by the metabolic team.)

Immunity booster / regenerative / stem-cell drugs

There are no FDA-approved “immunity boosters,” stem-cell drugs, or regenerative medicines that treat CPS1 deficiency today. What follows are research or procedural directions, not approved drug therapies:

1. Hepatocyte transplantation (cell therapy, bridge) – experimental; may provide temporary ureagenesis; used as a bridge to LT in select cases. Lippincott Journals

2. AAV gene therapy for CPS1 (preclinical) – oversized/split-AAV approaches restore ureagenesis and survival in mouse models; human trials have not established safety/efficacy yet. Cell+2PubMed+2

3. Liver-humanized models – research tools to test therapies. Wiley Online Library

4. General immunizations – routine vaccines protect against infections that can trigger catabolism, but they are not “immunity boosters” specific to CPS1. e-imd.org

5. Nutrition-based resilience – adequate calories/protein-free energy during illness lowers crisis risk; again, not a drug. PMC

6. Future gene-editing concepts – under investigation; no clinical approval. Wiley Online Library

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Procedures/surgeries (why done)

1. Liver transplantation (LT) – definitive source of a functioning urea cycle; improves metabolic stability, allows liberalized diet; survival generally high, though pre-LT brain injury may persist. PMC+2PMC+2

2. Living-donor LT – option in children; careful genetic evaluation of relatives required because carriers exist. Frontiers

3. Hemodialysis catheter placement – urgent access for rapid ammonia removal in crises. AJKD

4. Gastrostomy tube – long-term, reliable delivery of formulas/meds, especially in infants/feeding issues. FDA Access Data

5. Hepatocyte (cell) transplantation – experimental bridge; not standard of care. Lippincott Journals

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Prevention tips

1. Keep a written emergency letter/plan and bring it everywhere. Metabolic

2. Start sick-day regimen early (high-glucose intake; hold protein) at first sign of illness. PMC

3. Do not fast; eat regular meals/snacks; overnight strategies for infants. e-imd.org

4. Avoid/flag valproate; be cautious with topiramate combinations; review any new medication with the metabolic team. NCBI

5. Meet calorie goals daily to prevent catabolism. PMC

6. Follow the protein prescription exactly; do not self-increase protein or sports supplements. ScienceDirect

7. Vaccinate on schedule to reduce infection-triggered crises. e-imd.org

8. Travel prep: bring formulas, scavengers, syringes, written instructions, and contacts. Metabolic

9. School/work coordination: training for staff on early signs and action steps. Metabolic

10. Regular specialist follow-up to adjust diet/scavenger dose with growth or lab trends. MDPI

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When to see a doctor (or go to the ER)

• Immediately for vomiting, unusual sleepiness, confusion, behavior change, ataxia, severe headache, or seizures—assume possible hyperammonemia. Do not wait. Start the sick-day plan and seek urgent care for ammonia level and IV glucose. PMC

• For any fever/infection, poor intake, or dehydration—contact your metabolic team early. Çocuk Metabolizma

• For routine care: regular metabolic/dietetic visits and neurodevelopmental checks. NCBI

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What to eat / what to avoid

• Eat: the prescribed low-protein plan, measured servings; special EAA/citrulline supplements if ordered; starches, fruits, vegetables, oils for calories; glucose polymer drinks for sick days; adequate fluids daily. ScienceDirect+2PMC+2

• Avoid: extra protein beyond the prescription; body-building protein powders; prolonged fasting; alcohol binges (teens/adults); and valproate unless a specialist deems necessary (and then under close monitoring). NCBI

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FAQs

1. Is CPS1 deficiency curable with medicines? No—medicines control ammonia; only liver transplant provides a new, working enzyme source. Frontiers

2. What’s the difference between RAVICTI and sodium phenylbutyrate? Same active metabolite (phenylacetate); RAVICTI is a liquid prodrug with different dosing and often better tolerability. Both are chronic scavengers, not for acute crises. FDA Access Data+1

3. Is AMMONUL for home use? No—IV hospital drug for acute hyperammonemia, sometimes alongside dialysis. FDA Access Data

4. Why citrulline in CPS1? It bypasses the blocked step and is preferred over arginine for raising arginine levels in UCDs. PMC

5. Do lactulose or rifaximin help? They treat gut-derived ammonia in liver failure, not primary UCDs. NCBI

6. Can I exercise? Yes—moderate activity with good fueling and hydration; avoid prolonged, intense, fasting workouts. SpringerLink

7. Will transplant fix the brain injury already present? It prevents new crises, but pre-existing injury may persist; outcomes vary. PMC

8. Are stem-cell therapies available? Not approved; investigated as experimental bridges or future options. Lippincott Journals

9. Can newborn screening detect CPS1D? Sometimes, but not reliably; low citrulline can flag, yet many cases present before results. NCBI

10. Is carglumic acid useful in CPS1? Generally no; it’s for NAGS deficiency. NCBI

11. How fast should dialysis start? When ammonia is very high or there’s encephalopathy, urgent extracorporeal removal is recommended. AJKD+1

12. Can parents be living liver donors? Possibly, but carriers are common; thorough genetic assessment is required. Frontiers

13. What are long-term goals without transplant? Zero or minimal crises, normal growth, schooling, and neurodevelopment via diet + scavengers + plans. MDPI

14. Will my child “outgrow” CPS1D? No; it is lifelong. But many achieve good stability with careful management. NCBI

15. What new therapies are coming? AAV gene therapy approaches show promise in animals; human safety/effectiveness are still under study. Cell

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: November 10, 2025.

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