Adult-onset citrin deficiency is a rare, lifelong genetic disease that mainly affects the liver and the brain. In this condition, a gene called SLC25A13 does not work properly. This gene normally makes a protein called citrin, which helps liver cells handle energy and remove a waste chemical called ammonia.
Adult-onset citrin deficiency is a rare inherited liver disease where the liver cannot handle energy and protein in the normal way because of changes in the SLC25A13 gene. This causes a urea-cycle disorder called adult-onset type II citrullinemia (CTLN2). People may develop high blood ammonia, confusion, abnormal behavior, seizures, and even coma if it is not treated quickly.[]
In this condition, the liver cell “shuttle” protein called citrin does not work properly, so sugar (carbohydrate) is handled poorly, and the urea cycle is stressed. Many adults feel an unusual dislike of rice, noodles, and sweets, and prefer fatty or high-protein foods. Serious attacks are often triggered by alcohol, too many carbohydrates, infection, surgery, or strong physical or mental stress.[]
When citrin does not work, the liver has trouble using sugar for energy and trouble running the urea cycle, which is the main way the body clears ammonia. Ammonia can then build up in the blood, especially during stress, illness, or after eating a lot of sugar. High ammonia can harm the brain and cause confusion, strange behavior, or even coma if not treated.
Adult-onset citrin deficiency is the form that appears in teenagers or adults, usually from about 15 to 60 years of age. Many people have had milder problems in childhood but are only diagnosed later when they suddenly become very unwell with “attacks” of confusion and high ammonia. This adult form is considered the most severe stage of the citrin deficiency spectrum.
People with this disease often like high-protein, high-fat foods such as meat, fish, eggs, and cheese, and they dislike sugary or starchy foods like rice, bread, or sweets. This special food preference is very typical and can give doctors an important clue.
Other names and types
Adult-onset citrin deficiency is part of a group of related problems caused by the same gene change. Doctors use several names for these problems.
Other names you may see
Adult-onset citrin deficiency (AACD) – modern name for the adult stage.
Adolescent and adult citrin deficiency – similar meaning, stressing both teen and adult onset.
Citrullinemia type II (adult type, CTLN2) – older name, based on high citrulline levels in blood.
SLC25A13-related citrin deficiency – name that points to the gene involved.
Age-related types in the citrin deficiency spectrum
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) – appears in small babies with jaundice and liver problems.
Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) – appears in children who do not gain weight well and have abnormal blood fats.
Adolescent/adult citrin deficiency (AACD / CTLN2) – appears later with severe attacks of high ammonia and brain symptoms.
A single person can move through these stages during life. Some babies improve, seem “normal” for years, and then develop the adult form later.
How does adult-onset citrin deficiency happen?
The SLC25A13 gene gives instructions to make citrin, a transport protein in the inner wall of tiny power stations inside cells called mitochondria. Citrin moves certain amino acids (aspartate and glutamate) in and out of the mitochondria. This is important for both energy production and the urea cycle.
When citrin is missing or very weak, the liver cannot use sugar well to make ATP, the main energy molecule. Sugar (carbohydrate) stays in forms that disturb the normal balance of chemicals in the liver. The urea cycle also slows down, because it does not get enough aspartate, which it needs to turn ammonia into urea. Ammonia then builds up in the blood.
Because the liver cannot use sugar well, the body “asks” for other fuel. Many people with citrin deficiency therefore crave protein and fat, which can provide energy through pathways that do not depend as much on the damaged shuttle system. At the same time, sugary food or large glucose drips can overload the weak system and trigger a crisis.
The disease pattern is autosomal recessive. This means a person becomes sick only when they inherit one faulty copy of the gene from each parent. Each parent is usually healthy but carries one changed copy.
Causes and triggering factors
In truth, the main cause of adult-onset citrin deficiency is a genetic change. The other “causes” listed here are better understood as triggers or worsening factors in someone who already has the gene problem.
Inherited change in the SLC25A13 gene
This is the basic cause. A change (mutation) in both copies of the SLC25A13 gene stops citrin from working well in the liver. Without citrin, the urea cycle and energy system do not run normally, and ammonia builds up more easily.Autosomal recessive inheritance from carrier parents
A child gets one faulty gene copy from each parent, who are usually healthy carriers. When both parents carry the change, each pregnancy has a one-in-four chance to result in a child with citrin deficiency.Parents who are related by blood (consanguinity)
In some regions, marriage between relatives is more common. This increases the chance that both parents carry the same rare gene change, which raises the chance of a baby with citrin deficiency.High carbohydrate diet over time
Eating a lot of sugar, rice, bread, noodles, or sweet drinks stresses the weak liver pathways. In citrin deficiency, a high-carb diet is known to worsen symptoms and can even trigger the adult crisis stage.Sudden large sugar load (oral or IV)
Giving large amounts of glucose or sugary fluids during illness or surgery can sharply increase the liver’s workload. In people with this disease, this can quickly raise ammonia and bring on confusion or coma.Alcohol use
Alcohol harms liver cells and affects the same energy and detox pathways already weakened in citrin deficiency. Even small to moderate drinking can trigger attacks of high ammonia and brain symptoms in some adults.Acute infection or fever
When the body fights an infection, it needs more energy and breaks down more body protein. This produces extra ammonia and can push the liver beyond its limited capacity, leading to a crisis.Major surgery or physical stress
Surgery, heavy bleeding, or serious accidents cause strong stress hormones and changes in metabolism. These stresses can uncover citrin deficiency for the first time, or trigger new attacks in a known patient.Pregnancy and childbirth
Pregnancy changes hormone levels and energy needs. In some women with unrecognized citrin deficiency, late pregnancy or shortly after birth can be the time when serious episodes of confusion and high ammonia first appear.Long fasting or skipping meals
Not eating for long periods forces the body to break down its own muscle and fat. This increases ammonia production and can stress the damaged liver. Short fasts may still be risky, so careful planning is needed.Crash dieting or very rapid weight loss
Extreme diets or sudden weight loss act like a long fast. They increase protein breakdown in the body and may trigger liver fat build-up and high ammonia in citrin deficiency.Liver-toxic medicines
Some medicines place extra load on the liver. In a person with citrin deficiency, drugs that strongly affect liver function can make the underlying problem worse and bring out symptoms sooner.Anti-seizure drugs that affect ammonia handling
Certain epilepsy medicines, such as those that raise ammonia or stress the liver, may worsen brain symptoms in citrin deficiency patients. Doctors must choose such drugs with great care.Very high protein intake at one time
People with citrin deficiency often like protein, but a huge protein “binge” can still overload the urea cycle and raise ammonia. The risk is higher during illness or if the liver is already stressed.Dehydration
When a person is very dry (for example from vomiting or diarrhea), blood flow to the liver and kidneys can fall. This makes it harder to clear ammonia from the body and may make symptoms worse.Existing fatty liver or other liver disease
Many citrin deficiency patients develop fatty liver. If they also get another liver disease, such as viral hepatitis or alcohol-related damage, the liver may struggle even more, leading to adult-onset crises.Unrecognized childhood citrin deficiency (NICCD / FTTDCD)
Some adults had jaundice or feeding issues as babies or poor growth as children but were never diagnosed. Over years, the ongoing metabolic stress can set the stage for the later adult form.Wrong diet advice (high sugar, low fat)
Standard “healthy” diet rules that push low fat and high carbohydrate foods can be harmful in this disease. If doctors or family encourage such a diet, the person may feel worse and progress to adult-onset crises.Strong physical overwork without enough rest and food
Heavy physical labor or intense exercise without proper nutrition and rest may increase protein breakdown and energy demands beyond what the liver can meet, tipping the balance toward high ammonia.Unknown or random triggers
Even when no clear trigger is found, attacks can still happen. The underlying gene problem is always present, and small day-to-day changes in diet, illness, or stress can sometimes add up and cause a crisis.
Symptoms
Symptoms can be mild between attacks and very severe during attacks. Some people have long symptom-free periods. Others have frequent problems.
Recurrent episodes of confusion (encephalopathy)
Adults may have sudden spells where they seem confused, cannot think clearly, or do not know where they are. These episodes are due to high ammonia affecting the brain and can come and go.Abnormal behavior or personality change
Friends or family may notice that the person acts very differently during attacks. They may be aggressive, irritable, overly excited, or strangely quiet and withdrawn. This can be mistaken for a mental health problem at first.Nocturnal delirium (worse at night)
Some patients are more restless, confused, or agitated at night. They may talk nonsense, wander around, or see things that are not there. This pattern is quite typical in adult-onset citrin deficiency.Drowsiness and extreme tiredness
High ammonia makes the brain slow. People may sleep a lot, feel very tired, or find it hard to stay awake, especially during or after an attack.Memory loss and poor concentration
Patients may forget recent events, misplace objects, or struggle to follow conversations or work tasks. This can affect school or job performance and may be noticed as “brain fog.”Convulsions or seizures
Very high ammonia can trigger seizures. These are sudden bursts of abnormal brain activity, which may cause jerking movements, staring spells, or collapse.Flapping tremor (asterixis)
When the person holds out their hands, the hands may suddenly “flap” or jerk down. This is a sign of serious liver-related brain trouble and often appears when ammonia is high.Headache and nausea
High ammonia and brain swelling can cause headache, feeling sick, and vomiting. These signs are especially worrying if they appear together with confusion or behavior change.Poor appetite and weight loss
Many adults with citrin deficiency have long-term tiredness, stomach discomfort, and food dislikes. They may eat less and lose weight without trying.Strong preference for protein and fat, dislike of carbohydrates
A very typical symptom is craving meat, fish, eggs, cheese, and oily foods, while feeling unwell or “bloated” after eating rice, bread, noodles, or sweets. This unusual pattern is an important clue to the diagnosis.Abdominal pain and discomfort
Some patients have ongoing or repeated tummy pain, bloating, or discomfort, especially after eating sugary or starchy meals.Fatty liver and enlarged liver
Scans or blood tests may show fatty liver or a larger-than-normal liver, even in thin people. This happens because the liver cannot handle fats and sugars normally.Jaundice (yellow eyes or skin)
Some adults, especially those with earlier liver problems from childhood, may have yellowing of the whites of the eyes or skin due to poor bile flow or liver stress.Hypoglycemia-like symptoms (shaking, sweating, hunger)
During fasting or illness, blood sugar can drop. People may feel shaky, sweaty, dizzy, or very hungry. However, sugar drinks are not always the best treatment in this disease and must be used with care.Coma in severe cases
If ammonia becomes very high and treatment is delayed, the person can become unresponsive and slip into coma. This is a life-threatening emergency and needs urgent hospital care.
Diagnostic tests for adult-onset citrin deficiency
Doctors use a mix of physical exam, manual/bedside tests, laboratory and pathology tests, electrodiagnostic tests, and imaging tests to diagnose adult-onset citrin deficiency and to rule out other diseases.
Physical exam tests
General physical examination
The doctor checks weight, height, level of alertness, and overall appearance. They look for weight loss, muscle wasting, or signs of poor nutrition, which are common in long-standing citrin deficiency.Abdominal (tummy) examination
By gently pressing on the abdomen, the doctor can feel if the liver is enlarged or tender. They also look for fluid in the abdomen or signs of liver disease, which may suggest a metabolic liver problem like citrin deficiency.Neurological examination
This exam tests reflexes, strength, coordination, and balance. The doctor looks for tremors, flapping movements of the hands, or other signs of encephalopathy due to high ammonia.Mental status examination
The doctor asks questions to check memory, orientation (person, place, time), and thinking speed. Difficulty answering simple questions or keeping track of time can point to brain involvement in this liver-related condition.Nutritional and diet history review
A careful talk about what the person usually eats can show the typical pattern: strong liking for protein and fat and avoidance of carbohydrates. This “food story” is a powerful clinical clue even before lab results are back.
Manual or bedside tests
Orientation questions (person, place, time)
The doctor repeatedly asks, “What is your name? Where are you? What day is it?” Wrong answers or changing answers over time show that brain function is affected, as in ammonia-induced encephalopathy.Asterixis (hand-flap) test
The person is asked to stretch their arms out and bend their wrists back. If the hands suddenly flap down in short jerks, this supports the diagnosis of liver-related brain dysfunction.Simple balance and walking test
Walking in a straight line, turning, or standing with feet together can show subtle balance problems. Poor balance during an attack may reflect brain involvement from high ammonia.Hand-grip strength test
The person squeezes the doctor’s fingers or a handheld device. Low grip strength can indicate muscle wasting and poor nutrition, often seen in chronic citrin deficiency.Symptom diary or attack history review
The doctor may ask the patient or family to keep a simple diary of confusion spells, food eaten, and stresses. Patterns such as attacks after sugary meals or alcohol can help point toward citrin deficiency rather than other causes.
Laboratory and pathological tests
Blood ammonia level
This is one of the most important tests. In adult-onset citrin deficiency, ammonia levels often rise during attacks of confusion or behavior change. High ammonia strongly supports a urea cycle-related problem.Plasma amino acid profile (including citrulline)
A special blood test measures many amino acids. In this disease, citrulline and some other amino acids can be high, while others are low or unbalanced. This pattern helps separate citrin deficiency from other urea cycle disorders.Liver function tests (AST, ALT, GGT, bilirubin)
These blood tests show how well the liver is working. In citrin deficiency, they may be mildly to strongly abnormal, and GGT can be high, especially in earlier stages with cholestasis or fatty liver.Lipid profile and blood sugar tests
Blood fats (triglycerides, cholesterol) may be abnormal, and blood sugar may swing low during fasting. These findings support a metabolic liver disorder linked to energy handling.Lactate and pyruvate levels
Measuring these chemicals can show changes in energy production in cells. In some stages of citrin deficiency, the ratio between lactate and pyruvate is higher than normal, reflecting the redox imbalance in the liver.Coagulation tests (INR, PT)
The liver makes many clotting factors. If the liver is stressed or damaged, clotting can be slower, and these tests can be abnormal. This helps judge how sick the liver is during attacks.Newborn screening results (retrospective review)
In some countries, blood from birth is stored. If adult-onset citrin deficiency is suspected later, doctors may re-check the old newborn screening sample for certain amino acid patterns that fit NICCD.Genetic testing for SLC25A13 mutations
This is the gold-standard test. A blood or saliva sample is used to read the SLC25A13 gene. Finding disease-causing changes in both copies of this gene confirms citrin deficiency and supports the diagnosis of the adult form.
Electrodiagnostic tests
Electroencephalogram (EEG)
EEG records brain electrical activity using small wires on the scalp. In adult-onset citrin deficiency during an attack, EEG often shows slowing or other changes typical of metabolic encephalopathy, helping to distinguish it from primary epilepsy.Electrocardiogram (ECG) during acute crisis
An ECG is a simple heart tracing. During severe metabolic attacks, electrolyte shifts and stress can affect the heart rhythm. While not specific for citrin deficiency, it is important for safe monitoring during acute treatment.
Imaging tests (additional key tools often used)
Although we have already listed 20 named tests above, imaging studies are also very important in real practice:
Liver ultrasound – shows fatty liver, liver size, and bile flow problems without radiation.
Brain MRI – can show areas of swelling or signal change in brain regions (such as the insula and cingulate cortex) during high-ammonia attacks, supporting the diagnosis of hepatic encephalopathy.
Liver elastography or MRI – can measure liver stiffness and fat content, helping track long-term liver damage in citrin deficiency.
Non-pharmacological treatments (therapies and other measures)
1. Low-carbohydrate, higher-protein, higher-fat diet
This is the core non-drug therapy. Many guidelines advise reducing refined starches and sugars and increasing protein and healthy fats so the liver does not need to process large sugar loads. This pattern improves energy balance and may reduce high triglycerides and ammonia in adult-onset citrin deficiency.[]
2. Medium-chain triglyceride (MCT) oil supplementation
MCT oil gives energy that is easier for the liver to use and can “bypass” some of citrin’s metabolic block. In CTLN2 and other stages of citrin deficiency, adding MCT oil to the diet (under dietitian guidance) has been linked with better growth, fewer symptoms, and fewer crises.[]
3. Controlled total energy intake
Eating enough calories, but not huge carbohydrate-heavy meals, helps maintain a safe energy balance. Too little food triggers breakdown of body protein and raises ammonia, while too many carbohydrate calories overload the faulty metabolic pathway. Planned, balanced meals help stabilize metabolism.[]
4. Frequent small meals and bedtime snack
Instead of long fasting periods, small meals spaced through the day plus a bedtime snack can reduce catabolism (breakdown of body tissues) and keep ammonia more stable, especially in people who tend to decompensate overnight or during illness.[]
5. Individualized protein planning with a metabolic dietitian
Unlike some other urea-cycle disorders, many adults with citrin deficiency benefit from adequate or even relatively higher protein intake, adjusted to their tolerance. A specialist dietitian can calculate safe protein targets so the body gets enough amino acids without provoking high ammonia.[]
6. Avoidance of excessive refined carbohydrates
Large amounts of white rice, noodles, bread, sweet drinks, and desserts can worsen symptoms and trigger attacks because the liver cannot process glucose efficiently in citrin deficiency. Limiting these foods and spreading carbohydrate intake through the day is a key lifestyle strategy.[]
7. Strict avoidance of alcohol
Alcohol is a strong trigger for adult-onset citrin deficiency attacks and can push the liver into failure or encephalopathy. Completely avoiding alcohol is usually recommended to lower the risk of sudden hyperammonemia and brain injury.[]
8. Early management of infections and fevers
Any infection or fever increases catabolism and ammonia production. Having a “sick-day plan” with the metabolic team, including earlier review, lab tests, and sometimes temporary hospital care, can prevent a mild illness from turning into a serious encephalopathy episode.[]
9. Avoidance of prolonged fasting and crash dieting
Skipping meals, fasting for long religious or “detox” reasons, or extreme crash diets can quickly push the body to break down muscle, sharply raising ammonia. Patients are usually advised to avoid long fasts or to follow special protocols supervised by their team if fasting is unavoidable.[]
10. Gentle, regular physical activity
Moderate exercise, such as walking or light cycling, can improve muscle strength, insulin sensitivity, and overall well-being. Very intense or prolonged exercise without proper fueling, however, may increase catabolism, so patients are guided to “pace” activity and refuel appropriately.[]
11. Sleep and fatigue management
Chronic sleep loss and mental or physical over-work are reported triggers for CTLN2 attacks. Structuring daily routines to include regular sleep, rest breaks, and stress-recovery time can lower the risk of sudden decompensation.[]
12. Psychological support and counseling
Living with a rare, chronic metabolic disease is stressful and may cause anxiety or depression. Counseling, support groups, and psycho-education help patients recognize early warning signs, stick to treatment plans, and cope better with lifestyle limits.[]
13. Genetic counseling for patients and families
Adult-onset citrin deficiency is autosomal recessive. Genetic counseling explains inheritance, carrier testing, reproductive options, and early screening of relatives. Early diagnosis in family members allows early diet and monitoring before life-threatening crises occur.[]
14. Regular specialist follow-up and blood monitoring
Routine visits with a metabolic or hepatology team and periodic blood tests (ammonia, liver enzymes, amino acids, lipids) allow early detection of changes. Adjusting diet or medicines based on these results helps prevent accumulation of metabolic stress over time.[]
15. Emergency plan and information card
Patients are often advised to carry an emergency letter or card explaining their diagnosis and emergency treatment steps (for example, immediate ammonia check and early ammonia-lowering therapy). This reduces delays if they arrive confused or unconscious at a hospital.[]
16. Careful planning for surgery and anesthesia
Operations and general anesthesia are risky for people with urea-cycle disorders. Pre-operative planning, energy support, and close post-operative monitoring help prevent hyperammonemia. Reports of CTLN2 cases under anesthesia highlight the need for bespoke protocols.[]
17. Avoidance of known drug triggers where possible
Some medicines, such as valproic acid and very high-dose steroids, can raise ammonia or strain the liver. Whenever possible, safer alternatives are chosen, and if a risky drug is absolutely needed, closer ammonia monitoring is arranged.[]
18. Vaccination and infection prevention
Keeping up to date with routine vaccines (especially hepatitis A and B, influenza, COVID-19, and pneumonia shots if recommended) helps prevent serious infections that could destabilize ammonia control and liver function in citrin deficiency.[]
19. Education of family, friends, and local doctors
Teaching close contacts to recognize early signs of confusion, behavior change, or drowsiness makes it more likely that the patient is brought to hospital early—before ammonia rises to dangerous levels. Shared education is an important “non-drug” safety measure.[]
20. Lifestyle adaptation to personal food preferences
Many citrin-deficient adults naturally dislike sweet, starchy foods and prefer protein- and fat-rich meals. Working with this natural preference, and guiding it into a structured, safe diet plan, can make long-term adherence easier and improve quality of life.[]
Drug treatments (ammonia-lowering and supportive medicines)
Important: All drug choices and doses must be decided by a metabolic specialist or hepatologist. Information below is educational and based on FDA labels and scientific literature, not a self-treatment guide.
1. Sodium phenylbutyrate (BUPHENYL / PHEBURANE)
Sodium phenylbutyrate is an oral nitrogen-scavenger drug approved for long-term management of urea-cycle disorders. It provides an alternative pathway for waste nitrogen to leave the body by forming phenylacetylglutamine, which is excreted in urine. Typical adult total doses are calculated from body weight or body surface area and divided with meals. Common side effects include loss of appetite, menstrual changes, swelling, and taste changes.[]
2. Glycerol phenylbutyrate (RAVICTI)
Glycerol phenylbutyrate is another nitrogen-binding agent that gradually releases phenylbutyrate in the intestine. It is approved for chronic management of high ammonia in urea-cycle disorders and is taken several times a day with meals. It may cause nausea, diarrhea, headache, fatigue, and in high doses, symptoms of phenylacetate toxicity such as sleepiness or confusion.[]
3. Sodium phenylbutyrate (OLPRUVA granules)
OLPRUVA is a newer oral sodium phenylbutyrate formulation designed to improve taste and convenience. It is used along with diet and sometimes other therapies for long-term ammonia control in urea-cycle disorders. Dose is based on body weight and surface area. Side effects are similar to other phenylbutyrate products, including stomach upset and altered taste.[]
4. Intravenous sodium phenylacetate and sodium benzoate (AMMONUL and similar)
This IV combination is used in intensive care to treat acute hyperammonemia. It quickly provides alternative nitrogen excretion routes via phenylacetylglutamine and hippurate. Dosing is weight- or surface-area–based, with a loading infusion over 90–120 minutes followed by a 24-hour maintenance infusion. Side effects can include nausea, vomiting, metabolic disturbances, and risk of overdose if not carefully monitored.[]
5. Sodium benzoate (oral / IV)
Sodium benzoate is an ammonia scavenger that conjugates with glycine to form hippurate, which is then excreted in urine. It is widely used in urea-cycle disorders and studied in hyperammonemia due to liver disease. Doses are usually weight-based, and side effects may include sodium overload, low carnitine, and metabolic acidosis, so careful monitoring is essential.[]
6. L-arginine supplementation
Oral or IV L-arginine supplies a key urea-cycle amino acid that can help the body convert ammonia to urea more efficiently. Studies in urea-cycle disorders and citrin deficiency suggest that arginine (with diet control) can reduce post-meal ammonia spikes and help maintain metabolic stability. Typical doses are individualized and can sometimes cause gastrointestinal upset or electrolyte changes.[]
7. L-citrulline supplementation
L-citrulline is another amino acid that the body converts to arginine, supporting the urea cycle. It is often used together with, or instead of, arginine in some urea-cycle disorders and around liver transplantation to support ureagenesis. Side effects are usually mild, such as stomach discomfort or low blood pressure at very high doses.[]
8. Sodium pyruvate
In citrin deficiency, sodium pyruvate may help improve energy metabolism by feeding into pathways that bypass the citrin block and increase NAD⁺/NADH balance. Case reports show that combining sodium pyruvate with low-carbohydrate meals and arginine can improve weight and metabolic control, potentially delaying or avoiding liver transplantation in some patients.[]
9. Lactulose
Lactulose is a non-absorbable sugar used to treat hepatic encephalopathy by lowering ammonia produced in the gut. It acidifies the colon, traps ammonium, and alters gut bacteria. In patients with citrin deficiency who also have liver dysfunction or encephalopathy, lactulose can be used to reduce ammonia, but it must be balanced with the overall carbohydrate restriction plan.[]
10. Rifaximin
Rifaximin is a minimally absorbed antibiotic that reduces ammonia-producing intestinal bacteria. It is often used with lactulose to prevent recurrent hepatic encephalopathy and hospitalizations in chronic liver disease. In citrin-deficient adults with recurrent encephalopathy, rifaximin can support ammonia control but does not replace metabolic diet or scavenger drugs.[]
11. L-ornithine L-aspartate (LOLA)
LOLA provides substrates for ammonia detoxification in the liver and muscle by forming urea and glutamine. Studies in hepatic encephalopathy show that oral or IV LOLA combined with lactulose improves ammonia levels and mental state. It may be considered as an adjunct in selected citrin-deficient adults with significant liver dysfunction, under specialist supervision.[]
12. Intravenous glucose and lipid during acute crises
In many urea-cycle crises, IV glucose and lipids are used to stop catabolism and provide non-protein calories. In citrin deficiency, however, large glucose loads can worsen the metabolic block, so the composition and rate of IV nutrition must be individualized by experienced teams to avoid precipitating encephalopathy.[]
13. Intravenous arginine hydrochloride in emergencies
During severe hyperammonemia, IV arginine hydrochloride may be given together with ammonia scavengers to rapidly support the urea cycle. Guidelines recommend central-line infusion with close monitoring of potassium, acid–base status, and blood pressure.[]
14. Dialysis or hemofiltration
When ammonia is extremely high and not falling quickly enough with medicines, hemodialysis or continuous hemofiltration is used to physically remove ammonia from the blood. This is a life-saving bridge until other treatments, such as transplant, can be arranged.[]
15. Antiepileptic medicines for seizures
Seizures can occur during hyperammonemic crises. Safer antiepileptic drugs (avoiding valproate, which can raise ammonia) are used when needed. Dose and choice depend on age, liver function, and drug interactions, and the main goal is seizure control while protecting the liver and brain.[]
16. Osmotic agents for cerebral edema (for example, mannitol or hypertonic saline)
In extremely severe crises with brain swelling, ICU teams may use mannitol or hypertonic saline to lower intracranial pressure while ammonia is being removed. These treatments are supportive, short-term measures, not disease-specific therapies.[]
17. Vitamin and trace-element supplementation (B-complex, zinc)
Certain vitamins and minerals are important for liver function and ammonia metabolism. For example, zinc deficiency can worsen hyperammonemia in liver disease. Supplementation is usually guided by blood tests and dietitian assessment, and overdosing is avoided.[]
18. Carnitine supplementation when using benzoate-type drugs
Sodium benzoate therapy can lower carnitine levels. Carnitine helps transport fatty acids in mitochondria; deficiency may worsen weakness and energy problems. Supplementation can be considered when prolonged benzoate or phenylbutyrate use is planned.[]
19. Antibiotics and antivirals for intercurrent infections
Because infections can trigger metabolic crises, early and appropriate treatment of bacterial or viral infections is important. Drug choices must consider liver function and possible ammonia-raising effects—another reason to involve the metabolic team early.[]
20. Post-transplant immunosuppressive therapy
After liver transplantation, patients require immunosuppressive drugs (such as tacrolimus, cyclosporine, or mycophenolate) to prevent graft rejection. Doses are adjusted to avoid toxicity while maintaining graft health. After a successful transplant, the citrin deficiency in the liver is usually corrected and hyperammonemia episodes stop.[]
Dietary molecular supplements
1. Medium-chain triglyceride (MCT) oil
MCT oil is often used both as food and as a “molecular supplement.” It is absorbed and used for energy without needing normal bile and carnitine-dependent transport. In citrin deficiency, MCT oil supports calorie needs while reducing carbohydrate demand and may improve growth and reduce crises when used correctly.[]
2. Essential amino acid mixtures
Some patients benefit from mixtures rich in essential amino acids to support protein needs while avoiding excess non-essential amino acids that may worsen ammonia. These formulas can be tailored to age, liver function, and nutritional status.[]
3. L-arginine
As a supplement, L-arginine provides a direct substrate for urea formation, helping detoxify ammonia. It also supports nitric-oxide production and blood vessel function. In citrin deficiency and other urea-cycle disorders, arginine is often considered a core metabolic supplement, though dosing must be individualized.[]
4. L-citrulline
L-citrulline, converted in the body to arginine, can be used along with or instead of arginine to support the urea cycle. It may improve tolerance when arginine alone causes stomach upset. The combination has been used both before and after liver transplantation.[]
5. Sodium pyruvate
Sodium pyruvate supplementation can help correct energy and redox balance disturbed by citrin deficiency. It feeds into pathways that support ATP production without overloading carbohydrate metabolism and may improve appetite, growth, and ammonia levels when combined with diet therapy.[]
6. Omega-3 fatty acids (fish oil)
Omega-3 fatty acids have anti-inflammatory effects and may help improve triglyceride levels and fatty liver in some people with chronic liver disease. They are sometimes used as a supportive supplement in metabolic liver conditions, although evidence specific to citrin deficiency is limited.[]
7. Vitamin D
Vitamin D deficiency is common in chronic liver disease and can worsen bone health and muscle weakness. Correcting deficiency improves overall health and resilience. Doses are guided by blood levels and local guidelines.[]
8. Vitamin E and other antioxidants
Antioxidant vitamins may help reduce oxidative stress in fatty or inflamed liver tissue. While direct evidence in citrin deficiency is limited, they are sometimes used as part of a broader nutritional strategy.[]
9. B-complex vitamins (especially B1, B6, B12, folate)
B-vitamins serve as co-factors in many metabolic reactions, including energy and amino-acid metabolism. Ensuring adequate B-vitamin status supports overall metabolic health and may minimize risk of secondary deficiencies from restrictive diets.[]
10. Probiotics (with or without prebiotics)
Probiotics can help shift gut bacteria away from ammonia-producing species and may modestly lower ammonia when combined with lactulose in hepatic encephalopathy. In citrin deficiency with liver dysfunction, carefully selected probiotics may offer an extra small benefit.[]
Immune-booster and regenerative / stem-cell–related approaches
There are no approved stem-cell or gene-therapy drugs specifically for adult-onset citrin deficiency yet. The options below describe general directions of research and regenerative strategies related to urea-cycle disorders and metabolic liver disease.
1. Liver transplantation as functional “regenerative” therapy
Liver transplantation is currently the only proven way to fully correct the liver enzyme defect in CTLN2. After transplant, the new liver has normal citrin function, and hyperammonemic crises usually stop. This can be viewed as a whole-organ regenerative therapy rather than a drug.[]
2. Auxiliary partial orthotopic liver transplantation
Some centers have performed partial liver transplants where part of the patient’s liver is left in place and a donor liver segment is added. This can supply enough healthy enzyme activity while keeping some native liver tissue. It remains a highly specialized approach.[]
3. Hepatocyte transplantation (experimental)
Experimental trials in urea-cycle disorders have transplanted liver cells (hepatocytes), including cells derived from human embryonic stem cells, as a bridge until full liver transplant. These studies show that transplanted cells can temporarily control ammonia, but this therapy is not yet standard care.[]
4. Gene-therapy trials for urea-cycle disorders
Several gene-therapy studies using viral vectors target urea-cycle enzymes, such as ornithine transcarbamylase. These approaches aim to deliver a working gene to liver cells and restore urea-cycle function. Results in animal models and early human trials are promising but still experimental and not specific to citrin yet.[]
5. Emerging gene-regulation therapies
New platforms are being developed to modulate expression of genes involved in urea-cycle disorders using advanced gene-editing tools such as prime editing and RNA-based strategies. These could one day offer personalized treatments but are currently research-only.[]
6. Immune support after transplant (vaccination, nutrition, and careful immunosuppression)
After liver transplantation, the immune system must be carefully balanced with immunosuppressive drugs, vaccinations, and good nutrition to prevent both rejection and infection. While not an “immune booster pill,” this structured immune care is critical for long-term graft health and survival.[]
Surgeries and invasive procedures
1. Liver transplantation (living or deceased donor)
Liver transplant is the main definitive treatment for severe or unstable adult-onset citrin deficiency. It replaces the defective liver with a healthy one, correcting the metabolic block and stopping future hyperammonemia attacks. It is considered when conservative therapy cannot maintain stable brain and liver function.[]
2. Auxiliary partial liver transplantation
In this operation, surgeons implant a partial donor liver while leaving a part of the patient’s liver in place. This may offer metabolic correction with potentially less surgical trauma in selected cases, but it requires very experienced centers and careful follow-up.[]
3. Emergency placement of central venous lines for ammonia-scavenger infusion
During acute hyperammonemic crises, central venous catheters are often needed to safely infuse concentrated medicines such as sodium phenylacetate/benzoate and high-osmolar solutions. This is an invasive but sometimes life-saving procedure.[]
4. Hemodialysis or continuous renal replacement therapy access
To perform rapid ammonia removal by dialysis, vascular access catheters are inserted into large veins. These procedures are invasive but crucial when ammonia levels are dangerously high and not falling with medical therapy.[]
5. Gastrostomy tube placement (in selected patients)
Some patients with severe, long-term feeding difficulties or frequent encephalopathy may benefit from a feeding tube placed directly into the stomach. This allows reliable delivery of specialized formulas, medicines, and MCT oil even when appetite is poor.[]
Prevention strategies
1. Maintain a long-term low-carb, high-protein, high-fat diet as advised.
2. Avoid alcohol completely.
3. Treat infections early and follow sick-day instructions.
4. Do not fast for long periods or follow extreme diets.
5. Keep regular follow-up with a metabolic center and check ammonia when unwell.
6. Avoid or closely monitor medicines known to raise ammonia when alternatives exist.
7. Protect sleep and avoid severe physical or mental over-exertion.
8. Keep an emergency letter and medical ID available at all times.
9. Screen siblings and close relatives for citrin deficiency when appropriate.
10. Discuss timing of liver transplantation early in high-risk or unstable cases.[]
When to see a doctor
You should seek urgent medical help (emergency department) if you or someone with known or suspected adult-onset citrin deficiency develops:
New confusion, agitation, strange behavior, or personality changes
Excessive sleepiness, difficulty waking, or loss of consciousness
Repeated vomiting, severe nausea, or refusal to eat or drink
Sudden seizures, severe headache, or visual changes
Fast deep breathing, or any signs of severe illness
These can be signs of dangerous hyperammonemia or liver dysfunction and need immediate blood tests and treatment.[]
You should also contact your metabolic or liver specialist promptly if you notice:
Gradually worsening concentration, memory, or mood
New or persistent fatigue, weight loss, appetite change, or muscle weakness
Unexplained abdominal pain, jaundice (yellow eyes/skin), or swelling of legs or belly
Early intervention can often stop a small problem from becoming a crisis.[]
What to eat and what to avoid
1. Eat:
A structured low-carbohydrate, higher-protein and fat diet designed by a metabolic dietitian. This usually includes fish, eggs, meat, tofu, nuts, seeds, and healthy oils in amounts tailored to your needs.[]
2. Eat:
Foods rich in healthy fats, including olive oil, canola oil, avocado, and, where advised, MCT oil, to provide energy without overloading carbohydrate metabolism.[]
3. Eat:
Plenty of low-carbohydrate vegetables (leafy greens, cucumbers, peppers) and moderate amounts of lower-sugar fruits, as recommended, to supply vitamins, minerals, and fiber.[]
4. Eat:
Regular meals and snacks spread across the day, including a bedtime snack if recommended, to avoid long fasting periods.[]
5. Avoid or strictly limit:
White rice, noodles, white bread, sugary drinks, sweets, and large starchy portions, which can overload the defective carbohydrate-handling pathway.[]
6. Avoid:
Alcohol in any form, because it is a strong trigger for adult-onset citrin deficiency crises and worsens liver injury.[]
7. Avoid:
Crash diets, ketogenic fads without specialist supervision, and very high-protein binges; instead, follow the personalized plan from your metabolic team.[]
8. Avoid:
Over-the-counter herbal products or bodybuilding supplements without checking with your metabolic or liver doctor; some may stress the liver or interact with medicines.[]
9. Be cautious with:
Very salty processed foods, which add sodium load, especially when taking sodium-based scavenger drugs such as sodium benzoate or phenylbutyrate.[]
10. Be consistent:
Diet is not a temporary “treatment” but a central, lifelong therapy for adult-onset citrin deficiency, even when you feel well.[]
Frequently asked questions (FAQs)
1. Is adult-onset citrin deficiency the same as citrullinemia type II (CTLN2)?
Yes. Adult-onset citrin deficiency is the underlying genetic problem, and CTLN2 is the urea-cycle disorder that appears because of this defect. The terms are often used together in the medical literature.[]
2. Why do many patients dislike rice, sweets, and noodles?
Because the liver cannot handle carbohydrate efficiently, many people naturally avoid high-carb foods and prefer protein- and fat-rich meals. This “self-selected” preference has been documented in dietary studies of citrin-deficient patients.[]
3. Can diet alone control adult-onset citrin deficiency?
For some people, a carefully managed low-carb, high-protein, high-fat diet with MCT oil and supplements can control symptoms for many years. Others eventually need liver transplantation, especially if they continue to have recurrent hyperammonemia despite best conservative therapy.[]
4. When is liver transplantation considered?
Transplant is considered when recurrent encephalopathy, poor quality of life, or progressive liver dysfunction persists despite optimized diet and medicines. Studies show excellent survival and complete metabolic correction after transplant in most CTLN2 patients.[]
5. Will I still need a special diet after liver transplantation?
Most transplanted patients can gradually move towards a more normal diet, as the new liver has normal citrin function. However, they must follow transplant nutrition advice, take immunosuppressive medicines, and maintain a generally healthy eating pattern.[]
6. Are nitrogen-scavenger drugs like phenylbutyrate and glycerol phenylbutyrate used in all citrin-deficient adults?
Not always. They are especially used when ammonia is persistently high or during high-risk periods. Some CTLN2 patients can be managed mainly with diet, while others require drug combinations to keep ammonia in a safe range.[]
7. Are there specific risks with lactulose in a low-carb diet?
Lactulose is a sugar, but it is not absorbed in the usual way and stays in the colon. It can still add some fermentable carbohydrate load and cause bloating or diarrhea. The decision to use it balances its benefits for ammonia removal against these effects, especially in people who must limit other carbohydrates.[]
8. Can probiotics or synbiotics really help with ammonia?
Probiotics and synbiotics (probiotic + prebiotic) have shown modest benefits in lowering ammonia and improving hepatic encephalopathy when combined with lactulose in liver disease. They are supportive tools, not replacements for core metabolic treatments.[]
9. Is gene therapy available now for adult-onset citrin deficiency?
No. Gene therapy for urea-cycle disorders is being studied in clinical trials, but there is no approved gene therapy for CTLN2 at this time. Patients may, in the future, be able to join research studies if they meet criteria.[]
10. Can children in the same family be affected differently?
Yes. Citrin deficiency has different clinical stages (NICCD, FTTDCD, CTLN2), and even family members with the same gene changes may develop symptoms at different ages or with different severity. Environmental factors such as diet and stress also play roles.[]
11. Is pregnancy possible if I have adult-onset citrin deficiency?
Many women with urea-cycle disorders and metabolic liver diseases can have successful pregnancies with very careful planning, close monitoring, and specialist care. However, pregnancy increases metabolic stress and may raise ammonia, so pre-pregnancy counseling in a specialist center is essential.[]
12. Will I always feel tired if I have this condition?
Fatigue is common, especially if ammonia is not fully controlled or diet is inconsistent. However, many people feel significantly better once diet, medicines, and sleep are optimized and crises are avoided. A personalized plan can greatly improve day-to-day energy.[]
13. Can I manage this condition in a local hospital only?
Local hospitals are important for emergencies, but best long-term outcomes generally occur when care is led or co-managed by a specialist metabolic or liver center familiar with citrin deficiency and urea-cycle disorders, with clear communication between teams.[]
14. Are there ways to predict who will progress to severe CTLN2?
Research suggests that diet, lifestyle, and possibly other genetic or environmental factors influence who develops adult-onset encephalopathy. Excess carbohydrate intake, alcohol, and chronic stress appear to increase risk, while early dietary intervention may help prevention.[]
15. What is the most important thing I can do right now if I have adult-onset citrin deficiency?
The single most important step is to build a strong partnership with a metabolic team, follow the recommended low-carb, high-protein, high-fat diet with MCT as closely as possible, and have a clear emergency plan for any sudden change in mental state or health. These steps can greatly reduce the risk of life-threatening crises and improve long-term quality of life.[]
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: January 26, 2025.
Citrullinemia Type II
