What is Carnitine Deficiency?
Carnitine is a tiny molecule, soluble in water, primarily derived from proteins. For people who eat animal products, the main source of carnitine is their diet, specifically red meat, poultry, and dairy, which provides around 75% of their body’s supply. The body absorbs more than half of the carnitine obtained from food.
The body can also create carnitine itself using certain proteins mostly in the liver and kidneys, making up the remaining 25%. Among vegetarians, and especially among strict vegetarians, the body is responsible for producing over 90% of its carnitine. Regardless of how much carnitine one ingests through diet, our bodies recycle it efficiently through our kidneys. Any excess is swiftly removed through urine with about 90 to 99% being reused by the body.
Carnitine has an essential role in our body’s ability to break down and utilize fats. It transfers fatty acids into the compartments of the cells, where they are broken down to produce energy. Most carnitine in the body, over 95% in fact, is housed within the muscles as they require a significant amount of energy. The remainder is mostly stored in the liver, heart, and kidneys.
What Causes Carnitine Deficiency?
Primary carnitine deficiency (PCD) is a genetic disorder that is passed down in families and affects the body’s ability to use a substance called carnitine. This occurs due to a flaw in the transport system, specifically in the OCTN2 transporter (which moves carnitine into cells) that is determined by the SLC22A5 gene. Because of this defect, the body can’t accumulate sufficient carnitine inside the cells, leading to carnitine depletion.
Characteristics of PCD include low carnitine levels in the blood, reduced carnitine reserves within cells, and an increase in carnitine loss through the urine. The OCTN2 transporter is located mostly within the skeletal and heart muscle cells, as well as in the kidneys. A decrease in this transporter leads to less carnitine being moved into cells.
In the kidneys, this situation results in less reabsorption of carnitine. Therefore, a person with PCD may lose nearly 95% of their kidney-filtered carnitine in the urine. Parents of a child with PCD, who are carriers of the defective gene, may excrete two to three times the normal amount of carnitine in their urine. In addition, people with PCD have low levels of acyl-carnitine esters (a form of carnitine) in their blood.
Risk Factors and Frequency for Carnitine Deficiency
Primary carnitine deficiency (PCD) is a condition where the frequency varies among different countries and ethnicities. In the U.S., stats suggest 1 out of 142,000 people, based on newborn screening data, have PCD. In Japan, the rate stands at 1 in 40,000. However, the Faroe Islands, located in the North Atlantic, have the highest reported rate of PCD, with 1 in 300 people being affected.
It’s worth noting that some people with PCD have few or no symptoms, and may go their entire life without being diagnosed – this makes it difficult to know the exact number of people with all types of PCD. Men and women are equally likely to inherent PCD, as it’s passed down in an AR (alternatively recessive) manner.
Interestingly, a large number of women get diagnosed with PCD right after giving birth because their babies have low carnitine levels found during newborn screening. Pregnancies can also lead to more frequent clinical symptoms in women with PCD due to the additional stress on the body.
Signs and Symptoms of Carnitine Deficiency
Primary Carnitine Deficiency (PCD) is a disorder that has various symptoms and severity levels depending on the patient, which can differ based on the age at which the condition begins and which organs are affected.
About half of the patients with PCD start to see symptoms when they are very young, between three months and two years old. During this time, their bodies may struggle to break down and use fats and sugars, particularly while fasting or during illnesses like gastroenteritis. Symptoms can include poor feeding, feeling sluggish, and irritability. This can also lead to a larger than normal liver, low blood sugar, lactic acid build up, high ammonia levels in the blood, and increased amounts of certain liver enzymes.
The other half of patients might not start to see symptoms until they are slightly older, usually between 2 and 4 years old. Symptoms can include low muscle tone, weakness in their muscles, trouble exercising, breakdown of muscle tissue that can lead to a condition called rhabdomyolysis, and increased amounts of a molecule called creatine kinase. In some cases, there may also be heart problems like dilated cardiomyopathy, which can progress to heart failure and death if not treated promptly with a substance called carnitine.
In some cases, adults with PCD might not have any symptoms at all, or might only feel tired. However, even if they don’t show symptoms, they are still at risk of sudden cardiac death. Some women might only find out they have PCD after their newborns are found to have low carnitine levels during newborn screening. Other less common symptoms can include anemia, breathing difficulties, weak muscles near the body, developmental regression, and irregular heart rhythms.
Testing for Carnitine Deficiency
When a doctor suspects someone has carnitine deficiency, the first thing they do is check their blood carnitine levels. Patients with primary carnitine deficiency (PCD) usually have very low free carnitine levels in their blood. If this is the case, they should be quickly referred to a specialist who deals with metabolic disorders.
After this, genetic testing is carried out to confirm the diagnosis. Usually, a test examining the SLC22A5 gene is performed first. If this doesn’t give a clear result, other tests, like an array comparative genomic hybridization (aCGH), might be needed.
Interestingly, the type of genetic mutation a person with PCD has does not always match their symptoms. Some researchers have found certain types of mutation more often in patients with symptoms, whereas others have found different types of mutation in mothers without symptoms whose babies were identified as having PCD through newborn screening tests.
If the genetic testing doesn’t confirm PCD, another test, known as a cultured skin fibroblast carnitine assay, could be performed. In people with PCD, this test would show much less activity of something called the OCTN2 transporter.
Once PCD is diagnosed, patients are advised to get further medical tests, checking the heart’s health, blood sugar levels, and liver function, among others. Other bodily chemicals may be tested to check for other conditions that could lead to a secondary carnitine deficiency.
In the United States, newborns are screened for PCD. This screening would detect low blood carnitine levels that are a sign of PCD. As carnitine is transferred from the mother to the baby in the womb, low levels in the baby might be due to low levels in the mother. Therefore, if a baby’s screening test shows low carnitine levels, both the baby and the mother are tested again after two weeks to find out who has PCD.
Treatment Options for Carnitine Deficiency
When someone has primary carnitine deficiency, they usually need to take high doses of oral L-carnitine (100 to 200 mg/kg) for the rest of their life. This treatment can be taken throughout the day, usually in three doses. However, only about 5% to 18% of the medication is effectively absorbed by the body. Generally, L-carnitine is pretty safe, but taking high doses can sometimes lead to diarrhea and intestinal discomfort. Some people might notice a fishy smell as a result of bacteria in the bowel breaking down the unabsorbed L-carnitine. These side effects can typically be managed by reducing the L-carnitine dose or by taking oral metronidazole, a medicine that can reduce the overgrowth of bacteria in the intestines.
The dosage of L-carnitine is usually adjusted based on one’s plasma levels and their response to the medication. Continuous treatment with L-carnitine can help prevent episodes of dangerously low blood sugar (hypoglycemia) and improve symptoms related to muscle weakness. However, the levels of carnitine in the muscles may only go up slightly, due to abnormal OCTN2 which affects the uptake of carnitine into muscle cells. The increase gained is often just enough to prevent complications related to the muscles.
When children with primary carnitine deficiency experience acute episodes of hypoglycemia, immediate treatment with 10% dextrose, a sugar solution given through a vein, is needed. At the same time, efforts should also be made to correct related metabolic abnormalities. It’s very important to avoid episodes of hypoglycemia in these children. This can be done by ensuring they have frequent meals and snacks and avoid periods of fasting.
What else can Carnitine Deficiency be?
Secondary Carnitine Deficiency (SCD for short) may arise from several reasons. These reasons can include a reduced intake of carnitine, or more commonly, an increased flow of carnitine out of the body via the kidneys. SCD can occur due to intense undernourishment, strict fat-based diets, significant difficulties in absorbing nutrients, extreme premature births, and a diet sustained through intravenous feeding without enough L-carnitine provided.
Some conditions that affect kidney function, such as Fanconi syndrome, can increase the loss of carnitine from the body. Certain medications can also lead to a deficiency in carnitine. These include drugs like valproic acid, cyclosporine, pivampicillin, and some cancer-treating drugs, such as etoposide and vinblastine. For example, valproic acid treatment can exhaust carnitine in the body through various mechanisms, like increased removal via urine, reduced absorption in the kidneys, and decreased natural production. Similarly, the use of pivampicillin antibiotics can lower carnitine levels due to the creation of pivaloyl-carnitine ester, which is removed from the body through urination.
However, SCD is generally less severe and easier to manage than PCD because the blood levels of carnitine are relatively higher. Patients with SCD do not usually suffer from liver or heart complications. Yet they may experience moderate issues with their skeletal muscles.
Similarly to PCD, a medical condition called hypoketotic hypoglycemia points towards potential disorders involving mitochondria —the powerhouse of cells— and fatty acid metabolism. These can include disorders such as VLCAD or MCAD, or disorders related to problems in the carnitine cycle in the mitochondria due to defective enzymes.
In many types of SCD disorders with impaired fatty acid metabolism, excessive acylcarnitines can build up. These excessive acylcarnitines can get in the way of the absorption of carnitine in the kidneys, leading to an increased carnitine excretion through urine, which results in SCD.
The symptoms of defects in fatty acid metabolism and disorders of the carnitine cycle can vary widely and may be quite non-specific. They often include hypoketotic hypoglycemia and muscle diseases. These symptoms usually get worse with fasting or chronic illnesses. Metabolic irregularities can be checked by examining the profile of acylcarnitine in the blood.
Diagnosis is confirmed using molecular testing methods and/or experiments to examine the deficient enzyme. Management involves preventing fasting, regular meals, and the provision of nocturnal corn starch. Dietary therapy should focus on high carbohydrates and medium-chain triglycerides (which don’t require the carnitine cycle) and a lower intake of long-chain fatty acids. The use of L-carnitine in managing these disorders is a topic of debate.
Carnitine also plays a vital role in binding with the residue from amino acid metabolism. For disorders related to the metabolism of organic acids, SCD occurs because of the excessive binding of acyl-CoA intermediate products. It’s worth noting that defects in the body’s natural carnitine production usually do not lower blood carnitine levels because the level of carnitine in the blood can be maintained via efficient absorption in the kidneys.
What to expect with Carnitine Deficiency
In developed countries, most cases of PCD (Primary Ciliary Dyskinesia) are detected through newborn screening tests. Early diagnosis and quick treatment with L-carnitine have significantly improved chances of recovery. As long as patients continue with their L-carnitine treatment, the majority of PCD cases have a positive outcome. However, if left untreated, the condition can lead to fatal consequences. Untreated and undiagnosed cases can result in sudden death.
Possible Complications When Diagnosed with Carnitine Deficiency
Typically, a condition known as PCD is manageable and isn’t too severe if it’s diagnosed early and treated aggressively with a substance called L-carnitine. But it’s essential to remember that the symptoms and their intensity can differ from person to person. If PCD remains undiagnosed, or if it isn’t managed well, serious complications could arise.
Bouts of extremely low blood sugar, or “hypoglycemic episodes,” can trigger convulsions and brain damage. If left untreated, these low blood sugar events could even lead to coma or death. Metabolic imbalances could lead to liver dysfunction, possibly causing a condition known as “hepatic encephalopathy” that could also result in death.
There are also known risks for heart issues, such as cardiomyopathy which can be fatal, especially in newborns or young children. Other heart problems could be a thickening of the left side of the heart that could turn into dilated cardiomyopathy – a weakened, enlarged heart that can’t pump blood efficiently, causing a decrease in the “ejection fraction,” a measure of how much blood the left ventricle pumps out with each contraction. Other concerns include fluid around the heart, also known as “pericardial effusion”, and irregular heart rhythms, including a potentially dangerous condition called “long QT syndrome.”
Even adults who have PCD but show no symptoms are at risk; without treatment, they could develop heart rhythm problems or even suddenly die.
Preventing Carnitine Deficiency
Treatment for Primary Carnitine Deficiency (PCD) mainly involves taking dietary supplements such as carnitine and preventing low blood sugar. It’s essential to avoid situations that use up lots of energy (like fasting) as that can trigger the condition. There may be times (like during other illnesses or infections) when the body naturally uses more energy, and these should be managed quickly and effectively. Increasing blood glucose levels through sugar from an intravenous drip can be useful in these cases.
It is also crucial for PCD patients to constantly take their medication containing L-carnitine. Not doing so can lead to extremely low blood sugar and even sudden cardiac death. Therefore, it’s vital to educate patients and their caregivers about this and the overall treatment of PCD.
PCD is a serious condition that can worsen and lead to death if it’s not treated. It’s important for any women planning to become pregnant to understand that pregnancy is a demanding situation for the body’s energy and metabolism, and should be discussed with a metabolism and genetics specialist before conception.
For those with Secondary Carnitine Deficiency (SCD), it’s crucial to prevent low blood sugar by eating regularly through the day and to ensure a constant supply of corn starch at night. Their diet should include a lot of carbohydrates and low fat, where they get their energy from medium-chain triglycerides, that can enter the energy-producing parts of cells even without the presence of a carnitine transport system.
