What is the normal ALT range in liver function tests. How do high ALT levels indicate liver damage. When should doctors order an ALT test. What factors can affect ALT test results.

What is ALT and Why is it Important for Liver Health?

Alanine Aminotransferase (ALT) is a crucial enzyme primarily found in the liver. Its presence in the bloodstream serves as a key indicator of liver health and function. But what exactly does ALT do, and why is measuring its levels so important?

ALT plays a vital role in amino acid metabolism, helping to break down proteins into energy. Under normal circumstances, ALT is present in low concentrations in the blood. However, when liver cells are damaged or die, they release ALT into the bloodstream, causing levels to rise. This makes ALT an excellent biomarker for detecting liver injury or disease.

Understanding ALT levels can provide valuable insights into various liver conditions:

• Hepatitis (viral or alcoholic)
• Cirrhosis
• Fatty liver disease
• Drug-induced liver injury
• Liver cancer

By monitoring ALT levels, healthcare providers can assess the severity of liver damage, track disease progression, and evaluate the effectiveness of treatments. This enzyme is a cornerstone of liver function tests, offering a window into the complex workings of this vital organ.

Normal ALT Ranges: What Do They Mean for Your Liver?

Understanding what constitutes a normal ALT range is crucial for interpreting liver function test results. But what exactly is considered normal, and how do these values differ among various demographics?

The normal ALT range typically falls between 7 to 55 units per liter (U/L) of blood. However, it’s important to note that this range can vary depending on the specific laboratory and testing methods used. Furthermore, what’s considered normal can differ based on age, sex, and other individual factors.

Here’s a general breakdown of normal ALT ranges:

• Adult males: 7-55 U/L
• Adult females: 7-45 U/L
• Children: 7-40 U/L

It’s worth noting that men typically have slightly higher ALT levels than women. This difference is attributed to hormonal influences and body composition variations between sexes.

While these ranges provide a general guideline, it’s crucial to interpret ALT results in the context of an individual’s overall health profile. A value within the normal range doesn’t necessarily guarantee perfect liver health, just as a slightly elevated result doesn’t always indicate significant liver damage. Healthcare providers consider ALT levels alongside other liver function tests and clinical symptoms to form a comprehensive assessment of liver health.

High ALT Levels: Causes and Implications for Liver Health

Elevated ALT levels can be a red flag for liver health issues, but what exactly causes these spikes, and what do they mean for your overall well-being? Understanding the factors behind high ALT levels is crucial for proper diagnosis and treatment.

Several conditions and lifestyle factors can lead to increased ALT levels:

1. Viral hepatitis (Hepatitis A, B, C)
2. Alcoholic liver disease
3. Non-alcoholic fatty liver disease (NAFLD)
4. Drug-induced liver injury
5. Cirrhosis
6. Autoimmune hepatitis
7. Liver cancer
8. Heart failure
9. Muscle damage or intense exercise

The degree of ALT elevation can provide clues about the underlying cause. Mild elevations (less than 5 times the upper limit of normal) may indicate chronic conditions like NAFLD or early-stage viral hepatitis. Moderate elevations (5-15 times the upper limit) could suggest acute viral hepatitis or drug-induced liver injury. Severe elevations (more than 15 times the upper limit) might point to acute liver failure or ischemic liver injury.

It’s important to note that ALT levels don’t always correlate directly with the severity of liver damage. In some chronic liver diseases, ALT levels may fluctuate or even decrease as the condition progresses. This is why healthcare providers consider ALT results in conjunction with other liver function tests and clinical symptoms.

Low ALT Levels: Are They a Cause for Concern?

While high ALT levels often grab the spotlight in liver function discussions, low ALT levels can also provide valuable insights into overall health. But when should low ALT levels raise concerns, and what might they indicate?

Generally, ALT levels below the lower end of the normal range (typically 7 U/L) are considered low. While not as common as elevated levels, low ALT can occur and may be associated with certain conditions:

• Vitamin B6 deficiency
• Chronic kidney disease
• Frailty in elderly individuals
• Severe liver damage (in advanced cirrhosis)

In some cases, low ALT levels may actually be a positive sign. Studies have suggested that individuals with ALT levels at the lower end of the normal range may have a reduced risk of developing metabolic syndrome and cardiovascular disease.

However, extremely low ALT levels, particularly in the context of other abnormal liver function tests, could indicate severe liver damage. In advanced cirrhosis, for instance, the liver may have lost so much functional tissue that it can no longer produce normal amounts of ALT.

As with high ALT levels, low results should be interpreted in the context of an individual’s overall health profile. Healthcare providers will consider factors such as age, medical history, and other test results when evaluating the significance of low ALT levels.

When Should Your Doctor Order an ALT Test?

ALT tests are a valuable diagnostic tool, but when exactly should healthcare providers order this examination? Understanding the circumstances that warrant an ALT test can help patients better comprehend their medical care.

Doctors may recommend an ALT test in various scenarios:

1. Routine health screenings: ALT tests are often included in comprehensive metabolic panels during annual check-ups.
2. Suspected liver disease: If a patient presents symptoms like jaundice, abdominal pain, or unexplained fatigue, an ALT test can help assess liver function.
3. Monitoring known liver conditions: For patients with diagnosed liver diseases, regular ALT tests help track disease progression and treatment efficacy.
4. Medication management: Some medications can affect liver function. ALT tests may be ordered to monitor for potential drug-induced liver injury.
5. Alcohol abuse assessment: Chronic alcohol consumption can lead to liver damage, which ALT tests can help detect.
6. Viral hepatitis screening: ALT tests are crucial in diagnosing and monitoring viral hepatitis infections.
7. Evaluation of unexplained symptoms: Nonspecific symptoms like fatigue or weight loss might prompt a liver function panel, including ALT.

It’s important to note that ALT tests are typically ordered alongside other liver function tests for a comprehensive assessment. The frequency of testing can vary based on individual health needs and risk factors.

Patients should openly discuss their medical history, lifestyle factors, and any concerns with their healthcare provider. This information helps determine whether an ALT test is necessary and how often it should be performed.

Preparing for Your ALT Test: What You Need to Know

Proper preparation can ensure accurate ALT test results, helping healthcare providers make informed decisions about your liver health. But what steps should you take before the test, and are there any specific precautions to keep in mind?

Here’s a guide to help you prepare for your ALT test:

• Fasting: In most cases, fasting isn’t required for an ALT test. However, your doctor may recommend fasting for 10-12 hours if the ALT test is part of a comprehensive metabolic panel.
• Medication review: Inform your healthcare provider about all medications and supplements you’re taking. Some drugs can affect ALT levels, and your doctor may advise temporarily stopping certain medications before the test.
• Alcohol consumption: Avoid alcohol for at least 24 hours before the test, as it can temporarily elevate ALT levels.
• Exercise: Strenuous physical activity can sometimes increase ALT levels. Avoid intense workouts for 24-48 hours before the test.
• Hydration: Unless otherwise instructed, stay well-hydrated before the test. This can make it easier to draw blood.
• Timing: If you’re menstruating, your doctor may recommend scheduling the test after your period, as hormonal fluctuations can slightly affect ALT levels.

Remember, these are general guidelines. Always follow the specific instructions provided by your healthcare team, as they may have additional recommendations based on your individual health situation.

By properly preparing for your ALT test, you’re contributing to the accuracy of the results, which in turn helps ensure you receive the most appropriate care for your liver health.

Interpreting ALT Test Results: Beyond the Numbers

Receiving ALT test results can be confusing, especially if you’re unfamiliar with medical terminology. How can you make sense of these numbers, and what do they really mean for your liver health?

ALT results are typically reported in units per liter (U/L) of blood. Here’s a general interpretation guide:

• Normal: 7-55 U/L (may vary slightly between laboratories)
• Mildly elevated: 56-200 U/L
• Moderately elevated: 201-800 U/L
• Severely elevated: >800 U/L

However, it’s crucial to understand that interpreting ALT results isn’t just about the numbers. Several factors influence how healthcare providers analyze these results:

1. Individual baseline: Some people naturally have slightly higher or lower ALT levels. Comparing current results to previous tests can be more informative than looking at a single value.
2. Other liver function tests: ALT results are often interpreted alongside other tests like AST, ALP, and bilirubin for a comprehensive liver health assessment.
3. AST/ALT ratio: This ratio can provide clues about the nature of liver damage. For instance, an AST/ALT ratio greater than 2 might suggest alcoholic liver disease.
4. Clinical context: Symptoms, medical history, and risk factors all play a role in interpreting ALT results.
5. Trending: How ALT levels change over time can be more informative than a single elevated result.

It’s important to avoid self-diagnosis based solely on ALT numbers. Always discuss your results with a healthcare provider who can provide a comprehensive interpretation based on your overall health profile.

Remember, while ALT is a valuable indicator of liver health, it’s just one piece of the puzzle. A holistic approach to liver health assessment ensures the most accurate diagnosis and appropriate treatment plan.

Factors That Can Affect ALT Test Results

While ALT tests are generally reliable indicators of liver health, various factors can influence the results. Understanding these potential confounders is crucial for accurate interpretation of ALT levels. What elements might impact your ALT test outcomes?

Several factors can affect ALT test results:

• Age and gender: ALT levels tend to be higher in men and decrease with age in both sexes.
• Body mass index (BMI): Obesity is associated with higher ALT levels, often due to fatty liver disease.
• Medications: Certain drugs, including some antibiotics and pain relievers, can elevate ALT levels.
• Alcohol consumption: Even moderate alcohol intake before the test can temporarily raise ALT.
• Exercise: Intense physical activity can cause short-term ALT elevations.
• Diet: Some studies suggest that dietary factors, such as high fructose intake, may influence ALT levels.
• Time of day: ALT levels can fluctuate slightly throughout the day.
• Pregnancy: ALT levels may decrease during pregnancy.

Healthcare providers take these factors into account when interpreting ALT results. It’s crucial to provide your doctor with a comprehensive health history, including recent lifestyle changes or medication use, to ensure the most accurate interpretation of your ALT test results.

By understanding these influencing factors, patients can work with their healthcare providers to obtain the most meaningful insights from their ALT tests, leading to more precise diagnoses and effective treatment plans.

Alanine Aminotransferase (ALT) Test and Results (aka SGPT Test)

Written by WebMD Editorial Contributors

• Why Is ALT Important?
• Why Would My Doctor Order This Test?
• How Do I Prepare?
• What Happens During the Test?
• What Are the Risks?
• What Do the Results Mean?
• What Other Tests Will I Take?
• More

The alanine aminotransferase (ALT) test is a blood test that checks for liver damage. Your doctor can use this test to find out if a disease, drug, or injury has damaged your liver.

Your liver does a lot of important things for you:

• It makes a fluid called bile that helps your body digest food.
• It removes waste products and other toxins from your blood.
• It produces proteins and cholesterol.

Diseases such as hepatitis and cirrhosis can damage your liver and prevent it from doing its many jobs.

This enzyme is found mainly in your liver. Smaller amounts of ALT are in your muscle, kidneys , and other organs.

Your body uses ALT to break down food into energy. Normally, ALT levels in the blood are low. If your liver is damaged, it will release more ALT into your blood and levels will rise. (ALT used to be called serum glutamic-pyruvic transaminase, or SGPT).

Doctors often give the ALT test along with other liver tests.

Your doctor might recommend ALT if you have symptoms of liver disease or damage, such as:

• Stomach pain or swelling
• Nausea
• Vomiting
• Yellow skin or eyes (a condition called jaundice)
• Weakness
• Extreme tiredness (fatigue)
• Dark-colored urine
• Light-colored poop
• Itchy skin

Here are some reasons you might get this test:

• You’ve been exposed to the hepatitis virus.
• You drink a lot of alcohol.
• You have a family history of liver disease.
• You take medicine that’s known to cause liver damage.

The ALT test can be done as part of a blood panel during a regular exam. If you’ve already been diagnosed with liver disease, your doctor can use the ALT test to see how well your treatment is working.

You don’t need any special preparation for the ALT test. Your doctor might ask you to stop eating or drinking a few hours before the test.

Tell your doctor what prescription drugs or supplements you take. Some medicines can affect the results of this test.

A nurse or lab tech will take a sample of your blood, usually from a vein in your arm. They will first tie a band around the upper part of your arm to make your vein fill with blood and swell up. Then they will clean the area with an antiseptic and place a needle into your vein. Your blood will collect into a vial or tube.

The blood test should take only a couple of minutes. After your blood is taken, the lab tech will remove the needle and band, then put a piece of gauze and a bandage over the spot the needle went in to stop the bleeding.

The ALT blood test is safe. Risks are usually minor, and can include:

• Bleeding
• Bruising
• Infection
• Slight pain when the needle is inserted
• Fainting or feeling dizzy

You should get your results in about a day. A normal ALT test result can range from 7 to 55 units per liter (U/L), but it varies depending on the laboratory used. Levels are normally higher in men.

Slightly high ALT levels may be caused by:

• Alcohol abuse
• Cirrhosis (long-term damage and scarring of the liver)
• Mononucleosis
• Drugs such as statins, aspirin, and some sleep aids

Moderately high ALT levels may be because of:

• Chronic (ongoing) liver disease
• Alcohol abuse
• Cirrhosis
• Blockage of the bile ducts
• Heart attack or heart failure (when your heart can’t pump enough blood to your body)
• Kidney damage
• Muscle injury
• Damage to red blood cells
• Heat stroke
• Too much vitamin A

Very high ALT levels can be caused by:

• Acute viral hepatitis
• An overdose of drugs such as acetaminophen (Tylenol)
• Liver cancer
• Sepsis

ALT usually is done as part of a group of liver function tests called a liver panel.

This panel also includes an aspartate aminotransferase (AST) test. AST is another liver enzyme. As with ALT, the levels of AST in your blood rise if your liver is damaged.

Comparing ALT with AST levels gives your doctor more information about the health of your liver. The AST-to-ASL ratio can help your doctor figure out how severe the liver damage is and what might have caused it.

To find out what type of liver disease you have, your doctor might also test the levels of other enzymes and proteins found in your liver, including:

• Albumin
• Alkaline phosphatase
• Bilirubin
• Lactate dehydrogenase (LDH)
• Total protein
• GGT

Talk to your doctor to make sure you understand all of your liver test results. Also find out how these results might affect your treatment.

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Alanine Aminotransferase (ALT) Test and Results (aka SGPT Test)

Written by WebMD Editorial Contributors

• Why Is ALT Important?
• Why Would My Doctor Order This Test?
• How Do I Prepare?
• What Happens During the Test?
• What Are the Risks?
• What Do the Results Mean?
• What Other Tests Will I Take?
• More

The alanine aminotransferase (ALT) test is a blood test that checks for liver damage. Your doctor can use this test to find out if a disease, drug, or injury has damaged your liver.

Your liver does a lot of important things for you:

• It makes a fluid called bile that helps your body digest food.
• It removes waste products and other toxins from your blood.
• It produces proteins and cholesterol.

Diseases such as hepatitis and cirrhosis can damage your liver and prevent it from doing its many jobs.

This enzyme is found mainly in your liver. Smaller amounts of ALT are in your muscle, kidneys , and other organs.

Your body uses ALT to break down food into energy. Normally, ALT levels in the blood are low. If your liver is damaged, it will release more ALT into your blood and levels will rise. (ALT used to be called serum glutamic-pyruvic transaminase, or SGPT).

Doctors often give the ALT test along with other liver tests.

Your doctor might recommend ALT if you have symptoms of liver disease or damage, such as:

• Stomach pain or swelling
• Nausea
• Vomiting
• Yellow skin or eyes (a condition called jaundice)
• Weakness
• Extreme tiredness (fatigue)
• Dark-colored urine
• Light-colored poop
• Itchy skin

Here are some reasons you might get this test:

• You’ve been exposed to the hepatitis virus.
• You drink a lot of alcohol.
• You have a family history of liver disease.
• You take medicine that’s known to cause liver damage.

The ALT test can be done as part of a blood panel during a regular exam. If you’ve already been diagnosed with liver disease, your doctor can use the ALT test to see how well your treatment is working.

You don’t need any special preparation for the ALT test. Your doctor might ask you to stop eating or drinking a few hours before the test.

Tell your doctor what prescription drugs or supplements you take. Some medicines can affect the results of this test.

A nurse or lab tech will take a sample of your blood, usually from a vein in your arm. They will first tie a band around the upper part of your arm to make your vein fill with blood and swell up. Then they will clean the area with an antiseptic and place a needle into your vein. Your blood will collect into a vial or tube.

The blood test should take only a couple of minutes. After your blood is taken, the lab tech will remove the needle and band, then put a piece of gauze and a bandage over the spot the needle went in to stop the bleeding.

The ALT blood test is safe. Risks are usually minor, and can include:

• Bleeding
• Bruising
• Infection
• Slight pain when the needle is inserted
• Fainting or feeling dizzy

You should get your results in about a day. A normal ALT test result can range from 7 to 55 units per liter (U/L), but it varies depending on the laboratory used. Levels are normally higher in men.

Slightly high ALT levels may be caused by:

• Alcohol abuse
• Cirrhosis (long-term damage and scarring of the liver)
• Mononucleosis
• Drugs such as statins, aspirin, and some sleep aids

Moderately high ALT levels may be because of:

• Chronic (ongoing) liver disease
• Alcohol abuse
• Cirrhosis
• Blockage of the bile ducts
• Heart attack or heart failure (when your heart can’t pump enough blood to your body)
• Kidney damage
• Muscle injury
• Damage to red blood cells
• Heat stroke
• Too much vitamin A

Very high ALT levels can be caused by:

• Acute viral hepatitis
• An overdose of drugs such as acetaminophen (Tylenol)
• Liver cancer
• Sepsis

ALT usually is done as part of a group of liver function tests called a liver panel.

This panel also includes an aspartate aminotransferase (AST) test. AST is another liver enzyme. As with ALT, the levels of AST in your blood rise if your liver is damaged.

Comparing ALT with AST levels gives your doctor more information about the health of your liver. The AST-to-ASL ratio can help your doctor figure out how severe the liver damage is and what might have caused it.

To find out what type of liver disease you have, your doctor might also test the levels of other enzymes and proteins found in your liver, including:

• Albumin
• Alkaline phosphatase
• Bilirubin
• Lactate dehydrogenase (LDH)
• Total protein
• GGT

Talk to your doctor to make sure you understand all of your liver test results. Also find out how these results might affect your treatment.

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How to understand liver elastography results (FibroScan®)

This information will help you understand FibroScan results. Your doctor will discuss your results with you and provide additional information at the time of your appointment.

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About Liver Elastography and FibroScan

Liver Elastography is a non-invasive test your healthcare provider can use to look at your liver. “Non-invasive” means that no instruments are inserted into your body.

FibroScan is a type of liver elastography. FibroScan is a special ultrasound technology that measures the stiffness (hardness) of the liver and fatty liver. These measurements give the healthcare provider more information about your liver disease.

Below are some useful terms related to FibroScan results.

• Fibrosis: scarring of liver tissue.
• Stiffness of the liver: hardness of the liver associated with scarring of its tissues.
• Fatty degeneration: Abnormal accumulation of fat in the liver.
• Steatosis: a condition caused by excessive fat in the liver.
• CAP score: is the percentage of fat degeneration.

Fibrosis and steatosis are measured separately. Your health care provider will discuss your results at the time of your appointment.

The following is a more detailed explanation of the FibroScan results. As you continue reading, you will learn more about your results.

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About the CAP score

Your healthcare provider will use the CAP score to determine the degree of steatosis. The CAP score is measured in decibels per meter (dB/m). It varies in the range from 100 to 400 dB/m. The CAP score and the degree of steatosis may increase or decrease over time.

The table below shows the ranges of CAP scores and their respective degrees of steatosis. It shows which part of the liver is affected by the process of fat accumulation. In a healthy liver, the amount of fatty degeneration can be up to 5%. Values ​​below 238 dB / m mean that the amount of fatty degeneration in your liver does not exceed the norm.

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About the result of measuring liver stiffness

Liver stiffness is measured in kilopascals (kPa). Normal results are usually in the range of 2 to 7 kPa. If you have liver disease, your results may be higher than normal. The maximum possible result is 75 kPa.

Using a Liver Stiffness Test to Score Fibrosis

Your healthcare provider uses a Liver Stiffness test and your medical record to determine the stage of fibrosis. Your results may range from normal to advanced.

• Normal: liver scarring is absent or mild.
• Moderate or severe: scarring of liver tissue that can be corrected (removed) by treatment of liver disease. Proper nutrition and the transition to a healthy lifestyle can slow or reverse the process of scarring of liver tissue. With moderate scarring of the liver tissue, you may not have any symptoms.
• Running stage: cirrhosis is a late form of scarring of the liver tissues in the advanced stage. This condition develops over time with chronic (long-term) liver disease.

You can use the following chart to check your liver condition. It’s based on your diagnosis, liver stiffness and fibrosis. Not all diseases are listed in the table. If you do not see your condition, ask your healthcare provider to review your results with you. If you have been diagnosed with multiple liver diseases, this table may not apply.

How to use the table:

1. Find your diagnosed liver disease in the first column on the left.
2. Find your liver stiffness measurement in the second column from the left. Follow along the line with your result. The liver stiffness ranges shown in the table are estimates (inaccurate).
3. View the rest of the values ​​in this row from left to right. The fibrosis score is listed in the third column from the left. The last column indicates the degree of scarring of the liver tissue.

Disease diagnosis	Liver stiffness test result	Fibrosis stage	Your liver
Alcohol abuse disease	2-7 kPa	F0-F1	OK
	7–11 kPa	F2	Moderate hepatic scarring
	11–19 kPa	F3	Severe hepatic scarring
	19 kPa or more	F4	Cirrhosis present
Cholestatic disease	2-7 kPa	F0-F1	OK
	7-9 kPa	F2	Moderate hepatic scarring
	9-17 kPa	F3	Severe hepatic scarring
	17 kPa or more	F4	Cirrhosis present
Hepatitis B	2-7 kPa	F0-F1	OK
	8-9 kPa	F2	Moderate hepatic scarring
	8-11 kPa	F3	Severe hepatic scarring
	12 kPa or more	F4	Cirrhosis present
Hepatitis C	2-7 kPa	F0-F1	OK
	8-9 kPa	F2	Moderate hepatic scarring
	9-14 kPa	F3	Severe hepatic scarring
	14 kPa or more	F4	Cirrhosis present
HIV/hepatitis C co-infection	2-7 kPa	F0-F1	OK
	7–11 kPa	F2	Moderate hepatic scarring
	11–14 kPa	F3	Severe hepatic scarring
	14 kPa or more	F4	Cirrhosis present
Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH)	2-7 kPa	F0-F1	OK
	7. 5-10 kPa	F2	Moderate hepatic scarring
	10–14 kPa	F3	Severe hepatic scarring
	14 kPa or more	F4	Cirrhosis present

Pathological Conditions That May Influence the Fibrosis Result

Certain pathological conditions can cause the result of the liver stiffness measurement to be excessively high, causing it to be incorrect. Scarring may not be as pronounced as the result shows. It can be if you have:

• inflammation (edema) of the liver: it can be caused by recent liver disease, as well as long-term alcohol abuse;
• benign (noncancerous) or malignant (cancerous) tumors in the liver;
• liver congestion: this means that your liver is full of blood or other fluids; it usually occurs due to heart failure.

FibroScan results may be less accurate or not available at all if you have:

• Obesity: means that your body mass index (BMI) is above 30 (high, unhealthy amount of body fat).
• Ascites: accumulation of fluid in the abdominal cavity.
• Obstruction of the biliary tract: obstruction preventing sufficient flow of bile from the liver.
• Scar tissue: tissue formed near the liver as a result of surgery or radiotherapy.

Your health care provider may use imaging tests such as ultrasound, CT or MRI to see your liver. To measure liver tissue scarring and fatty liver, he may use a blood test or some type of MRI. Call your healthcare provider if you have any questions.

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Cholestatic liver diseases: diagnostic and treatment algorithms | Polunina T.E.

Introduction

Cholestatic liver diseases (CKD) begin to develop against the background of damage to the biliary ducts caused by a violation of the outflow of bile [1-3]. Damage to the cells of the bile ducts (cholangiocytes) leads to retention of bile acids (FA), bilirubin and other cholephils in the liver and blood, and deficiency of FA in the intestine. Clinical signs of CKD range from isolated abnormal liver function tests to acute liver failure or hepatobiliary malignancies (eg, cholangiocarcinoma). Long-term cholestasis (for several months or years) can lead to the development of liver cirrhosis [4]. The most common and studied CKD include primary biliary cholangitis and primary sclerosing cholangitis [2].

Cholestatic liver disease includes progressive cholangiopathy, which may progress to end-stage liver disease. In the United States, from 1988 to 2018, CKD accounted for 14.2% of all liver transplants [2]. High morbidity and mortality have become a big problem due to the lack of effective treatments. Moreover, from 10% to 40% of patients after liver transplantation experience a recurrence of the underlying disease [5].

Common pathogenic mechanisms of CKD

Violation of the outflow of bile can be due to several factors (Fig. 1), the main ones are antigenic stimuli, exotoxins, endotoxins, xenobiotics and microorganisms. These external factors cause an inflammatory reaction of cholangiocytes, which develops into a cholestatic state [6]. Obstruction of bile transport is another predisposing factor. Intrahepatic and extrahepatic obstruction may occur due to external benign compression (cystic diseases), the effect of a malignant tumor (cholangiocarcinoma), and also due to the formation or migration of gallstones along the biliary tract. Conditions that slow down the outflow of bile contribute to a cholestatic state with an increased concentration of fatty acids. Sepsis, hyperestrogenic conditions (pregnancy), chronic heart failure, and dysfunction of FA transporter genes can alter the basic characteristics of bile by activating the more cytotoxic component of FA.

The primary protective reaction of cholangiocytes allows to stop the damage. However, persistent disruption of pro-inflammatory genetic and/or epigenetic regulatory mechanisms can cause a permanent dysfunctional breakdown that will eventually lead to a fibrogenic state with biliary and periportal fibrosis, loss of tissue homeostasis, and autocrine and paracrine remodeling. Proliferation can cause cell cycle alteration, senescence, apoptosis, ductopenia, mesenchymal infiltration, and sometimes malignant transformation.

Currently, there are several concepts of the occurrence of cholestasis.

Ductular (tubular) reaction – the first basic concept of cholestasis . Intrahepatic and extrahepatic bile ducts of varying sizes are lined with cholangiocytes that regulate and alter the volume and composition of bile. They differ in size, metabolic rate, and ability to proliferate and plasticity. The ductular response is part of the response of liver cells to damage in CKD [7]. The response of cholangiocytes to inflammation can lead to a decrease in damage, and in the case of sustained inflammatory exposure, it leads to fibrosis of the bile ducts [8].

FA cytotoxicity and mitochondrial dysfunction is the second fundamental basis of the pathogenesis of CKD, described in several studies in extrahepatic cholestasis [9].

The influence of immunogenetic and epigenetic factors on the immune inflammatory response is the third fundamental aspect of the pathogenesis of CKD. There are many genetic changes in CKD patients that explain the different elements of each CKD. However, some of these genes may be directly involved in the progression of the cholestatic phenotype. Therefore, they can become a potential target for new therapeutic agents, or their transcription activators can indirectly serve as modulating targets. This modulation is a type of epigenetic control of gene expression as a pathogenic mechanism of cholestasis [2].

Clinical spectrum of CKD [2]:

Idiopathic: primary biliary cholangitis, primary sclerosing cholangitis, autoimmune cholangitis, IgG4-associated cholangitis, idiopathic ductopenia, biliary atresia.

Secondary sclerosing cholangitis : choledocholithiasis, drug-induced (toxic) cholangitis, portal hypertensive biliopathy, HIV-associated cholangitis, abdominal trauma, ABCB4 deficiency, iatrogenic biliary strictures, vascular/ischemic cholangitis, sickle cell disease, recurrent pyogenic cholangitis it.

Genetic : cystic fibrosis, Caroli syndrome, Alagille syndrome, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, autosomal dominant polycystic liver disease, cholestasis in pregnancy.

Oncological : cholangiocarcinoma.

Dysfunctional matrix rearrangements and fibrogenesis is the fourth concept of CKD pathogenesis. Fibrogenesis is a complex dynamic process associated with the interaction of immunoinflammatory mechanisms, changes in the secretion of tissue metalloproteinases, cytokine networks, and impaired infiltration of mesenchymal cells with the final loss of supporting tissue homeostasis. Fibrogenic processes affect damaged and intact bile ducts, as well as the periportal sinusoidal system, leading to progressive cholestasis [10].

Diagnosis

It is not always possible to distinguish types of cholestasis by clinical symptoms and biochemical parameters. It is extremely important to distinguish between extra- and intrahepatic cholestasis using a diagnostic algorithm (Fig. 2) [11].

The clinical picture of CKD is varied. In many patients, cholestasis is asymptomatic and is diagnosed by evaluation of persistent cholestatic laboratory abnormalities. Symptomatic patients may experience right upper quadrant discomfort, itching, fatigue, and weight loss.

Primary biliary cholangitis (PBC) is an autoimmune disease and is the most common chronic CKD. Its former name is “primary biliary cirrhosis”. However, this term has been abandoned in favor of “primary biliary cholangitis”, as most patients do not have cirrhosis. PBC is caused by a combination of genetic and environmental factors that trigger T cell-mediated destruction of the intrahepatic bile ducts. Majority (90%) of the diseased are women, and this disease is usually diagnosed between the ages of 40 and 60 years. Associated autoimmune diseases are common in patients with PBC, including Sjögren’s syndrome, thyroid disease, localized cutaneous scleroderma, and rheumatoid arthritis [12].

Approximately 60% of patients with PBC are asymptomatic at the time of diagnosis. Usually the diagnosis is made on the basis of abnormal biochemical tests of the liver. Fatigue and itching are the most common symptoms in patients with PBC. Physical examination may reveal hepatomegaly, skin hyperpigmentation, jaundice, xanthomas or stigmata of cirrhosis and portal hypertension in later stages. Characteristic laboratory abnormalities include an increase in alkaline phosphatase (AP) with a normal to moderate increase in serum aminotransferases. An increase in serum bilirubin usually occurs with disease progression and is a poor prognostic sign.

Lipid abnormalities are common in PBC. A slight increase in low-density lipoprotein (LDL) with a more pronounced increase in high-density lipoprotein (HDL) is common in the early stages of PBC, while a more marked increase in LDL and lower HDL levels are noted in the later stages of the disease. PBC may also be associated with metabolic bone disease, steatorrhea, and fat-soluble vitamin deficiencies.

Antimitochondrial antibodies (AMA) are specific antibodies that are considered a serological sign of PBC and are present in 95% of patients with this disease. Therefore, a positive AMA test in the context of an elevated cholestatic liver test is sufficient to establish a diagnosis of PBC.

Primary sclerosing cholangitis (PSC) is a chronic CKD characterized by inflammation and fibrosis of the intra- and extrahepatic bile ducts. Cholangitis may be diagnosed at a later stage of the disease secondary to obstruction due to strictures. An increase in serum ALP is the most common laboratory abnormality in patients with PSC. Approximately 50% of patients with PSC may have normal ALP values. Therefore, normal ALP values ​​do not exclude the diagnosis of PSC. Serum aminotransferase levels may be 2 to 3 times the upper limit of normal. Unlike PBC, serum autoantibodies are nonspecific and are not commonly used to make a diagnosis of PSC. The diagnosis of PSC associated with pathology of the large duct is based on the cholangiogram, and the absence of pathology on abdominal ultrasonography does not rule out PSC. Therefore, if PSC is suspected, magnetic resonance cholangiopancreatography is the diagnostic test of choice. Compared to endoscopic retrograde cholangiopancreatography, this is a non-invasive and accurate method for detecting PSC. Patients with PSC in the lesser duct have normal cholangiograms and require a liver biopsy to establish the diagnosis of PSC.

Secondary sclerosing cholangitis (SSC) is a chronic CKD that results in progressive hepatic fibrosis, irregular thickening and dilation of the bile ducts. The cholangiographic picture of VSC is similar to that of PSC. The most common obstructive causes of VLC include surgical trauma due to cholecystectomy, intraductal stones, recurrent pancreatitis, and biliary strictures. Biliary congestion caused by obstruction predisposes to recurrence of cholangitis and the formation of pigmented stones and inflammatory strictures, which then exacerbate cholestasis. Early changes that occur after biliary obstruction may regress with its treatment. However, over time, such changes can develop into irreversible extensive periportal and periductular fibrosis and secondary biliary cirrhosis.

In terms of clinical presentation and laboratory profile, VSC and PSC are very similar. Recurrent bacterial cholangitis is very common in the later stages of VCM.

In rare cases, a liver biopsy is required to establish the diagnosis of PBC when AMA is negative or when a more precise differential diagnosis is required with autoimmune hepatitis, drug-induced cholestasis, recurrent intrahepatic cholestasis, viral hepatitis, systemic diseases.

The prospects for a liver biopsy depend on lesions of the small bile ducts in: PSC, idiopathic ductopenia, granulomatous cholangitis, Hodgkin’s lymphoma.

CKD treatment

A common consequence of all forms of cholestasis is the retention of fatty acids in hepatocytes. Elevated FA levels lead to apoptosis or necrosis of hepatocytes and ultimately to chronic CKD [13]. In some cholestatic disorders, the penetration of FA into the peribiliary space also occurs, which causes inflammation of the portal vein and fibrosis due to the induction of chemokines and cytokines.

In this regard, the following pharmacological targets are distinguished for the treatment of intrahepatic cholestasis (Fig. 3) [13]:

stimulation of orthograde biliary tract secretion and retrograde secretion of fatty acids and other toxic cholephils into the systemic circulation for excretion by the kidneys;

stimulation of the metabolism of hydrophobic fatty acids and other toxic compounds to more hydrophilic but less toxic metabolites;

protection of affected cholangiocytes from the toxic effects of bile; inhibition of apoptosis caused by an increased level of cytotoxic fatty acids;

inhibition of fibrosis caused by leakage of fatty acids into the peribiliary space.

Drug therapy for CKD is presented in Table. 1. In the table. Tables 2 and 3 present the main symptoms that occur with CKD, and drugs for their relief.

Ursodeoxycholic acid (UDCA) is the only conventional drug for the medical treatment of most chronic CKD [12, 15–19]. The ability to treat cholestasis is considered one of the most important and most valuable properties of this drug. In table. Figure 4 shows the main properties of UDCA, which, in the author’s opinion, are most fully disclosed in articles [15, 16].

The positive effect of UDCA has been most convincingly proven in such cholestatic disease as PBC. In a combined analysis of French, Canadian, and North American patient cohorts at 2–4 years of follow-up, there was a decrease in mortality and the need for liver transplantation in groups with moderate and severe disease. Barcelona Study 192 patients treated with UDCA for a period of 1.5 to 14 years showed that the survival of patients who responded to UDCA therapy (response was assessed by the level of ALP reduction) was higher than predicted by the Mayo predictive model and consistent with the population [16].

The dose of UDCA 13-15 mg/kg/day in most cholestatic diseases has an advantage in biochemical response and cost compared to low and high doses. An exception is cystic fibrosis, where doses of 20–30 mg/kg/day are recommended [16]. For PSC, recommended doses have not been determined.

There is evidence of a positive effect of UDCA on drug-induced cholestasis, including that caused by one of the most commonly causing hepatotoxic drugs, amoxicillin/clavulanate [16].

The European Association for the Study of the Liver (2009) [20] and the Russian Gastroenterological Association [1] recommend the mandatory prescription of UDCA as a basic therapy for a number of CKD: primary biliary cirrhosis, PSC, cystic fibrosis, progressive familial cholestasis type 3 (Progressive Familial Intrahepatic Cholestasis 3), intrahepatic cholestasis of pregnancy, and also discuss its use in drug-induced cholestasis and benign familial cholestasis.

The concept of structured lifelong therapy for PBC is based on 3 main elements: 1) risk stratification and treatment compliance; 2) determination of the stage and observation in accordance with it; 3) active management. Help is always built taking into account the individual characteristics of the patient and the health care capabilities of a given country, but these 3 supporting elements ensure its effectiveness [21].

To date, the original drug UDCA – Urso (Japan) is not registered in Russia. In this situation, when choosing generic drugs that are widely represented on the domestic pharmaceutical market, one should be guided, first of all, by the ratio of price and quality. Appeared in recent years, the domestic drug UDCA Urdoksa ^® manufactured by Obolenskoye FP JSC is not inferior to generic forms previously registered in our country [16]. This domestic drug has characteristics that make it the drug of choice at any stage of medical care for patients with a wide range of nosologies, including those with chronic CKD. Urdoxa ^® is produced from a European substance (Italy, Industria Chimica Emiliana) at a Russian enterprise according to the international GMP (Good Manufacturing Practice) standard. The high safety profile allows the drug to be used in children older than 3 years [22].

The drug has successfully passed all the registration procedures prescribed by law, which allows us to speak of its bioequivalence to reference drugs containing UDCA [23, 24].

Pharmaceutical equivalence of UDCA preparations is confirmed not only by the same amount of active substance and excipients in 1 capsule of the preparation, but also by the presence of identical infrared spectra obtained by infrared spectroscopy of finished dosage forms of compared UDCA preparations [25–27].

The reliability of the dynamics of standard biochemical indicators of liver function during therapy, a simple and informative diagnostic tool, has been confirmed by the last 10 years of its wide use. The response to UDCA therapy can be assessed using a model of discrete binary variables or scoring systems based on the calculation of continuous variables [21]. So, according to the Paris criteria, a good biochemical response after 12 months. UDCA therapy is considered to be serum bilirubin ≤17 µmol/L (1 mg/dL), ALP ≤3 ULN, and aspartate aminotransferase ≤2 ULN.

Conclusion

Thus, cholestasis is very common and can occur in a variety of clinical settings. Understanding the features of the etiopathogenesis of cholestasis and the correct application of these features in the differential diagnosis and treatment of CKD contribute to the formation of an effective practical approach in the treatment of cholestasis of general etiology. Currently, UDCA is the drug of choice for the treatment of CKD because it provides symptomatic relief, improves biochemical and histological parameters of liver function, and, most importantly, increases the survival of patients with CKD [16]. The beneficial effects of UDCA have been documented in randomized controlled trials. Therapy with UDCA drugs is critical in a number of cholestatic disorders such as PBC, PSC, intrahepatic cholestasis of pregnancy, liver disease in cystic fibrosis, progressive familial intrahepatic cholestasis, and some forms of drug-induced cholestasis.