What is the significance of ALT in liver health assessment. How do ALT levels indicate liver damage. What are the normal, high, and low ALT ranges. What causes abnormal ALT levels. How is the ALT test performed. What other tests complement ALT for liver function evaluation.

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

Alanine Aminotransferase (ALT) is an enzyme primarily found in the liver, with smaller amounts present in the kidneys, muscles, and other organs. Its primary function is to assist in breaking down food into energy. Understanding ALT levels is crucial because they serve as a key indicator of liver health.

When the liver is damaged, ALT is released into the bloodstream, causing blood levels to rise. This makes the ALT test an invaluable tool for healthcare providers to assess liver function and detect potential liver damage or disease.

The Liver’s Vital Functions

• Bile production for digestion
• Removal of toxins and waste products from blood
• Synthesis of proteins and cholesterol
• Energy metabolism

Given these critical functions, maintaining liver health is essential for overall well-being. The ALT test provides a non-invasive method to monitor liver function and detect potential issues early.

When and Why Do Doctors Order ALT Tests?

Healthcare providers may recommend an ALT test for various reasons, often as part of a comprehensive liver function panel. Common scenarios that warrant ALT testing include:

1. Suspected liver disease or damage
2. Monitoring known liver conditions
3. Evaluating the effectiveness of liver treatments
4. Routine health check-ups

Specific symptoms that might prompt an ALT test include:

• Abdominal pain or swelling
• Nausea and vomiting
• Jaundice (yellowing of skin or eyes)
• Unexplained weakness or fatigue
• Dark urine or light-colored stools
• Persistent itching

Additionally, certain risk factors may lead a doctor to order an ALT test:

• Known exposure to hepatitis virus
• Heavy alcohol consumption
• Family history of liver disease
• Use of medications known to affect liver function

How is the ALT Test Performed and What Should You Expect?

The ALT test is a simple blood test that requires minimal preparation. Here’s what you can expect:

Preparation

Generally, no special preparation is needed for an ALT test. However, your healthcare provider may advise fasting for a few hours before the test. It’s crucial to inform your doctor about any medications or supplements you’re taking, as some can affect ALT levels.

The Procedure

1. A healthcare professional will clean the injection site, usually on your arm.
2. They will tie a band around your upper arm to make the vein more visible.
3. A needle will be inserted to draw a small amount of blood.
4. The blood sample is collected in a vial or tube.
5. The needle is removed, and pressure is applied to stop bleeding.
6. A bandage is placed over the site.

The entire process typically takes only a few minutes and is generally painless, with most people experiencing only a brief sting when the needle is inserted.

Interpreting ALT Test Results: Normal, High, and Low Ranges

Understanding your ALT test results is crucial for assessing liver health. While reference ranges may vary slightly between laboratories, generally:

Normal ALT Range

A typical normal range for ALT is between 7 to 55 units per liter (U/L). However, it’s important to note that normal levels can vary based on factors such as age, gender, and the specific laboratory’s reference range.

Elevated ALT Levels

Elevated ALT levels can indicate liver damage or disease. The degree of elevation often correlates with the severity of the liver issue:

• Slightly elevated (55-200 U/L): May indicate mild liver stress or damage
• Moderately elevated (200-1000 U/L): Often suggests more significant liver damage
• Severely elevated (>1000 U/L): Typically indicates severe liver injury or acute hepatitis

Low ALT Levels

While less common, low ALT levels (below 7 U/L) can also be significant. They may indicate:

• Vitamin B6 deficiency
• Chronic kidney disease
• Frailty in elderly individuals

It’s crucial to remember that ALT levels should always be interpreted in context with other liver function tests and clinical findings. A single abnormal result doesn’t necessarily indicate liver disease, and normal results don’t guarantee the absence of liver issues.

What Causes Elevated ALT Levels?

Various factors can lead to increased ALT levels in the blood. Understanding these causes can help in diagnosing and addressing potential liver issues:

Common Causes of Slightly Elevated ALT

• Alcohol consumption
• Certain medications (e.g., statins, aspirin, some sleep aids)
• Obesity
• Non-alcoholic fatty liver disease (NAFLD)
• Mild viral infections

Causes of Moderately Elevated ALT

• Chronic liver diseases (e.g., hepatitis B or C)
• Cirrhosis
• Alcoholic liver disease
• Bile duct obstruction
• Autoimmune hepatitis
• Certain medications in higher doses

Causes of Severely Elevated ALT

• Acute viral hepatitis
• Drug-induced liver injury (e.g., acetaminophen overdose)
• Ischemic hepatitis (reduced blood flow to the liver)
• Severe alcoholic hepatitis
• Liver cancer
• Acute biliary obstruction

It’s important to note that ALT elevations can also occur due to non-liver related causes, such as muscle injury, heart failure, or even intense exercise. This underscores the importance of comprehensive evaluation and consideration of other clinical factors when interpreting ALT results.

Complementary Tests for Comprehensive Liver Function Assessment

While the ALT test is a valuable indicator of liver health, it’s often performed as part of a broader liver function panel. This comprehensive approach provides a more complete picture of liver health and function. Some key tests that complement ALT include:

Aspartate Aminotransferase (AST)

AST is another enzyme found in the liver and other tissues. The AST to ALT ratio can provide insights into the nature and severity of liver damage. For instance, an AST/ALT ratio greater than 2:1 is often associated with alcoholic liver disease.

Alkaline Phosphatase (ALP)

ALP is an enzyme found in the liver, bones, and other tissues. Elevated levels can indicate liver or bone diseases, especially those affecting the bile ducts.

Bilirubin

Bilirubin is a byproduct of red blood cell breakdown. Elevated levels can cause jaundice and may indicate liver dysfunction or bile duct obstruction.

Albumin

Albumin is a protein produced by the liver. Low levels can indicate chronic liver disease or malnutrition.

Gamma-Glutamyl Transferase (GGT)

GGT is sensitive to alcohol consumption and certain medications. It can help differentiate between bone and liver disease when ALP is elevated.

Prothrombin Time (PT)

This test measures blood clotting ability, which can be affected by liver dysfunction.

These tests, when interpreted together, provide a comprehensive assessment of liver function, helping healthcare providers diagnose liver conditions more accurately and develop appropriate treatment plans.

Lifestyle Factors and ALT Levels: What You Can Do to Maintain Liver Health

While some causes of elevated ALT are beyond individual control, several lifestyle factors can significantly impact liver health and ALT levels. Understanding and addressing these factors can help maintain optimal liver function:

Alcohol Consumption

Excessive alcohol intake is a leading cause of liver damage. Limiting alcohol consumption or abstaining altogether can significantly benefit liver health. For those who choose to drink, moderation is key – generally defined as up to one drink per day for women and up to two drinks per day for men.

Diet and Nutrition

A balanced diet plays a crucial role in liver health. Consider the following dietary recommendations:

• Reduce intake of processed foods and added sugars
• Increase consumption of fruits, vegetables, and whole grains
• Choose lean proteins and healthy fats
• Stay hydrated with plenty of water

Weight Management

Obesity is closely linked to non-alcoholic fatty liver disease (NAFLD), a common cause of elevated ALT. Maintaining a healthy weight through balanced nutrition and regular exercise can significantly improve liver health.

Regular Exercise

Physical activity not only aids in weight management but also improves overall liver function. Aim for at least 150 minutes of moderate-intensity exercise or 75 minutes of vigorous-intensity exercise per week.

Medication Management

Some medications can affect liver function and ALT levels. Always follow prescribed dosages and inform your healthcare provider about all medications and supplements you’re taking, including over-the-counter drugs.

Avoid Toxins

Limit exposure to environmental toxins and chemicals that can harm the liver. This includes being cautious with cleaning products, pesticides, and other potentially harmful substances.

Manage Chronic Conditions

Certain chronic conditions, such as diabetes and heart disease, can impact liver health. Properly managing these conditions through medication, lifestyle changes, and regular check-ups can help maintain healthy ALT levels.

By incorporating these lifestyle factors into daily routines, individuals can play an active role in maintaining liver health and potentially improving ALT levels. However, it’s important to consult with healthcare providers before making significant lifestyle changes, especially for those with existing health conditions.

The Future of Liver Health Assessment: Emerging Technologies and Approaches

While ALT testing remains a cornerstone of liver health assessment, ongoing research and technological advancements are paving the way for more sophisticated and comprehensive liver evaluation methods. These emerging approaches promise to enhance our understanding of liver function and improve early detection of liver diseases:

Non-Invasive Imaging Techniques

Advanced imaging technologies are becoming increasingly important in liver health assessment:

• Transient Elastography (FibroScan): This ultrasound-based technique measures liver stiffness, providing insights into fibrosis and cirrhosis without the need for a biopsy.
• Magnetic Resonance Elastography (MRE): Combines MRI imaging with sound waves to create a visual map of liver stiffness, offering detailed information about liver tissue health.

Biomarker Panels

Researchers are developing comprehensive biomarker panels that can provide more nuanced information about liver health:

• FibroTest: A panel of six serum markers that help assess liver fibrosis.
• Enhanced Liver Fibrosis (ELF) Test: Combines three serum biomarkers to assess liver fibrosis in chronic liver disease.

Genetic Testing

Advances in genetic testing are opening new avenues for personalized liver health assessment:

• Identification of genetic variants associated with increased risk of liver diseases.
• Pharmacogenomic testing to predict individual responses to liver medications.

Artificial Intelligence and Machine Learning

AI and machine learning algorithms are being developed to:

• Analyze complex datasets of liver function tests and patient information for more accurate diagnosis.
• Predict disease progression and treatment outcomes based on multiple factors.

Metabolomics

This emerging field studies small molecule metabolites in biological samples, offering a comprehensive view of liver metabolism and potentially identifying new biomarkers for liver diseases.

Liquid Biopsy

Techniques are being developed to detect liver-specific DNA, RNA, and proteins in blood samples, potentially offering less invasive alternatives to traditional liver biopsies.

While these advanced technologies show great promise, it’s important to note that many are still in research phases or early stages of clinical implementation. Traditional liver function tests, including ALT, continue to play a crucial role in liver health assessment. As these new technologies evolve, they are likely to complement rather than replace existing methods, offering a more comprehensive and personalized approach to liver health evaluation.

The future of liver health assessment looks promising, with potential for earlier detection, more accurate diagnosis, and personalized treatment strategies. However, the fundamental principles of maintaining liver health through lifestyle choices and regular check-ups remain essential components of overall liver care.

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.

Top Picks

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.

Top Picks

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.

back to top of page

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.

back to top of page

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.

back to top of page

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.

back to top of page

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.