What are the main causes of elevated liver enzymes in dogs. How can pet owners identify and address liver enzyme issues. What steps should be taken when a dog’s blood work shows abnormal liver values.

Understanding Liver Enzymes in Dogs: A Crucial Health Indicator

Liver enzymes play a vital role in your dog’s overall health. These proteins, produced by the liver, are responsible for various metabolic functions, including detoxification and protein synthesis. When a veterinarian finds elevated liver enzymes in a dog’s blood work, it’s not a diagnosis in itself but rather a sign that something may be affecting the liver’s function.

The most commonly measured liver enzymes in canine blood tests are:

• Alanine transaminase (ALT)
• Aspartate transaminase (AST)
• Alkaline phosphatase (ALP)

ALT and AST are primarily found in liver cells, with AST also present in skeletal muscle. An increase in these enzymes often indicates liver damage or inflammation. ALP, found in both liver and bones, can signal liver issues or bone growth related to certain medications.

Why Are Elevated Liver Enzymes a Concern?

Elevated liver enzymes in dogs can be a red flag for various health issues. While not all elevations indicate liver disease, they often suggest that further diagnostic testing is necessary to determine the underlying cause. As a pet owner, understanding the potential reasons for high liver enzymes can help you work more effectively with your veterinarian to ensure your dog’s health.

Hepatic Causes of Elevated Liver Enzymes in Dogs

Hepatic causes directly affect the liver, leading to damage and subsequent increases in liver enzymes. Let’s explore some of the most common hepatic causes:

1. Hepatitis: Inflammation of the Liver

Hepatitis in dogs can be caused by various factors, including viral and bacterial infections, as well as inflammatory conditions. This inflammation can lead to liver damage and elevated enzyme levels.

2. Benign Nodular Hyperplasia: A Common Condition in Older Dogs

As dogs age, they may develop benign nodular hyperplasia, a condition characterized by multiple small, non-cancerous nodules in the liver. While generally not harmful, it can cause elevated liver enzymes.

3. Drug-Induced Liver Enzyme Elevation

Certain medications, particularly steroids like prednisone and anticonvulsants like phenobarbital, can cause liver enzyme levels to rise. This is often a normal response to the medication but should be monitored closely.

4. Congenital Liver Diseases

Some dogs are born with inherited liver conditions, such as portosystemic liver shunts or copper storage diseases. These genetic issues can lead to chronic liver problems and elevated enzyme levels.

5. Toxin Exposure

Exposure to certain toxins can dramatically increase liver enzyme activity in dogs. Common culprits include:

• Xylitol (found in sugar-free gum and some peanut butter)
• Aflatoxins (mold toxins sometimes found in pet food)
• Lead

Prompt veterinary care is crucial if toxin exposure is suspected.

Extrahepatic Causes: When Other Systems Affect Liver Enzymes

Extrahepatic causes of elevated liver enzymes in dogs originate outside the liver but can still impact liver function and enzyme levels. Understanding these causes is crucial for comprehensive pet care.

1. Pancreatitis: A Common Culprit

Inflammation of the pancreas, known as pancreatitis, can cause liver enzyme levels to rise. This occurs when the inflammation spreads to the nearby liver tissue. Pancreatitis in dogs can be acute or chronic and requires prompt veterinary attention.

2. Diabetes Mellitus: Metabolic Imbalance

Dogs with diabetes may experience elevated liver enzymes due to a condition called subclinical hepatic lipidosis. This occurs when the body’s altered metabolism leads to fat accumulation in the liver, affecting its function.

3. Cushing’s Disease: Hormonal Havoc

Cushing’s disease, or hyperadrenocorticism, can cause elevated liver enzymes in dogs. The excess production of steroids leads to liver enlargement and subsequent enzyme elevation. Regular monitoring is essential for dogs diagnosed with or suspected of having Cushing’s disease.

4. Heart Disease: The Liver Connection

Right-sided heart disease can lead to liver congestion, causing elevated liver enzyme levels. This connection highlights the importance of a comprehensive approach to pet health, considering multiple organ systems.

Diagnostic Approach: Decoding Elevated Liver Enzymes

When a dog’s blood work reveals elevated liver enzymes, veterinarians typically follow a systematic diagnostic approach to identify the underlying cause. This process may include:

1. Comprehensive blood work and urinalysis
2. Imaging studies (ultrasound, X-rays, CT scans)
3. Liver function tests
4. Liver biopsy (in some cases)

Each step helps narrow down the potential causes and guides the treatment plan. As a pet owner, your role in providing a detailed history and observing your dog’s symptoms is crucial in this diagnostic journey.

Key Questions Your Vet May Ask

To assist in the diagnostic process, be prepared to answer questions such as:

• Has your dog been exposed to any toxins or new medications?
• Have you noticed changes in appetite, thirst, or urination?
• Has there been any vomiting, diarrhea, or changes in stool color?
• Has your dog shown signs of jaundice (yellowing of the skin or eyes)?

Treatment Strategies for Dogs with Elevated Liver Enzymes

The treatment for elevated liver enzymes in dogs varies depending on the underlying cause. However, some general strategies often employed include:

1. Dietary Management

A liver-friendly diet, often low in protein and high in easily digestible carbohydrates, may be recommended. This helps reduce the workload on the liver and supports its recovery.

2. Medications and Supplements

Depending on the cause, various medications may be prescribed. These can include:

• Antibiotics for bacterial infections
• Antioxidants like SAM-e or milk thistle to support liver function
• Ursodeoxycholic acid to improve bile flow

3. Addressing Underlying Conditions

If an extrahepatic cause is identified, such as diabetes or Cushing’s disease, treating the primary condition is crucial for managing liver enzyme levels.

4. Ongoing Monitoring

Regular blood tests and check-ups are essential to track liver enzyme levels and assess the effectiveness of treatment.

Prevention: Safeguarding Your Dog’s Liver Health

While not all causes of elevated liver enzymes are preventable, there are steps you can take to promote your dog’s liver health:

1. Balanced Diet and Exercise

Providing a nutritionally balanced diet and maintaining a healthy weight through regular exercise can support overall liver function.

2. Regular Check-ups

Annual or bi-annual veterinary check-ups, including blood work, can help detect liver issues early.

3. Toxin Awareness

Be aware of common household toxins and keep them out of your dog’s reach. This includes certain human foods, medications, and plants that can be harmful to dogs.

4. Medication Management

Always follow your veterinarian’s instructions regarding medication dosages and duration. Some medications can affect liver function, so proper management is crucial.

When to Seek Immediate Veterinary Care

While elevated liver enzymes often require ongoing management, certain symptoms warrant immediate veterinary attention. These include:

• Sudden onset of vomiting or diarrhea
• Jaundice (yellowing of the skin, gums, or whites of the eyes)
• Severe lethargy or collapse
• Neurological symptoms such as seizures or disorientation
• Excessive thirst and urination

These symptoms could indicate a severe liver problem or a rapidly progressing condition that requires prompt intervention.

The Role of Complementary Therapies in Liver Health

In addition to conventional treatments, some pet owners and veterinarians explore complementary therapies to support liver health in dogs with elevated enzymes. These may include:

1. Herbal Supplements

Certain herbs, such as milk thistle and dandelion root, are believed to have hepatoprotective properties. However, it’s crucial to consult with a veterinarian before introducing any supplements, as some can interact with medications or exacerbate certain conditions.

2. Acupuncture

Some studies suggest that acupuncture may help improve liver function and reduce inflammation. While not a standalone treatment, it can be used as part of a comprehensive care plan under veterinary guidance.

3. Nutritional Therapy

Working with a veterinary nutritionist to develop a customized diet plan can support liver function and overall health. This may involve adjusting macro and micronutrient levels to meet your dog’s specific needs.

Remember, while these complementary approaches can be beneficial, they should always be used in conjunction with, not as a replacement for, conventional veterinary care.

Long-term Outlook: Living with a Dog with Liver Issues

The prognosis for dogs with elevated liver enzymes varies greatly depending on the underlying cause and the effectiveness of treatment. Many dogs with mild to moderate liver enzyme elevations can lead normal, healthy lives with proper management. However, some conditions may require lifelong care and monitoring.

Key Factors in Long-term Management

• Consistent veterinary care and regular check-ups
• Adherence to prescribed medications and dietary recommendations
• Monitoring for any changes in behavior, appetite, or physical symptoms
• Maintaining a low-stress environment to support overall health

With dedicated care and attention, many dogs with liver issues can enjoy a good quality of life. As a pet owner, your commitment to your dog’s health plays a crucial role in their long-term well-being.

Emerging Research: New Horizons in Canine Liver Health

The field of veterinary hepatology is continually evolving, with new research offering hope for improved diagnostics and treatments for dogs with liver issues. Some areas of ongoing research include:

1. Advanced Imaging Techniques

Researchers are exploring more sophisticated imaging methods, such as contrast-enhanced ultrasound and advanced MRI techniques, to provide earlier and more accurate diagnoses of liver diseases in dogs.

2. Genetic Testing

As our understanding of genetic factors in canine liver diseases grows, genetic testing may become a more common tool for identifying predispositions to certain liver conditions, allowing for earlier intervention and management.

3. Novel Therapies

Investigations into stem cell therapies, targeted drug delivery systems, and new hepatoprotective compounds offer potential for more effective treatments in the future.

Staying informed about these advancements can help pet owners make more informed decisions about their dog’s liver health care in consultation with their veterinarian.

In conclusion, elevated liver enzymes in dogs are a complex issue that requires careful diagnosis and management. By understanding the potential causes, working closely with your veterinarian, and staying proactive about your dog’s health, you can help ensure the best possible outcome for your furry friend. Remember, early detection and intervention are key to managing liver health issues effectively.

The Top Causes Of Elevated Liver Enzymes In Dogs

As a pet owner, you want the best for your furry friend. It can be concerning and overwhelming when your dog’s blood work comes back with elevated liver enzymes. However, it’s essential to understand that elevated liver enzymes in dogs are not a disease, but rather a sign that something is going on with the liver. The liver is a vital organ responsible for various metabolic functions, including detoxification and protein synthesis. When the liver is affected, it can lead to an increase in liver enzymes in the blood. There are many possible causes of elevated liver enzymes in dogs, ranging from benign conditions to severe diseases. In this article, we’ll explore the different causes of elevated liver enzymes in dogs so you can have a better understanding of what is going on with your dog.

What are liver enzymes?

Liver enzymes are proteins produced by the liver that help carry out various metabolic functions in the body. These enzymes are released into the bloodstream in small amounts and play a crucial role in breaking down and metabolizing different substances such as drugs, metabolites, and toxins. In dogs, the most commonly measured liver enzymes in blood tests are alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP).

ALT and AST are enzymes that are present in the liver cells, and their levels in the blood increase when there is damage or inflammation in the liver. AST is also found in skeletal muscle. ALP, on the other hand, is an enzyme that is present both in the liver and bones. An increase in ALP levels in the blood can indicate liver damage or disease, as well as bone growth secondary to certain medications such as prednisone and phenobarbital.

While it is important to understand that not all elevations in liver enzymes in dogs are suggestive of liver disease, in most cases, elevated liver enzymes in dogs are a sign that there is something going on in the liver, and further diagnostic testing is required to determine the underlying cause. It’s important to keep in mind that elevated liver enzymes in dogs are not a specific diagnosis, but rather an indication that something is affecting the liver.

What causes elevated liver enzymes in dogs?

There are many reasons for high liver enzymes in dogs. Veterinarians typically separate them into two categories: hepatic and extrahepatic.

Hepatic causes of elevated liver enzymes in dogs

Hepatic causes of high liver enzymes in dogs refer to conditions that affect the liver directly, leading to liver damage and subsequent increases in liver enzymes. Some common hepatic causes of elevated liver enzymes in dogs include:

• Hepatitis: Hepatitis refers to inflammation of the liver and can be caused by viral, bacterial, or inflammatory factors.
• Benign nodular hyperplasia: Benign nodular hyperplasia is a condition commonly seen in older dogs in which the liver develops multiple small non-cancerous nodules.
• Drug-induced: Certain drugs, such as steroids (e. g. prednisone) and phenobarbital, can cause elevated liver enzymes in dogs, especially ALP.
• Congenital liver diseases: Certain liver diseases, such as portosystemic liver shunts and copper storage diseases, are inherited and can cause liver enzyme levels to increase.
• Toxins: Certain toxins can induce the activity of liver enzymes in dogs. These can include xylitol, aflatoxins and lead toxicity for example.
• Cholangitis: Cholangitis refers to inflammation of the bile ducts that carry bile from the liver to the small intestine. It can cause liver damage and elevated liver enzymes.
• Cirrhosis: Cirrhosis is a chronic liver disease that leads to scarring and permanent damage to the liver. It can be caused by chronic infections, exposure to toxins, or chronic active hepatitis.
• Liver cancer: Diffuse cancer in the liver, whether malignant or benign, can cause liver enzyme levels to increase. Common cancers that can affect the liver include lymphoma, carcinoma and hemangiosarcoma.

Extrahepatic causes of elevated liver enzymes in dogs

Extrahepatic causes of elevated liver enzymes in dogs refer to conditions outside the liver that can affect liver enzyme levels. Some common extrahepatic causes of elevated liver enzymes in dogs include:

• Pancreatitis: Pancreatitis is inflammation of the pancreas and can cause liver enzyme levels to rise due to inflammation spreading to the liver.
• Diabetes: Dogs with diabetes can have elevated liver enzymes due to the negative metabolic state (subclinical hepatic lipidosis).
• Cushing’s disease: Dogs with Cushing’s disease, or hyperadrenocorticism, can have elevated liver enzymes due to excess steroid production leading to swelling of the liver.
• Heart disease: Right-sided heart disease can cause liver congestion, leading to elevated liver enzyme levels.
• Inflammatory bowel disease: Inflammatory bowel disease (IBD) can cause elevated liver enzyme levels due to inflammation in the gastrointestinal tract.

These illnesses can lead to a reactive/vacuolar hepatopathy, causing an increase in liver enzymes but normally there is no impact on the functioning of the liver.

Do all elevated liver enzymes need to be investigated further?

No, elevated liver enzymes in dogs do not always need to be investigated further. In mild cases of elevated liver enzymes, your veterinarian may recommend periodic blood testing to start trending the values before recommending further testing. Generally speaking, liver enzyme values greater than 2-3 times the upper limit of normal should be investigated as they can indicate a more serious condition. This is also assuming the dog is asymptomatic and there are no abnormalities on its physical exam.

Certain medications such as corticosteroids (prednisone) and phenobarbital will predictably cause elevated liver enzymes in dogs, especially the ALP. In these cases, the elevated liver enzyme values are not indicative of liver disease and will usually resolve with the discontinuation of the medication.

Additionally, young dogs with an elevated ALP may not need to be investigated further as this could be due to skeletal growth and development. Your veterinarian may recommend periodic blood testing to ensure the elevated liver enzyme values do not persist or cause any issues.

Finally, elevated liver enzymes in dogs can be observed as part of an aging process, as normal age-related changes occur to cause increased activity of certain enzymes. Examples include nodular and vacuolar hepatopathy. In this case, your veterinarian may recommend periodic blood testing every 4-6 months.

In conclusion, elevated liver enzymes in dogs can be caused by a variety of conditions, both within and outside the liver. In mild cases of elevated liver enzymes, periodic blood testing may be all that is needed to ensure there are no more serious underlying issues. However, if your dog’s elevated enzyme levels persist or become particularly high (greater than 2-3 times the upper limit of normal), further investigation should be done as soon as possible. Additionally, certain medications such as corticosteroids and phenobarbital will predictably cause elevated values but these usually resolve with discontinuation of the medication. Finally, elevated liver enzymes in young dogs could be due to skeletal growth and development, or part of an aging process. It is important to work with your veterinarian to determine the best course of action for your individual dog.

Enzyme Activity in Hepatic Disease in Small Animals – Digestive System

Liver disease is often first suspected based on increased liver enzyme activity. However, abnormally increased liver enzyme activity is considerably more common than the prevalence of liver disease. A wide spectrum of nonhepatic disorders may influence liver enzyme activity. It is important to recognize that liver enzyme measurements are not liver function tests but rather reflect hepatocyte membrane integrity, hepatocyte or biliary epithelial necrosis, cholestasis, or induction phenomenon.

The pattern of liver enzyme abnormalities in relation to the signalment, history, total bilirubin concentration, serum bile acid values, and comorbid conditions/medications provides the first indication of a liver-specific disorder. A full assessment of liver enzyme aberration considers: 1) the predominant pattern of enzyme change (hepatocellular leakage enzymes vs cholestatic enzymes), 2) the magnitude of increase of enzyme activity above the normal reference range (mild is 10 times), 3) the rate of change (increase or resolution) with sequential sampling, and 4) the nature of the course of change (fluctuation vs progressive increase or decrement). Up to 2.5% of clinically “normal” animals can have borderline abnormal enzyme values.

Recognizing whether enzyme abnormalities are persistent or cyclic helps categorize likely causes. Investigating liver function with paired fasting and postprandial total serum bile acids (TSBAs) or urine bile acid/creatinine measurements (urine collected 4–8 hr after meal ingestion) may expedite a decision to pursue liver biopsy when clinical signs remain vague and enzymes are only mildly increased. Imaging studies help detect primary underlying disorders that have secondarily influenced the liver, causing increased enzyme activity. Ultrasonographic assessment may help determine the method of liver biopsy; needle biopsies are ill advised in animals with microhepatica, ascites, or difficult-to-sample focal liver lesions.

Age-appropriate reference ranges for serum liver enzyme activity are essential to interpret laboratory values in puppies and kittens. Plasma enzyme activities of ALP and GGT in neonatal dogs and cats are remarkably higher than those of adults. Differences reflect physiologic adaptations during the transition from fetal and neonatal life stages, colostrum ingestion, maturation of metabolic pathways, growth effects, differences in volume of distribution and body composition, and nutritional intake. Serum activities of ALP, AST, CK, and LDH in neonates usually increase greatly during the first 24 hr of life. In kittens, serum activities of ALP, CK, and LDH exceed adult values through 8 wk of age. Serum ALP increases remarkably in day-old puppies and kittens after colostrum ingestion, as also observed in neonatal calves, lambs, pigs, and foals.

AST and ALT are commonly measured to detect liver injury; however, both enzymes are present in high concentrations in liver and several other tissues. AST activity is higher in kidney, heart, and skeletal muscle than liver, whereas ALT activity is highest in liver. Because hepatic ALT activity is 10,000-fold greater than plasma enzyme activity in healthy animals, it has high diagnostic utility to detect “liver lesions.” The cytosolic location of transaminases allows their immediate release with even minor change in hepatocellular membrane integrity. Unfortunately, indiscriminate leakage limits their diagnostic utility. Nonetheless, duration and magnitude of transaminase activities measured sequentially can predict disease activity and severity and roughly estimate the number of involved cells.

Hepatic transaminases increase with muscle injury as well as vigorous physical activity in dogs. Persistence of transaminases in plasma contributes to their sustained high activities in certain disorders. Because transaminase catabolism occurs by absorptive endocytosis at the hepatocyte sinusoidal border, slow enzyme clearance may sustain plasma enzyme activity in hepatic insufficiency associated with liver fibrosis, nodular regeneration, and development of APSSs.

The largest increases in ALT develop with hepatocellular necrosis and inflammation. After acute severe hepatocyte necrosis, serum ALT activity increases sharply within 24–48 hr to values often >100-fold normal, peaking during the first 5 days of injury. If the injurious event resolves, ALT activity gradually declines to normal over 2–3 wk. Although this pattern is considered classic, some severe hepatotoxins are not associated with increased ALT activity, because they inhibit gene transcription or interfere with ALT biosynthesis (eg, aflatoxin B1 hepatotoxicity, microcystin hepatotoxicity). A declining ALT also may represent a paucity of viable hepatocytes in end-stage chronic hepatitis or severe acute liver disease.

Examples of classic necrotizing hepatotoxins are carbon tetrachloride, acetaminophen, and nitrosamine. A single exposure to carbon tetrachloride causes an acute sharp increase in ALT that resolves over the ensuing week. Hepatotoxicity induced by acetaminophen causes a marked increase in ALT and AST within 24 hr that may decline within 72 hr to near normal values. This toxin is highly dose dependent in dogs and cats. Cats are exceedingly susceptible, with hematologic signs dominating after ingestion of as little as 125 mg. However, in dogs, a dosage of 200 mg/kg may be life-threatening, with susceptibility heightened by antecedent exposure to phenobarbital. Hepatocellular necrosis induced by nitrosamines increases plasma ALT activity, but not significantly, until after 1 wk of intermittent chronic exposure. The ALT activity persists for weeks until necrosis resolves. Low-grade hepatocellular degeneration, observed in some dogs with congenital portosystemic shunts, reflects delayed enzyme clearance and low-grade hepatocyte dropout; most of these dogs have small lipogranulomas reflecting single hepatocyte dropout/necrosis in the absence of an inflammatory response.

Acute hepatic necrosis caused by infectious canine hepatitis increases plasma ALT activity by 30-fold, peaking within 4 days. Thereafter, chronic sustained ALT activity persists as chronic hepatitis develops in dogs unable to clear the virus. Hepatic injury induced by toxins usually causes plasma ALT activity to increase, peak, and return to normal sooner than it does in infectious viral hepatitis. Chronic hepatitis, an idiopathic or copper-associated persistent or cyclic necroinflammatory liver injury in dogs is associated with varying severities of necrosis and fibrosis. Cyclic disease activity is reflected by plasma enzyme “flares.” At times, plasma ALT activity is >10-fold normal. Enzyme fluctuations contrast with profiles associated with single injurious events. In dogs with hepatitis, serum ALT activity declines as injury resolves, but serum ALP activity may increase as a result of regenerative responses (progenitor cell proliferation, ductal or oval cell response). Dogs treated with glucocorticoids may develop mildly increased ALT activity that resolves within several weeks of glucocorticoid withdrawal.

Despite high sensitivity of ALT to identify liver disorders, its lack of specificity to differentiate clinically significant liver disease, specific histologic abnormalities, or hepatic dysfunction requires that it be interpreted in conjunction with other diagnostic tests.

AST is present in substantial concentrations in a wide variety of tissues, especially muscle. Increased AST activity can reflect reversible or irreversible changes in hepatocellular membrane permeability, cell necrosis, hepatic inflammation, and in dogs, microsomal enzyme induction. After acute diffuse severe hepatic necrosis, serum AST sharply increases during the first 3 days to values 10- to 30-fold above normal in dogs and up to 50-fold above normal in cats. If necrosis resolves, AST activity gradually declines over 2–3 wk. In most cases, AST parallels changes in ALT activity.

Although increased AST activity in the absence of abnormal ALT activity implicates an extrahepatic enzyme source (notably in muscle injury), there are clinical exceptions that may relate to severity and zonal location of hepatic damage. In some cats with liver disease, AST is a more sensitive marker of liver injury than ALT (eg, hepatic necrosis, cholangiohepatitis, myeloproliferative disease, hepatic infiltrative lymphoma, and EHBDO). A similar trend is evident in some dogs. Because AST is located within the mitochondria and free within the cytosol of hepatocytes, AST in fold increases greater than those of ALT may reflect mitochrondrial injury. Dogs treated with glucocorticoids may develop mildly increased AST activity that resolves within several weeks of glucocorticoid withdrawal.

Increased ALP activity in dogs is the most common abnormality on routine biochemical testing; its high sensitivity and low specificity can defy diagnostic interpretation without a liver biopsy. ALP activity in dogs has the lowest specificity of routinely used liver enzymes as a result of its complexity associated with induction of different isozymes.

In dogs and cats, tissues containing highest ALP activity (in descending order) are intestine, kidney (cortex), placenta (dogs only), liver, and bone. Distinct serum ALP isozymes can be extracted from some of these tissues in each species; eg, bone (B-ALP), liver (L-ALP), and glucocorticoid-induced (G-ALP) isoenzymes in canine serum. In dogs, L-ALP and G-ALP are primarily responsible for high serum ALP activity, whereas L-ALP is primarily responsible in cats. Increased ALP activity develops in up to 75% of hyperthyroid cats, depending on the chronicity of the condition, with B-ALP substantially contributing.

The comparably small magnitudes of ALP activity in cats with liver disease (2- to 3-fold normal) relative to dogs (usually >4- to 5-fold) reflect the lower specific activity of ALP in feline liver and its shorter half-life. Nevertheless, ALP activity remains clinically useful in the diagnosis of feline liver disease when the species-appropriate perspective is maintained.

The utility of serum ALP activity as a diagnostic indicator in dogs is complicated by the common accumulation of L-ALP and G-ALP isozymes, which can both be induced by steroidogenic hormones.

Because the B-ALP isozyme increases secondary to osteoblast activity, it is detected in young growing animals and in animals with bone tumors, secondary renal hyperparathyroidism, and osteomyelitis. However, the minor contribution of B-ALP to total serum ALP activity usually does not lead to an erroneous diagnosis of cholestatic liver disease. Bone remodeling secondary to neoplasia may not substantially affect serum ALP activity or may cause only a trivial increase (2- to 3-fold) in dogs. In young growing cats, increased B-ALP activity may simulate enzyme activity seen in hepatobiliary disease.

Although ALT is immediately released from the hepatocellular cytosol in acute hepatic necrosis, the small quantities of membrane-bound ALP are not. It takes several days for induction of membrane-associated enzyme to “gear up” and spill into the systemic circulation. Increased serum ALP reflects enhanced de novo hepatic synthesis, canalicular injury, cholestasis, and solubilization of its membrane anchor (by bile salts). The largest increases in serum ALP activity (L-ALP and/or G-ALP ≥100-fold normal) develop in dogs with diffuse or focal cholestatic disorders, massive hepatocellular carcinoma, bile duct carcinoma, and those exposed to steroidogenic hormones.

Although serum activity of ALP may be normal or only modestly increased in dogs with metastatic neoplasia involving the liver, it may also increase dramatically in dogs with mammary neoplasia. High serum ALP activity develops in ~55% of dogs with malignant and 47% with benign mammary tumors, with highest ALP activity seen in dogs with malignant mixed tumors. Nevertheless, serum ALP has no value as a diagnostic or prognostic marker in mammary cancer; it remains unclear whether disease remission (surgical, chemotherapy) is followed by a regression in serum ALP activity or whether serum ALP activity functions as a paraneoplastic marker.

After acute severe hepatic necrosis, ALP activity increases 2- to 5-fold in dogs and cats, stabilizes, and then gradually declines over 2–3 wk. Sustained ALP activity usually correlates with a reparative ductal response (progenitor or oval cell hyperplasia). In cats, EHBDO results in a 2-fold increase in ALP within 2 days, as much as a 4-fold increase within 1 wk, and up to a 9-fold increase within 2–3 wk. Thereafter, activity stabilizes and gradually declines but usually not into the normal range; the declining enzyme activity coordinates with developing biliary cirrhosis ( see Extrahepatic Bile Duct Obstruction in Small Animals Extrahepatic Bile Duct Obstruction in Small Animals Obstruction of the common bile duct is associated with a number of diverse primary conditions, including inflammation (eg, pancreatitis, duodenitis, duodenal foreign body, etc), cholelithiasis… read more ). Inflammatory disorders involving biliary or canalicular structures or disorders compromising bile flow increase serum ALP activity secondary to membrane inflammation/disruption and local bile acid accumulation. In both dogs and cats, similar increases in serum ALP activity develop in intrahepatic (metabolic, biochemical, sepsis) associated cholestasis or obstruction involving the extrahepatic biliary structures. Consequently, ALP activity cannot differentiate between intra- and extrahepatic cholestatic disorders.

Many extrahepatic and primary hepatic conditions are associated with increased L-ALP. In cats, HL ( see Feline Hepatic Lipidosis Feline Hepatic Lipidosis Hepatic lipidosis (HL), the most common acquired and potentially lethal feline liver disease, is a multifactorial syndrome. In most cases, a primary disease process causing anorexia sets the… read more ) is associated with marked increase in ALP activity and jaundice. The increased ALP seemingly reflects canalicular dysfunction or compression. Although ALP in cats is rarely affected by anticonvulsants or glucocorticoids, it can increase with diabetes mellitus, hyperthyroidism, and pancreatitis.

In dogs, primary hepatic inflammation as well as systemic infection or inflammation and exposure to steroidogenic hormones may induce a glycogen-associated vacuolar hepatopathy (VH). When severe, VH has a cholestatic effect that seemingly causes canalicular compression. Although glycogen-associated VH was initially characterized as a glucocorticoid-initiated lesion, it is now established that nearly 50% of dogs with glycogen-associated VH lack overt exposure to steroidogenic substances. Chronically ill dogs may produce the G-ALP isozymes secondary to stress-induced glucocorticoid release. Such dogs with glycogen-associated VH (lacking exogenous glucocorticoid exposure) may demonstrate normal dexamethasone suppression and adrenocorticotropic hormone (ACTH) response tests. However, in some dogs, high ALP with a glycogen-associated VH signals the presence of atypical adrenal hyperplasia associated with abnormal sex hormone production. There is no consistent relationship between the magnitude of serum ALP activity, the presence of high G-ALP activity, or histologic lesions. Unfortunately, G-ALP is not useful for syndrome characterization because it can become the predominant ALP isoenzyme in dogs treated with glucocorticoids and in dogs with spontaneous or iatrogenic hyperadrenocorticism, hepatic or nonhepatic neoplasia, hepatic inflammation, or numerous diverse chronic illnesses, including primary liver disease.

The magnitude of ALP activity induced by glucocorticoid administration depends on the type of drug and dose given, as well as the individual’s response. The production of G-ALP does not imply that a dog treated with cortisone has iatrogenic hyperadrenocorticism, a suppressed pituitary-adrenal axis, or a clinically important glycogen-associated VH. By comparison, the feline liver is relatively insensitive to glucocorticoids, with rare development of a glycogen-associated VH or acceleration of hepatocyte lipid vacuole accumulation.

In dogs, serum total ALP activity and L-ALP isozyme also may be induced by administration of certain anticonvulsants (phenobarbital, primidone, and phenytoin) and other drugs; in this circumstance, the ALP activity usually increases 2- to 6-fold normal. In contrast, serum ALP and L-ALP did not increase in cats after administration of phenobarbital (0.25 grain, bid) for 30 days.

Gamma-glutamyl transferase (GGT) is a membrane-bound glycoprotein that plays a critical role in cellular detoxification (involved with glutathione availability), conferring resistance against a number of toxins and drugs. Tissue concentrations of GGT in dogs and cats are highest in the kidney and pancreas, with lesser amounts in the liver, gallbladder, intestines, spleen, heart, lungs, skeletal muscle, and erythrocytes. However, serum GGT activity is largely derived from the liver, although there is considerable species variation in its localization within this organ.

Acute, severe, diffuse necrosis is associated with either no change or only mild increases (1- to 3-fold normal) in GGT activity that resolve in ~10 days. In dogs with EHBDO, serum GGT activity increases 1- to 4-fold above normal within 4 days, and 10- to 50-fold within 1–2 wk. Thereafter, values may plateau or continue to increase as high as 100-fold. In cats with EHBDO, serum GGT activity may increase up to 2-fold within 3 days, 2- to 6-fold within 5 days, 3- to 12-fold within 1 wk, and 4- to 16-fold within 2 wk. Glucocorticoids and certain other microsomal enzyme inducers may stimulate GGT production in dogs, similar to their influence on ALP. Administration of dexamethasone (3 mg/kg/day) or prednisone (4.4 mg/kg/day, IM) may increase GGT activity within 1 wk to 4- to 7-fold above normal and up to 10-fold within 2 wk. Dogs treated with phenytoin or primidone develop only a modest increase in serum GGT activity (up to 2- to 3-fold), unless they develop anticonvulsant hepatotoxicosis that is often associated with marked enzyme activity.

Cats with advanced necroinflammatory liver disease, EHBDO, or inflammatory intrahepatic cholestasis can develop a larger increase in GGT activity relative to ALP. Glucocorticoids and other enzyme inducers in dogs do not clinically influence serum GGT in cats. The normal range for serum GGT activity in cats is much narrower and lower than that in dogs; therefore, assays must be sensitive enough to detect low GGT activity.

GGT values can be markedly increased in dogs and cats with primary hepatic or pancreatic neoplasia. However, GGT does not appear to be suitable for surveillance of hepatic metastasis in either species.

Like ALP, GGT lacks specificity in differentiating between parenchymal hepatic disease and obstructive biliary disease. It is not as sensitive in dogs as ALP but does have higher specificity. In cats with inflammatory liver disease, it is more sensitive but less specific than ALP; these two enzymes should be interpreted simultaneously. The likelihood that HL has developed secondary to necroinflammatory liver disease, EHBDO, or pancreatic disease can be predicted by examining the relative increases in GGT and ALP. Necroinflammatory disorders involving biliary structures, the portal triad, or pancreas are often associated with a greater fold increase in GGT than in ALP. With the exclusion of these underlying disorders, cats with HL usually have a higher fold increase in ALP relative to GGT; this has important diagnostic utility in discerning the underlying cause of HL.

Neonatal animals of several species, including dogs but not cats, develop high serum GGT activity secondary to colostrum ingestion.

Liver enzymes as a marker of insulin resistance

Obesity is becoming an increasingly common medical problem throughout the world and is one of the main factors affecting insulin resistance, which, in turn, is a risk factor for the development of a number of chronic pathological conditions, such as arterial hypertension, dyslipidemia , type 2 diabetes, and cardiovascular disease. The level of insulin in the blood is not measured during routine medical examinations, which makes the use of this index limited. Thus, to assess insulin resistance, it is necessary to find a more general, reliable and simple indicator.

Non-alcoholic fatty liver disease is considered the hepatic manifestation of the metabolic syndrome, and insulin resistance and obesity are two major risk factors for its development. Elevated blood levels of liver enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase, as well as the ALT/AST ratio, are commonly used as surrogate markers for non-alcoholic fatty liver disease.

Numerous studies have shown a positive correlation between elevated blood levels of liver enzymes and obesity-related pathologies, including type 2 diabetes, metabolic syndrome, and cardiovascular disease. It is also known that the level of liver enzymes is associated with markers of insulin resistance, such as fasting blood insulin levels and the homeostatic model for assessing insulin resistance (HOMA-IR).

However, few studies report an association between the ALT/AST ratio and insulin resistance. Based on this, Chinese scientists conducted a study, the purpose of which was to study this relationship, taking into account waist circumference among the Chinese population. The results of this work were published on October 10, 2017 in the journal Nutrition & Metabolism.

Based on the SPECT-China cross-sectional study of metabolic disease prevalence and risk factors in East China, which included 10,441 participants. This study excluded participants with missing laboratory (AlAT, AST, fasting blood glucose and insulin levels) and anthropometric data (n=746), viral hepatitis (n=99) or taking antihypertensive, antidiabetic or antihyperlipidemic drugs (n=1198). As a result, the study included 8398 people aged 52.16±13.16 years.

Among the 8398 study subjects, 3414 (40.7%) were men aged 53.04±13.46 years and 4984 (59.3%) were women aged 51.57±12.91 years. The average waist circumference was 79.63±10.16 cm, and 30.9% of the subjects had central obesity. Among non-obese participants, the prevalence of insulin resistance was 8.7%, and among patients with central obesity – 29,9%. At the same time, patients with central obesity turned out to be older, had a significantly higher body mass index, blood pressure, ALT, AST and the ALT/AST ratio, and the level of high density lipoproteins was significantly lower in this group. In addition, the differences between the two groups in terms of economic status, smoking, and alcohol consumption were statistically significant.

In both patients with and without central obesity, HOMA-IR was significantly positively correlated with waist circumference, body mass index, blood pressure, triglycerides and ALT levels, as well as the ALT/AST ratio, and negatively correlated with the level high-density lipoprotein cholesterol in the blood. The authors state that, of all the variables studied, the ALT/AST ratio is the marker that, in this study, correlates best with HOMA-IR among participants with and without central obesity.

Additional linear regression analysis showed that the ALT/AST ratio was independently and strongly associated with HOMA-IR in all participants (with and without obesity) after adjusting for age, gender, smoking and alcohol consumption status, economic status, index body weight, systolic blood pressure, glycosylated hemoglobin and triglycerides in the blood.

The authors emphasize that the present study has some limitations. Firstly, due to its cross nature, a causal relationship between the ALT/AsAT ratio and insulin resistance has not been established. Second, this study is limited to the Chinese population, so the data cannot be generalized to other ethnic groups. Thirdly, despite the exclusion of patients with existing viral hepatitis based on the data provided by the subjects themselves, the scientists could not completely exclude other types of hepatitis among the participants, since the survey in this direction was not conducted. Finally, gamma-glutamyl transferase is also a marker used to diagnose non-alcoholic fatty liver disease, but the researchers did not measure blood levels of this enzyme in this study.

Based on these results, the authors concluded that the ALT/AST ratio may be a better biomarker of insulin resistance than blood ALT or AST levels, blood pressure, lipid profile, and obesity in the Chinese population. The question of whether the ALT/AST ratio can be considered as an additional component of the metabolic syndrome among the Chinese population requires further study. Since the measurement of liver enzymes in the blood is relatively inexpensive and fairly routinely performed in clinical settings, the results provided may have important public health implications.

Oleg Martyshin

Liver damage and concomitant pathology: a rational combination of hepatoprotectors | Vyalov S.S.

When patients visit a doctor, perform screening diagnostics or regular medical examinations, examinations for various diseases, an often accompanying finding is an increase in the level of hepatic transaminases – alanine aminotransferase (ALT) and aspartate aminotransferase (AST) – indicators of cytolysis. Usually, patients do not present any specific complaints in connection with liver disease, and often the detection of cytolysis presents a problem for the doctor in terms of both diagnosis and treatment until the final diagnosis is made.

Cytolysis syndrome (unspecified, or nonspecific hepatitis) is a clinical and laboratory syndrome characterized by an increase in the level of AST and ALT as a nonspecific reaction of liver cells to the action of damaging factors, and manifests itself at the cellular level by the destruction of hepatocytes. The essence of the process of cytolysis is the destruction of the cell membrane of the hepatocyte, and the damaging factors depending on the etiology of the disease may be different. These include the destructive effect of hepatotropic viruses in viral hepatitis, the toxic effect of alcohol, drugs, lipotoxicity in non-alcoholic liver disease, the effect of impaired secretion and transport of bile pigments in cholestatic diseases, various autoimmune disorders, storage diseases, deficiencies of various enzymes, hereditary and genetic disorders. , parasitic diseases, etc.
Alcoholic and non-alcoholic fatty liver disease (NAFLD) occupies an important place in the structure of pathology, not only gastroenterological, but also cardiological and general therapeutic in general. The occurrence of NAFLD is associated with the risk of developing cardiovascular pathology and a decrease in the life expectancy of patients. The deposition of lipids in the liver is the first stage in the development of the disease and can lead to the effect of lipotoxicity, the initiation of inflammation and the progression of the disease [1].
Currently, much attention in determining the pathogenesis of NAFLD is paid to the relationship with overweight, dyslipidemia, insulin resistance, metabolic syndrome, type 2 diabetes mellitus (DM). Similar morphological lesions of the liver can be observed in drug-induced hepatitis, acute alcoholic liver damage, septic and enterogenic hepatitis.
The leading risk factors for the development of NAFLD are age increase, metabolic syndrome and its components, abdominal obesity, hypertriglyceridemia, hyperglycemia, diabetes, and arterial hypertension. In addition to traditional ideas about the etiology and pathogenesis of NAFLD, a lot of new information has appeared about the links of pathogenesis that affect the course and prognosis of the disease [2].
The close relationship between diseases of the cardiovascular system and liver diseases is due to many different factors with different mechanisms, the joint unidirectional action of which leads to a worsening of the course of diseases of both organ systems. In cardiac pathology, liver damage can be both primary (developing independently) and secondary (due to worsening of cardiovascular pathology, lack of correction of dyslipidemia, obesity, DM) [3, 4].
When considering the incidence rates, a number of researchers pay attention to the fact that among Europeans with cardiovascular pathology, violations of the function of the biliary system are more common and cholelithiasis (GSD) develops approximately 1.5 times more often. Thus, among Europeans older than 70 years, the prevalence of cholelithiasis is about 14%, which is significantly higher than the average values ​​in the population. The majority of these patients are men with cardiovascular disease (CVD). These changes are caused by secondary NAFLD, the accumulation of lipids in the liver and the deterioration of the qualitative composition of the synthesized bile. Excessive saturation of bile with cholesterol (CS) leads to its crystallization and the formation of stones. Increased secretion of cholesterol into bile is accompanied by a decrease in the secretion of bile acids and, as a result, the development of biliary insufficiency. This mechanism contributes to the progression of atherosclerosis [5, 6].
The course of NAFLD in women has a number of features associated with changes in hormonal levels. The presence of steatosis or steatohepatitis in menopausal women complicates the course of CVD, increases the risk of complications by 3 times and worsens the prognosis. During menopause, the development of metabolic syndrome and insulin resistance against the background of reduced hormonal activity often leads to the development of polycystic ovary syndrome. This, in turn, contributes to the progression of the metabolic syndrome and further deterioration of the liver. Approximately 2/3 of these patients have non-alcoholic steatohepatitis. The development of atherosclerotic lesions of the heart and aorta in menopausal women occurs approximately 1.8 times more often [Ramilli, 2009]. The development of hormonal changes can affect the structure of the thrombus, which increases the incidence of cardiovascular complications [Hickman, 2009]. In recent years, menopause has been considered as a new independent predictor of CVD development [7].
In addition to the established pathogenetic links between diseases of the liver and the cardiovascular system, which can be considered as a comorbidity, there are a number of background diseases. Thus, the presence of alcoholic or non-alcoholic liver disease does not exclude the occurrence of autoimmune liver diseases in a patient, which can often be diagnosed in young women. With liver pathology, the occurrence of toxic or drug damage, the addition of viral hepatitis are also possible. Against the background of hereditary diseases or diseases with a genetic predisposition, for example, hemochromatosis, pigment metabolism disorders, enzyme deficiency or storage diseases, the development and progression of fatty liver disease or toxic damage is possible. Unfortunately, most patients suggest the possibility of the presence of only one of the diseases, excluding the occurrence of another pathology.
Differential Diagnosis
Differential diagnosis of liver diseases presents a certain difficulty, since in some cases there are no reliable and specific signs to identify liver damage, such as alcoholic and non-alcoholic fatty liver disease or drug-induced hepatitis. Often, key data from the anamnesis help out, it is important to clarify the habits of drinking and its amount, taking medications for all diseases in the patient, drug use, the duration of the onset of symptoms, if any, and the relationship with various factors.
Despite the huge variety of etiological factors and causes leading to the development of liver diseases, it is important that the pathogenesis of liver diseases occurs in a sequence called the hepatic continuum. Only the triggers and the prevailing outcomes are different.
All liver diseases (if we consider the morphological picture and changes in the structure of the organ) proceed in a certain sequence. This set of stages of liver damage constitutes a hepatic continuum with liver failure or hepatocellular carcinoma (primary liver cancer) as outcomes [8].
Classical diagnostics is based on determining changes in the structure of the liver and the stage of the process, as well as elucidating the etiology of the disease. Differential diagnosis is formed on the basis of 4 hepatic syndromes: cytolysis, cholestasis, hepatocellular insufficiency, immune inflammation [8]. However, from the standpoint of the Russian medical school and the clinical point of view, it is advisable to single out other therapeutic categories, such as membrane damage (cytolysis), intrahepatic cholestasis, lipid peroxidation, and toxic damage. International protocols and recommendations offer a variant for the differential diagnosis of cytolysis and cholestasis syndromes, shown in Figure 1 [9].
Choice of drugs for treatment,
hepatoprotectors
Differential diagnosis often requires a lot of time, however, during this period, the patient must receive some kind of therapy. Treatment of liver diseases should be comprehensive and include several components. Symptomatic treatment aimed at improving the patient’s well-being is usually not required due to poor symptoms. Etiotropic treatment can be prescribed only when the final diagnosis is established, and the fact of detecting cytolysis allows starting treatment with pathogenetic therapy [10].
The goals of pathogenetic treatment are the restoration of hepatocyte membranes and, as a result, a decrease in cytolysis, a decrease in liver damage, and a decrease in the risk of complications. The treatment standards of the European Society for the Study of the Liver (EASL) and the American Gastroenterological Association (AGA) provide for the appointment of cytoprotectors (hepatoprotectors) for this purpose [11, 12].
Russian standards for the treatment of liver diseases, approved by orders of the Ministry of Health and Social Development, also provide for the appointment of hepatoprotectors, which include essential phospholipids, ursodeoxycholic acid, milk thistle preparations (silibinin), ademetionine [13, 14]. However, treatment issues remain controversial to this day.
Hepatoprotectors (cytoprotectors) are a heterogeneous group of drugs, incl. and mechanisms of action. There are products of both plant and animal origin, as well as synthetic drugs.
The history of the treatment of liver diseases began with the use of methionine and the impact on the methionine cycle in hepatocytes (Fig. 2) [15, 16]. The special role of the essential amino acid methionine is associated with a mobile methyl group. With its help, methionine is involved in remethylation, deamination, decarboxylation (Fig. 3).
Remethylation is associated with the synthesis of creatine, adrenaline and choline, which is the precursor of acetylcholine and the most important lipotropic factor. An increase in the content of choline contributes to an increase in the synthesis of endogenous phospholipids and a decrease in the deposition of fats in the liver. The ability of methionine to donate a methyl group is due to its lipotropic effect. So, in atherosclerosis, methionine reduces the concentration of cholesterol and increases the concentration of blood phospholipids. The introduction of methionine causes a decrease in cholesterol levels in the blood and an increase in the level of phospholipids.
Methionine is involved in the metabolism of sulfur-containing amino acids, in the synthesis of epinephrine, creatinine, hormones, neurotransmitters, and vitamins. When there is a deficiency of active methionine, the synthesis of choline, lecithin and sphingomyelin, which are components of the nervous tissue, is disrupted.
An important positive aspect of the influence of methionine is its participation in maintaining a sufficient level of glutathione, a sulfur-containing peptide that protects hepatocytes from toxic damage by free radicals. Finally, by participating in sulfation reactions, methionine plays an important role in the detoxification of a number of metabolites. These effects are directly related to the protection of the liver from the toxic effect of ethanol [8, 17].
One of the stages in the development of hepatoprotective therapy was the use of ademetionine preparations, originally synthesized as antidepressants. Their mechanism of action is focused primarily on the methionine cycle and intrahepatic cholestasis.
Ursodeoxycholic acid preparations have a more choleretic effect, have a stabilizing effect on hepatocytes in intrahepatic cholestasis and viral hepatitis.
Milk thistle flavonoids were originally used in injectable forms as a specific antidote for toadstool poisoning. Their action is based on the normalization of intrahepatic transport of bile acids, glutathione interactions and detoxification processes; stimulation of protein synthesis on ribosomes is also noted, which is used in the treatment of toxic and viral hepatitis.
L-ornithine-L-aspartate preparations are used in the treatment and prevention of hepatic encephalopathy, their action is based on the effect on the ornithine cycle, nitrogen utilization and synthesis of glutathione [18, 19].
In the treatment of liver diseases, antioxidants that bind products of lipid peroxidation are used. However, their use currently does not have a sufficient evidence base. Pentoxifylline is used in the treatment of NAFLD as a tumor necrosis factor inhibitor. Metformin has also been used in the complex treatment of steatohepatitis in recent years, a number of studies show better results from the use of thiazolides [20–22].
Today, essential phospholipids remain the standard of therapy – indispensable means for the development and functioning of liver cells. The main fraction of essential phospholipids is represented by phosphatidylcholine, which is the main component of biological membranes. The pathogenetic basis for the implementation of this effect is associated with the regenerative properties of the liver, which determine the ability to produce new cell membranes, 65% consisting of phospholipids. Once in the body, phosphatidylcholine restores the integrity of the membranes of affected liver cells and activates phospholipid-dependent enzymes located in the membrane, thereby normalizing permeability and enhancing the detoxification and excretory potential of liver cells (Fig. 4) [23].
The main actions that phosphatidylcholine performs in the body are the restoration of the structure of hepatocyte membranes, antioxidant action (inhibition of lipid peroxidation and binding of free radicals), antifibrotic effect (prevention of the accumulation of type 1 collagen, increase in collagenase activity).
In addition to affecting cell membranes, essential phospholipids improve receptor functions, incl. insulin; increase the activity of lipoprotein lipase, which increases the breakdown of chylomicrons and very low density lipoproteins, and lecithin-cholesterol acyltransferase, which is involved in the formation of high density lipoproteins. Stimulation of triglyceride lipase by phosphatidylcholine promotes the release of fatty acids into the bloodstream and reduces hepatic steatosis. Essential phospholipids reduce the severity of liver steatosis not only in non-alcoholic steatohepatitis, but also in alcoholic, toxic liver damage [23].
The history of the study of essential phospholipid preparations began with research by F. Knüchel, published in 1979. He conducted experimental studies using hepatotoxic doses of alcohol. Control of changes in hepatocytes was carried out using a morphological study. As a result, data were obtained on the deformation and destruction of cell membranes under the influence of alcohol. The experimental group received the preparation of essential phospholipids, the control group did not receive therapy. At the end of the observation, the cytolysis rates in the treatment group decreased, and based on morphological studies, convincing data were obtained on the restoration of cell membranes [24].
To date, more than 250 studies of essential phospholipids have been conducted, showing the possibility of effective use of this group of drugs in various liver diseases. Allegations of an insufficient evidence base regarding essential phospholipids cannot be considered substantiated [25].
In particular, only in recent years, many randomized controlled trials have been conducted in patients with liver damage, incl. with associated pathology. Evidence was obtained of the positive effects of essential phospholipids (decrease in cytolysis, improvement in the morphological picture) [26, 27].
Four studies have also been published involving over 300 NAFLD patients with diabetes, obesity, or both. All studies have shown a significant improvement in liver function in those taking essential phospholipids compared with the control group, a decrease in the level of transaminases and lipids in the blood, as well as a decrease in signs of steatosis on ultrasound [28-30].
The management of patients with alcoholic liver disease using essential phospholipids has been studied in randomized and double-blind placebo-controlled trials. All studies have shown an improvement in liver function in patients treated with essential phospholipids compared to those in control patients. A trend towards an increase in long-term outcomes (3-year survival) has been shown [31, 32].
Based on the availability of high-quality clinical studies that determine the presence of a clinical base of essential phospholipids from the standpoint of evidence-based medicine, it can be recommended to make a choice in their favor if therapy with hepatoprotectors is necessary.
Foreign textbooks and standards include recommendations on the use of phosphatidylcholine in cytolysis syndrome as a pathogenetic therapy in order to restore the structure of cell membranes in combination with etiotropic treatment [33].
In recent years, combination preparations of essential phospholipids have become increasingly common. So, there are combinations with B vitamins, silibinin, glycyrrhizic acid, etc. At the same time, some of these combinations are ineffective or have a number of limitations in use. For example, the use of long-term courses of essential phospholipids combined with silibinin may be limited in patients with cholelithiasis.
Depending on the severity of cytolysis and the severity of the patient’s condition, it is necessary to use various hepatoprotectors. With moderately high and high cytolysis or the addition of signs of intrahepatic cholestasis, it is advisable to add ademetionine and ursodeoxycholic acid preparations to the complex therapy in an intensive short course. With high cytolysis or a general severe condition of the patient, pulse therapy with prednisolone is necessary with an initial dosage of 50 mg and a gradual decrease by 5 mg / week. The indication for hospitalization is moderately high and high cytolysis.
Choice of combination of hepatoprotectors
Taking into account the etiological significance of lipid metabolism disorders in the pathogenesis of liver lesions, it is advisable to use hepatoprotectors with the properties of metabolic correction [34–36]. This aspect is very important in the treatment of liver diseases in combined cardiovascular pathology, when the combination of several active substances with different mechanisms of action has a faster and more pronounced effect compared to monotherapy.
One such example is the combination of essential phospholipids 300 mg with methionine 100 mg (Eslidine). When taken simultaneously, methionine and essential phospholipids enhance each other’s action, being a source of endogenous and exogenous phospholipids, respectively.
Of interest are the results of one of the many studies conducted with the participation of 46 patients with NAFLD, which demonstrate a high hepatoprotective effect of combination therapy with methionine and essential phospholipids (Eslidine), faster normalization of clinical parameters, early positive dynamics of cytolysis and blood lipid spectrum, restoration of the liver structure [4, 10, 37].
Thus, the initially elevated level of total cholesterol decreased as a result of treatment without the use of lipid-lowering therapy (Fig. 5). In the control group, the cholesterol level decreased to 7.2 mmol / l (by 11%), in the group of patients taking Eslidin, to 5.6 mmol / l (by 28.7%). The decrease was mainly due to low density lipoproteins, the level of which fell by 25. 4%. Differences between groups were statistically significant. The data obtained indicate the mutual potentiation of action in the joint appointment of phospholipids and methionine [38].
In this regard, it seems appropriate to use combination therapy with methionine and essential phospholipids (Eslidin) in the treatment of combined liver pathology with predominant processes of cytolysis and peroxidation, lipid metabolism disorders. Against the background of complex therapy with drugs metabolized in the liver cytochrome system, the detoxification and hepatoprotective properties of the combination of methionine and essential phospholipids seem to be important.
Findings
It is necessary to conduct a qualitative differential diagnosis and determine the stage of liver damage in identifying syndromes of cytolysis and cholestasis in patients. It is unacceptable to make a diagnosis without excluding possible causes of cytolysis.
If a patient has a combined pathology, etiotropic and pathogenetic therapy should be prescribed, taking into account the prevailing processes in certain diseases or the current status of the patient.
Treatment of liver diseases should be comprehensive and include etiotropic (after diagnosis) and pathogenetic therapy (from the moment of detection of cytolysis or cholestasis).
It seems reasonable to use the combined drug Eslidin, containing essential phospholipids and methionine, when a cytolysis syndrome is detected as an undifferentiated pathogenetic therapy.

Literature
1. Vyalov S.S. Non-alcoholic fatty liver disease as a component of the metabolic syndrome: fatty liver and atherosclerosis // Consilium Medicum. Cardiology. 2012. No. 5. V. 14. S. 41–45.
2. Mednez N., Sanchez N.C., Chevez J. Strong association between gallstones and cardiovascular disease // Am J Gastroenterol. 2007 Vol. 50(3). R. 183-187.
3. Storozhakov G.I., Ivkova A.N. Pathogenetic aspects of fibrogenesis in chronic liver diseases. Klin. perspectives of gastroenterology, hepatology. 2009. No. 2. S. 3–10.
4. Vyalov S.S. Changes in the spectrum of immune markers and lipid spectrum in chronic liver pathology // Cardiosomatics. 2011. V. 2. No. 3. S. 67–73.
5. Targher G., Bertolini L., Pandovani R. et al. Prevalence of non-alcoholic fatty liver disease and its association with cardiovascular disease among Type 2 diabetic patients // Diab Care. 2007 Vol. 30(6). R. 1212–1218.
6. Vovk E.I. Treatment of non-alcoholic fatty liver disease in the practice of a therapist: what? Where? When? // RMJ. 2011. Vol. 19. No. 16 (409).
7. Drapkina O., Ivashkin V. The present and future of therapy for non-alcoholic fatty liver disease // Vrach. 2011. No. 7.
8. Vyalov S.S. Cytolysis syndrome in gastroenterology: management of patients in general practice // Consilium Medicum. Gastroenterology. 2013. No. 1. P. 42–48.
9. Vyalov S.S. Cholestasis syndrome: tactics of diagnosis and management of patients // Effective pharmacotherapy in gastroenterology. 2012. No. 6. P. 10–15.
10. Vyalov S.S. Clinical and pathophysiological aspects of hepatoprotective therapy in young people // Doktor.ru. 2011. No. 5 (64). pp. 42–48.
11. Ratziu V. et al. A proposal for current and future therapeutic strategies for NAFLD // EASL Special Conference “NAFLD/NASH and Related Metabolic Disease”, Bologna, Italy, 2009.
12. Chalasani N., Younossi Z. The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by AGA, AASLD, ACG // Gastroenterology. 2012. Vol. 142. R. 1592–1609.
13. Standard of care for patients with chronic active hepatitis, not elsewhere classified. Order of the Ministry of Health and Social Development No. 123, 2006.
14. Standard of care for patients with cirrhosis of the liver, not elsewhere classified. Order of the Ministry of Health and Social Development No. 122, 2006.
15. Wang H., Liu J. Descriptive study of possible link between cardioankle vascular index and homocysteine ​​in vascular-related diseases // BMJ Open. 2013 Mar 25. Vol. 3(3).
16. Unal E., Mungan S., Bilen S. The effects of lipoprotein(a) and homocysteine ​​on prognosis and risk factors in acute ischemic stroke // Int J Neurosci. 2013 Mar 11.
17. Mouralidarane A., Lin C., Suleyman N. et al. Practical management of the increasing burden of non-alcoholic fatty liver disease // Frontline Gastroenterol. 2010 Vol. 1. R. 149-155.
18. Kucheryavyi Yu.A., Morozov S.V. Hepatoprotectors: rational aspects of application. M., 2012.
19. Minushkin O.N. Ursodeoxycholic acid in the practice of a therapist. M., 2012.
20. Zein C.O., Yerian L.M. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial // Hepatology. Nov. 2011 Vol. 54(5). R. 1610–1619.
21. McCullough A.J. Thiazolidinediones for nonalcoholic steatohepatitis-promising but not ready for prime time // N Engl J Med. 2006 Nov 30 Vol. 355(22). R. 2361–2363.
22. Lavine J.E., Schwimmer J.B., Van Natta M.L. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial // JAMA. 2011 Apr 27. Vol. 305(16). R. 1659–1668.
23. Gundermann K.J., Kuenker A. et al. Activity of essential phospholipids (EPL) form soybean in liver disease // Pharmacological Report. 2011 Vol. 63. R. 643-659.
24. Knuechel F. Double-blind study in patients with alcoholic toxic fatty liver. Effect of essential phospholipids on enzyme behavior and lipid composition of the serum // Med Welt. 1979 Vol. 30. R. 411-416.
25. Guo S. Observation on treatment of fatty liver disease with polyene phosphatidylcholine // China Foreign Med J. 2007.
26. Du Q. Treatment of 52 cases with hepatic dysfunctional fatty liver with Essentiale // Chin J Gastro Hepa. 2004 Vol. 13.
27. Liang H. Discussion of treatment of fatty liver using polyene phosphatidylcholine capsules // Chinese med Fact Mine. 2006 Vol. 19.
28. Sun C., Zheng X., Tan Z., Cui F., Zhang R., Zhang H. Clinical observation on polyene phosphatidylcholine and metformin in the treatment of type-2 diabetes and non-alcoholic fatty liver disease // Clin focus. 2008 Vol. 23.
29. Yin D., Kong L. Observation for curative effect of Essentiale in treatment of fatty liver caused by diabetes mellitus // Med J Q ilu. 2000 Vol. 15. R. 277-278.
30. Arvind N., Savaikar P., Rajkumar J. Therapy for NAFLD. A comparative study of essential phospholipids vs ursodeoxycholic acid // Indian J Clin Pract. 2006 Vol. 16. R. 21–24.
31. Xu B., Ren C., Long B. Clinical Observation of 24 Cases of Essentiale Treating Alcoholic Fatty Liver // Sichuan Medical Journal. 2007 Vol. 28. R. 1116-1117.
32. Sas E., Grinevich V., Kravchuk U., Efimov O. Polyunsaturated phosphatidylcholine reduces insulin resistance and hepatic fibrosis in patients with alcoholic liver disease. Results of randomized blinded prospective clinical study // Journal of Hepatology. 2011 Vol. 54. R. 207.
33. Kuntz E., Kuntz H.-D. hepatology. Springer Press, Heidelberg, 2008.
34 Ratziu V. et al. A proposal for current and future therapeutic strategies for NAFLD // EASL Special Conference “NAFLD/NASH and Related Metabolic Disease”, Bologna, Italy, 2009.