Symptoms, diagnosis and treatment of pulmonary fibrosis after coronavirus

Pulmonary fibrosis - a process in which tissue grows - it gradually replaces alveolar tissue. The disease is dangerous because the patient suffers from respiratory failure, and the level of oxygen deficiency can shift to critical. The tissue that makes up the lungs loses volume, natural elasticity and stretchability. The compaction prevents normal gas exchange, and the patient experiences difficulty breathing due to the fact that oxygen and carbon dioxide cannot fully penetrate the walls of the alveoli. As a result, the lungs gradually lose their ability to function normally. How exactly the disease progresses largely depends on the location of the compaction, as well as on the causes that provoked the disease.

Lung tissue fibrosis can occur in one or both lungs. Therefore, there are several types of pathology: unilateral or bilateral. Also, the pathology can be focal or total. In the first case, a relatively small area of the lung suffers, in the second, the pathological process affects the entire organ.

Causes of the disease

Fibrosis can occur due to various reasons, for example:

Diseases associated with the respiratory system. As a rule, they occur in a chronic form: bronchitis, pneumonia, tuberculosis, etc.
Connective tissue pathologies.
The presence of external factors such as unfavorable environmental conditions, hazardous production.
Long-term treatment with certain medications.
Vasculitis.

The prognosis of the disease is unfavorable, and if measures are not taken, progression is observed, leading to pneumosclerosis and cirrhosis of the lungs. This significantly affects life expectancy and also reduces its quality.

Stages

The disease is usually classified into five stages:

Stage 0
– no disease;
Stage 1
– mild fibrosis (deposition of connective tissue around liver cells - hepatocytes and intrahepatic bile ducts);
Stage 2
– moderate fibrosis (formation of connective tissue septa – fibrous septa between the portal tracts located at the junctions of the hepatic lobules);
Stage 3
– pronounced fibrosis (formation of fibrous septa between the portal tracts and the central veins located in the center of the hepatic lobules);
Stage 4
– cirrhosis (disruption of the normal lobular structure of the liver – the formation of false lobules due to the formation of fibrous septa).

Symptoms of pulmonary fibrosis

At the first stage, the symptoms of pulmonary fibrosis include general malaise, decreased productivity, and fatigue. The skin turns pale, sometimes a bluish tint appears - this symptom often occurs on the fingers of the lower and upper extremities, above the upper lip. The patient suffers from insomnia, or, on the contrary, constantly wants to sleep. Shortness of breath also occurs, which occurs even in a calm state. Some patients experience rapid weight loss. Moreover, there is a risk of developing a dry cough, during which a small amount of sputum is released.

If pulmonary fibrosis is left untreated , it provokes changes in the shape of the fingers - the phalanges thicken and become spherical, and the nail plate becomes triangular.

Severe lung damage and lack of supportive therapy can cause heart failure. The condition is called cor pulmonale, which is manifested by the following symptoms:

The feet become swollen. Gradually the swelling spreads to the knees and thighs.
There is progressive shortness of breath.
The veins in the neck enlarge and pulsation is noticeable.
The patient experiences pain or discomfort in the heart area.

If left untreated

Ignoring the disease is a movement in the direction of cirrhosis, ascites, internal bleeding, and malignant neoplasms. These diseases should not be joked about. Thousands of people die because of them every year.

If you suffer from alcoholism and feel pain in the right hypochondrium

, stop and think: where will you go? Don't risk your health. Make an appointment with a narcologist and get coded, and then undergo effective treatment for fibrosis under the supervision of a hepatologist.

Diagnostics

Diagnosis of pulmonary fibrosis is accompanied by anamnesis. The doctor pays attention to shortness of breath, which can appear both with and without exertion. The specialist also finds out whether the patient has diseases that provoke fibrosis, for example, bronchial asthma, chronic bronchitis.

After a conversation with a visitor to the office, the doctor conducts an examination. He pays attention to the skin, the presence of swelling, changes in the shape of the fingers and toes. Next, listen and tap the lungs.

The doctor also prescribes a number of laboratory tests that will help establish an accurate diagnosis. This is a urine and blood test, biochemistry. Spirography is also prescribed, which allows you to determine the exact volume of the lungs and the speed at which the patient exhales air.

To visualize the disease, a chest x-ray is taken - as part of the study, it is possible to identify changes in the organ. If necessary, computed tomography and MRI are prescribed. If the patient is in serious condition, these techniques make it possible to quickly establish a diagnosis and begin treatment. In difficult cases, a biopsy is performed, which can confirm the presence of scar tissue.

Phosphogliv* – reliable protection

Domestic drug Phosphogliv *

represents an exception to this series.
Its active component - glycyrrhizic acid - in numerous experimental studies has demonstrated the ability to influence the key link in fibrogenesis - to suppress the production of connective tissue by stellate cells. This ability was confirmed in clinical studies of the drug Phosphogliv *
, which showed its beneficial effect on fibrosis in various liver diseases.

The drug has long been successfully used by doctors in the complex treatment of liver diseases. In addition, in patients with viral hepatitis who cannot, for one reason or another, receive antiviral treatment and are at particular risk for the development of fibrosis and cirrhosis, Phosphogliv *

used as a means of pathogenetic action.
The accumulated experience of medical use and the results of clinical studies have made it possible to include Phosphogliv *
in clinical recommendations and standards for the treatment of liver diseases.

Remember that only a doctor can diagnose a disease and prescribe appropriate treatment!

Pulmonary fibrosis after coronavirus

Pulmonary fibrosis after Covid is one of the complications that occurs after the virus. Penetrating into the body, it causes severe inflammation, which is why the immune system uses every opportunity to destroy the virus. However, this response triggers the release of inflammatory cytokines. It is the activity of these elements that makes it possible to determine the extent of lung damage. As part of the coronavirus, the alveoli and pulmonary vessels are affected.

After suffering from the virus, the lungs become less elastic, the damaged tissue is replaced by scar tissue and fibrosis forms. Despite the fact that the inflammation has been eliminated, breathing difficulties continue. If left untreated, fibrosis can progress.

With pulmonary fibrosis after coronavirus, the patient may complain of:

Shortness of breath that appears even when talking.
Headaches and dizziness.
Dry cough.
Weakness and feeling of fatigue.
Low level of endurance and performance.

Prevention and treatment of the disease

In liver diseases accompanied by the formation of fibrosis, its treatment is an extremely important task. But much more relevant and justified is the prevention of the development and progression of this condition. Despite the large number of studies in this direction, there are currently no specific drugs for the treatment and prevention of fibrosis. Thus, the most rational approach is to use drugs in the treatment of liver pathology that can prevent the development and progression of the disease.

At the present stage, a large number of drugs used for liver diseases are available. However, not many of them have a mechanism of action that allows us to discuss the possibility of their use for the prevention of the development and progression of fibrosis. And practically none of these drugs have demonstrated this capability in clinical studies.

Treatment of pulmonary fibrosis in Kaliningrad

If you are bothered by a cough, shortness of breath, wheezing, or need a preventive examination, make an appointment with us for a consultation. The Pulmonology Center is staffed by competent, responsible and caring paid pulmonologists.

We offer:

personal approach to each patient;
rapid laboratory diagnosis of lung diseases;
safe therapy at any stage of treatment: treatment of COPD, asthma;
recovery programs, including rehabilitation after coronavirus in Kaliningrad.

Make an appointment at the Pulmonology Center by phone 8 (4012) 971-961.

Is liver fibrosis reversible: pros and cons

Lecture transcript

XXV All-Russian Educational Internet Session for doctors
Total duration: 29:02

00:00

Oksana Mikhailovna Drapkina, Secretary of the Interdepartmental Scientific Council on Therapy of the Russian Academy of Medical Sciences, Doctor of Medical Sciences, Professor:

— We continue our work. Let's move on to the next section. Section "Hepatology". I am looking forward to this section with pleasure, since I will be conducting it in a team of two charming men (manly men). The first word is Professor Pavlov Chavdar Savovich. Is liver fibrosis reversible: pros and cons.

Chavdar Savovich, if I may. I want to say that all 5 thousand people who are watching us now. I want them to know that they will now be communicating with an expert who has just returned from the Cochrane Center. They have a unique opportunity to ask questions and get answers directly from your lips.

Chavdar Savovich Pavlov, Doctor of Medical Sciences:

— Thank you very much, Oksana Mikhailovna! With such heartfelt words from an incredible woman in front of our esteemed audience, I will certainly try to bring you all up to speed with my presentation on where we are currently with liver fibrosis.

As was said here in the previous meeting, where Elena Alexandrovna said that if she had spoken 5 years ago. I would say the same thing. If I spoke 5 years ago, the pros and cons that we are discussing now, I would probably divide them into 50% pros and 50% cons in order to look serious in this audience.

But speaking here today, I would say - of course, the arguments in favor of the reversibility of liver fibrosis and the data that have been accumulated to date allow me to say with a greater degree of confidence that liver fibrosis is now reversible. We are talking, first of all, about the extent to which we have the opportunity to reverse this process. Either achieve positive dynamics in the stage of liver fibrosis, or completely restore the liver structure.

02:13

So, liver fibrosis is a natural consequence of almost all liver diseases of any etiology. Here we are faced with a number of standard stereotypical processes that unfold in the liver. These are, on the one hand, the processes of chronic inflammation, which are opposed by the processes of regeneration of liver tissue.

At the heart of the imbalance between the processes of fibrosis and regeneration is the accumulation of extracellular matrix. This accumulation during chronic liver damage is 6-10 times higher than normal levels. The main source today (this has been shown in a number of studies), the main generator of excess extracellular matrix are Ito cells.

Normally, the pool of these cells in the liver constitutes approximately 10%–15% of all cellular structures in liver tissue.

I want to tell you right away that liver fibrosis, to one degree or another, is detected in approximately 45% of sectional cases that are carried out in connection with the death of people in developed countries.

If we approach that substrate, namely, Ito cells, which are the main producer of fibrosis in liver tissue. They are located in the so-called Disse spaces. These are functional spaces that are located between functional hepatocytes, between the main cells of the liver tissues and the endothelial vessels in the liver tissues.

As a result of excess accumulation and production of extracellular matrix. At rest, Ito cells are one of the depots of retinoids, vitamin A. As a result of an increase in their activity, they lose a pool of retinoids. They turn into active myofibroblast cells and begin to fill the space of Disse and the functional spaces that exist between endothelial cells in the vessels of the hepatic lobule. They begin to fill with components of the extracellular matrix.

04:40

Our lecture today is introductory and my goal is not to tell you the subtle links in the pathogenesis of fibrotic changes in chronic liver diseases of various etiologies. I am showing this slide so that in the future (when we discuss modern approaches to the treatment of liver fibrosis with the drugs that are being discussed with the goal of reversing this process) you will have a rough idea of the links at which these drugs act.

As stated here, the first link is liver damage. This is certainly the etiological factor that leads to liver damage. The next stage or next link, which is the target of most drugs that are either used to treat liver fibrosis, to prevent its further development or to reverse the process, are drugs aimed at reducing the necroinflammatory reaction in liver tissue.

The next link and final point that seems to be our goal in relation to the treatment of liver fibrosis is drugs that selectively affect the activity of Ito cells. To those specific cells that synthesize components of the extracellular matrix.

Of course, in the case when we have this imbalance (in particular, an imbalance that is characterized by a violation of components such as metalproteinase). These are matrix metalproteinases, which are responsible for the breakdown and synthesis of the extracellular matrix.

Naturally, at the level of this link in the synthesis of the extracellular matrix, potential drugs are currently being considered and developed. They can affect the balance of proteinases, which are responsible for the breakdown of the extracellular matrix.

On this slide you can see two main components that are responsible for either the progression process or the fibrinolysis process in liver tissue. These are matrix metalproteinases and their inhibitors. To date, 28 types of metalloproteinases are known - proteases that are responsible for the breakdown of the extracellular matrix.

Of course, depending on which components predominate in the composition of this extracellular matrix, we are dealing with the activity of various proteases that break down these components.

Violation of the delicate balance... Unfortunately, today it is difficult to achieve this balance. Why? There are many metalproteinases - this leads to the fact that proteases lead to necrosis and the development of severe inflammation of the liver. On the contrary, when their number decreases (tissue metalproteinase inhibitors predominate), we will face the progression of liver fibrosis.

08:05

Those models that were developed mainly in animals (researchers tried to get to the bottom of the delicate balance) could not maintain the fine line between the number of profibrotic factors and antifibrotic factors. In particular, this is the concentration and efficiency of matrix metalloproteinases.

One example is chronic hepatitis C. This is the etiological factor on the basis of which today a lot of evidence has been accumulated indicating the possibility of reverse development of liver fibrosis. Including at the stage of severe liver fibrosis - at the stage of liver cirrhosis.

Here we present long-term fibrosis against the background of chronic infection with the hepatitis C virus, which over 30-40 years leads to the development of liver cirrhosis. It must be said that today enough new clinical data have been accumulated that indicate that such a course of events... There are, of course, a lot of problems with regard to how to prove how severe fibrosis is.

Why? We very rarely resort to repeat liver biopsies in people, even if we are talking about ineffectiveness or lack of response to antiviral therapy. This is an opportunity to monitor the rate of progression of liver fibrosis.

I can only cite two studies that were conducted with patients with chronic hepatitis C. The data were published in 2005. In one study, 370 people (patients) from Ireland were included in the study. The second study is from Germany. There is a fairly large number of patients there - almost 2 thousand women who have been infected with the hepatitis C virus for 25 years.

They were given immunoglobulin for vaccination against viral hepatitis delta. These two thousand patients were followed for 25 years. The rate of development of liver fibrosis after such a massive infection with the hepatitis C virus was 4.4%. These patients showed advanced stages of liver fibrosis. Liver cirrhosis was present in 1.2% of patients. Hepatocellular carcinoma was recorded in only 0.1% of cases.

10:56

This slide presents the logical stages that I just talked about. Those additional etiological factors that may affect the rate of progression of liver fibrosis.

If an example is given here with chronic viral hepatitis C, co-factors of liver damage may include alcohol, co-infection with other hepatotropic viruses, lack of therapy, genetic factors that can lead to the predominance of certain factors of liver damage (obesity).

If we take alcoholic liver damage, then we can calmly consider the above factors. This is the presence of a viral infection, obesity, and so on. They can also aggravate and accelerate the progression of fibrosis in liver tissue. Age at the time of infection and unfavorable heredity also matter.

Listed here are several clinical examples of diseases that are accompanied by the development of liver fibrosis, and those factors that can affect the rate of progression of liver fibrosis.

If we talk about chronic viral hepatitis C, it is the presence of mutations in the hemochromatosis gene. You all know very well that excess iron aggravates the progression of liver fibrosis. The presence of angiotensin genes, a specific vector of the TGF-β gene, which is actively one of the mediators that stimulate Ito cells, cytokines such as TNF-β, microsomal epoxide hydroxylase, monocyte chemotoxic protein, and so on.

Here, of course, we are dealing with modified factors, that is, with those environmental factors that we can influence and successfully combat the influence of these factors. These are alcohol abuse, the presence of chronic co-infections with hepatitis B and delta viruses, and age of infection.

Why? Of course, if we talk about hepatitis B, if we are talking about vertical transmission of the virus, then the probability of developing chronic hepatitis B infection is 80-90%. If you acquire this virus at an older age, then the likelihood of developing chronic processes in the liver tissue is less likely.

Availability of liver transplants. Diabetes. Lack of therapy for its indications.

13:36

If we take alcoholic illness, here, as you can see, there are cytokines that play a certain role in the pathogenesis of alcoholic illness. I think now Alexey Olegovich will continue to talk about this in detail. These are cytokines such as interleukin 10. These are alcohol dehydrogenase, aldehyde dehydrogenase. This is a certain cytochrome P450 phenotype, the presence of TNF-? and so on.

If we talk about alcoholic liver disease, among the modified factors, first of all, we need to discuss alcohol consumption and repeated episodes of acute alcoholic hepatitis. Why? Of course, in patients (especially in patients with severe liver fibrosis), repeated episodes of acute alcoholic hepatitis worsen their life prognosis by approximately two times.

Other factors: infection with chronic viral hepatitis B and C.

If we look at non-alcoholic fatty liver disease, the genetic factors that matter are the presence of the hemochromatosis gene, a certain angiotensin genotype, and a certain TGF-? activity. Here, among the modified factors, it is necessary to mention: age, gender, degree of obesity of our patients.

Returning to the question that I asked at the beginning of my speech and which today is based on the clinical material that was discussed. On the treatment of patients with chronic viral hepatitis, patients with chronic viral hepatitis C, antiviral combination therapy, including at the stage of liver cirrhosis. This may lead to us blocking the further development of liver fibrosis and achieving positive dynamics in these patients.

When we are dealing with advanced fibrosis, already established changes in liver tissue, the presence of porto-, in particular the presence of portocentral septa, this is the factor that is one of the substrates for the development of portal hypertension. This fibrosis is best targeted. In these patients, it will be a matter of stopping further progression of liver fibrosis and achieving minimal improvement.

There will still be a certain group in which we can talk about partial restoration of liver tissue. These are patients with more advanced stages of liver fibrosis. Of course, this is a group of patients in whom we have enough time to achieve liver tissue remodeling and rapid and complete recovery.

16:34

So, factors influencing the reversibility of liver fibrosis. This is the genetic predisposition that I talked about, the variation of etiological factors (the duration and severity of the impact of these factors on the liver tissue), the localization, prevalence and stage of the fibrotic process (which we just talked about), the duration of the existence of fibrous tissue. In particular its components.

Why? There are certain components of fibrous tissue that are easily broken down by matrix metalproteinases; there are other components (type I, III, IV collagen) that are very difficult to break down and reverse development.

The balance discussed is between matrix metalproteinases and their inhibitors, which must be maintained to prevent further progression of liver fibrosis.

A few words about modern diagnostics of liver fibrosis, without which we cannot speak and cannot monitor the progression that we have in our patients. Why? In order to compare different rates of progression of liver fibrosis, we need at least a puncture biopsy of the liver over time: before the start of treatment and after the end of the course of treatment, in order to assess the dynamics of these processes.

Today we have another opportunity. This is a non-invasive diagnosis of liver fibrosis. Here I just presented our data, which has already been published in the Cochrane Database of Systematic Reviews. They relate to those serum blood tests (fibrotest and elastography of liver tissue) and ultrasound examination, which allows one to assess the dynamics of liver fibrosis over time during treatment.

18:34

Today's strategic directions for the development of those drugs that make it possible to simulate the process of fibrosis in liver tissue. The first and logical one. Elimination of etiological factors that lead to chronic liver damage.

This is the elimination of hepatotropic viruses (antiviral treatment). This is abstinence (refusing to drink alcohol).

This is the elimination of biliary obstruction when it comes to diseases involving the biliary tree.

Reducing the autoimmune process in our patients with autoimmune hepatitis, autoimmune crossover.

Correction of metabolic disorders in patients with non-alcoholic steatohepatitis.

Correction of the accumulation of those metals that accumulate in patients with hemochromatosis and Wilson's disease.

Taking antifibrotic drugs. This will be discussed further.

Of course, eliminating additional environmental factors (smoking cessation and weight loss), which may also contribute to the progression of liver fibrosis.

This slide presents the drugs that are currently used depending on the etiology of the corresponding chronic liver disease. They have undergone quite a large clinical examination and quite a lot of international studies. They have proven effective in terms of treatment and in terms of their antifibrotic effect.

If we talk about chronic viral hepatitis C, respectively, -interferon and ribaverin. If we talk about chronic viral hepatitis B, these are lamivudine, entecavir, and also interferons.

Alcohol disease: of course, here without such measures as giving up alcohol, abstinence, it is impossible to do with further or other therapeutic measures. Here two drugs are corticosteroids and pentoxifylline (a phosphodiesterase inhibitor), which were currently recommended in the guideline by the American Association for the Study of the Liver (in 2010). These are two drugs that are used to treat patients with acute alcoholic hepatitis.

These are essential phospholipids. They have their place in reducing the activity of Ito cells and allow them to restore their functional state.

21:30

If we talk about non-alcoholic fatty liver disease, this is the next large group of liver diseases. This is the correction of insulin resistance and lipid spectrum. Loss of body weight. Modifiable factors. Also the use of essential phospholipids.

The last group of diseases that I have the opportunity to mention is a group of diseases of the biliary tract. Here we are talking about the prescription of ursodeoxycholic acid.

Data again. Today, as I have already said, there are more and more of them. These are some of the first to be published. This is Poynard data from 2005. 160 patients with liver cirrhosis were observed. As you can see, against the background of antiviral therapy, it was possible to improve the condition of the liver tissue and reduce the stage of liver fibrosis.

As you can see, at baseline almost all 160 patients had cirrhosis of the liver. At the end of the treatment result, depending on the presence or absence of the virological response obtained, you can see that these patients were distributed across almost all stages that are less severe than F4 (that is, liver cirrhosis).

22:57

What are the current challenges in developing an ideal antifibrotic drug?

Of course, this is the very fact that the regression of liver fibrosis, like the process of fibrogenesis itself in liver tissue, is a process extended over time. It lasts more than three years. Whenever it comes to prescribing such drugs, this fact must be taken into account.

Those studies that are currently being carried out, of course, are conducted, again, I repeat, with different groups of drugs that act on different levels of regulation of the activity of this process. Those phenomena reported in the foreign press are associated (more to do with) laboratory animals than people.

One of the problems (I have already said) is the lack of methods that allow us to evaluate dynamic changes in liver tissue.

Lack of optimal risk stratification for fibrosis progression. One more problem. Why? As I already mentioned, several studies have shown that the rate of fibrosis, for example, in patients with chronic viral hepatitis C is quite slow.

The data that is being reported requires very careful verification so that we can be sure that this is not a real process of regeneration in liver tissue, which runs parallel to the inflammation we are talking about, but the results of the effectiveness of those antiviral and antifibrotic drugs that are used in this groups of patients.

I have already mentioned a liver biopsy, which is necessary over time to monitor the dynamics of liver fibrosis.

Of course, further development and the current lack of reliable non-invasive markers that would allow monitoring of this process over time.

The ideal profile, based on the above, of an antifibrotic drug should affect key pathogenetic mechanisms. In particular, it should, if possible, suppress the activity of Ito cells. When assessing its effectiveness, speaking from the perspective of evidence-based medicine and from the perspective of meta-analyses that are conducted to prove the effectiveness of a particular drug, it should reduce mortality from these liver diseases. Should lead to a decrease in the stage of liver fibrosis.

Must have a good safety profile and be suitable for long-term therapy. The tablet form has an advantage when it comes to this. Another important thing: an affordable price, which will allow you to use these drugs for a long time.

25:57

There are quite a lot of drugs on this slide. They are used to treat the main nosological forms of liver diseases, which we discussed above. These are also drugs that affect etiological factors (which I talked about). If we are talking about chronic viral hepatitis, these are drugs that have an antiviral effect. If we are talking about alcoholic liver damage, this is abstinence, which will lead to the elimination of the factor of damage to liver tissue.

The second group of drugs, as I mentioned above, are drugs that affect the necroinflammatory reaction in liver tissue. These are corticosteroid drugs. If we are talking about the same alcoholic liver - pentoxifylline. These are some cytokines.

Unfortunately, hopes for the treatment of acute alcoholic hepatitis were directed towards the clinical use of anti-cytokine drugs in clinical trials, many of which were discontinued due to the fact that higher mortality was observed in patients in whom combination therapy with anti-cytokine drugs was used , today do not live up to expectations.

The next group of drugs. This is the most targeted group of drugs. These are drugs with a selective effect on the activity of Ito cells. These are antioxidants, essential phospholipids, which help regulate the activity of Ito cells.

If we are talking about an imbalance between metalproteinases and their inhibitors, then there are a number of genetically engineered drugs. They are undergoing preclinical trials to correct the imbalance of factors that influence the progression of liver fibrosis.

In conclusion, allow me to once again recall the main points of my speech today.

Liver fibrosis is a natural consequence of chronic liver disease of any etiology. Liver fibrosis in its development leads to liver cirrhosis and hepatocellular carcinoma (an increase in incidence is observed throughout the world).

Liver fibrosis is a genetically determined process, but modifiable factors, as you have hopefully seen, play an important role in the progression of this disease.

Current evidence suggests the possibility of reversible liver fibrosis. Unfortunately, the results that were obtained in experimental animals do not currently receive the same confirmation of effectiveness in humans.

The ideal drug that we can talk about today is a drug that could selectively suppress the activity of Ito cells.

Thank you for your attention.

29:02

Literature:

Gazatova N. D. Changes in cellular and humoral blood parameters in alcoholic liver fibrosis. Dissertation of a candidate of biological sciences: 14.03.03. Place of protection: Institute of Experimental Medicine. - Kaliningrad, 2022. - 23 p.
Podymova S. D. Liver diseases: a guide for doctors. 4th edition, revised and expanded. - M.: Medicine, 2005. - 766 p.
Ivashkin V. T. Liver fibrosis. - Moscow: GEOTAR-Media, 2011. - 168 p.

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