RU2593007C1 - Method of treatment hepatic cirrhosis of various etiology - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention can be used for treatment of hepatic cirrhosis of various aetiologies. For this purpose, in case of hepatic cirrhosis of alimentary aetiology use is made, under pressure of complex therapy, of mesenchymal stromal cells in a dose of 180-190×10⁶ cells twice within 7 days, and, in case of hepatic cirrhosis of HCV etiology - of 200-210×10⁶ cells three times within 7 days, in case of primary biliary cirrhosis - of 220-240×10⁶ cells three times within 9 days.

EFFECT: method increases efficiency of treatment of hepatic cirrhosis of various aetiologies.

1 cl, 2 tbl, 3 ex

Description

The invention relates to medicine, namely to gastroenterology and can be used as a method of treating cirrhosis of the liver of various etiologies.

There is a method of treating hepatic cell failure in chronic hepatitis, including the appointment of essentials, legalon and cholistiramine, taken as an analogue (1 - Digestive diseases in children. A.V. Mazurin (ed.) M., 1989).

A known method of treating patients with Hbe Ag - negative chronic hepatitis B using lamivudine (2 - S.J. Hadziyannis et al. Hepatology. 2000, 32, 847-851), adopted as a prototype.

However, lamivudine monotherapy, according to the prototype method, the process is quite laborious and lengthy, requiring a three-year course of use, and with primary biliary cirrhosis its effectiveness is limited.

The aim of the invention is to increase the effectiveness of the treatment of cirrhosis of the liver of various etiologies.

The technical result is achieved by the fact that in cirrhosis of the liver of nutritional etiology, mesenchymal stromal cells are used in complex therapy at a dose of 180-190 × 10 ⁶ cells twice within 7 days, with cirrhosis of the liver of etiology, 200-210 × 10 ⁶ cells three times in 7 days, with primary biliary cirrhosis - 220-240 × 10 ⁶ cells three times within 9 days.

The method is implemented as follows.

Patients are admitted with a diagnosis of cirrhosis of the liver of mixed etiology. Class A-B-C in Child-Pugh (5-10 points). MELD (11-13 points). Portal hypertension: VRVP 2-3 degrees, expansion of the portal and splenic veins. Hypersplenism: thrombocytopenia of varying degrees. Dilated cardiomyopathy. NK 1. Encephalopathy of mixed origin.

Complaints of heaviness and discomfort in the right hypochondrium, aggravated after eating, general weakness.

From the anamnesis it is known that 10-12 years ago, the first diagnosis was made: Cirrhosis of the liver of nutritional etiology, class C according to Child-Pugh. Portal hypertension: splenomegaly, VRVP. After ligation of the veins of the esophagus, patients continued to lead an incorrect lifestyle. After 7 years, a virological examination revealed HBsAg and aHCV. Objective status: moderate state. Normostenic type of physique. The skin and visible mucous membranes are subicteric. Teleangiectasias. Palmar erythema. Gynecomastia In the lungs, vesicular breathing with a hard tint. ChDTs 14-16 per minute. Heart sounds are muffled. Heart rate 76-92 beats per minute. HELL 100/65 mm Hg The tongue is overlaid. The abdomen is enlarged due to subcutaneous fat, palpation sensitive in the right hypochondrium, the liver + 2.0-3.0 cm below the edge of the costal arch, dense texture with a sharp edge. The "striking" symptom is negative on both sides.

SURVEY DATA:

Ultrasound conclusion: diffuse changes in the liver. Hepatosplenomegaly. Portal hypertension. Enlargement and diffuse changes in the pancreas. Indirect ultrasound liver elastometry: liver elasticity corresponds to the stage of fibrosis - F 3-4 according to Metavir.

EFGDS. Conclusion: Varicose veins of the esophagus 2-3 degrees, endoscopic ligation, cardia failure.

ECG: normal position of EOS. Sinus rhythm, correct. Heart rate 76-92 beats. in 1 min. Echocardiography - conclusion: Aortic root of increased echogenicity, compaction of the walls of the aorta, MK cusps, sufficient opening, compaction of the MK cusps.

Puncture biopsy of the liver. Histological examination: conclusion - active cirrhosis, histological activity according to Metavir AT F3-4.

LABORATORY DATA: Urinalysis: specific gravity - 1025-30, white blood cells - no, urobilinogen - 42-45, glucose - no. Urinalysis: specific gravity - 1025, protein 0.1.,

IMMUNOLOGICAL SURVEY: RW - negative, HIV - no, anti HCV - detected, anti HBV detected. AFP - 1.3-5.2 IU / ml (normal 0-14.4); apolipoprotein - 112-132 mg / dl (normal - 90-170). AMA M2 - 0.3.

Cardiologist consultation: diagnosis - Dilated cardiomyopathy of mixed etiology. Recommended: Preductal MB 35 mg × 2 times (course 2-3 months × 2 times a year), healthy lifestyle. Observation of a cardiologist at the place of residence. Neurologist consultation: diagnosis - toxic encephalopathy. Mild cognitive impairment is predominantly dynamic.

In addition to the main therapy, MSC transplantation was performed. Mesenchymal stromal cells at a dose of 180-190 × 10 ⁶ cells are used twice during 7 days for liver cirrhosis of alimentary etiology, 200-210 × 10 ⁶ cells are thrice used for cirrhosis of HCV etiology three times within 7 days, and 220 for primary biliary cirrhosis -240 × 10 ⁶ cells three times for 9 days.

Against the background of the therapy, the condition of the patients improved. Pain and dyspeptic syndromes were stopped, b / chem decreased. blood counts, decreased phenomena of encephalopathy. Patients are discharged in satisfactory condition.

The method is further explained by examples of its implementation.

Example 1

Patient S., born in 1947, was admitted with a diagnosis of primary biliary cirrhosis, AMA-M2 - positive, stage 2. Child-Pugh Class A (5 points). Portal hypertension. Concomitant diseases: Chronic pancreatitis, remission stage. Chronic gastritis, remission phase.

Complaints of weakness, intense itching of the skin, worse in the evening, heaviness in the right hypochondrium after eating, darkening of the skin. Anamnesis: In 2000, she underwent examination and treatment, where she was diagnosed with primary biliary cirrhosis. Ursosan was prescribed, after which the itching of the skin intensified, in connection with which it was replaced by ursofalk. In 2007, aHCV was detected in the patient; HCV RNA was not detected. The last hospitalization with a diagnosis of Primary biliary cirrhosis, AMA M2 - positive. Class A (5 points) by Child-Pugh. Portal hypertension. Chronic pancreatitis, exacerbation. Examination in a blood test revealed a minimal increase in transaminases (ACT - 50.1 U / L; ALT - 58.0 U / L;) and cholestasis indicators (ALF - 204.1 U / L; GGTP-142.1 U / L). Ultrasound of the abdominal organs - diffuse changes in the liver. With ultrasound of the vessels of the abdominal cavity - portal hypertension. With EFGDS - chronic gastritis. AMA M2 - more than 200.0 U / L, ANA - 6.5. Anti HCV - not detected; RNA HCV - not detected. A liver biopsy was performed: conclusion - METAVIR A1 F2; chronic portal, periportal and lobular hepatitis of a low degree of activity. Primary biliary cirrhosis 2 stages. Ursofalk was treated with 1000 mg / day, heptral 400 mg iv. The patient revealed the presence of ANA. However, data for the cross syndrome during histological examination was not obtained, and therefore the diagnosis of autoimmune hepatitis is not confirmed.

In addition to the main therapy, a course of MSC transplantation was carried out (iv administration of 240 × 10 ⁶ cells, three times within 9 days). Last hospitalization in September 2013.

After discharge, she continued taking ursofalk. Received for a liver biopsy to evaluate MSC - therapy after 12 months.

Objective status: satisfactory condition. The skin is "dark" in color. Sclera is subicteric. Palmar erythema. In the lungs, vesicular breathing, no wheezing, NPV 16 per min. Heart sounds are muffled, the rhythm is correct heart rate 78 per min. HELL = 130/80 mm Hg The tongue is coated with white plaque. The abdomen is soft, painful in the right hypochondrium on palpation. The liver is enlarged +1.0 cm, below the edge of the costal arch. The spleen is not palpable.

SURVEY DATA:

Ultrasound scan: Liver - dimensions are increased (thickness of the right lobe - 13.4 cm, thickness of the left lobe - 6.3 cm), echogenicity of the liver tissue is increased, the structure is heterogeneous. The vascular pattern is depleted. The portal vein is 10-11 mm, not dilated. Gall bladder: Shape - not changed: Length - 4.9 cm, diameter - 2.0 cm. Walls not changed - 1.0 mm. Echogenicity is average. The structure is heterogeneous, the content is homogeneous, there are no calculi. Caliber of the common bile duct 3 mm. Pancreas: normal location, dimensions unchanged. Head - 23 mm, body - 12 mm, tail - 20 mm. The contours are uneven, clear, the structure is heterogeneous, the echogenicity of the tissue is increased. Wirsung duct 1.0 mm. The spleen is not enlarged. Contours - smooth, clear. The length is 114 mm, the diameter is 52 mm. Area - 38 cm ² . Splenic vein - 6 mm, not dilated. The sound properties of the kidneys are not changed. There is no free fluid in the abdominal cavity. Conclusion: diffuse liver change, enlarged liver, chronic pancreatitis. Ultrasound OBP: after a liver biopsy, the structure of the liver and kidneys is not broken, free fluid in the abdominal cavity is not detected.

Indirect ultrasound liver elastometry (fibroscan). Conclusion: liver elasticity - 4.8 kPa. The interquartile scatter is (1.2) kPa. The number of successful studies is 91%. Conclusion: the elasticity of the liver corresponds to the degree of fibrosis F 0 according to Metavir (absence of fibrosis).

Laboratory data

General urine analysis: ud weight - 1012, sugar - no, protein - neg., L - neg. Eritre. - no. Immunological examination: RW - negative, and HIV - not detected; HBsAg - not detected., Anti HCV - detected, HCV RNA - detected in the amount of 2.4 × 10 ³ ME.

Liver-9-Line: Myosin - 0.14; Desmin - 0.19; F-Actin - 0.14; LCl - 0.31; LKM 0.23; SLA / LP - 0.19; gpl2 () - 0.14; sp100 - 7.09; AMA M2 - 4.42; Cutoff-1.00 (+/-); Conjugate Control - 3.63 (+++); Serum Control - 5.14 (+++). Conclusion: AT sp100 and AMA M2, characteristic for PBC, AMA M2 (quantitative) <160 IU / ml. (Normal - 10.0) were revealed.

It is discharged in satisfactory condition. The prognosis of the disease is positive.

Example 2

Patient A., born in 1960. was admitted with a diagnosis of liver cirrhosis of nutritional etiology, minimal activity with cholestasis. Child-Pugh Class A (5 points). MELD (11 points). Portal hypertension: VRVP 3 degrees (Endoscopic ligation of VRVP), expansion of the portal and splenic veins. Hypersplenism: mild thrombocytopenia. Dilated cardiomyopathy with tricuspid valve insufficiency, NK 1. Toxic encephalopathy. Distal sensory polyneuropathy.

Concomitant diseases: Chronic pancreatitis, stage of moderate exacerbation. Chronic gastritis with erosion.

Complaints of heaviness and discomfort in the right hypochondrium, aggravated after eating, general weakness.

In the anamnesis: in 2009, the diagnosis was first made: Cirrhosis of the liver of nutritional etiology, class C according to Child-Pugh. Portal hypertension: splenomegaly, VRVP. The esophagus veins were ligated in 2009, and in 2010 sclerosis of the saphenous veins of the anterior abdominal wall. He continued to violate the prohibitions on lifestyle and nutrition. In 2012, the procedure was performed on the MARS apparatus. For the first time in January 2013 thrombocytopenia, edematous ascites syndrome was detected. Consulted, recommended examination and selection of therapy in the department of liver diseases. Objective status: moderate state. Normostenic type of physique. Increased nutrition. BMI - 31 kg / m2 The skin and visible mucous membranes are subicteric. Teleangiectasias. Palmar erythema. Gynecomastia In the lungs, vesicular breathing with a hard tint. NPV 14 min Heart sounds are muffled, the rhythm is correct. Heart rate 88 beats per minute. HELL 110/70 mm Hg The tongue is covered with a yellow coating on the root. The abdomen is enlarged due to subcutaneous fat, palpation sensitive in the right hypochondrium, the liver +2.0 cm below the edge of the costal arch, dense texture with a sharp edge. The lower pole of the spleen is palpated. The "striking" symptom is negative on both sides.

SURVEY DATA:

Ultrasound: conclusion: diffuse changes in the liver. Hepatosplenomegaly. Portal hypertension. Enlargement and diffuse changes in the pancreas. Indirect ultrasound liver elastometry. Conclusion: liver elasticity - 20.0 kPa. Conclusion: the elasticity of the liver corresponds to the stage of fibrosis - F 4 according to Metavir. An endoscopic examination: Varicose veins of the esophagus, grade 3, endoscopic ligation, cardia failure, chronic gastritis, stomach deformity, duodeno-gastric reflux.

MSCT of the brain. Conclusion: Organic pathology of the brain was not detected.

ECG: normal position of EOS. Sinus rhythm, correct. Heart rate 82 beats. in 1 min. Echocardiography - conclusion: Aortic root of increased echogenicity, densification of the walls of the aorta, MK cusps, sufficient opening, compaction of the MK cusps, antiphase movement. Dilation of the LP and the right heart. Global systolic function is not reduced. Violation of local contractility is not detected. Pericardium without features. With DCG: Mitral regurgitation 1 tbsp. Tricuspid regurgitation 3 tbsp. Pulmonary regurgitation 0-1 tbsp. Severe pulmonary hypertension.

Puncture biopsy of the liver. Histological examination: conclusion - active cirrhosis, histological activity according to Metavir AT F4.

LABORATORY DATA: Urinalysis: specific gravity - 1030, protein - OD., White blood cells - no, urobilinogen - 42, glucose - no. Urinalysis: specific gravity - 1025, protein 0.1., White blood cells, no red blood cells - no, urobilinogen - 200, glucose - no.

IMMUNOLOGICAL SURVEY: RW - negative, HIV - no. Anti HCV - not detected, anti HBV not found. AFP - 1.3 IU / ml (normal 0-14.4). 09/26/14 g: haptoglobin - 5.83 mg / dl (normal - 36-195); apolipoprotein - 122 mg / dl (normal - 90-170). AMA M2 - 0.3. Conclusion: Autoantibodies not detected.

In addition to the main therapy, MSCs were transplanted (iv administration of 190 × 10 ⁶ cells, twice within 7 days. A reaction in the form of hyperthermia was noted for the second administration of MSCs. Stopped: prednisone 30 mg.

Against the background of the therapy, the patient's condition improved. Pain and dyspeptic syndromes were stopped, b / chem decreased. blood counts, decreased phenomena of encephalopathy.

The patient is discharged in satisfactory condition.

Example 3

Patient K., born in 1952 was admitted with a diagnosis of liver cirrhosis of HCV etiology, minimal activity. Child-Pugh Class A (6 points). Portal hypertension: varicose veins of the esophagus 2 degrees. The expansion of the portal vein. Cardia insufficiency. GPOD 1 Art. Chronic gastritis. Duodenogastric reflux. Chronic pancreatitis, stage of remission. Cerebrovascular disease. Hypertension stage 2.

Complaints of heaviness in the right hypochondrium after eating, periodically skin itching, general weakness. anamnesis: there were no CVH and blood transfusions. At the age of 20 she suffered malaria, was twice treated, took quinine. Since 2000, suffers from cerebrovascular disease. In 2002-2005, she transferred ONMK. High levels of triglycerides and cholesterol were detected in the blood, and therefore took statins from 2007 to 2009. In March 2009, elevated levels of transaminases were detected (AcT - 271.0 U / L, ALT - 200.0 U / L). In September 2009, treatment with a diagnosis of Chronic cerebral ischemia. Cerebrovascular disease. Hypertension stage 2. ONMK (2002, 2005). ” In b.h. blood test: AcT - 181.0 U / L, Alt - 98.0 U / L; ALP 435.0 U / L. Ultrasound - hepatomegaly, diffuse changes in the liver. The treatment was carried out: Korenitec, thromboass, Magne-B6. Discharged with clinical and laboratory improvement. After discharge, she took essentiale for 3 months. In June 2010, during a control study in b / x. blood analysis, elevated levels of transaminases persisted (AcT - 248.0 U / L, ALT - 275.0 U / L). Ultrasound - hepatomegaly, diffuse changes in the liver (fatty degeneration). With endoscopic examination, varicose veins of the esophagus 2-3 degrees. Cardia insufficiency, subatrophic gastritis. In July 2010, inpatient treatment with a diagnosis of Cryptogenic cirrhosis of the liver, class A according to Child-Pugh (6 points). Portal hypertension: In the GDP of 2-3 degrees. Hypertension - stage 3. Hyperlipidemia. Type 2 diabetes mellitus, mild. ” In b.h. blood test - AcT - 108.0 U / L, Alt - 106.0 U / L; Alkaline phosphatase - 506.0 units / liter. AM A - 1.4 IU / ml (normal - 0-10), ANA - 0.4 IU / ml (0-1). With ultrasound, hepatomegaly, diffuse changes in the liver, pancreas. With EFGDS - varicose veins of the esophagus 2-3 degrees. Cardia insufficiency. The treatment was carried out: omez, anaprilin, enap, ursosan, heptral. Discharged with clinical and laboratory improvement. It has been observed since September 2010. Last hospitalization in November 2011 with a diagnosis of Cirrhosis, HCV etiology, moderate activity with cholestasis. Child-Pugh Class A (6 points). Portal hypertension: varicose veins of the esophagus 1 degree. Chronic pancreatitis, stage of moderate exacerbation. Chronic gastritis, remission phase. Cerebrovascular disease. Hypertension stage 2. An increase in the thyroid gland of 1 degree with a tendency to nodulation, euthyroidism. Psoriasis. In b.h. blood test - AcT - 66.4 U / l, ALT - 63.7 U / l; Alkaline phosphatase - 170.6 units / liter. AMA - 1.4 IU / ml (normal - 0-10), ANA - 0.4 IU / ml (normal - 0-1). Ultrasound - diffuse liver damage, chronic pancreatitis, chronic cholecystitis. With ultrasound of the vessels - portal hypertension. With ultrasound liver elastometry - F4 according to Metavir, corresponds to cirrhosis of the liver. With EFGDS - VRVP 1 degree, gastritis, duodeno-gastric reflux. A 2-fold infusion of mesenchymal stem cells was performed. Discharged with clinical and laboratory improvement. Received a routine examination 6 months after iv administration of MSCs.

Objectively: The condition is satisfactory. The skin and visible mucous membranes of normal color. Geleangioectasia. Palmar erythema. In the lungs, vesicular breathing. NPV 17 min Heart sounds are muffled, the rhythm is correct. Heart rate 80 per minute. HELL 120/80 mm Hg The tongue is coated with white plaque. The abdomen is not enlarged, painful in the right hypochondrium and epigastric region. The liver is enlarged +2.0 cm below the edge of the costal arch. The spleen is not palpable. The symptom of striking is negative on both sides.

Survey data

Ultrasound: Liver - increased in size (thickness of the right lobe - 16.7 cm, thickness of the left lobe - 5.4 cm), echogenicity of the liver tissue is increased, the structure is heterogeneous. The vascular pattern is depleted. The portal vein is dilated - 14 mm., The bile ducts are not dilated. The common bile duct is not expanded - 3.5 mm. Gall bladder: the form is not changed, the dimensions are not changed. The length is 6.2 mm, the diameter is 1.9 mm, the walls are not changed - 1.0 mm, the echogenicity is medium, the structure is homogeneous, the contents are homogeneous. Pancreas: normal location, enlarged. The head is 36 mm, the body is 18 mm, the tail is not visualized. The contours are even, fuzzy, the structure is heterogeneous, echogenicity is increased. Wirsung duct is not visualized.

The spleen is not enlarged. The contours are even, clear. Area - 40 cm ² . Splenic vein - 6 mm, not dilated. There is no free fluid in the abdominal cavity. CONCLUSION: moderate diffuse changes in the liver. The expansion of the portal vein. Enlargement and diffuse changes in the pancreas.

Indirect ultrasound liver elastometry (fibroscan). Conclusion: liver elasticity - 20.0 kPa. Conclusion: the elasticity of the liver corresponds to - F 4 for Metavir - severe fibrosis, cirrhosis.

Endoscopy: Cardia deficiency. GPOD 1 Art. Chronic gastritis. Duodenogastric reflux. X-ray examination of the chest organs: fresh focal and infiltrative shadows are not determined on the chest x-ray of the chest organs, the pulmonary pattern is not sharply enhanced due to the interstitial component. The roots of the lungs are structural. The aperture is not changed. The sinuses are free. The shadow of the heart is somewhat widened to the left. The thoracic aorta is sealed. Conclusion: mild pneumosclerosis. Dose load - 0.3 (mSv).

ECG: horizontal position of EOS, sinus rhythm, correct heart rate 94. Weakly expressed diffuse changes in the myocardium.

General urine analysis: ud weight - 1011, sugar - no, protein - no, l - neg.

Neurologist consultation: diagnosis: symptomatic focal fever of epilepsy with secondary generalized convulsive seizures. Mixed encephalopathy. It is recommended to continue treatment with antiepileptic drugs on an outpatient basis.

Treatment: table 5p, essential phospholipids with glycyrrhizic acid, pancreatic enzymes, vitamins B, C, PP inhibitor. Additionally, MSCs were transplanted (iv administration of 210 × 10 ^-6 cells (according to the protocol), three times within 7 days.

IMMUNOLOGICAL SURVEY: HBsAg - not detected, anti HCV - not found. Wasserman reaction - neg. At HIV - not detected. IgM - 211 mg%, IgG -1250 mg%, Ig A - 389 mg%.

Against the background of the therapy, improvement is noted, pain and epileptic syndromes stopped. It is discharged in satisfactory condition. The prognosis of the disease is favorable.

According to the claimed method, 21 patients with cirrhosis of the liver of various etiologies were treated. Patients were placed in clinical remission and discharged in satisfactory condition.

Claims (1)

A method for the treatment of cirrhosis of the liver, including drug therapy and the introduction of mesenchymal stromal cells, characterized in that the etiology of liver cirrhosis is preliminarily determined, and in case of liver cirrhosis of alimentary etiology, mesenchymal stromal cells are used in a dose of 180-190 × 10 ⁶ cells twice within 7 days, with cirrhosis of the HCV etiology, mesenchymal stromal cells at a dose of 200-210 × 10 ⁶ cells three times for 7 days, with primary biliary cirrhosis - mesenchymal stromal cells at a dose of 220-240 × 10 ⁶ cells three times s within 9 days.