Liver Diseases

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There are many German publications starting with 1950’s that confirm the value of fetal precursor cell therapy in the treatment of incurable liver diseases.

Compensated cirrhosis of the liver and chronic non-aggressive hepatitis have been treated by fetal precursor cell transplantation with success for the last four decades. Cirrhosis of liver and chronic hepatitis were very common in Germany in 1940 - 50 - ies. This was a result of severe epidemic (actually a pandemic) of viral hepatitis in Germany during WW2 and thereafter.

Since even today there is no effective therapy for damaged liver, fetal precursor cell therapy became a treatment of choice for incurable / untreatable liver diseases. 

All patients with hepatitis can be helped unless their disease is in the stage of acute inflammatory exacerbation or has advanced into the stage of portal hypertension (edema, ascites, bleeding esophageal varices, etc.).

If chronic alcoholism is the cause of liver cirrhosis, fetal precursor cell transplantation would be of value only if the patient would become a total abstinent.

For patients with chronic hepatitis it is mandatory to suppress an inflammatory process in the liver first, by other therapeutic means. With such approach the success of fetal precursor cell transplantation can be unexpectedly high. This applies also to chronic hepatitis C, the biggest menace of modern medicine. One cannot cure chronic hepatitis C because it is impossible to eliminate the virus causing it, but by repeated fetal precursor cell transplantation it is possible to keep viral load at low levels.

Liver cirrhosis is in 50% of cases due to alcohol abuse, particularly due to its metabolite acetaldehyde. But cirrhosis can be the end-stage of viral hepatitis, late result of storage diseases, or genetic enzymopathies, or due to blood flow obstruction. Here side-by-side necrosis, inflammation, fibrosis, nodular regeneration and vascular anastomoses development, take place. Hepatocyte damage is from lack of ATP due to disorder of cell energetic metabolism, from increased production of highly reactive oxygen metabolites, i.e. O2-, HO2, H2O2, and simultaneous lack of antioxidants, such as glutathione, or a lack of protective enzymes, i.e. glutathionperoxidase, superoxiddismutase, or due to blood flow obstruction.

Damaged hepatocytes release lysosomal enzymes that in turn release cytokines, and cytokines with cellular debris trigger activation of Kupffer cells in liver sinusoids, and attract inflammatory cells. Kupffer cells and inflammatory cells release growth factors and cytokines which

- change fat collecting Ito cells into myofibroblasts,

- turn incoming monocytes into active macrophages and

- trigger fibroblast proliferation.

Myofibroblasts and fibroblasts increase production of extracellular matrix which fills up Disse space. This fibrosis limits metabolism between blood in sinusoids and hepatocytes.

Increased extracellular matrix can break down and hepatocytes can regenerate. If necrosis took place only in the centers of liver lobules restitution ad integrum is possible. But if necrosis passed beyond the peripheral parenchyma of lobules, fibrotic septa develop and full functional regeneration cannot take place and nodules develop, i.e. cirrhosis, with cholestasis, portal hypertension, and metabolic liver insufficiency.

Harbers in 1954 induced severe liver damage by 24 intraperitoneal injections of carbontetrachloride over 12 weeks and then used bromsulfalein test to determine the extent of liver damage. In controls the liver disease had a progressive course, and all animals died. After cell transplantation bromsulfalein test values decreased considerably and animals survived. Oetzmann reported in 1959 on his treatment of rats with an experimental model of liver cirrhosis induced by thioacetamide. Rats treated by cell transplantation showed the highest survival rate of 36.6.% while those taking Prohepars only 13.3%. Rietschel in 1958 carried out a prophylactic cell transplantation prior to oral feeding via gastric tube of 2.0% solution of allyl alcohol, but that did not work, because one of the cardinal rules for the clinical effectiveness of cell transplants is the presence of damaged organ or tissue in the body of the recipient. [321]

After extensive experimental studies, major clinical studies were carried out in Germany by Rietschel [255] and Oetzman [95]. In Oetzman’s study the patients were divided into 3 groups: 1st group was treated by cholin, vitamins and diet, 2nd group by the same and prednisone, while 3rd group by cholin, diet and cell transplantation of liver, adrenal cortex, placenta. The 3rd group consisted of 210 patients, and the final evaluation was 2 years after cell transplantation. A success rate of 69% was obtained in the 3rd group of patients, for both chronic hepatitis and liver cirrhosis. Clinically it amounted to a diminished icterus, decreased hepatosplenomegaly, improved appetite and psychic state, normalization of laboratory tests, and even disappearance of palmar erythema and spider nevi. The general physical condition was improved for as long as 6 to 14 months, particularly in patients with chronic hepatitis or with transitional stages of chronic hepatitis leaning toward cirrhosis. [321]

A group of 22 patients with chronic liver diseases from a general medical practice that underwent any & all known therapies for chronic liver disease over many years, without any success, was offered a trial of cell transplantation: 7 patients had chronic hepatitis, 5 chronic hepatitis turning into cirrhosis, 3 patients liver cirrhosis, and 7 patients had hepatoses due to chronic alcoholism and drug abuse. Chronic alcoholism was a dominant clinical feature in 40.9% of patients, drug abuse in 22%, diabetes mellitus in 9.1%. The history of ascites was present in 13.6%.

Patients with chronic hepatitis received cell transplantation of mesenchyme only, 4 to 6 times a year. Patients with chronic hepatitis turning into cirrhosis received cell transplantation of liver and mesenchyme, 4 to 6 times a year. Patients with cirrhosis of liver received cell transplantation of liver only, 4 to 6 times a year. Patients with hepatoses received cell transplantation of liver only, 4 – 6 times a year, and they were not asked to change their lifestyle, i.e. they could drink or take drugs as before.

The most dramatic changes of SGOT, SGPT and LDH occurred in the group of hepatoses, where SGPT decreased 78%, and SGOT nearly as much, and also LDH improved. Patients with cirrhosis had a decrease of SGOT and SGPT by 38%, and LDH by 63.5%, which is remarkable. Patients with chronic hepatitis had a decrease of SGPT by 29%, SGOT by 26% and LDH by 43%, and those with chronic hepatitis turning into cirrhosis had a decrease of SGPT by 44%, SGOT by 33%, and LDH by 35%. The best results were obtained in patients where the duration of disease was between 1 and 4 years, while after 5 years the success was noticeably lower. In retrospect the patients with chronic hepatitis should have received cell transplantation of liver as well. [322]

German authors recommend that the patients with chronic hepatitis and liver cirrhosis receive fetal cell transplantation of liver, but also of adrenal cortex, spleen, placenta, exocrine portion of pancreas, mesenchyme, stomach/duodenum, intestine, hypothalamus. Patients with acute hepatitis, chronic hepatitis in active inflammatory stage, decompensated liver cirrhosis with ascites, portal hypertension, esophageal varices, must not be treated by cell transplantation.

A 38 years’ old male who ill in 1980 with hepatopathy of unknown etiology, i.e. the patient refused liver biopsy. Patient was treated by cortisone, etc., but was not feeling well and laboratory tests were abnormal at all times. Patient was advised that there is no treatment for him. Patient seeked another opinion and received lyophilized mesenchyme every 6 weeks altogether 8 times. All laboratory tests improved significantly and patient was feeling well. [300]

If chronic alcoholism is the cause of liver cirrhosis, fetal precursor cell transplantation would be of no value for a patient that could stop the addiction. A study of 87 alcoholic patients, one half of them men, with median age of 46 years, treated by a complex protocol of cell transplantation with 12 treatments by autohemotherapy, ozonetherapy, psychotherapy, including group therapy, brought on 95 - 100 % success based on a 13 months’ follow-up after the complex treatment in terms of general condition, overall performance, ability to concentrate, and the relapse frequency was reduced from 85% to 44%. Cell transplantation of placenta, heart muscle, liver, exocrine pancreas, spleen, thymus, gonads, anterior lobe of pituitary, brain cortex, cerebellum, thalamus, hypothalamus, spinal cord, was used. Two detailed case histories are included. [298]

For patients with chronic hepatitis it is mandatory to suppress an inflammatory process in the liver first by all other therapeutic means. With such approach the success of fetal cell transplantation can be unexpectedly high. 

Our own study of children with chronic persistent hepatitis and chronic aggressive hepatitis was presented at the 1st Symposium of Human Fetal Tissue Transplantation in Moscow, December 4 – 7, 1995, under the title “Experience with the use of human fetal tissues in chronic viral hepatitis and liver cirrhosis in children”. In 8 children, from 9 – 12 years of age, with chronic persistent hepatitis, the right lobe of liver decreased in size by 2/3, the left lobe by ½. and spleen by 2/3 in already 7 days after cell transplantation of liver, spleen, placenta, stomach/intestine, adrenal cortex, mesenchyme, total bilirubin level dropped 1/3, AST from 41 to 31 U., ALT from 40 to 34 U. Clinical appearance of toxicity disappeared in all children, ecchymoses decreased, spider nevi were less pronounced, skin re-gained healthy pink color, and all children were feeling better. Re-testing 4 - 6 months after cell transplantation showed that right lobe of liver was still decreased by 35%, left lobe of liver by 15%, while spleen reached the pre-treatment size. In 2 patients a Doppler study of portal vein and splenic vein were carried out before and after cell transplantation. The abnormally high parameters for portal vein were further increased after fetal cell transplantation in one patient, but decreased in the 2nd patient. The abnormally high parameters for splenic vein decreased substantially in both patients.

In 8 patients with chronic aggressive hepatitis, from 6 – 12 years of age, the right lobe of liver decreased in size 45%, left lobe by 30%, and spleen by 60% already 7 days after cell transplantation. Total bilirubin, AST, ALT, were lower to a similar degree as for chronic persistent hepatitis group. All children were feeling better, the toxicity disappeared, skin became rosy, the ecchymoses were substantially diminished, and so were spider nevi, subicterus present in one child decreased. All children were discharged home after 7 days.

Icterus causing malfunctions: Bilirubin from hemoglobin breakdown enters hepatocytes, and by glucuronyltransferase is conjugated into conjugated, i.e. ‘direct’ bilirubin, more hydrophilic, excreted into biliary tract, and thereby to intestines.

- pre-hepatic icterus is due to exaggerated bilirubin production, or resorption of large hematomas,

- intrahepatic icterus develops from the specific defect of bilirubin intake by hepatocytes, i.e. in Gilbert syndrome, defect of conjugation, i.e. in Crigler-Najjar syndrome, icterus neonatorum, or from a secretion of bilirubin into biliary pathways, i.e. Dubin-Johnson syndrome, Rotor syndrome,

- post-hepatic icterus is due to blockage of extrahepatic biliary passages.

For treatment of Crigler-Najjar syndrome fetal precursor cell transplantation of liver, placenta, basal ganglia, cerebellum, is advised.

Portal hypertension: Venous blood from stomach, intestine, pancreas, spleen, gallbladder, is brought via portal vein into liver, where after mixing with oxygenated blood from hepatic artery it comes in contact with hepatocytes. Approximately 25% of minute blood volume passes through liver. Resistance in portal vein is small: 4 - 8 mm Hg. With restriction of lumen of portal circulation the pressure in portal vein rises and portal hypertension develops. It can be

- pre-hepatic: portal vein thrombosis,

- post-hepatic: right heart insufficiency, constrictive pericarditis,

- intrahepatic:

pre-sinusoidal-chron. hepatitis,primary biliary cirrhosis

sinusoidal – ac. hepatitis, cirrhosis from chron. alcoholism

post-sinusoidal – Budd-Chiari syndrome, i.e. obstruction of large hepatic veins.

Portal hypertension leads to malfunction of all pre-hepatic organs: malabsorption, splenomegaly with anemia and thrombocytopenia, and diversion of blood via porta-caval anastomoses, whereby toxic substances from colon, i.e. NH3, biogenic amines, short-chain fatty acids, etc., by-pass liver, enter CNS and cause portal encephalopathy.

Intraportal implantation of fetal precursor cell transplants is the fastest way to get the clinical response in this therapeutic method.

Hepatorenal syndrome: Liver cirrhosis causes relatively frequently renal ischemia and subsequent oliguric kidney failure, and such clinical course is known as hepatorenal syndrome. In liver cirrhosis there is blood stasis in portal circulation due to fibrosis- caused narrowing of blood vessels. Capillary hydrostatic pressure grows and there is substantial increase of filtration of fluid intraperitoneally, i.e. ascites. As a result of high permeability of liver sinuses for proteins there is a substantial loss of proteins into extracellular space. Besides that damaged liver parenchyma produces less proteins. Hypoproteinemia develops, with increased filtration of plasma water and thereby development of peripheral edemas.