Can cirrhosis be represented with hepatomegaly

Liver damage from alcohol

Pathomechanisms and Therapyby Manfred V. Singer, Stephan L. Haas, Mannheim

High alcohol consumption can damage all organ systems, with damage to the liver playing a key role. Here, in turn, three stages can be distinguished, ranging from simple fatty liver to alcoholic hepatitis to cirrhosis of the liver.

Every German citizen consumes around 160 liters of alcoholic beverages per year (1). The average per capita consumption of pure alcohol in 2003 in Germany, which is one of the top European countries, was 10.2 liters. In general, consumption has decreased slightly over the past three decades. In the past few years, however, there has been a dangerous increase in the consumption of mixed alcoholic beverages such as "alcopops" in the group of young people in particular.

Excessive alcohol consumption not only leads to serious damage to health. It also has negative consequences for the national economy: 1.6 million people in Germany are considered to be dependent on alcohol. 2.6 million people abuse alcohol. Around eight million people tend to consume alcohol at risk. 40,000 people die each year as a result of alcohol abuse. Every fifth patient admitted to hospital has alcohol-related problems.

Overall, the economy incurs costs of more than 20 billion euros annually. Nevertheless, over half a billion euros are invested annually in advertising for alcoholic beverages. The state earns almost 3.5 billion euros a year through the taxation of alcoholic beverages.

High alcohol consumption can damage all organ systems, especially the liver, esophagus, stomach and intestines, pancreas and brain. At the same time, it is certain that the risk of carcinoma of the mouth and throat, esophagus, liver, intestines and breast is significantly increased. There is no knowledge of threshold values ​​for daily alcohol consumption that lead to the carcinomas mentioned. Moderate alcohol consumption is given protective significance due to the reduction in the risk of coronary heart disease and acute myocardial infarction by around 20 percent, with moderate consumption being the maximum daily intake of 20 grams of alcohol (corresponding to 0.5 liters of beer, 0.2 liters Wine) for men and 10 grams of alcohol (equivalent to 0.25 liters of beer, 0.1 liters of wine) for women (2).

Three clinical pictures

70 to 85 percent of the alcohol in the human body is absorbed in the duodenum and upper small intestine. Only about 20 percent are absorbed through the gastric mucosa (3). The absorbed alcohol reaches the liver via the portal vein, which is of the greatest importance with regard to the breakdown of alcohol. Over 90 percent is metabolized here. With the alcohol dehydrogenases - ADH, the microsomal ethanol oxidizing system - MEOS and the catalase, three enzyme systems are involved in the breakdown of ethanol to acetaldehyde.

Alcohol dehydrogenases can be detected in the cytoplasm and catalyze the conversion of ethanol to acetaldehyde with the reduction of NAD + to NADH. There are different ADH isoenzymes, which are divided into classes I to III, whereby subgroups are again differentiated. Class I ADH 1 has the highest substrate specificity for ethanol.

The microsomal ethanol oxidizing system - MEOS - is only used when the blood alcohol concentration is high. This enzyme system can be detected in the membrane of the smooth endoplasmic reticulum (ER). The most important enzyme in this protein complex is cytochrome P450, which is assigned a central role not only in alcohol metabolism, but also in the breakdown of numerous hydrophobic endogenous and foreign substances and, for example, numerous drugs.

The subtype cytochrome P450 2E1 (CYP 2E1) has the most important role in the breakdown of alcohol to acetaldehyde. Charles Lieber was able to show for the first time in 1968 that regular alcohol consumption leads to the induction of this enzyme system by a factor of up to 10 (4). A special feature is that oxygen radicals are released during this reaction. The percentage of catalase that can be detected in the peroxisomes is only responsible for the oxidation of ethanol.

The acetaldehyde released by the oxidation of ethanol is converted to acetate by aldehyde dehydrogenases - ALDH, whereby 1 to 4 different isoenzymes are known with ALDH. ALDH 1, 3 and 4 are in the cytoplasm of the liver cells, ALDH 2 in the mitochondria.

With regular high alcohol consumption, two other enzymes are important in the breakdown of acetaldehyde to acetate: Both xanthine oxidase and aldehyde oxidase produce free toxic radicals that contribute to alcohol-mediated liver damage.

The pattern of alcohol-degrading enzymes shows clear ethnic differences: Asians, for example, primarily have the β2 subtype of ADH, which, in contrast to the β1 variant of ADH found in Caucasians, converts alcohol into acetaldehyde 20 percent faster. At the same time, 50 percent of Asians lack a functional ALDH. As a result, ethanol is quickly converted to acetaldehyde, but cannot be further metabolized and so accumulates. The result is alcohol intolerance with nausea, vomiting and flushing symptoms.

With fatty liver (steatosis hepatis), alcoholic hepatitis (alcoholic steatohepatitis - ASH) and alcoholic liver cirrhosis, a distinction is made between three clinical pictures as a result of alcohol damage to the liver. It should be noted that there are often overlaps: in alcoholic hepatitis there is often fatty liver disease, in alcoholic liver cirrhosis there may be signs of alcoholic hepatitis.

Fatty liver regression is possible

Up to 40 percent of people whose daily alcohol intake exceeds the limit values ​​for moderate alcohol consumption develop fatty liver disease, which can regress within three to four weeks, depending on the degree of obesity (5).

Fatty liver is when more than 50 percent of the liver cells are fatty. Strictly speaking, a puncture of the liver is required to establish the diagnosis, but this is only done in a few cases in practice. The simplest method for detecting fatty liver is sonography, which has a sensitivity of over 90 percent. A dense, "light" liver parenchyma is typical. The liver is usually enlarged (hepatomegaly) and the edges of the liver are rounded. Even during the physical examination, percussion, i.e. tapping the body surface, can detect an enlarged liver, whereby the enlargement of the liver alone can have a variety of causes. In addition to excessive alcohol consumption, obesity, diabetes mellitus or the use of medication such as corticosteroids and tetracyclines can lead to fatty liver disease.

As a rule, patients with fatty liver do not report any complaints. Occasionally, the enlarged liver can cause uncharacteristic upper abdominal complaints. In some cases, an increase in the g-GT or the transaminases GOT and GPT can be demonstrated in laboratory tests. Usually, however, the liver values ​​are not elevated.

 

Diagnostic parametersg-GT or Gamma Glutamyl Transferase (GGT): GGT or g-GT is a membrane-bound enzyme that is found in the tubular cells of the kidneys, in the pancreas and in the liver, among other things. The GGT is suitable for the differential diagnosis and monitoring of the progression of liver diseases as well as for the control of chronic alcoholism. Reference ranges: men up to 55 U / l, women up to 38 U / l. The increase in GGT is one of the most sensitive indicators of hepatobiliary disease, but it is only indicative of liver damage if liver-specific enzymes such as ALT and GLDH are also increased. Normal GGT values ​​rule out hepatobiliary disease with a high degree of probability.
GOT - Glutamate oxaloacetate transaminase, old name for AST - Aspartate aminotransferase: AST is also present in a large number of tissues, with the liver being the organ with the highest AST activity alongside skeletal muscle. The AST is of great importance for the diagnosis, prognosis and early detection of liver diseases, among other things. It is usually determined together with other liver enzymes such as ALT, cholinesterase - CHE, alkaline phosphatase - AP and lactate dehydrogenase - LDH. Reference ranges: men up to 35 U / l, women up to 30 U / l. Chronic liver diseases such as chronic hepatitis and liver cirrhosis usually show smaller increases in AST, while acute flare-ups lead to a stronger temporary increase in the activity of the enzyme.
GPT ­ Glutamate pyruvate transaminase, old name for OLD ­ Alanine aminotransferase: ALT is an enzyme that is mainly dissolved in the cytoplasm of the liver cells. If you measure elevated ALT levels in the blood, this indicates a disruption or destruction of the cell membrane. The level of the ALT concentration correlates with the number of liver cells affected. With a relatively short half-life of around 47 hours, ALT is suitable for monitoring the progression of liver damage. Reference ranges: men up to 45 U / l, women up to 35 U / l. ALT values ​​above a factor of 15 of the normal value indicate acute liver cell death. If the de-ritis quotient (AST / ALT) is below 1.0, it is more likely to be caused by slight liver damage.

 

In addition to the g-GT, the so-called mean corpuscular volume - MCV and the carbohydrate-deficient transferrin - CDT are diagnostic parameters for a regular alcohol consumption and can help to clarify the cause of fatty liver in practice. In combination, these parameters achieve a specificity of> 85 percent as evidence of regular and excessive alcohol consumption. If 60 g of alcohol are consumed per day for at least two weeks, an increase in the CDT value is to be expected (6). However, an isolated increase in g-GT should be attributed with caution to regular alcohol consumption, since a low specificity can be assumed here.

 

glossary MCV = mean corpuscular volume, mean volume of the individual erythrocytes; MCV (fl) = hematocrit (l / l) / erythrocyte count (1012 / l). Increased in alcoholism.
CDT = carbohydrate deficient transferrin, also desialotransferrin, syn. Carbohydrate-deficient transferrin, transferrin characterized by a reduced content of carbohydrates, determination in the serum for the detection of chronic alcohol consumption or alcohol abstinence after previous abuse.

 

The most important measure in the case of proven alcoholic fatty liver disease is the restriction of alcohol consumption or abstinence, which then usually leads to a complete normalization of the liver changes. Contrary to previous beliefs, we now know that fatty liver is significantly more vulnerable to noxious substances such as drugs than non-fatty liver (7).

Hepatitis as a precursor to cirrhosis

Alcoholic hepatitis (alcoholic steatohepatitis, ASH) is characterized by regular alcohol consumption in connection with histological changes in the liver, which F.B. Mallory were described in detail and still apply unchanged today. In 1981, an expert conference established the following histological changes that are found in this clinical picture: ballooning degeneration of the hepatocytes, Mallory's bodies, inflammatory infiltrates and, above all, neutrophils, fibrosis and fatty liver (non-obligatory) (8).

The ballooning degeneration of hepatocytes is understood to mean an enlargement of the hepatocytes, which is based on an accumulation of proteins in the liver cell. If the cytoskeleton is damaged by acetaldehyde, the release of proteins is restricted. In these altered hepatocytes there are often intracellular protein aggregates known as Mallory bodies.

According to recent studies, alcohol leads to damage to the intermediate filaments of the cytoskeleton. Characteristic features are increased phosphorylation of the intermediate filaments, a shift in the ratio in favor of cytokeratin 8 to cytokeratin 18, and the binding of protein p62 and ubiquitin to the altered intermediate filaments (9).

Histologically, these changes can be shown impressively using antibodies against cytokeratin or ubiquitin. Mallory bodies, however, are not specific for alcohol-induced liver damage, but are also found in non-alcoholic steatohepatitis (NASH), copper storage disease Wilson's disease, primary biliary cirrhosis (PBC), and focal nodular hyperplasia (FNH) ) or liver cell carcinoma.

The inflammatory cells are primarily represented by neutrophils, which are found in particular around ballooned hepatocytes with Mallory bodies. An obligatory characteristic of alcoholic hepatitis is the evidence of fibrosis, i.e. increased extracellular deposition of collagen, which is found in the center of the lobule around the liver veins and from here can spread over the entire liver.

The clinical picture of patients with alcoholic hepatitis is very variable and ranges from complete freedom from symptoms to life-threatening liver failure and high mortality. It is difficult to make precise statements about the frequency of alcoholic hepatitis, since alcoholic hepatitis can be present even if the patient is completely free of symptoms. The average 30 day mortality in hospitalized patients is 15 percent, in severe cases the short-term mortality increases to over 50 percent. In addition to the volume of alcohol consumption, it is gender (higher risk in women), concomitant diseases such as diabetes mellitus or obesity, and genetic factors that have an impact on the education and severity of alcoholic hepatitis.

Laboratory chemistry shows an increase in transaminases (GOT / AST and GPT / ALT) as an expression of liver inflammation. A higher increase in GOT compared to GPT (De Ritis quotient: GOT / GPT> 2) is indicative of an alcoholic genesis of the liver inflammation. Often the g-glutamyltransferase (g-GT) and the serum bilirubin are also pathologically elevated. In severe cases, which can lead to liver failure, there is leukocytosis and the liver synthesis parameters (Quick value, coagulation factors) are limited to such an extent that bleeding can occur.

High serum bilirubin levels, impaired kidney function, and impaired coagulation are predictive markers for high hospital mortality. However, if the serum bilirubin value falls below 5 mg / dl, the four-week hospital mortality is zero and the mortality after an average of 30 months is 22 percent (10). A significant number of ASH patients with severe disease already have cirrhosis of the liver. It can be assumed that two thirds of all patients with severe alcoholic hepatitis develop cirrhosis of the liver as the disease progresses. After all, a quarter of all patients with mild to moderate alcoholic hepatitis will develop cirrhosis of the liver in the following years.

Abstinence is inevitable

The most important measure in the treatment of alcoholic hepatitis is to completely abstain from alcohol. However, in contrast to men, complete abstinence from alcohol appears to prevent the transition to cirrhosis of the liver in women only to a lesser extent.

Alcoholic patients often show malnutrition, which at the same time has an adverse effect on the survival of patients with severe alcoholic hepatitis. Therefore, vitamin deficiencies should be treated by giving thiamine (vitamin B1), vitamin B6, folic acid and, if necessary, vitamin K. In particular, patients who have already developed cirrhosis of the liver often show protein malnutrition. Adequate protein intake must be ensured, as cirrhotic patients have an increased protein requirement of 1 to 1.5 g / kg body weight (11).

Although it has been investigated in around 15 randomized studies with a total of over 900 alcohol hepatitis patients, the benefit of glucocortocoid therapy continues to be controversial. Meta-analyzes have shown that short-term mortality is only reduced by up to 37 percent in patients with severe forms of alcoholic hepatitis (12). Concurrent infections are a contraindication, as glucocorticoid therapy increases the likelihood of fatal infections due to its immunosuppressive effect.

The phosphodiesterase inhibitor pentoxifylline, which is used to treat peripheral and central nervous circulatory disorders, represents a new therapeutic strategy for the treatment of severe alcoholic hepatitis, although studies on large patient populations are still pending. In a first pilot study, short-term mortality was reduced from 46 to 25 percent compared with the placebo group (13). The mechanism of action originally discussed was the inhibition of the synthesis of TNFα as one of the most important proinflammatory inflammation mediators. Studies show that pentoxifylline as a hemorheological agent improves kidney perfusion and thus ultimately reduces the risk of kidney failure in alcoholic hepatitis.

Destruction of the liver architecture

17,000 people die in Germany every year as a result of alcoholic liver cirrhosis, with around 50 percent of all liver cirrhosis resulting from excessive alcohol consumption. Years of high alcohol consumption can lead to a complete destruction of the liver architecture. The death of hepatocytes is accompanied by a massive, uncontrolled formation of new connective tissue.

Already drinking 30 g of alcohol per day significantly increases the risk of liver cirrhosis (14). If the early stages of liver fibrosis are still reversible, liver cirrhosis is an irreversible condition that leads to impaired liver function in the later stages.

Portal hypertension, the increased pressure in the supplying portal vein, favors the development of ascites, i.e. an accumulation of tissue fluid in the abdominal cavity, as well as the formation of esophageal varices, which can lead to life-threatening heavy bleeding if ruptured. Furthermore, the limited hepatic detoxification function in the late stage leads to hepatic encephalopathy, which is characterized by tiredness and even comatose states.

The diagnosis of cirrhosis of the liver can be made with the help of sonography. Here, there is a "clumped" liver with an inhomogeneous internal echo and a wavy surface contour. The laboratory parameters can be normal in the early stages and are therefore not a sufficient detection method for liver cirrhosis.

Laparoscopy or laparoscopy, in which the liver can be inspected directly through small access points and also targeted samples of the liver can be obtained for histological evaluation, is a modern method of reliably diagnosing liver cirrhosis. Alcoholic cirrhosis of the liver is typically a nodular liver cirrhosis, whereas cirrhosis of other etiologies has a large nodular aspect.

Manifest liver cirrhosis can only be treated symptomatically with medication. Complications require frequent inpatient hospital stays. The only causal form of therapy is liver transplantation, which, however, requires at least six months of abstinence and an intact social and family network.

Liver cell carcinoma can be viewed as a late complication of alcoholic liver cirrhosis. Chronic alcohol consumption of 80 g / day for more than ten years increases the risk tenfold (15).

Multifactorial process

Damage to the liver by alcohol is a highly complex, multifactorial process that has been described more and more precisely in recent years, especially through the use of animal studies. Different processes can be differentiated with changes in the redox potential due to the metabolism of alcohol, damage to the liver due to acetaldehyde or autoantibodies, the release of inflammatory mediators (cytokines), oxidative stress, hepatic hypoxia and the activation of hepatic stellate cells and fibrosis.

With regular high alcohol consumption, the metabolism of ethanol in the liver leads to fundamental changes in a large number of biochemical reactions. The breakdown to acetaldehyde by ADH results in a change in the redox potential in the hepatocytes due to an increase in NADH and a decrease in NAD +.

The most important consequence is the restriction of the metabolism of fatty acids via the β-oxidation with at the same time increased fatty acid new synthesis due to the alcohol-mediated activation of the enzyme fatty acid synthase. These fatty acids are increasingly esterified with glycerine and deposited as triglycerides in the hepatocytes. The result is fatty degeneration of the liver. The inhibition of pyruvate oxidation also results in reduced gluconeogenesis, which favors the development of hypoglycaemia. But the function of the citrate cycle is also influenced by the changed redox potential.

Acetaldehyde as a breakdown product of ethanol is toxic and forms stable bonds with proteins and DNA that damage the function of the liver cells. The release of secretory proteins is impaired by binding to structures of the cytoskeleton. The membranes of the mitochondria are also transformed in such a way that the hepatocytes are destroyed. In addition, the cell components are modified in such a way that they are recognized as foreign antigens and trigger immunological reactions that contribute to antibody-mediated liver damage. As a result, autoantibodies can be detected in alcoholics (16, 17).

The release of inflammatory mediators such as TNFα, interleukin-1, interleukin-6, and interleukin-8 contribute significantly to liver damage (18, 19). High alcohol consumption leads to a reduction in the intestinal barrier function through damage to the intestinal mucosa and promotes the overgrowth of bacteria in the small intestine (20). As a result, more components of the cell wall of Gram-negative bacteria reach the liver via the portal vein (21). These endotoxins activate so-called Kupffer cells in the liver as local macrophages in the liver, which produce numerous cytokines such as TNFFα, IL-1,

Release IL-6 and IL-8 (22). These cytokines lead to inflammation of the liver and mediate the migration of neutrophils and T lymphocytes from the blood system to the liver. The cytokines released by the Kupffer cells in turn induce the production of cytokines in the liver cells. The release of highly reactive oxygen radicals, which attack all structures of the liver cell (membranes, DNA, enzymes, structural proteins), is referred to as oxidative stress (23). Membranes in particular are damaged by lipid peroxidation.

Oxygen radicals are not only formed when ethanol is broken down via cytochrome P450 and when acetaldehyde is broken down via xanthine oxidase and aldehyde oxidase (24). Immigrating neutrophils and Kupffer cells also release them. The oxidative stress is also intensified by the breakdown of physiological protective mechanisms. Alcohol leads to a reduction in glutathione, which has a central function as a radical scavenger (25). The degradation of ethanol in the liver is accompanied by a lack of oxygen and thus causes hypoxic damage. Hepatic stellate cells, which make up five to 15 percent of all liver cells, play a central role in the excessive formation of new connective tissue in liver fibrosis and cirrhosis. Acetaldehyde, the main metabolite of ethanol, stimulates cytokines and radicals to activate these dormant cells, which undergo a fundamental change: They differentiate into myofibroblasts, which produce large amounts of collagen, proteoglycans and glycoproteins such as fibronectin and laminin and deposit them extracellularly. This results in increasing fibrosis of the liver, which ultimately leads to liver cirrhosis (26, 27).

 

Little history of alcohol The consumption of alcohol has been a cultural part of human life for thousands of years, with alcohol having different functions over time. It served as food, pleasure, intoxication, sacred and finally also medicine. Alcohol was and is used to facilitate interpersonal contacts and solve social problems.
The oldest records of the production of beer can be found with the Sumerians, who lived in Mesopotamia around 5000 BC. Between Euphrates and Tigris - today's Iraq - lived. Beer production was monitored by the state or priests and part of the wages was paid in beer. While workers were entitled to two liters of beer a day, officials and priests were entitled to five liters a day. However, it must be noted here that the alcohol content probably did not exceed two percent by volume.
For the Egyptians too, beer was of great importance alongside wine, which was reserved for the higher classes. 20 different varieties were known. Beer was a staple food. It served as a salary for civil servants and slaves and was drunk with the help of drinking tubes from clay jugs to hold back solid residues. It was shipped and exported in hermetically sealed containers. As king of the Babylonians, Hammurabi (1728 - 1686 BC) established a collection of laws. His "Codex Hammurabi" contains the oldest wine law known to man. The collection of paragraphs strictly regulated not only the proper production, but also the serving of beer. Failure to comply could face draconian penalties. Bierpanscher were drowned in their stretched beer. The Greeks and Romans preferred wine and expressed themselves disparagingly about the "drink of the Teutons".
It was only with the development of distillation that higher-percentage alcoholic beverages could be produced. The Arabs developed distillation around AD 700. Much later, in the
11th century, this technique came to Europe. The meaning of the word alcohol, which originally stood for "something fine", is also derived from the Arabic. In the Middle Ages, monasteries were important places for beer and wine production. The Benedictine monks took a leading position in this. St. Gallen was one of the first monasteries to produce beer on a large scale. Every monk was entitled to 5 liters of beer a day, which was also known as "liquid bread" because of its high nutritional value. The purity law, according to which beer may not be made from anything other than water, hops and barley, goes back to the decree of Duke George the Rich of Bavaria-Landshut (1493). For millennia, alcoholic beverages have also played an important role as medicinal products. The Egyptians used beer for enemas and to treat worm infections, stomach pain, and constipation. Different medicinal extracts were added to the beer. Until 100 years ago, alcohol was the only analgesic. The Chinese used hashish-mixed wine as an effective pain reliever (600 BC). Hippocrates and his disciples (400 BC) treated wounds with bandages soaked in wine. In addition, wine was used as a sedative and a remedy for cardiovascular diseases and fever. Caesar's soldiers were given a ration of two liters of wine a day to protect against contagious diseases. During the Second World War, the Italian troops were given red wine every day to protect them from infectious diseases.
The Arab physician Avicenna (980-1037 AD) recommended daily wine consumption and one or two noises per month as preventive and curative. The Swedish Archbishop (16th century) also considered daily beer consumption to be the healthiest form of diet that protects against coughs, gallstones and stomach pains. Throughout Europe, the consumption of brandy increased dramatically at the time of the plague epidemics in 1348 and 1710, as it was assumed that it protects against the "black death".

 

Literature from the authors

 

the authors

Manfred V. Singer studied medicine at the Universities of Mainz, Vienna and Heidelberg, where he passed the state examination in 1971 and was awarded a Dr. med. In 1980 he completed his habilitation in internal medicine with experimental evidence of enteropancreatic reflexes. In 1982 he was appointed senior physician and in 1985 an adjunct professor at the Medical University Clinic in Essen. In 1990 he was offered the chair for internal medicine (focus on gastroenterology) at the Faculty of Clinical Medicine Mannheim at the University of Heidelberg. On August 1, 1990, he also took over the management of the newly founded IV. Medical Clinic (focus on gastroenterology) (since April 2001 II. Medical Clinic) at the University Medical Center Mannheim at the University of Heidelberg. His research focuses on diseases of the stomach, intestines and pancreas. He is particularly concerned with the alcohol-associated diseases of these organs. Singer is the author or editor of more than 120 original publications and over 200 reviews in national and international journals as well as 11 books. In 1980 he received the Theodor Frerichs Prize from the German Society for Internal Medicine, in 1983 the Thannhauser Prize from the German Society for Digestive and Metabolic Diseases, in 2002 an honorary doctorate from the University of "Iuliu Hatieganu" in Cluj-Napoca, Romania, and in 2004 an honorary doctorate from the university "Vasile Goldis" by Arad.

Stephan R. L. Haas studied medicine at the Universities of Hamburg and Heidelberg. After his license to practice medicine in 1999, after a practical year 2000, he did his doctorate in London on the subject of "Synthesis of fusion proteins from antibodies and thrombolytic and thrombin-inhibiting substances". Since 2000 Haas has been a research assistant at the 2nd Medical University Clinic of the University Clinic Mannheim. His research focuses on alcohol-related diseases, the pathomechanisms of liver damage caused by alcohol, and genetic risk factors for chronic alcoholic pancreatitis.

 

Author's address:
Professor Dr. med. Dr. h.c. mult. Manfred. V. Singer
Dr. med. Stephan Haas
II. University Medical Clinic
Mannheim University Hospital
Theodor-Kutzer-Ufer 1-3
68167 Mannheim
[email protected]

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