Cirrhosis of the liver K76.4

Liver cirrhosis (from the Greek kirros - yellow-orange, lemon-yellow) is a chronic, progressive and irreversible destruction of the lobular and vascular structure of the liver parenchyma with inflammatory fibrosis, the formation of connective tissue bridges between protal fields (portoportal), between portal fields and central veins (portocentral) as well as regenerative nodes.

The functional consequences are liver dysfunction with signs of insufficiency, portal hypertension with formation of intrahepatic porto-systemic shunts (between portal vessels and hepatic veins) with reduced perfusion of the liver parenchyma. In Europe, alcohol abuse, non-alcoholic fatty liver disease (NAFLD) and chronic viral hepatitis are the most common causes of liver cirrhosis.

Classification (pathological-anatomical classification):

• Micronodular liver cirrhosis (regenerated nodules up to 3mm)
• Macronodular liver cirrhosis (regenerated nodules up to 3mm - 30mm)
• Mixed liver cirrhosis (mixed picture of 1+2)

Incidence: 200-250/100,000 inhabitants. m>w=2:1 In Germany, around 1.0 million people suffer from liver cirrhosis. Liver cirrhosis is the 14th most common cause of death worldwide and the 4th most common cause of death in Europe (Tsochatzis EA et al. 2014).

Etiopathogenetically, cirrhosis is based on the necrosis of hepatocytes. Regardless of the actual cause, cell death leads to an inflammatory reaction with the release of cytokines that activate liver macrophages (v. Kupffer cells) and fat storage cells of the liver (Ito cells) as well as monocytes and granulocytes (Zhou WC et al. 2014). This chronic inflammatory reaction leads to a destructive remodeling of the organ structure with parenchymal necrosis, formation of regenerative nodules (pseudolobules) and connective tissue septa with a profound disruption of the functionality of the liver.

The consequences are signs of decompensation (jaundice, bleeding tendency, malnutrition, cachexia, hepatic encephalopathy, hepatic failure coma), portal hypertension with venous collateralization (oesophageal varices, hypertensive gastropathy, hypersplenism, ascites).

Underlying causes (diseases):

• Alcoholic cirrhosis of the liver: alcoholic cirrhosis of the liver is the most common cause in industrialized countries with approx. 30-40% (men >60g/day, women >20-30g/day).
• Viral hepatitis (B,C,D): chronic viral hepatitis is the second most common cause in industrialized countries (30%) and the most common cause in Africa (90%).
• Congestive cirrhosis (cirrhosis cardiaque) in right heart failure
• Autoimmune hepatitis
• Toxic cirrhosis of the liver (cirrhosis of the liver caused by liver-toxic substances such as tetrachloromethane (metal processing) and rarely also by drugs such as methotrexate.

Metabolic diseases

• Haemochromatosis
• Wilson's disease
• Cystic fibrosis: development of biliary cirrhosis in 10% of cases
• Hepatopathy in coeliac disease (gluten-sensitive enteropathy)
• Cirrhosis in the homozygous form of alpha-1-antitrypsin deficiency (phenotype PIZZ)

Other causes

• Primary biliary cirrhosis
• Primary sclerosing cholangitis
• Secondary biliary cirrhosis
• Budd-Chiari syndrome
• Tropical infectious diseases (schistosomiasis, liver flukes)

Clinical symptoms of liver cirrhosis are reduced performance, lack of concentration and fatigue. In addition, there is a feeling of pressure and fullness in the upper abdomen, meteorism.

Further dermatological signs (hepatic skin signs) such as palmar and plantar erythema, jaundice, spidernaevi, varnished lips, varnished tongue, corner of the mouth rhagades, pruritus, leukonychia (white nails), skin atrophy (banknote skin with telangiectasia), Dupuytren's contracture.

Hormonal disorders (reduced testosterone, increased oestrogen in men), in women menstrual disorders

Signs of decompensation: jaundice, bleeding tendency, malnutrition, cachexia, hepatic encephalopathy, hepatic coma, hepatopulmonary syndrome (arterial hypoxaemia in advanced cirrhosis due to functional disturbance of pulmonary circulation without primary lung disease).

Portal hypertension with consequences: venous collateralization (esophageal, corpus and fundus varices, hepatic gastropathy), edema (e.g. hepatic hydrothorax), ascites and complications of ascites such as spontaneous bacterial peritonitis, splenomegaly, hypersplenimus.

Late effects: Hepatocellular carcinoma

Sonography: Sonographically the liver is inhomogeneous with irregular liver surface and wavy liver margin; internal vessels rarefied. The caudate lobe may be enlarged; thickened gallbladder, dilated spleen vessels, possibly visible collateral vessels. Ascites (even small amounts <500ml can be detected) and splenomegaly can be well visualized by sonography.

Transient elastography (e.g. Fibroscan®) can be used to determine the fibrosis and stiffness of the parenchyma.

Colour duplex sonography can be used to detect the reduced flow velocity in the hepatic veins and portal vein (<20cm/s). Increased resistance in the hepatic artery.

Indicators of reduced synthesis performance of the liver:

• Decreased vitamin K-dependent coagulation factors of the prothrombin complex (factors II, VII, IX, X)

Decreased: antithrombin, albumin in serum, cholinesterase, thrombocytes in hypersplenism

Increased: bilirubin, gamma globulins (hypergammaglobulimia)

In hepatic encephalopathy:

• Ammonia ↑, possibly hypokalemia, possibly respiratory alkalosis

In case of inflammatory relapse activity: increase in liver enzymes (transaminases, GLDH)

Clinic: Diagnosis often only with signs of clinical decompensation: icterus, increased abdominal girth, possibly ascites-related, edema, gynecomastia, abdominal baldness, skin hemorrhages; with portal hypertension: varicose veins in esophagus, hypertensive gastropathy; with hepatic encephalopathy: Fhttps://www.altmeyers.org/de/innere-medizin/asterixis-102689lappingtremor, impaired consciousness. Late manifest clinical phenomena are the "hepatic skin signs" such as: spidernaevi, leuconychia, pruritus, lacquer tongue, skin atrophy ("bill skin"), and palmar or plantar erythema).

Imaging: sonography, CT, elastography

Laboratory: Vitamin K dependent coagulation factors of the prothrombin complex, liver enzymes GOT, GPT as well as gamma-GT, bilirubin and ammonia may be elevated; often hypergammaglobulinemia - typical serum electrophoresis), Imaging: Sonography of the abdomen in liver cirrhosis with nodular formation; computed tomography of the abdomen in liver cirrhosis.

Histology: Definitive diagnosis made by sonography-guided (or laparascopic) liver biopsy.

The Child-Pugh score is generated from various examination findings and is used for both staging (Child A-C) and prognostic assessment.

Hepatomegaly of other origin: metastatic liver, hepatocellular carcinoma

Splenomegaly of other etiology.

jaundice of other origin

Ascites of non-hepatic origin

Nutritional therapy measures: These consist of omitting liver-toxic substances (alcohol, medication), compensating for a vitamin deficiency (e.g. vitamin B1 in alcoholism) and providing sufficient energy. Malnourished patients have an increased mortality rate in the spontaneous course of the disease as well as an increased complication rate.

• Protein intake: A daily protein intake of 1.2-1.5 g protein per kg bw is recommended. Protein restriction only in patients with refractory chronic hepatic encephalopathy. Substitution of leucine, isoleucine and valine if necessary.
• Osteoporosis prophylaxis: This should be initiated at an early stage (calcium substitution 1200-1500 mg/day). For cholestatic liver diseases: additional vitamin D3 substitution (400-800 IU/day).
• Vitamin supplementation: Enteral absorption of vitamin K reduced in cholestasis. In this respect, vitamin K substitution is necessary if there is an increased risk of bleeding and low Quick values (in an increased dose: 10 mg every 10 weeks p.o.). In alcoholics (vitamin B1 deficiency in 50 % of patients) additional substitution of folic acid and vitamin B1.

Other measures:

• With alcoholism, withdrawal treatment is essential.
• Patients with autoimmune hepatitis are treated accordingly (immunosuppression?).
• For chronic hepatitis:
  • Hepatitis B: virus elimination with interferons if necessary
  • Hepatitis C: antiviral therapy if necessary.
• In hemochromatosis: iron removal (phlebotomy, chelator therapy)
• Copper removal (Trientine, D-penicillamine) in Wilson's disease

Complicative events of liver cirrhosis: targeted therapy by means of specific measures.

• Esophageal variceal bleeding: acute hemostasis via esophagogastrodudoenoscopy (sclerotherapy, rubber band ligation). Mortality in variceal bleeding is high (about 30%).
• Hepatic (portosystemic) encephalopathy: drug therapy, dietary changes (aim: to reduce further production of ammonia).
• Ascites: In principle, any new ascites should be punctured to rule out spontaneous bacterial peritonitis or other causes (e.g. peritoneal carcinomatosis, tuberculosis). Therapy: moderate sodium restriction (3-5g/day), spironolactone (100-200mg/day), furosemide.
• Hepatocellular carcinoma: as there are usually no clinical symptoms - early detection by imaging.
• In advanced liver cirrhosis: in many cases, the last resort is liver transplantation.

Depending on the cause, successful causal treatment, complications and stage. A partial regression of fibrosis is possible if the damaging noxious agents can be eliminated.

The one-year survival rates are 100% for patients in stage Child A, 85% for stage Child B and 35% for stage Child C.

The MELD-Score allows statements to be made about survival in the next three months. A patient in hospital with a score of 20-30 has a 25 % risk of dying in the next 3 months. A cirrhhotic patient with a MELD of 40 has a very high risk of dying in the next 3 months.

The most frequent cause of death in cirrhosis of the liver: liver failure, bleeding from varices, consequences of hepatocellular carcinoma.

In the so-called Child-Pugh score classification, several of these factors are included (bilirubin, Quick value, albumin, hepatic encephalopathy and ascites) and combined to form an overall score. The resulting classification into stages A to C allows a statement to be made about the prognosis of the disease (Child A: 5-6; Child B: 7-9; Child C: 10-15). Patients in stage C according to Child-Pugh have a very poor prognosis with regard to their survival time.

1. Bloom S et al (2015) Portal hypertension: pathophysiology, diagnosis and management. Internal Med J 45:16-26.
2. Bajaj JS et al (2010) Persistence of cognitive impairment after resolution of overt hepatic encephalopathy. Gastroenterology 138: 2332-2340
3. Classen M et al (2008) Repetitorium Internal Medicine. Urban&Fischer Publisher Munich S 287-288
4. Hahn JM (2013) Checklist Internal Medicine. Georg Thieme Publishing House, Stuttgart S 422-424
5. Herold G (2016) Internal Medicine. 2016, S. 553-555
6. Pillai AK et al (2015) Portal hypertension: a review of portosystemic collateral pathways and endovascular interventions. Clin Radiol 70:1047-1059.
7. Schouten JN et al (2015) Idiopathic non-cirrhotic portal hypertension: a review. Orphanet J Rare Dis 10:67
8. Tsochatzis EA et al. (2014) Liver cirrhosis. Lancet 383:1749-1761.
9. Vilstrup H et al (2014) Hepatic Encephalopathy in Chronic Liver Disease. J Hepatol 61: 642-59
10. Zhan T et al (2012) The diagnosis and treatment of minimal hepatic encephalopathy. Dtsch Ärztebl. Int 109: 180-187
11. Zhou WC et al (2014) Pathogenesis of liver cirrhosis.World J Gastroenterol 20:7312-7324.