Cirrhosis of the liver K76.4

Liver cirrhosis (from 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 fibrotic bridge formations and regenerative nodes. The consequences are dysfunctions of the liver with signs of insufficiency, portal hypertension with formation of intrahepatic porto-systemic shunts (between portal vessels and liver veins). In Europe, alcohol abuse, non-alcoholic fatty liver (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 - 3cm)
• Mixed liver cirrhosis (mixed picture of 1+2)

Incidence: 200-250/100,000 inhabitants. m>w=2:1 In Germany, about 1.0 million people in Germany suffer from cirrhosis of the liver. 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).

Aetiopathogenetically, cirrhosis is based on the necrosis of hepatocytes. Regardless of the actual cause, cell death leads to an inflammatory reaction with 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 remodelling of the organ structure with parenchyma necroses, formation of regenerative nodes (pseudolobuli) as well as connective tissue septums with a profound disturbance of the functionality of the liver.

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

Underlying causes (diseases):

• Alcoholic liver cirrhosis: Alcoholic liver cirrhosis is the most common cause in industrialized countries with about 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 with 30%, in Africa with 90%).
• Congestive cirrhosis (Cirrhosis cardiaque) in right heart failure
• Autoimmune hepatitis
• Toxic cirrhosis of the liver (cirrhosis of the liver caused by substances toxic to the liver such as tetrachloromethane (metal processing) and rarely by drugs such as methotrexate.

Metabolic diseases

• Hemochromatosis
• Wilson's disease
• Cystic fibrosis: in 10% of cases development of biliary cirrhosis
• Hepatopathy in celiac 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 (bilharzia, liver fluke)

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.

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 genesis: metastatic liver, hepatocellular carcinoma
• Splenomegaly of other genesis.
• Icterus of other genesis
• Ascites of non-hepatic genesis

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

• 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. If necessary, substitution of leucine, isoleucine and valine.
• Osteoporosis prophylaxis: This should be initiated early (calcium substitution 1200-1500 mg/day). For cholestatic liver diseases: additional vitamin D3 substituted (400-800 IU/day).
• Vitamin substitution: enteral absorption of vitamin K in cholestasis reduced. In this respect, vitamin K substitution is necessary in cases of increased risk of bleeding and low quick values (in 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:

• In case of alcoholism withdrawal treatment is mandatory.
• Patients with autoimmune hepatitis are treated accordingly (immunosuppression?).
• For chronic hepatitis:
  • Hepatis B: if necessary virus elimination with interferons
  • Hepatitis C: antiviral therapy if necessary.
• For hemochromatosis iron removal (bloodletting, chelator therapy)
• For Wilson's disease Copper removal (Trentine, D-Penicillamine)

Complications of liver cirrhosis: targeted therapy using specific measures.

• Hemorrhage of esophageal varices: acute hemostasis via esophagogastrodudoenoscopy (sclerotherapy, rubber band ligatures). The mortality rate for varicose vein bleeding is high (about 30%).
• Hepatic (portosystemic) encephalopathy: drug therapy, change of diet (aim: to reduce further production of ammonia).
• Ascites: Basically, every new ascites should be punctured to rule out spontaneous bacterial peritonitis or other causes (e.g. peritoneal carcinosis, tuberculosis). Therapy: moderate sodium restriction (3-5g/day), spironolactone (100-200mg/day), furosemide.
• Hepatocellular carcinoma: because of the lack of clinical symptoms and early diagnosis.
• In advanced liver cirrhosis: ultima ratio is in many cases the 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 added to an overall score. The resulting classification into stages A to C allows a statement about the prognosis of the disease (Child A: 5-6; Child B: 7-9; Child C: 10-15). Patients in stage C after Child-Pugh have a very poor prognosis regarding survival time.

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