Non-infectious chronic liver diseases

Chronic liver diseases caused by various mechanisms have a similar course and their final stage is liver cirrhosis.

After the liver tissue meets the damaging substance, cellular apoptosis occurs. Mediators are released, which activate Kupffer and stellate cells, that in turn trigger an inflammatory response via their cytokines and other mediators, followed by fibroproduction. At the same time, regenerative processes take place with the formation of nodules, which lead to the reconstruction of the structure of liver tissue - liver cirrhosis. Impaired circulation in the tissue leads to further damage to hepatocytes. Portal hypertension develops. The reduction in the number of hepatocytes underlies the functional changes that lead to chronic liver failiure.
 * Autoimmune liver disease
 * autoimmune hepatitis, autoimmune sclerosing cholangitis;


 * Metabolic diseases of the liver
 * hepatic impairment due to the important role of the liver in the metabolism:
 * hereditary disorders of lipid metabolism : Wolman's disease and cholesterol storage disease, Niemann-Pick disease complex, Gaucher's disease, abetalipoproteinemia, fatty acid β-oxidation disorders;
 * hereditary disorders of carbohydrate metabolism: glycogenosis, galactosemia, hereditary frucose intolerance;
 * hereditary disorders of amino acid metabolism: tyrosinemia and defects in branched-chain amino acid metabolism;
 * congenital disorders of urea metabolism;
 * congenital disorders of metal metabolism: hemochromatosis, Wilson´s disease;
 * congenital disorders of porphyrin metabolism: hepatic porphyria;
 * hereditary disorders of bile dye transport;
 * α1-antitrypsin deficiency;


 * Other chronic hepatitis
 * drug-induced chronic hepatitis (paracetamol, halothane, valproate, tetracycline, isoniazid, sulfonamides, methotrexate, etc.), non-alcoholic steatohepatitis, cryptogenic chronic hepatitis (excluding all previous causes).

Autoimmune hepatitis
2 types according to the spectrum of autoantibodies: AIH mainly affects women (75-85%). The pathogenesis is not clear. About 20% of patients have other autoimmune disease associated.
 * Type 1 AIH: antinuclear antibodies (ANA) and / or anti-smooth muscle antibodies (ASMA), sometimes antibodies to the cytoplasmic components of neutrophilic leukocytes (p-ANCA);
 * more common type, starting at puberty or during adolescence;
 * Type 2 AIH: antibodies against cytochrome P450 type 1 in liver and kidney (LKM) or  antibodies to hepatic cytosol type 1 antigen (LC-1);
 * it manifests itself in young children and is more aggressive;
 * in both types, antibodies to liposoluble liver antigen (anti-SLA) can worsen the condition;


 * Clinical picture
 * often sudden development - picture of viral hepatitis: fatigue, anorexia, abdominal pain, development of jaundice;
 * in type 2, the picture of fulminant liver failure with development of encephalopathy;
 * long-term symptoms: fatigue, headache, loss of appetite, weight loss, intermittent subictterus;
 * the course may be fluctuating and without therapy, cirrhosis develops rapidly.


 * Diagnostics
 * elevated aminotransferases, IgG (greater than 16 g / l) and some autoantibodies;
 * ALP and GGT usually normal or slightly elevated; decreased level of complement C4;
 * liver biopsy - a typical picture (hepatitis interface), often already cirrhotic reconstruction.


 * Therapy
 * immunosuppressants: prednisone, azathioprine.

Wilson's disease

 * AR hereditary degenerative disease - a large number of mutations;
 * abnormal accumulation of copper in the liver, brain, cornea and other organs;
 * a gene defect that is important for the incorporation of copper into ceruloplasmin (or apoceruloplasmin, respectively) and for the excretion of excess copper into bile;
 * copper is toxic to hepatocyte organelles - causes cell necrosis → liver steatosis → chronic active hepatitis → liver cirrhosis;
 * in hepatocyte necrosis, unbound copper is released into the circulation and is toxic to erythrocytes and the brain (basal ganglia), eye tissues, kidneys, bones, etc.


 * Clinical picture
 * initially asymptomatic course - only copper accumulation in the liver and histological changes;
 * manifests usually after 12 years of age but also significantly later: fatigue, anorexia, abdominal pain in hepatomegaly, subicterus to jaundice;
 * later symptoms from cirrhotic reconstruction: portal hypertension, splenomegaly, ascites, bleeding from esophageal varices, spider nevi, coagulation disorders;
 * neurological symptoms: lack of concentration, mild tremor, dysarthria, dystonia, hyperkinesia, increased salivation, rigidity;
 * ocular manifestations: green-brown Kayser-Fleischer ring at the edge of the cornea on the back of the Descemet's membrane;
 * rarely, can present as fulminant liver failure: massive necrosis in the liver, large amounts of circulating copper, Coombs negative hemolytic anemia with hemoglobinuria and multiorgan failure;


 * Diagnostics:
 * low to trace levels of ceruloplasmin, elevated aminotransferases and bilirubin, increased urinary copper waste, molecular genetic testing, liver biopsy (copper quantification);


 * Therapy:
 * chelating effect of D-penicillamine with pyridoxine (penicillamine leads to pyridoxine deficiency), liver transplantation;
 * untreated Wilson's disease is progressive and lethal.

Alpha1-antitrypsin deficiency

 * the most common genetic liver disease of childhood;
 * a genetic defect of the protease inhibitor α1-antitrypsin;
 * different phenotypes; the most clinically significant is the PiZZ mutation, which causes pulmonary emphysema and liver disease (cirrhosis, hepatoma);
 * the proteolytic activity of neutrophil elastase in the lung epithelium is not hindered (+ smoking, air pollution → COPD already in the 3rd decade);


 * Clinical pictures
 * cholestatic jaundice with acholic stools, pruritus and hepatosplenomegaly may occur as early as neonatal age;
 * liver disease usually occurs benign;


 * Diagnostics:
 * decreased serum levels of α1 -antitrypsin; serum protein electrophoresis - reduced α-fraction;


 * Therapy
 * in adults with COPD: substitution with recombinant synthetic α1 -antitrypsin (bronchial or iv); in fulminant liver disease - liver transplantation.

Non-alcoholic steatohepatitis
Hepatic steatosis is a condition in which the amount of fat (especially triacylglycerols) in the liver exceeds 5% of its weight.


 * Pathogenesis
 * increased dietary fat intake;
 * increased mitochondrial fatty acid synthesis or decreased oxidation;
 * impaired release of triacylglycerols from the hepatocyte;
 * excess sugars which are converted into fatty acids;
 * hyperalimentation, diabetes mellitus, Wilson's disease, parenteral nutrition, Reye's syndrome.


 * Clinical picture
 * asymptomatic course or non-specific symptoms: hepatomegaly, abdominal pain, + symptoms of the underlying disease;


 * Diagnostics
 * mildly elevated aminotransferases, hypertension, hypertriacylglycerolemia, insulin resistance;
 * liver ultrasound: increased echogenicity;
 * histological picture (small or large droplet, simple steatosis or steatohepatitis);


 * Therapy
 * elimination of the causative cause, treatment of metabolic disease.

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