Hemolytic jaundice, also known as prehepatic jaundice, is a type of jaundice arising from hemolysis or excessive destruction of red blood cells, when the byproduct bilirubin is not excreted by the hepatic cells quickly enough. Unless the patient is concurrently affected by hepatic dysfunctions or is experiencing hepatocellular damage, the liver does not contribute to this type of jaundice. As one of the three categories of jaundice, the most obvious sign of hemolytic jaundice is the discolouration or yellowing of the sclera and the skin of the patient, but additional symptoms may be observed depending on the underlying causes of hemolysis. Hemolytic causes associated with bilirubin overproduction are diverse and include disorders such as sickle cell anemia, hereditary spherocytosis, thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, hemolysis secondary to drug toxicity, thalassemia minor, and congenital dyserythropoietic anemias. Pathophysiology of hemolytic jaundice directly involves the metabolism of bilirubin, where overproduction of bilirubin due to hemolysis exceeds the liver's ability to conjugate bilirubin to glucuronic acid. Diagnosis of hemolytic jaundice is based mainly on visual assessment of the yellowing of the patient's skin and sclera, while the cause of hemolysis must be determined using laboratory tests. Treatment of the condition is specific to the cause of hemolysis, but intense phototherapy and exchange transfusion can be used to help the patient excrete accumulated bilirubin. Complications related to hemolytic jaundice include hyperbilirubinemia and chronic bilirubin encephalopathy, which may be deadly without proper treatment.
Signs and symptoms
The signs and symptoms additional to the development of a yellowish colour in the sclera and skin are specific to the causes of hemolysis. For example, if the patient has hemolytic jaundice resulting from sickle cell disease, vaso-occlusive phenomena like acute vaso-occlusive pain and acute chest syndrome may be observed in the acute phases, while in anemia, neurologic deficits and various pulmonary conditions may manifest in the chronic phase. Regardless of the causes, laboratory-confirmed elevation is predominantly seen in unconjugated bilirubin. Serum bilirubin concentration rarely exceeds 4 mg/dL, unless the patient has concurrent liver disease.
Causes The underlying causes of hemolytic jaundice, as its name suggests, are disorders associated with hemolysis. Such disorders are manifold and the common causes include:
Sickle cell disease, in which a mutation in the globin gene causes the formation of sickle hemoglobin. This disease is marked by the manifestation of chronic compensated hemolytic anemia, with laboratory findings not limited to unconjugated hyperbilirubinemia but also elevated serum lactate dehydrogenase and low serum haptoglobin. Thrombotic thrombocytopenic purpura, in which the reduced activity of the von Willebrand factor-cleaving protease ADAMTS13 causes a thrombotic microangiopathy. This disease, acquired or hereditary, is marked by very severe microangiopathic hemolytic anemia, with laboratory findings including extremely high serum lactate dehydrogenase and negative anti-RBC antibodies and Coombs test. Clinically, dark urine from hemoglobinuria may be observed because the hemolysis is intravascular (see Pathophysiology below). Autoimmune hemolytic anemia (AIHA), in which autoantibodies react with self red blood cells and cause their destruction. This disease is marked by increased extravascular hemolysis, with laboratory findings including increased lactate dehydrogenase and decreased or absent haptoglobin in both warm and cold AIHA, and positive Coombs test. Clinically, jaundice or dark urine present in approximately one-third of the cases, and most of the symptoms are related to anemia. Other less commonly observed causes of hemolysis include:
Hemolysis secondary to drug toxicity Thalassemia minor Congenital dyserythropoietic anemia The above list is not exhaustive, and rare causes of hemolysis such as Bartonella infection, hemolysis due to transfusion reactions, and microangiopathic hemolytic anemia should be suspected when symptoms specific to those causes manifest.
Pathophysiology
Bilirubin overproduction The mechanisms by which bilirubin is overproduced in hemolytic jaundice can be understood in relation to the two major sites of hemolysis: intravascular and extravascular.During intravascular hemolysis, red blood cells are broken down within the vasculature, allowing hemoglobin from the ruptured red blood cells to form haptoglobin-hemoglobin complexes with haptoglobin, which will be internalized and degraded by hepatocytes and the spleen. If the degree of hemolysis is abnormally high, the unbound hemoglobin is converted to methemoglobin from which the heme moiety is bound to hemopexin or to albumin, and both heme-hemopexin and heme-bound albumin are internalized by hepatocytes and subsequently degraded to bilirubin.
During extravascular hemolysis, red blood cells are destroyed by phagocytosis by macrophages in the reticuloendothelial system and digested by phagosomes. Hemoglobin within red blood cells are then degraded to release heme, which will be converted by microsomal heme oxygenase to iron, carbon monoxide and biliverdin, and are immediately reduced to unconjugated bilirubin by biliverdin reductase and released into the plasma.
Affinity of unconjugated bilirubin to albumin In both settings of hemolysis mentioned above, only low levels of conjugated bilirubin may accumulate in the serum, with the amount falling within the normal limits of 4 percent of total bilirubin as conjugated bilirubin can be efficiently excreted in bile through being secreted across canalicular membrane. Increased levels of conjugated bilirubin will only be observed with coexisting hepatobiliary abnormalities. Only when the canalicular excretion capacity is exceeded, conjugated bilirubin will accumulate in the plasma. As unconjugated bilirubin has a high affinity to albumin, at high level it is not efficiently cleared through glomerular filtration and it binds to the elastic tissue of the skin and sclera, where high albumin content can be found. This explains the yellow discolouration observed in these tissues in hemolytic jaundice.
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