Hemolytic jaundice

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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. [1] Unless the patient is concurrently affected by hepatic dysfunctions or is experiencing hepatocellular damage, the liver does not contribute to this type of jaundice. [1]

Contents

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, [2] hereditary spherocytosis, [3] thrombotic thrombocytopenic purpura, [4] autoimmune hemolytic anemia, [5] hemolysis secondary to drug toxicity, [6] thalassemia minor, [7] and congenital dyserythropoietic anemias. [8] 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. [9]

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. [10] 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. [11] Complications related to hemolytic jaundice include hyperbilirubinemia and chronic bilirubin encephalopathy, which may be deadly without proper treatment. [12] [13]

Signs and symptoms

Yellowing of the sclera due to jaundice. Jaundice eye new.jpg
Yellowing of the sclera due to jaundice.

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. [2]

Regardless of the causes, laboratory-confirmed elevation is predominantly seen in unconjugated bilirubin. [10] Serum bilirubin concentration rarely exceeds 4 mg/dL, unless the patient has concurrent liver disease. [14]

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:

Other less commonly observed causes of hemolysis include:

The above list is not exhaustive, and rare causes of hemolysis such as Bartonella infection, [18] hemolysis due to transfusion reactions, [19] and microangiopathic hemolytic anemia [20] 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.

Process of heme breakdown that leads to the production of bilirubin, in extravascular hemolysis. Heme Breakdown.png
Process of heme breakdown that leads to the production of bilirubin, in extravascular hemolysis.

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. [21] 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. [22] [10]

Zones of cephalocaudal jaundice progression according to the Kramer's scale. Neonatal jaundice.png
Zones of cephalocaudal jaundice progression according to the Kramer's scale.

During extravascular hemolysis, red blood cells are destroyed by phagocytosis by macrophages in the reticuloendothelial system and digested by phagosomes. [23] 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. [24]

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. [25] 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. [26] 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. [25] This explains the yellow discolouration observed in these tissues in hemolytic jaundice.

Diagnosis

Symptoms of jaundice can be observed superficially, thus visual methods are used to identify the condition. [27] However, underlying causes of jaundice must be diagnosed through laboratory testing. [28]

Visual assessment

In both newborns and adults, yellowing of the skin is a marker for jaundice. [27] As most cases of jaundice are observed in newborns, healthcare workers use visual methods to identify the presence of this condition. [29] A clinical jaundice scale, an adapted version of the Kramer's scale, is used to quantify the severity of jaundice through the spread of skin discoloration from zone 1, the head, to zone 5, the palms and soles of the neonate's body. [29] [30] Cephalocaudal progression of jaundice to zone 4 and 5 of the Kramer's scale shows a significant positive correlation with serum bilirubin concentration of at least 11.0 mg per 100 ml, indicating the need for treatment. [29]

Jaundice Eye Colour Index (JECI)

Conjunctival icterus can be quantified by the Jaundice Eye Colour Index (JECI) through digital photography of the sclera, where a JECI of 0 indicates a white colour, and a JECI of 0.1 indicates an intense yellow colour, which is a sign of hemolytic jaundice. [31]

Screening laboratory tests

Multiple tests can be used to diagnose jaundice, but results of different parameters must be compared to determine its etiology. [10]

Laboratory tests for hemolytic jaundice
MethodParameterResults
Urinalysis Urobilinogen Increased
Bilirubin Absent
Colour of urine Normal
Stool analysisColour of faeces Darker than normal
Complete blood count Hemoglobin Decreased [28]
Schistocytes Present
Reticulocytes Increased
Serum testingTotal serum bilirubin Increased [27]
Conjugated bilirubin Normal
Unconjugated bilirubin Increased
Liver enzymes Alkaline phosphatase Normal
Aspartate transaminase (AST)Normal
Alanine transaminase (ALT)Normal

When a patient shows signs of jaundice such as the yellowing of the skin and sclera, a urine test is performed to check the levels of urobilinogen present. [32] The presence of urobilinogen and its increased levels indicate that there are more than normal amounts of bilirubin in the intestine, showing that jaundice observed is not due to the blockage of bile flow, and is of pre-hepatic or hepatic causes. [32] Normal colour of the patient's urine indicates the absence of unconjugated bilirubin. [27]

Results from the urine test should be confirmed by a complete blood count (CBC) and serum testing for total serum bilirubin and fractionated bilirubin. [32] Increased reticulocytes and the presence of schistocytes in the blood smear of the patient observed during CBC indicates hemolysis. [28] If the patient has hemolytic jaundice, serum testing will show that conjugated bilirubin will only account for less than 15% of the total serum bilirubin due to the increase of unconjugated bilirubin. [33]

Analysis of liver biopsies will show the levels of alkaline phosphatase, aspartate transaminase, and alanine transaminase in the patient, which has a negative correlation with liver function. [27] Normal levels of these enzymes indicate that there is no significant hepatocellular damage. [27]

When an infant is suspected to have hemolytic jaundice, abnormal morphologies of erythrocytes can be analyzed to find out the causes of hemolysis. [34] A Coomb's test should be performed, and end-tidal carbon monoxide concentration should be monitored to understand the rate of hemolysis in the infant's body. [35] If chronic hemolytic jaundice is diagnosed in a newborn, development of anemia and bilirubin cholelithiasis should be monitored as well. [34]

Haptoglobin testing

If other symptoms of anemia is present, the amount of serum haptoglobin in the patient can be measured to test for hemolysis. [36] During hemolysis, hemoglobin in blood dissociates and forms complexes with haptoglobins in the plasma, which are then catabolized. [37] Low levels of haptoglobin resulting from the test shows that there are large amounts of free hemoglobin in the blood to be bound, acting as an indicator of hemolysis. [36]

Treatment

As jaundice is not common in adults, most treatment methods for this condition are centered around neonates, of which 50% develop jaundice. [27] [38]

Neonates

Phototherapy for newborns with jaundice. Jaundice phototherapy.jpg
Phototherapy for newborns with jaundice.

Intensive phototherapy at saturation dose is used as a first-line clinical treatment which decreases the amount of accumulated unconjugated bilirubin in the infant's serum by the addition of oxygen, thus allowing it to dissolve in water so the liver can more easily convert it into products which can be excreted without further metabolism. [38] For infants with hemolytic jaundice, severe and prolonged cases of hyperbilirubinemia, or high serum bilirubin that does not decrease after phototherapy, blood exchange transfusion is carried out at the umbilical venous catheter to mechanically remove bilirubin. [38] [39] [40] In cases of immune hemolytic jaundice, intravenous immunoglobulin therapy may be used to treat the condition. [41] Administration of intravenous immunoglobulin can block monocyte Fc-receptors, preventing or reducing further hemolysis. [11]

Adults

In adults, hemolytic jaundice is uncommon, and medical treatment methods should be determined by recognizing the underlying causes of hemolysis in the patient. [42]

Complications

In cases where patients receive poor or no treatment of jaundice, neurodevelopmental complications may follow the condition, eventually leading to hearing loss, visual impairment, and in severe cases, mortality. [38]

Hyperbilirubinemia

Hyperbilirubinemia may be observed when hemolysis produces too much bilirubin through the excessive breakdown of red blood cells, and the bilirubin builds up in the patient's blood and tissue fluids without proper excretion. [43] Untreated or inadequately treated hyperbilirubinemia will lead to other complications such as kernicterus. [12]

Kernicterus

Chronic bilirubin encephalopathy, also known as kernicterus, is a brain-damaging complication associated with both preterm and full term infants with jaundice, where the large amounts of unconjugated bilirubin in the infants become neurotoxic. [39] [44] Kernicterus affects mainly the basal ganglia, and its effects can spread to the hippocampus, geniculate nuclei, and cranial nerve nuclei. [13] Symptoms of kernicterus include athetoid cerebral palsy and in severe cases, may lead to death of the patient. [39] Most cases of kernicterus develop in infants following early hospital discharge from phototherapy. [44]

Related Research Articles

<span class="mw-page-title-main">Jaundice</span> Abnormal pigmentation symptom for disease of the liver

Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme metabolism, liver dysfunction, or biliary-tract obstruction. The prevalence of jaundice in adults is rare, while jaundice in babies is common, with an estimated 80% affected during their first week of life. The most commonly associated symptoms of jaundice are itchiness, pale feces, and dark urine.

<span class="mw-page-title-main">Bilirubin</span> Chemical compound

Bilirubin (BR) is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the destruction of aged or abnormal red blood cells. In the first step of bilirubin synthesis, the heme molecule is stripped from the hemoglobin molecule. Heme then passes through various processes of porphyrin catabolism, which varies according to the region of the body in which the breakdown occurs. For example, the molecules excreted in the urine differ from those in the feces. The production of biliverdin from heme is the first major step in the catabolic pathway, after which the enzyme biliverdin reductase performs the second step, producing bilirubin from biliverdin.

<span class="mw-page-title-main">Hemolysis</span> Rupturing of red blood cells and release of their contents

Hemolysis or haemolysis, also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid. Hemolysis may occur in vivo or in vitro.

<span class="mw-page-title-main">Kernicterus</span> Medical condition

Kernicterus is a bilirubin-induced brain dysfunction. The term was coined in 1904 by Christian Georg Schmorl. Bilirubin is a naturally occurring substance in the body of humans and many other animals, but it is neurotoxic when its concentration in the blood is too high, a condition known as hyperbilirubinemia. Hyperbilirubinemia may cause bilirubin to accumulate in the grey matter of the central nervous system, potentially causing irreversible neurological damage. Depending on the level of exposure, the effects range from clinically unnoticeable to severe brain damage and even death.

<span class="mw-page-title-main">Gilbert's syndrome</span> Medical condition

Gilbert syndrome (GS) is a syndrome in which the liver of affected individuals processes bilirubin more slowly than the majority. Many people never have symptoms. Occasionally jaundice may occur.

<span class="mw-page-title-main">Hereditary spherocytosis</span> Medical condition

Hereditary spherocytosis (HS) is a congenital hemolytic disorder, wherein a genetic mutation coding for a structural membrane protein phenotype leads to a spherical shaping of erythrocytic cellular morphology. As erythrocytes are sphere-shaped (spherocytosis), rather than the normal biconcave disk-shaped, their morphology interferes with these cells' abilities to be flexible during circulation throughout the entirety of the body - arteries, arterioles, capillaries, venules, veins, and organs. This difference in shape also makes the red blood cells more prone to rupture under osmotic and/or mechanical stress. Cells with these dysfunctional proteins are degraded in the spleen, which leads to a shortage of erythrocytes resulting in hemolytic anemia.

<span class="mw-page-title-main">Hemolytic anemia</span> Medical condition

Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels or elsewhere in the human body (extravascular). This most commonly occurs within the spleen, but also can occur in the reticuloendothelial system or mechanically. Hemolytic anemia accounts for 5% of all existing anemias. It has numerous possible consequences, ranging from general symptoms to life-threatening systemic effects. The general classification of hemolytic anemia is either intrinsic or extrinsic. Treatment depends on the type and cause of the hemolytic anemia.

<span class="mw-page-title-main">Hemolytic disease of the newborn</span> Fetal and neonatal alloimmune blood condition

Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis foetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells. The fetus can develop reticulocytosis and anemia. The intensity of this fetal disease ranges from mild to very severe, and fetal death from heart failure can occur. When the disease is moderate or severe, many erythroblasts are present in the fetal blood, earning these forms of the disease the name erythroblastosis fetalis.

<span class="mw-page-title-main">Bili light</span> Medical therapeutic tool to treat newborn jaundice

A bili light is a light therapy tool to treat newborn jaundice (hyperbilirubinemia). High levels of bilirubin can cause brain damage (kernicterus), leading to cerebral palsy, auditory neuropathy, gaze abnormalities and dental enamel hypoplasia. The therapy uses a blue light (420–470 nm) that converts bilirubin into an (E,Z)-isomer that can be excreted in the urine and feces. Soft goggles are put on the child to reduce eye damage from the high intensity light. The baby is kept naked or only wearing a diaper, and is turned over frequently to expose more of the skin.

<span class="mw-page-title-main">Neonatal jaundice</span> Medical condition

Neonatal jaundice is a yellowish discoloration of the white part of the eyes and skin in a newborn baby due to high bilirubin levels. Other symptoms may include excess sleepiness or poor feeding. Complications may include seizures, cerebral palsy, or kernicterus.

<span class="mw-page-title-main">Crigler–Najjar syndrome</span> Rare inherited disorder affecting the metabolism of bilirubin

Crigler–Najjar syndrome is a rare inherited disorder affecting the metabolism of bilirubin, a chemical formed from the breakdown of the heme in red blood cells. The disorder results in a form of nonhemolytic jaundice, which results in high levels of unconjugated bilirubin and often leads to brain damage in infants. The disorder is inherited in an autosomal recessive manner. The annual incidence is estimated at 1 in 1,000,000.

Autoimmune hemolytic anemia (AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in the circulation. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs. AIHA is a relatively rare condition, with an incidence of 5–10 cases per 1 million persons per year in the warm-antibody type and 0.45 to 1.9 cases per 1 million persons per year in the cold antibody type. Autoimmune hemolysis might be a precursor of later onset systemic lupus erythematosus.

In ABO hemolytic disease of the newborn maternal IgG antibodies with specificity for the ABO blood group system pass through the placenta to the fetal circulation where they can cause hemolysis of fetal red blood cells which can lead to fetal anemia and HDN. In contrast to Rh disease, about half of the cases of ABO HDN occur in a firstborn baby and ABO HDN does not become more severe after further pregnancies.

Hemolytic disease of the newborn (anti-Kell1) is the second most common cause of severe hemolytic disease of the newborn (HDN) after Rh disease. Anti-Kell1 is becoming relatively more important as prevention of Rh disease is also becoming more effective.

Hemolytic disease of the newborn (anti-Rhc) can range from a mild to a severe disease. It is the third most common cause of severe HDN. Rh disease is the most common and hemolytic disease of the newborn (anti-Kell) is the second most common cause of severe HDN. It occurs more commonly in women who are Rh D negative.

Neonatal cholestasis refers to elevated levels of conjugated bilirubin identified in newborn infants within the first few months of life. Conjugated hyperbilirubinemia is clinically defined as >20% of total serum bilirubin or conjugated bilirubin concentration greater than 1.0 mg/dL regardless of total serum bilirubin concentration. The differential diagnosis for neonatal cholestasis can vary extensively. However, the underlying disease pathology is caused by improper transport and/or defects in excretion of bile from hepatocytes leading to an accumulation of conjugated bilirubin in the body. Generally, symptoms associated with neonatal cholestasis can vary based on the underlying cause of the disease. However, most infants affected will present with jaundice, scleral icterus, failure to thrive, acholic or pale stools, and dark urine.

Hemolytic disease of the newborn (anti-RhE) is caused by the anti-RhE antibody of the Rh blood group system. The anti-RhE antibody can be naturally occurring, or arise following immune sensitization after a blood transfusion or pregnancy.

<span class="mw-page-title-main">6-phosphogluconate dehydrogenase deficiency</span> Medical condition

6-Phosphogluconate dehydrogenase deficiency, or partial deficiency, is an autosomal hereditary disease characterized by abnormally low levels of 6-phosphogluconate dehydrogenase (6PGD), a metabolic enzyme involved in the Pentose phosphate pathway. It is very important in the metabolism of red blood cells (erythrocytes). 6PDG deficiency affects less than 1% of the population, and studies suggest that there may be race variant involved in many of the reported cases. Although it is similar, 6PDG deficiency is not linked to glucose-6-phosphate dehydrogenase (G6PD) deficiency, as they are located on different chromosomes. However, a few people have had both of these metabolic diseases.

<span class="mw-page-title-main">Bilirubin glucuronide</span> Chemical compound

Bilirubin glucuronide is a water-soluble reaction intermediate over the process of conjugation of indirect bilirubin. Bilirubin glucuronide itself belongs to the category of conjugated bilirubin along with bilirubin di-glucuronide. However, only the latter one is primarily excreted into the bile in the normal setting.

Hyperbilirubinemia is a clinical condition describing an elevation of blood bilirubin level due to the inability to properly metabolise or excrete bilirubin, a product of erythrocytes breakdown. In severe cases, it is manifested as jaundice, the yellowing of tissues like skin and the sclera when excess bilirubin deposits in them. The US records 52,500 jaundice patients annually. By definition, bilirubin concentration of greater than 3 mg/ml is considered hyperbilirubinemia, following which jaundice progressively develops and becomes apparent when plasma levels reach 20 mg/ml. Rather than a disease itself, hyperbilirubinemia is indicative of multifactorial underlying disorders that trace back to deviations from regular bilirubin metabolism. Diagnosis of hyperbilirubinemia depends on physical examination, urinalysis, serum tests, medical history and imaging to identify the cause. Genetic diseases, alcohol, pregnancy and hepatitis viruses affect the likelihood of hyperbilirubinemia. Causes of hyperbilirubinemia mainly arise from the liver. These include haemolytic anaemias, enzymatic disorders, liver damage and gallstones. Hyperbilirubinemia itself is often benign. Only in extreme cases does kernicterus, a type of brain injury, occur. Therapy for adult hyperbilirubinemia targets the underlying diseases but patients with jaundice often have poor outcomes.

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  39. 1 2 3 Murki S, Kumar P (June 2011). "Blood exchange transfusion for infants with severe neonatal hyperbilirubinemia". Seminars in Perinatology. Newborn Jaundice Technologies. 35 (3): 175–84. doi:10.1053/j.semperi.2011.02.013. PMID   21641492. S2CID   206275955.
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