Yellow discoloration of the skin, especially on the palms and the soles, but not of the sclera or inside the mouth is due to carotenemia—a harmless condition.

"Breastfeeding jaundice" or "lack of breastfeeding jaundice," is caused by insufficient breast milk intake, resulting in inadequate quantities of bowel movements to remove bilirubin from the body. This leads to increased enterohepatic circulation, resulting in increased reabsorption of bilirubin from the intestines. Usually occurring in the first week of life, most cases can be ameliorated by frequent breastfeeding sessions of sufficient duration to stimulate adequate milk production.

"Neonatal jaundice" is usually harmless: this condition is often seen in infants around the second day after birth, lasting until day 8 in normal births, or to around day 14 in premature births. Typical causes for neonatal jaundice include normal physiologic jaundice, jaundice due to formula supplementation, and hemolytic disorders that include hereditary spherocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, ABO/Rh blood type autoantibodies, or infantile pyknocytosis. Serum bilirubin normally drops to a low level without any intervention required. In cases where bilirubin rises higher, a brain-damaging condition known as kernicterus can occur, leading to significant disability. This condition has been rising in recent years due to less time spent outdoors. A Bili light is often the tool used for early treatment, which often consists of exposing the baby to intensive phototherapy. Sunbathing is effective treatment, and has the advantage of ultra-violet-B, which promotes Vitamin D production. Bilirubin count is lowered through bowel movements and urination, so frequent and effective feedings are especially important.

Prolonged hyperbilirubinemia (severe jaundice) can result in chronic bilirubin encephalopathy (kernicterus). Quick and accurate treatment of neonatal jaundice helps to reduce the risk of neonates developing kernicterus.

Infants with kernicterus may have a fever or seizures. High pitched crying is an effect of kernicterus. Scientists used a computer to record and measure cranial nerves 8, 9 and 12 in 50 infants who were divided into two groups equally depending upon bilirubin concentrations. Of the 50 infants, 43 had tracings of high pitched crying.

Exchange transfusions performed to lower high bilirubin levels are an aggressive treatment.

Cholestatic pruritus is the sensation of itch due to nearly any liver disease, but the most commonly associated entities are primary biliary cirrhosis, primary sclerosing cholangitis, obstructive choledocholithiasis, carcinoma of the bile duct, cholestasis (also see drug-induced pruritus), and chronic hepatitis C viral infection and other forms of viral hepatitis.

Cholestasis means "the slowing or stopping of bile flow" which can be caused by any number of diseases of the liver (which produces the bile), the gallbladder (which stores the bile), or biliary tract (also known as the biliary tree, the conduit that allows the bile to leave the liver and gallbladder and enter the small intestine). When this occurs, conjugated bilirubin and the waste products that usually would be cleared in bile reflux back into the bloodstream. This causes a primarily conjugated hyperbilirubinemia and jaundice; the liver conjugates the bile to make it water-soluble and because the bile has already been processed by the liver, when it gets backed up because of a blockage and is refluxed into the blood, the blood will have high levels of conjugated bilirubin. This is in contrast to primarily unconjugated hyperbilirubinemia which is the water-insoluble form that is bound to serum albumin; the liver has not had a chance to conjugate the bilirubin yet and can be caused either because too much unconjugated bilirubin is made (such as in massive hemolysis or ineffective erythropoiesis) or because too little is conjugated (Gilbert's disease or Crigler-Najjar syndrome). Unconjugated hyperbilirubinemia does not typically cause pruritus.

It is thought that bile salts that deposit into the skin are responsible for the pruritus (itching) but the levels of bilirubin in the bloodstream and the severity of the pruritus does not appear to be highly correlated. Patients that have been administered bile salt chelating agents do report some relief, however, and patients that have complete liver cell failure (and therefore cannot make these products to begin with) do not have pruritus. This suggests that products made by the liver must have some role in pruritus although it is not known exactly which product is responsible.

Neonatal cholestasis defines persisting conjugated hyperbilirubinemia in the newborn with conjugated bilirubin levels exceeding 15% (5.0 mg/dL) of total bilirubin level. The disease is either due to defects in bile excretion from hepatocytes or impaired bile flow.

General presentations in neonates include abdominal pain and general GI upset. Physical examination may show palpable liver and enlarged spleen. Differential diagnosis typically presents with a host of possibilities, many of them not treatable. Histopathology shows dilated bile duct system at all levels and bile duct proliferation in response to back pressure. The incidence has been found to be about 1:2,500 live births.

Complications of HDN could include kernicterus, hepatosplenomegaly, inspissated (thickened or dried) bile syndrome and/or greenish staining of the teeth, hemolytic anemia and damage to the liver due to excess bilirubin. Similar conditions include acquired hemolytic anemia, congenital toxoplasma and syphilis infection, congenital obstruction of the bile duct and cytomegalovirus infection.

- High at birth or rapidly rising bilirubin

- Prolonged hyperbilirubinemia

- Bilirubin Induced Neuorlogical Dysfunction

- Cerebral Palsy

- Kernicterus

- Neutropenia

- Thrombocytopenia

- Hemolytic Anemia - MUST NOT be treated with iron

- Late onset anemia - Must NOT be treated with iron. Can persist up to 12 weeks after birth.

Gilbert's syndrome and G6PD deficiency occurring together especially increases the risk for kernicterus.

In 2003, the incidence of Rh(D) sensitization in the United States was 6.8 per 1000 live births; 0.27% of women with an Rh incompatible fetus experience alloimmunization.

Unconjugated hyperbilirubinemia during the neonatal period describes the history of nearly all individuals who suffer from kernicterus. It is thought that the blood–brain barrier is not fully functional in neonates and therefore bilirubin is able to cross the barrier. Moreover, neonates have much higher levels of bilirubin in their blood due to:

1. Although the severe anemia of erythroblastosis fetalis is usually the cause of death, many children who barely survive the anemia exhibit permanent mental impairment or damage to motor areas of the brain because of precipitation of bilirubin in the neuronal cells, causing destruction of many, a condition called kernicterus. The rapid breakdown of fetal red blood cells immediately prior to birth (and subsequent replacement by normal adult human red blood cells). This breakdown of fetal red blood cells releases large amounts of bilirubin. Following on from this

2. Neonates cannot metabolize and eliminate bilirubin. The sole path for bilirubin elimination is through the uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) proteins that perform a (SN2 conjugation) reaction called "glucuronidation". This reaction adds a large sugar to the bilirubin and makes it more water-soluble, so more readily excreted via the urine and/or the feces. The UGT1A1 enzymes are present, but not active until several months after birth in the newborn liver. Apparently, this is a developmental compromise since the maternal liver and placenta perform glucuronidation for the fetus. In the early 1980s a late-fetal change (30 – 40 weeks of gestation) in hepatic UGT1A1 (from 0.1% to 1.0% of adult activity levels) and post-natal changes that are related to birth age not gestational age were reported. Similar development of activities to pan-specific substrates were observed except for serotonin (1A4), where adult activities were observed in fetal (16 – 25 weeks) and neonatal liver up to 10 days old. More recently, individual UGT isoform development in infants and young children, including two fetal liver samples, were analyzed and showed that pediatric levels of mRNA and protein for UGT1A1 did not differ from adults, but activities were lower. Hence, the effects of UGT1A1 developmental delay in activation have been illuminated over the last 20–30 years. The molecular mechanism(s) for activating UGT1A1 remain unknown.

3. Administration of aspirin to neonates and infants. Aspirin displaces the bilirubin that was non-covalently attached to albumin in the blood stream, thus generating an increased level of free bilirubin which can cross the developing blood brain barrier. This can be life-threatening.

Bilirubin is known to accumulate in the gray matter of neurological tissue where it exerts direct neurotoxic effects. It appears that its neurotoxicity is due to mass-destruction of neurons by apoptosis and necrosis.

Hereditary spherocytosis is the most common disorder of the red cell membrane and affects 1 in 2,000 people of Northern European ancestry. According to Harrison's Principles of Internal Medicine, the frequency is at least 1 in 5,000.

It has been suggested that women of child bearing age or young girls should not be given a transfusion with Rhc positive blood (or Kell positive blood for similar reasons). This would require a lot of extra work in blood transfusion departments and it is considered not economical to do the blood group screening at the present time.

It is theoretically likely that IgG anti-Rhc antibody injections would prevent sensitization to RBC surface Rhc antigens in a similar way that IgG anti-D antibodies (Rho(D) Immune Globulin) are used to prevent Rh disease, but the methods for IgG anti-Rhc antibodies have not been developed at the present time.

Gilbert's syndrome (GS) is a mild liver disorder in which the liver does not properly process bilirubin. Many people never have symptoms. Occasionally a slight yellowish color of the skin or whites of the eyes may occur. Other possible symptoms include feeling tired, weakness, and abdominal pain.

Gilbert's syndrome is due to a mutation in the UGT1A1 gene which results in decreased activity of the bilirubin uridine diphosphate glucuronosyltransferase enzyme. It is typically inherited in an autosomal recessive pattern and occasionally in an autosomal dominant pattern depending on the type of mutation. Episodes of jaundice may be triggered by stress such as exercise, menstruation, or not eating. Diagnosis is based on higher levels of unconjugated bilirubin in the blood without either signs of other liver problems or red blood cell breakdown.

Typically no treatment is needed. If jaundice is significant phenobarbital may be used. Gilbert's syndrome affects about 5% of people in the United States. Males are more often diagnosed than females. It is often not noticed until late childhood to early adulthood. The condition was first described in 1901 by Augustin Nicolas Gilbert.

A Rhc negative mother can become sensitised by red blood cell (RBC) Rhc antigens by her first pregnancy with a Rhc positive fetus. The mother can make IgG anti-Rhc antibodies, which are able to pass through the placenta and enter the fetal circulation. If the fetus is Rhc positive alloimmune hemolysis can occur leading to HDN. This is similar as for Rh disease, which is usually caused when a RhD negative mother is sensitised by her first pregnancy with a RhD positive fetus.

Sensitization to Rhc antigens can also be caused by blood transfusion.

The enzymes that are defective in GS - UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) - are also responsible for some of the liver's ability to detoxify certain drugs. For example, Gilbert's syndrome is associated with severe diarrhea and neutropenia in patients who are treated with irinotecan, which is metabolized by UGT1A1.

While paracetamol (acetaminophen) is not metabolized by UGT1A1, it is metabolized by one of the other enzymes also deficient in some people with GS. A subset of people with GS may have an increased risk of paracetamol toxicity.

Experimental gene therapy exists to treat hereditary spherocytosis in lab mice; however, this treatment has not yet been tried on humans due to all of the risks involved in human gene therapy.

Suggestions have been made that women of child bearing age or young girls should not be given a transfusion with Kell positive blood. Donated blood is not currently screened (in the U.S.A.) for the Kell blood group antigens as it is not considered cost effective at this time.

It has been hypothesized that IgG anti-Kell antibody injections would prevent sensitization to RBC surface Kell antigens in a similar way that IgG anti-D antibodies (Rho(D) Immune Globulin) are used to prevent Rh disease, but the methods for IgG anti-Kell antibodies have not been developed at the present time.

Mothers who are negative for the Kell antigen develop antibodies after being exposed to red blood cells that are positive for Kell. Over half of the cases of hemolytic disease of the newborn owing the anti-Kell antibodies are caused by multiple blood transfusions, with the remainder due to a previous pregnancy with a Kell positive baby.

A study performed at Strong Memorial Hospital in Rochester, New York, showed that infants ≤ 60 days old meeting the following criteria were at low-risk for having a serious bacterial illness:

- generally well-appearing

- previously healthy

- full term (at ≥37 weeks gestation)

- no antibiotics perinatally

- no unexplained hyperbilirubinemia that required treatment

- no antibiotics since discharge

- no hospitalizations

- no chronic illness

- discharged at the same time or before the mother

- no evidence of skin, soft tissue, bone, joint, or ear infection

- White blood cells (WBCs) count 5,000-15,000/mm

- absolute band count ≤ 1,500/mm

- urine WBC count ≤ 10 per high power field (hpf)

- stool WBC count ≤ 5 per high power field (hpf) "only in infants with diarrhea"

Those meeting these criteria likely do not require a lumbar puncture, and are felt to be safe for discharge home without antibiotic treatment, or with a single dose of intramuscular antibiotics, but will still require close outpatient follow-up.

One risk for Group B streptococcal infection (GBS) is Preterm rupture of membranes. Screening women for GBS (via vaginal and rectal swabbing) and treating culture positive women with intrapartum chemoprophylaxis is reducing the number of neonatal sepsis caused by GBS.

Dubin–Johnson syndrome (DJS) is a rare, autosomal recessive, benign disorder that causes an isolated increase of conjugated bilirubin in the serum. Classically, the condition causes a black liver due to the deposition of a pigment similar to melanin. This condition is associated with a defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile, and is similar to Rotor syndrome. It is usually asymptomatic, but may be diagnosed in early infancy based on laboratory tests. No treatment is usually needed.

Once a woman has antibodies, she is at high risk for a transfusion reaction. For this reason, she must carry a medical alert card at all times and inform all doctors of her antibody status.

"Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A,B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions. Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures"

Summary of transfusion reactions in the US

AIHA may be:

- Idiopathic, that is, without any known cause

- Secondary to another disease, such as an antecedent upper respiratory tract infection, systemic lupus erythematosus or a malignancy, such as chronic lymphocytic leukemia (CLL)

There are several intervention options available in early, mid and late pregnancies.

One 10-year-old girl with Crigler–Najjar syndrome type I was successfully treated by liver cell transplantation.

The homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase (UDPGT), is an animal model for the study of Crigler–Najjar syndrome. Since only one enzyme is working improperly, gene therapy for Crigler-Najjar is a theoretical option which is being investigated.