presentation of jaundice

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Last updated: October 25, 2022 Revisions: 26

• 1.1.1 Types of Jaundice
• 1.2 Bilirubinuria
• 2.1.1 Liver Screen
• 2.2 Imaging
• 3 Management
• 4 Key Points

Introduction

Jaundice refers to the yellow discolouration of the sclera and skin (Fig. 1) that is due to hyperbilirubinaemia , occurring at bilirubin levels roughly greater than 50 µmol/L.  

Figure 1 – Yellowing of the sclera

Pathophysiology

Jaundice results from high levels of bilirubin in the blood. Bilirubin is the normal breakdown product from the catabolism of haem , and thus is formed from the destruction of red blood cells.

Under normal circumstances, bilirubin undergoes conjugation within the liver , making it water-soluble. It is then excreted via the bile into the GI tract, the majority of which is egested in the faeces as urobilinogen and stercobilin (the metabolic breakdown product of urobilingoen). Around 10% of urobilinogen is reabsorbed into the bloodstream and excreted through the kidneys. Jaundice occurs when this pathway is disrupted .

Figure 2 – Bilirubin is produced as a byproduct of haem metabolism

Types of Jaundice

There are three main types of jaundice: pre-hepatic, hepatocellular, and post-hepatic.

Pre-Hepatic

In pre-hepatic jaundice, there is excessive red cell breakdown  which overwhelms the liver’s ability to conjugate bilirubin. This causes an unconjugated hyperbilirubinaemia.

Any bilirubin that manages to become conjugated will be excreted normally, yet it is the unconjugated bilirubin that remains in the blood stream to cause the jaundice.

Hepatocellular

In hepatocellular (or intrahepatic) jaundice, there is dysfunction of the hepatic cells . The liver loses the ability to conjugate bilirubin, but in cases where it also may become cirrhotic, it compresses the intra-hepatic portions of the biliary tree to cause a degree of obstruction.

This leads to both unconjugated and conjugated bilirubin in the blood, termed a ‘mixed picture’.

Post-Hepatic

Post-hepatic jaundice refers to obstruction of biliary drainage . The bilirubin that is not excreted will have been conjugated by the liver, hence the result is a conjugated hyperbilirubinaemia.

Table 1 – Potential Causes for Jaundice, divided into pre-hepatic, hepatocellular, and post-hepatic

Bilirubinuria

A good estimation of which type of jaundice is present (prior to any further investigation) can be made from observing the colour of the urine.

Conjugated bilirubin can be excreted via the urine (as it is water soluble), whereas unconjugated cannot. Consequently, dark (‘coca-cola’) urine manifests in conjugated or mixed hyperbilirubinaemias, whereas normal urine is seen in unconjugated disease.

Moreover, those with an obstructive picture will likely note pale stools, due to the reduced levels of stercobilin entering the GI tract, which normally colours the stool.

Investigations

In many cases, the likely underlying cause can be elicited from the history , with the investigations simply confirming suspicions. Hence, whilst a complete list of investigations is given below, these should be tailored to the clinical features of the patient.

Laboratory Tests

Any patient presenting with jaundice should have the following bloods taken:

• Liver function tests (LFTs), as summarised in Table 2
• Coagulation studies (PT can be used as a marker of liver synthesis function)
• FBC (anaemia, raised MCV, and thrombocytopenia all seen in liver disease) and U&Es
• Specialist blood tests , as summarised below as part of a liver screen

Table 2 – LFT serum markers. *as an estimate, if the AST:ALT ratio >2, this is likely alcoholic liver disease, whilst if AST:ALT is around 1, then likely viral hepatitis as the cause

Liver Screen

A liver screen can be performed for patients whereby there is no initial cause for liver dysfunction , tailored to whether acute or chronic liver failure

Table 3 – Acute and Chronic Liver Screens *Autoantibodies include anti-mitochondrial antibody (AMA), anti-smooth-muscle antibody (Anti-SMA), and anti-nuclear antibody (ANA), used to identify a variety of autoimmune liver conditions, such as primary sclerosing cholangitis (PSC)

The imaging used will depend on the presumed aetiology. An  u ltrasound abdomen is usually first line, identifying any obstructive pathology present or gross liver pathology (albeit often user dependent).

Magnetic Resonance Cholangiopancreatography (MRCP) is used to visual the biliary tree, typically performed if the jaundice is obstructive , but US abdomen was inconclusive or limited, or as further work-up for surgical intervention.

A liver biopsy can be performed when the diagnosis has not been made despite the above investigations.

The definitive treatment of jaundice will be dependent on the underlying cause . Obstructive causes may require removal of a gallstone through Endoscopic Retrograde CholangioPancreatography (ERCP) or stenting of the common bile duct.

Symptomatic treatment is often needed for the itching caused by hyperbilirubinaemia. An obstructive cause may warrant cholestyramine (acting to increase biliary drainage), whilst other causes may respond to simple anti-histamines.

Identify and manage any complications where possible. Monitor for  coagulopathy , treating promptly (either vitamin K or fresh frozen plasma (FFP) is needed) if any evidence of bleeding or rapid coagulopathy, and treat hypoglycaemia orally if possible (otherwise 5% dextrose is needed).

Where patients become confused from decompensating chronic liver disease (‘hepatic encephalopathy’), laxatives (lactulose or senna) +/- neomycin or rifaximin may be used, in attempt to reduce the number of ammonia-producing bacteria in the bowel.

Figure 3 – Images from a laparoscopic cholecystectomy

• Jaundice refers to the yellow discolouration of the sclera and skin that is due to hyperbilirubinaemia
• Causes can be broken down into pre-hepatic, hepatocellular, and post-hepatic
• Most cases will warrant initial blood tests and ultrasound imaging, however this should be tailored to the clinical presentation
• Definitive treatment of jaundice will be dependent on the underlying cause
• Ensure to monitor for complications, such as coagulopathy, encephalopathy, or infective sequelae

This leads to both unconjugated and conjugated bilirubin in the blood, termed a ‘mixed picture'.

[start-clinical]

[end-clinical]

Table 3 - Acute and Chronic Liver Screens *Autoantibodies include anti-mitochondrial antibody (AMA), anti-smooth-muscle antibody (Anti-SMA), and anti-nuclear antibody (ANA), used to identify a variety of autoimmune liver conditions, such as primary sclerosing cholangitis (PSC)

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Introduction

This article is intended to provide healthcare students with an overview of jaundice , which includes potential causes (pre-hepatic, hepatic and post-hepatic), examination findings, investigations and management strategies.

What is jaundice?

Jaundice is the name given when excess bilirubin (typically greater than 35 µmol/L ) accumulates and becomes visible as a yellow discolouration of the sclera  and/or skin dependent on skin pigmentation. 1

Jaundice can be a symptom of a wide range of diseases. Understanding the mechanism of bilirubin metabolism can help identify the underlying disease process. 

Pathophysiology

Bilirubin is a yellow pigment produced when the reticuloendothelial system breaks down red blood cells in a process known as haemolysis .

Macrophages (reticuloendothelial cells) break down haemoglobin into haem and globin . Then, haem is further broken down into iron (which is recycled) and biliverdin by haem oxygenase. Biliverdin is then broken down further into bilirubin .  

Bilirubin is not water-soluble , so it relies on a transport protein ( albumin ) to be transported to the liver in the bloodstream.

Once in the liver, glucuronic acid is added to the unconjugated bilirubin by glucuronyl transferase to form conjugated bilirubin , which is water soluble and can be excreted into the duodenum .

Once the conjugated bilirubin reaches the colon , it is then deconjugated by colonic bacteria to form urobilinogen . The majority ( 80% ) of urobilogen is oxidised by intestinal bacteria to create stercobilin , which is excreted via faeces and gives them their brown colour.

The remaining 20% is reabsorbed into the bloodstream and transported to the liver , where some is used for bile production. The remainder is carried to the kidneys, oxidised into urobilin and excreted in urine (which gives urine its yellow colour).

Understanding bilirubin metabolism is crucial in understanding the different disease processes that can cause jaundice, as it will affect investigation and management strategies.

Causes of jaundice

Jaundice can be broadly divided into:

Pre-hepatic jaundice

• Intrahepatic jaundice
• Post-hepatic jaundice

Table 1 . Summary of conditions which cause jaundice. 

Pre-hepatic jaundice occurs when bilirubin metabolism has been affected before bilirubin reaches the liver  (i.e., unconjugated bilirubin).

Generally, this type of jaundice is caused by issues relating to red cell breakdown , where increased haemolysis results in excess bilirubin.

As bilirubin is unconjugated at this stage, this is called unconjugated hyperbilirubinaemia .

Haemolytic anaemias (i.e. spherocytosis)

Increased haemolytic activity increases bilirubin. Haemolysis can occur intravascularly (less common) or extravascularly (where phagocytes remove red cells due to red cell defects or immunoglobulins bound to their surface). 2

Disorders resulting in increased haemolysis can be genetic or acquired .

Genetic causes

Genetic causes include red cell membrane abnormalities (in the case of hereditary spherocytosis), abnormalities of haemoglobin ( sickle cell anaemia , thalassaemias) or enzyme defects (G6PD deficiency, pyruvate kinase deficiency).

Acquired causes

Acquired haemolytic anaemias tend to be immune-mediated  and can either be isoimmune (e.g. a blood transfusion reaction) or autoimmune ( SLE , haematological abnormalities such as lymphoma or leukaemia, or may be drug-related).

Non-immune causes do occur but tend to be associated with poorer outcomes. Examples include disseminated intravascular coagulation , haemolytic uraemic syndrome, thrombotic thrombocytopenia, hypersplenism and cirrhosis.  

Patients who experience excessive intravascular haemolysis may also experience haemoglobinuria (presence of haemoglobin in the urine), resulting in the patient reporting red or amber-coloured urine.

Gilbert’s syndrome

Gilbert’s syndrome is a benign genetic condition in which bilirubin is not transported into bile at the usual rate, resulting in an accumulation in the bloodstream and resultant jaundice. 3

The presence of jaundice is intermittent and can be precipitated by several factors, including stress, current infection, sleep deprivation and menstruation. Gilbert’s syndrome does not usually require treatment, as the disease does not progress or cause any organ damage (such as chronic liver disease).

Crigler-Najjar syndrome

Crigler-Najjar syndrome is a very rare autosomal recessive inherited disorder where deficiency of diphosphate glucuronosyltransferase results in the impairment of the ability to conjugate and excrete bilirubin. This is seen in neonates .

Unlike Gilbert syndrome, Crigler-Najjar type 1 can be life-threatening due to neurological damage from bilirubin encephalopathy. A liver transplant is the only option to cure this disease.

Intrahepatic (hepatocellular or intrahepatic cholestasis)

Intrahepatic jaundice occurs when hepatocyte damage  results in reduced bilirubin conjugation or structural abnormalities that cause cholestasis .

Hepatocytes can be damaged by viruses, alcohol, autoimmune processes or drugs and can result in permanent scarring, which, if left untreated, can progress to cirrhosis .

Viral hepatitis

Viral hepatitis (inflammation of the liver) is caused by a group of hepatitis viruses labelled from A-E , which can result in both short and long-term hepatocellular damage.

These viruses are variable in prevalence around the globe and have different routes of transmission:

• Hepatitis A and E are transmitted via contaminated food and water ( faeco-oral route )
• Hepatitis B and C are blood-borne viruses (spread by contaminated bodily fluids such as blood or semen)
• Hepatitis D can only be contracted if a person is already infected with hepatitis B .

Most viral hepatitis follows a similar clinical course with three distinct phases: prodromal , icteric and convalescent . 4

The prodromal phase includes non-specific flu-like and gastrointestinal symptoms (such as nausea, vomiting, right upper quadrant pain) but no specific signs on examination.

During the icteric phase, patients will experience jaundice (and pale stools/dark urine if there is cholestasis), pruritis, fatigue, nausea and vomiting, with symptoms improving once jaundice occurs. There may be hepatomegaly , splenomegaly , lymphadenopathy and hepatic tenderness on examination.

The final phase ( convalescent ) will usually present with malaise and hepatic tenderness .

The prognosis for viral hepatitis’ is variable . For example, hepatitis A and E tend to be self-limiting and do not cause chronic liver disease. Conversely, hepatitis B and C will progress to chronic liver disease (i.e. cirrhosis) if left untreated, which can ultimately be fatal .

Alcoholic hepatitis

As the name suggests, this is hepatitis caused by the use of excess alcohol .

The liver metabolises alcohol and produces acetaldehyde as a by-product, which subsequently binds to proteins within liver cells, causing hepatocyte injury . Alcoholic hepatitis is usually treated supportively , although in some cases, steroids can be used to improve prognosis.

Autoimmune hepatitis

As the name suggests, this is a condition where autoimmune processes result in damage to hepatocytes. The clinical presentation is variable, ranging from asymptomatic to fulminant liver failure, although unfortunately, by the time patients have become symptomatic, cirrhosis is usually present.

Symptoms include jaundice, weight loss, nausea, upper abdominal discomfort, fatigue, oedema and arthralgias. On examination, hepatomegaly , jaundice , splenomegaly and ascites are common.

Drug-induced hepatitis

Hepatocytes can become damaged due to medications , which may be related to the dose prescribed or the medication itself. Common culprits include antimicrobials (such as nitrofurantoin and co-amoxiclav), paracetamol, methotrexate, carbimazole, anabolic steroids, azathioprine and oestrogens.

There is not a singular specific treatment beyond stopping the medication that is causing the problem. Whilst some medications may have an antidote (such as N-acetylcysteine for paracetamol ), treatment may not be successful, and subsequent hepatic damage may be permanent .

In the case of liver failure due to a drug-induced liver injury, a liver transplant may be considered. However, trict criteria must be met (such as the King’s College Criteria for paracetamol toxicity ).

Decompensated cirrhosis

Perhaps one of the most common presentations of jaundice is decompensated cirrhosis .

Cirrhosis is widespread irreversible scarring of hepatic tissue, resulting in abnormal nodules . Evidence of liver failure only becomes apparent once 80-90% of hepatic tissue has been affected by cirrhosis. 5

Intrahepatic vasculature becomes distorted by fibrosis of hepatic tissue, resulting in increased intrahepatic resistance and subsequent portal hypertension .

Portal hypertension, in turn, can lead to the formation of oesophageal varices , fluid retention and decreased renal perfusion .

Cirrhosis can occur due to a variety of reasons. However, excess alcohol use and hepatitis B and C are the most common causes worldwide.

Patients with cirrhosis can be stable for long periods but can decompensate after a trigger event, which could be an infection (i.e. spontaneous bacterial peritonitis), bleeding (such as a variceal bleed), alcohol binge, or in some cases, decompensation will have no identified cause .

Intrahepatic cholestasis

Intrahepatic jaundice may also occur due t o intrahepatic cholestasis .

One potential cause of intrahepatic cholestasis is primary biliary cholangitis (PBC), a slowly progressive autoimmune disease which destroys small interlobular bile ducts .

Intrahepatic cholestasis then causes damage to hepatocytes , resulting in fibrosis, which may then progress to cirrhosis. PBC is associated with multiple other autoimmune diseases, including systemic sclerosis and thyroid disease .

Another cause of intrahepatic jaundice is Dubin-Johnson syndrome , which is a rare benign disorder in which there is excess conjugated hyperbilirubinaemia due to impaired secretion of conjugated bilirubin and the presence of abnormal pigment within hepatic parenchymal cells. 6 Unlike PBC, this condition cannot progress to cirrhosis due to the excretion of bilirubin glucuronides, resulting in a milder form of conjugated hyperbilirubinaemia.

Extrahepatic jaundice

Extrahepatic jaundice generally occurs when there is extrahepatic cholestasis , which often occurs due to distortion of the biliary tree due to intraluminal structural abnormalities (such as strictures) or extrinsic compression .

Common bile duct stone

Gallstones in the common bile duct are one of the most common causes of extrahepatic cholestasis. This occurs when a gallstone leaves the gallbladder but becomes lodged within the common bile duct . Cholestasis then occurs due to obstruction of biliary drainage by gallstone.

Treatment usually involves endoscopic retrocholangiopancreatography (ERCP) , where the stone can be removed via endoscopic methods. Occasionally, this will be unsuccessful and rely on open surgical management .

Cholangitis

Cholangitis is an acute infection of the biliary tree. Typically, symptoms include Charcot’s triad of fever, jaundice and right upper quadrant pain. Prompt treatment with antibiotics is required to treat this condition.

Bile duct strictures

Inflammation within the walls of the bile duct can cause strictures, which then narrow the intraluminal space and prevent the adequate anterograde flow of bile.

These can occur for several reasons, including recurrent insults such as biliary stones or pancreatitis , or can occur due to an autoimmune condition such as primary sclerosing cholangitis (PSC). Management of the stricture will depend on the underlying cause, but the management principle is to improve the bile flow  through the biliary tree.

Malignancy (head of pancreas, cholangiocarcinoma)

Bile ducts can be obstructed due to malignancy either inside the common bile duct or gallbladder or due to malignancy outside of the biliary tree, which causes extrinsic compression.

Cholangiocarcinoma is a cancer of the gallbladder and bile duct, which sadly often presents in the more advanced stages of the disease with jaundice, upper quadrant pain and weight loss. Jaundice occurs due to intraluminal obstruction of anterograde bile flow. Unfortunately, often, by the time symptoms become apparent, malignancy has already spread, and treatment will be palliative.

Conversely, cancer of the head of the pancreas can cause cholestasis through extrinsic compression of the biliary tree. Again, symptoms tend to be present late in the disease process, with key symptoms being jaundice, weight loss and abdominal pain.

If malignancy is discovered at the point where the disease is still localised to the pancreas, then curative treatment in the form of pancreaticoduodenectomy (Whipple procedure) with neoadjuvant chemotherapy may be considered. However, again, unfortunately, treatment is largely palliative  due to advanced disease at presentation. 

Pancreatitis

Inflammation of the pancreas, or pancreatitis , results in the release of exocrine enzymes, which then destroy pancreatic tissue.

The most common causes for this are gallstone disease and excess alcohol consumption, and typically, patients will present with severe epigastric pain and vomiting .

Jaundice can occur for several reasons when pancreatitis is present: this may be due to a common bile duct stone, excess alcohol use, or extrinsic compression of the common bile duct due to an increase in the size of the pancreas due to severe inflammation .

Treatment is primarily supportive . However, pancreatitis is a serious condition that may require intensive care treatment .

Assessment of the patient with jaundice

Clinical features.

As discussed, there is a wide range of underlying causes of jaundice. Some causes will be associated with specific  clinical signs or symptoms:

• Fever : suggested an infective cause (e.g. cholangitis , viral hepatitis)
• Pallor/pale conjunctivae : haemolytic anaemias
• Weight loss : malignancies such as head of pancreas cancer and cholangiocarcinoma
• Gynaecomastia : excess fatty breast tissue in male patients as a result of oestrogen and testosterone imbalance
• Caput medusa : portal hypertension occurs as a result of cirrhosis. Due to this, collateral blood vessels form and enlarge, including peri-umbilical vessels, which form the ‘head of Medusa’ around the umbilicus
• Liver flap : this occurs primarily in decompensated cirrhosis, where excess ammonia results in asterixis
• Ascites : this is excess fluid accumulation in the abdomen and occurs in multiple conditions (including intra-abdominal malignancies) but occurs in advanced liver disease due to fluid retention
• Spider naevi (aka spider telangiectasia) : small red lesions with a central spot and outward reaching lines (much like a spider’s web). Pressing the lesion will result in temporary obliteration of the lesion, which will then be refilled when pressure is removed. These occur due to excess oestrogen
• Splenomegaly : this occurs as a late stage of cirrhosis due to portal hypertension. Increased resistance of blood through vessels in the liver results in a backflow and splenomegaly as a result
• Peripheral oedema : usually seen as swelling of the lower legs, this occurs as a result of fluid retention that occurs as a side effect of cirrhosis.

Laboratory investigations

In suspected  pre-hepatic jaundice and haemolytic anaemia , relevant blood tests include:

• Haptoglobin : a protein which attaches to haemoglobin; decreased when there is an increase in red cell breakdown, usually low or non-detectable in haemolytic anaemia
• Lactase dehydrogenase (LDH) : released when cells are destroyed, so increased in haemolytic anaemia due to increased cell turnover
• Blood film : as jaundice can be caused by haemolytic anaemia secondary to haematological malignancy, a blood film can help identify abnormalities consistent with cancer.

Split bilirubin

A “split bilirubin” is useful to check whether jaundice is pre-hepatic or intrahepatic/posthepatic. To do this, you simultaneously check conjugated and unconjugated bilirubin. If the problem is pre-hepatic , then the unconjugated bilirubin will be higher.

In cases of hepatocellular jaundice , liver function tests (LFTs) will be most helpful and indicate hepatocyte damage.

AST and ALT are transaminases (enzymes) found in liver cells, which means there will be raised serum levels if there is any evidence of liver injury.

The AST : ALT ratio can help to determine the mechanism of hepatocellular injury: a ratio of more than 2:1 is indicative of alcoholic liver disease . Likewise, an isolated GGT rise is a sign of excess alcohol use.

For more information, see the Geeky Medics guide to interpreting liver function tests (LFTs) .

Viral hepatitis screen

As viral hepatitis is a cause of jaundice, these are typically screened for.

Table 1 . Basic viral hepatitis screen. 

Additionally, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and HIV should be tested as potential causes of viral hepatitis.

Further blood tests

Further blood tests are usually sent as part of a non-invasive liver screen to exclude other causes of jaundice.

Table 2 . Additional biochemistry investigations for jaundice. 

Table 3 . Immunoglobulins

Autoantibodies will be tested for if autoimmune hepatitis is suspected as the cause of jaundice.

Table 4 . Common autoantibodies that may be tested for as part of a non-invasive liver screen.

Ascitic fluid analysis

If a patient presents with jaundice and ascites, a sample of ascitic fluid may be sent to confirm or rule out specific diagnoses.

Ascitic fluid is collected during an ascitic aspiration (ascitic tap) and can be sent for microscopy, culture and sensitivities (M, C &S). Gram staining is used to identify any organisms initially and count numbers of white cells .

If the white cell count of the ascitic fluid is >250/ µL , this indicates spontaneous bacterial peritonitis (SBP). SBP is a spontaneous bacterial infection of fluid in the peritoneum. If the white cell count is predominantly polymorphs , this confirms that bacteria is the likely cause. If the white cell count is >250/ µL and predominantly lymphocytes , this may indicate tuberculosis .

Abdominal ultrasound is a minimally invasive imaging method that can assess the liver and gallbladder for pathology. Ultrasound can detect pathologies such as steatosis, fibrosis, some nodules, cholecystitis and gallstone disease .

Computed tomography (CT)

This is likely to be used in the case of suspected malignancy , where more detailed imaging over a larger area than can be achieved via ultrasound is required. However, the nephrotoxic impact of contrast and radiation burden must be considered.

Magnetic resonance imaging (MRI)

Magnetic resonance cholangiopancreatography (MRCP) can be used to assess disease of the pancreaticobiliary ductal system .

This is often used in cases where pathology of the biliary tree is suspected but not visible on other imaging such as ultrasound or computed tomography, such as gallstones, or for patients where endoscopy is considered too high risk . Possible contraindications to an MRCP include certain pacemakers or metal replacement body parts.

Endoscopic retrograde cholangiopancreatography (ERCP) is a diagnostic and interventional procedure generally carried out by gastroenterologists, which uses endoscopy and fluoroscopy to visualise the pancreaticobiliary ductal system. 3

An endoscope is passed until it cannulates the ampulla of Vater  before contrast is injected to visualise the biliary tree. Therapeutic procedures such as biliary stenting, removal of stones or balloon dilatation can then be performed. Conventional practice is obtaining CT imaging or an MRCP before a therapeutic ERCP.

Liver biopsy

Ultimately, histology can give a definitive answer as to the cause of hepatocellular injury. There are multiple ways of taking a liver biopsy, including:

• Percutaneous : using ultrasound or CT guiding with a transthoracic or subcostal approach
• Transvenous : the preferred approach for patients with coagulopathy due to a lower risk of bleeding. Interventional radiologists perform this procedure, and a transjugular approach is used.
• Endoscopic ultrasound-guided : ultrasound imaging is used to guide an endoscopic biopsy needle
• Laparoscopic : often used to biopsy lesions found incidentally during routine laparoscopic surgery

Liver tissue can be reviewed to assess the degree of inflammation/fibrosis , exclude malignancy , and look for Mallory-Denk bodies (typical in alcoholic hepatitis due to intracellular oxidative stress).

Management of jaundice

There is no “standard management” of jaundice, as the  underlying condition causing jaundice should be managed. 

Common management strategies include:

• Supportive management for patients with cirrhosis : cirrhosis is not a curative condition, and so management is focused on minimising symptoms. This may include medication such as carvedilol (non-selective beta blocker) to reduce the risk of variceal bleeding and therapeutic ascitic paracentesis (ascitic drainage) to reduce discomfort from tense ascites. Patients with cirrhosis are also screened with ultrasound every six months for hepatocellular carcinoma .
• Antibiotics : for patients who have jaundice caused by an infective bacterial cause (e.g. ascending cholangitis/cholecystitis)
• Endoscopic removal of gallstones obstructing the common bile duct (ERCP)
• Support with alcohol cessation : patients may be referred to community or in-hospital alcohol teams. Detox regimens can also be used in hospital settings with benzodiazepines (commonly lorazepam or chlordiazepoxide) and vitamin replacement (intravenous thiamine/B12 in the form of Pabrinex).
• Ursodeoxycholic acid is a medication used for patients with gallstone disease . It reduces the production of gallstones by removing some bile acids.
• Symptomatic management of pruritis caused by jaundice : colestyramine is a bile acid sequestrant (i.e. it prevents reabsorption of bile acids). It can reduce pruritis in primary biliary cirrhosis or obstructive biliary pathology.

Dr Chris Jefferies

• Patient.info. Jaundice – Causes and Treatment. Published in 2021. Available from: [ LINK ]
• Patient.info. Haemolytic Anaemia: Causes, Symptoms and Treatment. Published in 2021. Available from: [ LINK ]
• Patient.info. Gilbert’s Syndrome: Causes, Symptoms and Treatment . Published in 2022. Available from: [ LINK ]
• NICE CKS. Hepatitis A . Published in 2021. Available from: [ LINK ]
• Patient.info. Cirrhosis (End Stage Liver Disease) . Published in 2023. Available from: [ LINK ]
• Patient.info. Dubin-Johnson Syndrome . Published in 2023. Available from: [ LINK ]
• Patient info. Primary Biliary Cirrhosis. Published in 2019. Available from: [ LINK ]
• Radiopaedia.org. Endoscopic Retrograde Cholangiopancreatography . Published in 2023. Available from: [ LINK ]

Image references

• Figure 1. CDC/Dr. Thomas F. Sellers/Emory University. License: [Public domain]
• Figure 2. Rim Halaby / Wikidoc. Bilirubin metabolism . License: [ CC BY-SA ]
• Figure 3. James Heilman, MD. Hepaticfailure . License: [ CC BY-SA ]
• Figure 4. Dr. Gannavarapu Narasimhamurthy. Caput Medusae . License: [ CC BY-SA ]

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What Is Jaundice? Symptoms, Causes, Diagnosis, Treatment, and Prevention

Jaundice is common in newborns. When babies have jaundice, it usually goes away on its own, but in some cases, it can become severe and cause bigger issues. It can also occur in adults from specific diseases.

Signs and Symptoms of Jaundice

• Very yellow or orange skin color
• Extreme fussiness
• Difficulty waking up
• Not sleeping
• Poor feeding
• Limited wet or dirty diapers

If your baby exhibits any of the following symptoms, seek emergency medical assistance:

• Inconsolable or high-pitched crying
• Arching their body like a bow
• Stiff, limp, or floppy body
• Unusual eye movements
• Change in skin color
• Flu-like symptoms, like fever and chills
• Clay-colored stool
• Weight loss
• Blood in vomit or stool
• Tarry black stool
• Extreme abdominal pain and tenderness
• Sudden drowsiness, agitation, or confusion
• Easy bruising or bleeding, sometimes causing a rash of tiny reddish-purple dots or larger splotches

Causes and Risk Factors of Jaundice

There are a few different reasons babies might get jaundice. They include:

Breast Milk Jaundice  This type of jaundice generally occurs in the baby’s second or later week of life. While it’s unclear the exact reason for breast milk jaundice, it’s thought that substances in the breast milk may hinder the baby’s liver from properly processing bilirubin.

This occurs when the mother’s blood type is O and the baby’s blood type is A or B or the mother’s Rh factor (a protein found on red blood cells) is negative and the baby is Rh positive.

G6PD deficiency is most common in males of African heritage.

“Infants of Mediterranean descent may also be at increased risk for G6PD deficiency,” explains David L. Hill, MD , adjunct assistant professor of pediatrics at the University of North Carolina School of Medicine in Chapel Hill. “But as long as doctors follow standard bilirubin monitoring guidelines, these issues shouldn’t overly concern parents.”

• Internal bleeding
• Blood infection (sepsis)
• Viral or bacterial infections
• Blocked or scarred bile ducts
• Red blood cell abnormality

Risk Factors

While jaundice is very common in infants, there are several factors that can elevate a baby’s chance of getting the condition, including:

Sibling With Jaundice  If you have one child that developed jaundice as a baby, there’s a higher chance that your other children will get jaundice as well.

• Reabsorption of a large hematoma (a collection of clotted blood underneath the skin)
• Hemolytic anemias, where blood cells are prematurely destroyed and removed from the bloodstream
• Medications, including acetaminophen (Tylenol), penicillin, oral contraceptives, chlorpromazine (Thorazine), and estrogenic or anabolic steroids
• Viruses, including hepatitis A, chronic hepatitis B and C, and Epstein-Barr
• Autoimmune disorders
• Alcohol overuse leading to hepatitis
• Rare genetic metabolic defects
• Inflammation of the gallbladder
• Gallbladder cancer
• Pancreatic cancer
• Nonalcoholic fatty liver disease from risk factors including diabetes and obesity

How Is Jaundice Diagnosed?

Testing options include:

Light Meter  Here, a light meter is placed on a baby’s head to check the transcutaneous bilirubin (TcB) level.

Blood Test The baby’s total serum bilirubin (TSB) level is tested after a small blood sample is taken from baby’s heel. This is the best way to accurately measure bilirubin levels in an infant.

• Blood Tests Various blood tests may be utilized, including a complete blood count, blood cultures, liver enzyme tests, and hepatitis tests.
• Imaging Tests Ultrasonography of the abdomen is often used to detect blockages in bile ducts. A computerized tomography (CT) scan, magnetic resonance imaging (MRI), or other tests to evaluate the flow of bile through the liver may also be used.
• Liver Biopsy If viral hepatitis, drug use, or exposure to a toxin are suspected (or if a diagnosis is unclear), a biopsy may be required.
• Laparoscopy (Rarely)  Here, your doctor makes a small incision below the navel and inserts a tube fitted with a camera (laparoscope) to examine the liver and gallbladder. (If a larger incision is required, this procedure is then called a laparotomy.)

Prognosis of Jaundice

Duration of jaundice, treatment and medication options for jaundice.

• Additional Feeding  Your doctor may advise more frequent feedings or supplementation.
• Phototherapy  Here, the baby is undressed down to a diaper and put under special blue-green lights that help break down bilirubin in the skin so that it can be excreted.
• Blood Protein Transfusion  When baby’s jaundice is related to blood type incompatibility with mom, an IV transfusion of immunoglobulin (IVIg) may be required. Immunoglobulin is a blood protein that can reduce the level of antibodies that are contributing to the breakdown of baby's red blood cells.
• Exchange Transfusion  On rare occasions when severe jaundice doesn’t respond to earlier treatments, the baby may require what’s called an exchange transfusion of blood. Here, small amounts of blood are repeatedly withdrawn and then replaced with donor blood. This process helps dilute bilirubin and antibodies from the mother.

Medication Options

Treatment focus is always on the underlying causes. Taking cholestyramine (Questran) by mouth can relieve itchy skin caused by jaundice, yet many patients do not have itchy skin.

Alternative and Complementary Therapies

Prevention of jaundice.

“Regular feeding can help bring the bilirubin level down, so be sure your newborn is going no longer than four hours between feeds,” says Dr. Hill.

• Avoid hepatitis infection
• If you drink alcohol, drink in moderation, or stop if you have a history of hepatitis or liver injury
• Avoid becoming overweight or obese
• Keep your cholesterol levels healthy

Complications of Jaundice

Kernicterus  This condition, a type of brain damage, can occur in babies when severe jaundice goes too long without treatment. It can cause athetoid cerebral palsy and hearing loss, as well as issues with vision and teeth and sometimes intellectual disabilities.

• Listlessness
• Trouble waking up
• High-pitched crying
• Poor feeding or sucking
• Arching the body like a bow

Research and Statistics: How Many Babies and Adults Get Jaundice?

Bipoc communities and jaundice, asian babies and jaundice, black babies and jaundice.

In addition, “it can be more difficult to identify jaundice in darker-skinned babies,” says pediatrician Whitney Casares, MD, author of The New Baby Blueprint: Caring for You and Your Little One. That’s because melanin, the substance that adds color to our skin, can hide the yellow tone from bilirubin, the chemical that causes jaundice. This doesn’t mean it’s impossible to spot jaundice in darker-skinned babies. It simply means that it takes more effort.

“Checking the gums or inner lips for a yellow hue can help, as can pressing down gently on the skin with a finger,” explains Dr. Casares. And jaundice can often show up in the whites of the eyes before anywhere else, including the gums. If there is any doubt, a bilirubin test should be ordered.

Related Conditions and Causes of Jaundice

• Liver infections from a virus (hepatitis A, hepatitis B, hepatitis C, hepatitis D , and hepatitis E ) or a parasite
• Birth defects or disorders that makes it difficult for the body to break down bilirubin (such as Gilbert syndrome, Dubin-Johnson syndrome, Rotor syndrome, or Crigler-Najjar syndrome)
• Chronic liver disease
• Gallstones or gallbladder disorders
• Blood disorders
• Bile buildup in the gallbladder due to pressure in the abdominal area during pregnancy

Common Questions & Answers

Resources we trust.

• Mayo Clinic:  Infant Jaundice
• Cleveland Clinic: Adult Jaundice
• Centers for Disease Control and Prevention: Jaundice
• MedlinePlus: Jaundice
• Harvard Health Publishing: New Guidelines on Newborn Jaundice: What Parents Need to Know

Everyday Health follows strict sourcing guidelines to ensure the accuracy of its content, outlined in our editorial policy . We use only trustworthy sources, including peer-reviewed studies, board-certified medical experts, patients with lived experience, and information from top institutions.

• What Are Jaundice and Kernicterus? Centers for Disease Control and Prevention .
• Jaundice in Adults. Merck Manual .
• Adult Jaundice. Cleveland Clinic .
• Breastfeeding: Jaundice. Centers for Disease Control and Prevention .
• Jaundice in Newborns. KidsHealth .
• G6PD Deficiency. KidsHealth .
• Infant Jaundice: Symptoms and Causes. Mayo Clinic .
• Newborn Jaundice. NHS .
• ERCP. MedlinePlus .
• Newborn Jaundice. MedlinePlus .
• Jaundice in Newborns: Parent FAQs. HealthyChildren.org .
• Jaundice in Adults. American Family Physician .
• Infant Jaundice: Diagnosis and Treatment. Mayo Clinic .
• Effect of Natural Products on Jaundice in Iranian Neonates. Jundishapur Journal of Natural Pharmaceutical Products .
• Newborn Jaundice: Overview. NHS .
• Evaluation and Treatment of Neonatal Hyperbilirubinemia. American Family Physician .
• Jaundice in the Adult Patient. American Family Physician .
• Beyond “Asian”: Specific East and Southeast Asian Races or Ethnicities Associated With Jaundice Readmission. Hospital Pediatrics .
• Combating the Hidden Health Disparity of Kernicterus in Black Infants: A Review. JAMA Pediatrics .
• Jaundice Causes. MedlinePlus .
• What Are Jaundice and Kernicterus?  Centers for Disease Control and Prevention . December 8, 2020.
• Jaundice in Adults.  Merck Manual . January 2023.
• Jaundice in the Newborn.  Merck Manual . September 2022.
• Adult Jaundice.  Cleveland Clinic . July 23, 2018.
• Breastfeeding: Jaundice.  Centers for Disease Control and Prevention . November 16, 2021.
• Jaundice in Newborns.  KidsHealth . April 2023.
• G6PD Deficiency.  KidsHealth . July 2018.
• Infant Jaundice: Symptoms and Causes.  Mayo Clinic . January 6, 2022.
• Newborn Jaundice: Overview. NHS . February 3, 2022.
• ERCP.  MedlinePlus . April 22, 2021.
• Newborn Jaundice.  MedlinePlus . February 24, 2022.
• Jaundice in Adults.  American Family Physician . February 1, 2017.
• Jaundice in Newborns: Parent FAQs.  HealthyChildren.org . August 5, 2022.
• Fakhri M, Farhadi R, Mousavinasab SN, et al. Effect of Natural Products on Jaundice in Iranian Neonates.  Jundishapur Journal of Natural Pharmaceutical Products . February 2019.
• Muchowski KE. Evaluation and Treatment of Neonatal Hyperbilirubinemia.  American Family Physician . June 1, 2014.
• Roche SP, Kobos R. Jaundice in the Adult Patient.  American Family Physician . January 6, 2004.
• Bentz MG, Carmona N, Bhagwat MM, et al. Beyond “Asian”: Specific East and Southeast Asian Races or Ethnicities Associated With Jaundice Readmission. Hospital Pediatrics . May 2018.
• Okolie F, South-Paul JE, Watchko JF. Combating the Hidden Health Disparity of Kernicterus in Black Infants: A Review.  JAMA Pediatrics . December 1, 2020.
• Jaundice Causes.  MedlinePlus . July 1, 2021.
• Chapter 42: Jaundice and Evaluation of Liver Function. Harrison’s Manual of Medicine . 2016.

Grant Chu, MD

Medical reviewer.

Grant Chu, MD, is an assistant clinical professor at the David Geffen School of Medicine at UCLA . Dr. Chu is also the associate director of education at the UCLA Center for East-West Medicine, using technology to further medical education.

He is board-certified in internal medicine by the American Board of Internal Medicine and is a diplomate of the National Certification Commission for Acupuncture and Oriental Medicine. He received a bachelor's degree in neuroscience from Brown University, where he also earned his medical degree. He has a master's in acupuncture and oriental medicine from South Baylo University and a master's in business administration from the University of Illinois. He completed his residency in internal medicine at the University of California in Los Angeles and a fellowship at the Center for East-West Medicine at UCLA. He has held academic appointments at the University of California in Irvine and the University of Queensland in Australia.

Holly Pevzner

Holly Pevzner is a writer who specializes in health, nutrition, parenting, and pregnancy. She is currently a staff writer at Happiest Baby. Her work, including essays, columns, features, and more, spans a variety of publications, websites, and brands, such as EatingWell, Family Circle, Fisher-Price, Parents, Real Simple , and The Bump. Pevzner has written several monthly health columns, including for First for Women and Prevention  magazines. She previously held senior staff positions at Prevention , Fitness , and Self magazines, covering medical health and psychology. She was also a contributing editor at Scholastic's Parent & Child magazine.

Understanding Jaundice: What You Need to Know

What Is Jaundice? 

When red blood cells die, they leave behind bilirubin, a yellow-orange pigment in the blood. The liver filters bilirubin from the bloodstream to be removed in your stool. If too much is in your system or your liver is overloaded, it causes a buildup known as hyperbilirubinemia. This causes jaundice, where your skin and the whites of your eyes look yellow.

Newborn babies often get it. About 60% have jaundice, also known as icterus, within the first couple of days after birth. Adults can get it, too, although it's less common. See a doctor right away if you think you have jaundice. It could be a symptom of a liver, blood, or gallbladder problem.

Types of Jaundice

There are four main types of jaundice, which are grouped by where the bilirubin collects in your body. A blood test can determine which type you have. 

If bilirubin builds up before blood enters the liver, it's known as prehepatic jaundice. This means you're breaking down red blood cells and creating more bilirubin than your liver can process. 

If your liver isn't able to process bilirubin well, it's called hepatic jaundice.

Posthepatic

Posthepatic jaundice is when bilirubin builds up after passing through the liver and your body can't clear it quickly enough. 

Obstructive jaundice  

This condition is when bile isn't able to drain into your intestines because of a blocked or narrow bile or pancreatic duct. This type of jaundice has a high death rate, so it's important to catch and treat it early.

Jaundice Symptoms

Jaundice may have no symptoms. Any signs you have may depend on how quickly the condition is getting worse. Well-known symptoms are yellowing of the skin and jaundice eyes (also called scleral icterus ). But there are others to watch for, including: 

• Stomach pain
• Tar- or clay-colored stools
• Flu-like symptoms
• Weight loss
• Feeling unusually irritated
• Abnormal drowsiness
• Bruising or bleeding easily
• Bloody vomit

How long does jaundice last in adults? 

How long jaundice lasts depends on what's causing it and the treatment you need. If a medication is causing it, jaundice will fade after you stop taking it. If hepatitis is causing it, medications can be taken to treat the condition. If there is a blocked bile duct or gallstones, surgery may be required. 

Jaundice Causes

Jaundice in adults is rare, but you can get it for many reasons. These include:

• Hepatitis : Liver inflammation can be caused by a virus, autoimmune disorder, alcohol or drug use, or chemical exposure. It may be short-lived (acute) or chronic, which means it lasts for at least 6 months. Long-term inflammation can damage the liver, causing jaundice.
• Alcohol-related liver disease: If you drink heavily over a long period of time – typically 8 to 10 years – you could seriously damage your liver. Two diseases in particular, alcoholic hepatitis and alcoholic cirrhosis, harm the liver.
• Other liver disease: Cirrhosis can also be caused by autoimmune diseases, genetic conditions that are passed down in your family, and hepatitis. A severe condition known as n onalcoholic steatohepatitis can cause nonalcoholic fatty liver disease. With this kind of liver disease, fat builds up in your liver along with inflammation, which damages it over time. 
• Blocked bile ducts : These are thin tubes that carry a fluid called bile from your liver and gallbladder to your small intestine. If the tubes are blocked by gallstones, cancer , inflammation, or rare liver diseases, you could get jaundice.
• Pancreatic cancer : This is the 10th most common cancer in men and the ninth in women. It can block the bile duct, causing jaundice.
• Certain medicines: Drugs like acetaminophen, penicillin, birth control pills, and steroids have been linked to liver disease.
• Blood clots: If your body reabsorbs a large blot clot (hematoma) under the skin, it can increase bilirubin levels.
• Hemolytic anemias: Destroyed blood cells are sometimes removed from the bloodstream too quickly, increasing bilirubin levels. 

Diagnosing Jaundice

Your doctor will ask you about your symptoms and medical history. They'll then give you a physical exam to see if there's swelling in your liver. 

To get more information, your doctor will likely order blood tests to measure bilirubin and cholesterol levels and get a complete blood count ( CBC ). If you have jaundice, your level of bilirubin will be high. Your doctor may order other tests to find the cause of your jaundice and how severe it is, including:

• A hepatitis panel, which is a blood test that shows if you have, or have had, hepatitis. It tests for hepatitis A, hepatitis B, and hepatitis C. If there are no hepatitis antibodies in your blood, it means you don't have the condition, or you had it in the past, but your body has cleared it. 
• Tests to check enzyme levels in the liver to see how well it is functioning. If enzyme levels are higher or lower than normal, it can mean you have disease or damage to the liver or bile ducts. 
• Imaging, like a CT scan , ultrasound, or m agnetic resonance cholangiopancreatography, a type of MRI that checks for blocked ducts near the gallbladder 
• A liver biopsy, to show if you have damage to, or disease in, your liver. During the test, a small piece of your liver is removed either with a needle inserted into the belly to the liver, through a vein in your neck, or through a cut in your belly.
• Prothrombin time, which measures how long it takes for blood plasma to clot. Your blood will be taken, and a laboratory will test it to see if it clots faster or slower than the normal range (which is between 10 and 13 seconds). If it clots too slowly, that may mean there are problems with your liver. 

Jaundice Treatment

In adults, jaundice itself usually isn’t treated. But your doctor will treat the condition that’s causing it. If you have acute viral hepatitis, jaundice will go away on its own as your liver heals. If a blocked bile duct is to blame, your doctor may suggest surgery to open it. If your skin is itching, your doctor can prescribe cholestyramine to be taken by mouth. This medication is used to remove bile acids from your body, which cause itching. 

Phototherapy for jaundice

Phototherapy uses a fluorescent white or blue-spectrum light that breaks down bilirubin so it can be released from the body. This treatment is used for newborns , but phototherapy has not been shown to be effective for treating jaundice in adults. 

Preventing Jaundice

You may have a higher risk for jaundice if you drink too much alcohol or have hepatitis. It is also more common in people during middle age. 

You can reduce your risk of jaundice through lifestyle changes like:

• Avoid herbal supplements (which can be toxic to the liver) unless recommended by your doctor 
• Stop smoking
• Reduce or cut out all alcohol (the CDC recommends no more than two alcoholic drinks per day for men and one daily for women)
• Don't use intravenous drugs (drugs that go into your vein)
• Don't take more prescription medication than you are prescribed
• Get all recommended vaccines before traveling overseas
• Use safe sex practices
• Maintain a healthy weight
• Keep your cholesterol in a healthy range

Unlike newborn jaundice, jaundice is not common in adults. It usually goes away on its own, but your doctor may recommend treatment if there is a condition causing it. If you have jaundice symptoms, including yellowish skin or eyes, flu-like symptoms, dark urine , or belly pain, talk to your doctor right away. 

Jaundice FAQs

• Is jaundice very serious? For infants with high neonatal bilirubin levels, or jaundice, it is usually not serious and goes away on its own. But if it lasts more than 2 weeks, your doctor may suggest treatments to lower bilirubin levels or find out if it's caused by another illness. Jaundice is usually not harmful in adults and goes away over time. If you have symptoms, talk to your doctor right away to see if they suggest tests, imaging, or treatment. 
• How do they fix jaundice? Your doctor will test you to figure out if there is a condition like hepatitis, liver disease , cancer, or blocked bile ducts causing jaundice. If so, that condition will be treated. 
• What does jaundice in adults feel like? Sometimes there are no symptoms. Or you may feel like you have the flu, a stomachache, or itchy skin.
• Can adults recover from jaundice? Yes, sometimes without treatment. If a health condition is the cause, that will need to be treated.

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Jaundice in Adults

• Diagnosis |
• Treatment |
• Essentials in Older People: Jaundice |
• Key Points |

In jaundice, the skin and whites of the eyes look yellow. Jaundice occurs when there is too much bilirubin (a yellow pigment) in the blood—a condition called hyperbilirubinemia.

(See also Overview of Liver Disease and Jaundice in the Newborn .)

DR P. MARAZZI/SCIENCE PHOTO LIBRARY

Bilirubin is formed when hemoglobin (the part of red blood cells that carries oxygen) is broken down as part of the normal process of recycling old or damaged red blood cells. Bilirubin is carried in the bloodstream to the liver and is excreted in the bile (the digestive juice produced by the liver). Bilirubin is then moved through the bile ducts into the digestive tract, so that it can be eliminated from the body. Most bilirubin is eliminated in stool, but a small amount is eliminated in urine. If bilirubin cannot be moved through the liver and bile ducts quickly enough, it builds up in the blood and is deposited in the skin. The result is jaundice.

Many people with jaundice also have dark urine and light-colored stool. These changes occur when a blockage or other problem prevents bilirubin from being eliminated in stool, causing more bilirubin to be eliminated in urine.

If bilirubin levels are high, substances formed when bile is broken down may accumulate, causing itching all over the body. But jaundice itself causes few other symptoms in adults. However, in newborns with jaundice high bilirubin levels (hyperbilirubinemia) can cause a form of brain damage called kernicterus.

Also, many disorders that cause jaundice, particularly severe liver disease, cause other symptoms or serious problems. In people with liver disease, these symptoms may include nausea, vomiting and abdominal pain, and small spiderlike blood vessels that are visible in the skin (spider angiomas). Men may have enlarged breasts, shrunken testes, and pubic hair that grows as it does in women.

Image provided by Thomas Habif, MD.

Serious problems caused by liver disease can include

Ascites : Accumulation of fluid within the abdomen

Coagulopathy: A tendency to bleed or bruise

Hepatic encephalopathy : Deterioration of brain function because the liver malfunctions, allowing toxic substances to build up in the blood, reach the brain, and cause changes in mental function (such as confusion and drowsiness)

Portal hypertension : High blood pressure in the veins that bring blood to the liver, which can lead to bleeding in the esophagus and sometimes stomach

If people eat large amounts of food rich in beta-carotene (such as carrots, squash, and some melons), their skin may look slightly yellow, but their eyes do not turn yellow. This condition is not jaundice and is unrelated to liver disease.

Did You Know...

Causes of Jaundice

Jaundice in adults has many causes. Most causes involve disorders and drugs that

Damage the liver

Interfere with the flow of bile

Trigger the destruction of red blood cells (hemolysis), thus producing more bilirubin than the liver can handle

View of the Liver and Gallbladder

The most common causes of jaundice are

Alcohol-related liver disease

A blockage of a bile duct by a gallstone (usually) or tumor

A toxic reaction to a drug or medicinal herb

Hepatitis is liver inflammation that is usually caused by a virus but can be caused by an autoimmune disorder or use of certain drugs. Hepatitis damages the liver, making it less able to move bilirubin into the bile ducts. Hepatitis may be acute (short-lived) or chronic (lasting at least 6 months). Acute viral hepatitis is a common cause of jaundice, particularly jaundice that occurs in young and otherwise healthy people. When hepatitis is caused by an autoimmune disorder or a drug, it cannot be spread from person to person.

Drinking large amounts of alcohol over a long period of time damages the liver. The amount of alcohol and time required to cause damage varies, but typically, people must drink heavily for at least 8 to 10 years.

Bile duct obstruction

If the bile ducts are blocked, bilirubin can build up in the blood. Most blockages are caused by a gallstone, but some are caused by cancer (such as cancer in the pancreas or bile ducts) or rare liver disorders (such as primary biliary cholangitis or primary sclerosing cholangitis ).

Other causes of jaundice

Some drugs, toxins, and herbal products can also damage the liver (see table Some Causes and Features of Jaundice ).

Less common causes of jaundice include hereditary disorders that interfere with how the body processes bilirubin. They include Gilbert syndrome and other, less common disorders such as Dubin-Johnson syndrome. In Gilbert syndrome, bilirubin levels are slightly increased but usually not enough to cause jaundice. This disorder is most often detected during routine screening tests in young adults. It causes no other symptoms and no problems.

Disorders that cause excessive breakdown of red blood cells (hemolysis) often cause jaundice (see Autoimmune Hemolytic Anemia and Hemolytic Disease of the Newborn ).

Diagnosis of Jaundice

Jaundice is obvious, but identifying its cause requires a doctor's examination, blood tests , and sometimes other tests.

Warning signs

In people with jaundice, the following symptoms are cause for concern:

Severe abdominal pain and tenderness

Changes in mental function, such as drowsiness, agitation, or confusion

Blood in stool or tarry black stool

Blood in vomit

A tendency to bruise or to bleed easily, sometimes resulting in a reddish purple rash of tiny dots or larger splotches (which indicate bleeding in the skin)

When to see a doctor

If people have any warning signs, they should see a doctor as soon as possible. People with no warning signs should see a doctor within a few days.

What the doctor does

Doctors first ask questions about the person's symptoms and medical history. Doctors then do a physical examination. What they find during the history and physical examination often suggests a cause and the tests that may need to be done (see table Some Causes and Features of Jaundice ).

Doctors ask when the jaundice started and how long it has been present. They also ask when urine started to look dark (which usually occurs before jaundice develops). People are asked about other symptoms, such as itching, fatigue, changes in stool, and abdominal pain. Doctors are particularly interested in symptoms that suggest a serious cause. For example, sudden loss of appetite, nausea, vomiting, pain in the abdomen, and fever suggest hepatitis, particularly in young people and people with risk factors for hepatitis. Fever and severe, constant pain in the upper right part of the abdomen suggest acute cholangitis (infection of the bile ducts), usually in people with a blockage in a bile duct. Acute cholangitis is considered a medical emergency.

Because hepatitis is a common cause, doctors ask particularly about conditions that increase the risk of hepatitis, such as

Working at a day care center

Living in or working at an institution with long-term residents, such as a mental health care facility, prison, or long-term care facility

Living in or traveling to an area where hepatitis is widespread

Participating in anal sex

Eating raw shellfish

Injecting illegal or recreational drugs

Having hemodialysis

Sharing razor blades or toothbrushes

Getting a tattoo or body piercing

Working in a health care facility without being vaccinated against hepatitis

Having had a blood transfusion before 1992

Having sex with someone who has hepatitis

Having been born between 1945 and 1965

During the physical examination, doctors look for signs of serious disorders (such as fever, very low blood pressure, and a rapid heart rate) and for signs that liver function is greatly impaired (such as easy bruising, a rash of tiny dots or splotches, or changes in mental function). They gently press on the abdomen to check for lumps, tenderness, swelling, and other abnormalities, such as an enlarged liver or spleen.

Some Causes and Features of Jaundice

Tests include the following:

Blood tests to evaluate how well the liver is functioning and whether it is damaged (liver tests)

Usually imaging tests such as ultrasonography , computed tomography (CT), or magnetic resonance imaging (MRI)

Sometimes biopsy or laparoscopy

Liver tests (also called liver enzyme tests) involve measuring blood levels of enzymes and other substances produced by the liver. These tests help doctors determine whether the cause is liver malfunction or a blocked bile duct. If a bile duct is blocked, imaging tests, such as ultrasonography, are usually required.

Other blood tests are done based on the disorder doctors suspect and the results of the examination and the initial tests. They may include

Tests to assess the blood's ability to clot (prothrombin time and partial thromboplastin time)

Tests to check for hepatitis viruses or abnormal antibodies (due to autoimmune disorders)

A complete blood count

Blood cultures to check for infection of the bloodstream

Examination of a blood sample under a microscope to check for excessive destruction of red blood cells

If imaging is needed, ultrasonography of the abdomen is often done first. It can usually detect blockages in the bile ducts. Alternatively, computed tomography (CT) or magnetic resonance imaging (MRI) may be done.

If ultrasonography shows a blockage in a bile duct, other tests may be needed to determine the cause. Typically, magnetic resonance cholangiopancreatography ( MRCP ) or endoscopic retrograde cholangiopancreatography ( ERCP ) is used. MRCP is MRI of the bile and pancreatic ducts, done with specialized techniques that make the fluid in the ducts appear bright and the surrounding tissues appear dark. Thus, MRCP provides better images of the ducts than conventional MRI. For ERCP, a flexible viewing tube (endoscope) is inserted through the mouth and into the small intestine, and a radiopaque contrast agent is injected through the tube into the bile and pancreatic ducts. Then x-rays are taken. When available, MRCP is usually preferred because it is just as accurate and is safer. But ERCP may be used because it enables doctors to take a biopsy sample, remove a gallstone, or do other procedures.

Occasionally, liver biopsy is needed. It may be done when certain causes (such as viral hepatitis, use of a drug, or exposure to a toxin) are suspected or when the diagnosis is unclear after doctors have the results of other tests.

Laparoscopy may be done when other tests have not identified why bile flow is blocked. For this procedure, doctors make a small incision just below the navel and insert a viewing tube (laparoscope) to examine the liver and gallbladder directly. Rarely, a larger incision is needed (a procedure called laparotomy).

Treatment of Jaundice

Treatment of cause

For a blocked bile duct, a procedure to open it (such as endoscopic retrograde cholangiopancreatography [ ERCP ])

The underlying disorder and any problems it causes are treated as needed. If jaundice is due to acute viral hepatitis , it may disappear gradually, without treatment, as the condition of the liver improves. However, hepatitis may become chronic, even if the jaundice disappears. Jaundice itself requires no treatment in adults (unlike in newborns—see Hyperbilirubinemia ).

If the cause is a blocked bile duct, a procedure may be done to open the bile duct. This procedure can usually be done during ERCP, using instruments threaded through the endoscope .

Essentials in Older People: Jaundice

In older people, the disorder causing jaundice may not cause the same symptoms as it typically does in younger people, or the symptoms may be milder or harder to recognize. For example, if older people have acute viral hepatitis, they often have much less abdominal pain than younger people. When older people become confused, doctors may mistakenly diagnose dementia and not realize that the cause is hepatic encephalopathy . That is, doctors may not realize that brain function is deteriorating because the liver is unable to remove toxic substances from the blood (as it usually does) and, thus, the toxic substances can reach the brain.

In older people, jaundice usually results from a blockage in the bile ducts, and the blockage is more likely to be cancer. Doctors suspect that the blockage is cancer when older people have lost weight, have only mild itching, have no abdominal pain, and have a lump in the abdomen.

If damage to the liver is severe, jaundice may be accompanied by serious problems, such as deterioration of brain function and a tendency to bleed or bruise.

Acute viral hepatitis is a common cause of jaundice, particularly in young and otherwise healthy people.

People should see a doctor promptly if they have jaundice so that the doctor can check for serious causes.

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Pathophysiology of jaundice

• Increased breakdown of red cells leads to increased serum bilirubin. This unconjugated bilirubin isn’t water-soluble so can’t be excreted in the urine. Intestinal bacteria convert some of the extra bilirubin into urobilinogen, some of which is re-absorbed and IS excreted by the kidneys – hence urinary urobilinogen is increased.
• Disorders of uptake, conjugation or secretion of bilirubin.
• Usually divided into conjugated or unconjugated bilirubinaemia

The various causes of jaundice are traditionally classified into pre-hepatic, hepatic and post-hepatic (or cholestatic) groups according to the mechanism of the jaundice.

Pre-hepatic causes of jaundice

• Sickle cell disease
• Hereditary spherocytosis
• Hereditary elliptocytosis
• G6PD deficiency
• Pyruvate kinase deficiency
• Thalassemia
• Autoimmune haemolytic anaemia
• Penicillins
• Sulphasalazine
• Metallic valve prostheses
• Transfusion reactions
• Paroxysmal nocturnal haemoglobinuria

Hepatic causes of jaundice

• Cirrhosis (see chronic liver disease for further causes)
• Primary or metastases
• Viral hepatitis
• Isoniazid, rifampicin, atenolol, enalapril, verapamil, nifedipine, amiodarone, ketoconazole, cytotoxics, halothane
• Ciclosporin, azathioprine, chlorpromazine, cimetidine, erythromycin, nitro, ibuprofen, hypoglycaemics
• Leads to pigmented liver.
• Increase in conjugated bilirubin with no other enzyme changes
• High coproporphyrin
• Similar to DJS
• Liver not pigmented
• Normal coproporphyrin
• Congenital hypo-activity of conjugation enzyme UGT-1. Benign and common (5%)
• Normal LFTs except mildly elevated bilirubin, especially in times of physiological stress/illness
• Normal life expectancy
• Autosomal recessive (type I) or dominant (type II). Severe unconjugated hyperbilirubinaemia.
• Congenital absence (I) or decrease (II) of glucoronyl transferase.
• Normal liver histology.
• Treatment is liver transplant (only type II survive to adulthood)

Post-hepatic causes of jaundice

• Compression  e.g. pancreatitis, pancreatic tumour, lymph nodes, biliary atresia
• Cholangiocarcinoma
• Post-operative stricture
• And anti-centromere for prognosis (though more association with CREST)
• 80% of PSC have UC
• ANCA, anti-smooth muscle antibodies
• Association with cholangiocarcinoma

Pregnancy-associated jaundice

• 0.1-0.2% of pregnancies
• Itching – jaundice later
• Raised liver markers, esp ALP
• Fetal mortality 3.5%
• Often recurs in further pregnancies
• Ursodeoxycholic acid
• Occurs in 1-2 out of 1000 pregnancies and 10-20% of severe pre-eclampsia
• Leads to a variant of DIC
• Needs steroids and prompt delivery
• Maternal mortality 1-24%
• All LFTs including synthetic function go off
• Hyperemesis gravidum
• Associated with abnormal LFTs in 20% cases

History in jaundice

• Onset of jaundice
• Pain/Painless
• Constitutional symptoms
• Bowel symptoms
• Dark urine/Pale stools
• Blood transfusions
• Heart valve surgery
• Autoimmune disorders
• See drug causes above
• Thalassaemia/Sickle cell/
• Alcohol consumption
• Travel history: viral hepatitis, malaria
• Ideas; concerns; expectations

Examination in jaundice

• Hands: clubbing, Dupuytren’s contracture, palmar erythema
• Spider naevi
• Gynaecomastia
• Portal hypertension: splenomegaly and caput medusae
• Encephalopathy
• Abdominal masses
• Lymphadenopathy
• Splenomegaly

Initial management of jaundice

• Liver function tests (including bili, ALP, ALT, AST, GGT)
• Full blood count, urea and electrolytes
• Clotting screen
• Autoimmune screen (ENA, ANA, ANCA)
• Viral screen (Hep A,B,C)
• Alfafetoprotein (AFP)
• Serum caeruloplasmin
• Ultrasound of the abdomen

Further management of jaundice

• Further investigation and management will be dictated by the aetiology – see the various sections for more information on this.

Click here for medical student OSCE and PACES questions about Presentation of Jaundice

Common jaundice exam questions for medical students, finals, osces and mrcp paces, click here to download free teaching notes on presentation of jaundice: jaundice, perfect revision for medical students, finals, osces and mrcp paces.

Infant jaundice

On this page, when to see a doctor, risk factors, complications.

Infant jaundice is yellow discoloration of a newborn baby's skin and eyes. Infant jaundice occurs because the baby's blood contains an excess of bilirubin (bil-ih-ROO-bin), a yellow pigment of red blood cells.

Infant jaundice is a common condition, particularly in babies born before 38 weeks' gestation (preterm babies) and some breast-fed babies. Infant jaundice usually occurs because a baby's liver isn't mature enough to get rid of bilirubin in the bloodstream. In some babies, an underlying disease may cause infant jaundice.

Most infants born between 35 weeks' gestation and full term need no treatment for jaundice. Rarely, an unusually high blood level of bilirubin can place a newborn at risk of brain damage, particularly in the presence of certain risk factors for severe jaundice.

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Yellowing of the skin and the whites of the eyes — the main sign of infant jaundice — usually appears between the second and fourth day after birth.

To check for infant jaundice, press gently on your baby's forehead or nose. If the skin looks yellow where you pressed, it's likely your baby has mild jaundice. If your baby doesn't have jaundice, the skin color should simply look slightly lighter than its normal color for a moment.

Examine your baby in good lighting conditions, preferably in natural daylight.

Most hospitals have a policy of examining babies for jaundice before discharge. The American Academy of Pediatrics recommends that newborns be examined for jaundice during routine medical checks and at least every eight to 12 hours while in the hospital.

Your baby should be examined for jaundice between the third and seventh day after birth, when bilirubin levels usually peak. If your baby is discharged earlier than 72 hours after birth, make a follow-up appointment to look for jaundice within two days of discharge.

The following signs or symptoms may indicate severe jaundice or complications from excess bilirubin. Call your doctor if:

• Your baby's skin becomes more yellow
• The skin on your baby's the abdomen, arms or legs looks yellow
• The whites of your baby's eyes look yellow
• Your baby seems listless or sick or is difficult to awaken
• Your baby isn't gaining weight or is feeding poorly
• Your baby makes high-pitched cries
• Your baby develops any other signs or symptoms that concern you

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Excess bilirubin (hyperbilirubinemia) is the main cause of jaundice. Bilirubin, which is responsible for the yellow color of jaundice, is a normal part of the pigment released from the breakdown of "used" red blood cells.

Newborns produce more bilirubin than adults do because of greater production and faster breakdown of red blood cells in the first few days of life. Normally, the liver filters bilirubin from the bloodstream and releases it into the intestinal tract. A newborn's immature liver often can't remove bilirubin quickly enough, causing an excess of bilirubin. Jaundice due to these normal newborn conditions is called physiologic jaundice, and it typically appears on the second or third day of life.

Other causes

An underlying disorder may cause infant jaundice. In these cases, jaundice often appears much earlier or much later than does the more common form of infant jaundice. Diseases or conditions that can cause jaundice include:

• Internal bleeding (hemorrhage)
• An infection in your baby's blood (sepsis)
• Other viral or bacterial infections
• An incompatibility between the mother's blood and the baby's blood
• A liver malfunction
• Biliary atresia, a condition in which the baby's bile ducts are blocked or scarred
• An enzyme deficiency
• An abnormality of your baby's red blood cells that causes them to break down rapidly

Major risk factors for jaundice, particularly severe jaundice that can cause complications, include:

• Premature birth. A baby born before 38 weeks of gestation may not be able to process bilirubin as quickly as full-term babies do. Premature babies also may feed less and have fewer bowel movements, resulting in less bilirubin eliminated through stool.
• Significant bruising during birth. Newborns who become bruised during delivery gets bruises from the delivery may have higher levels of bilirubin from the breakdown of more red blood cells.
• Blood type. If the mother's blood type is different from her baby's, the baby may have received antibodies through the placenta that cause abnormally rapid breakdown of red blood cells.
• Breast-feeding. Breast-fed babies, particularly those who have difficulty nursing or getting enough nutrition from breast-feeding, are at higher risk of jaundice. Dehydration or a low caloric intake may contribute to the onset of jaundice. However, because of the benefits of breast-feeding, experts still recommend it. It's important to make sure your baby gets enough to eat and is adequately hydrated.
• Race. Studies show that babies of East Asian ancestry have an increased risk of developing jaundice.

High levels of bilirubin that cause severe jaundice can result in serious complications if not treated.

Acute bilirubin encephalopathy

Bilirubin is toxic to cells of the brain. If a baby has severe jaundice, there's a risk of bilirubin passing into the brain, a condition called acute bilirubin encephalopathy. Prompt treatment may prevent significant lasting damage.

Signs of acute bilirubin encephalopathy in a baby with jaundice include:

• Listlessness
• Difficulty waking
• High-pitched crying
• Poor sucking or feeding
• Backward arching of the neck and body

Kernicterus

Kernicterus is the syndrome that occurs if acute bilirubin encephalopathy causes permanent damage to the brain. Kernicterus may result in:

• Involuntary and uncontrolled movements (athetoid cerebral palsy)
• Permanent upward gaze
• Hearing loss
• Improper development of tooth enamel

The best preventive of infant jaundice is adequate feeding. Breast-fed infants should have eight to 12 feedings a day for the first several days of life. Formula-fed infants usually should have 1 to 2 ounces (about 30 to 60 milliliters) of formula every two to three hours for the first week.

Jan 06, 2022

• Wong RJ, et al. Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants. https://www.uptodate.com/contents/search. Accessed April 2, 2018.
• Maisels MJ, et al. Hyperbilirubinemia in the newborn infant ≥ 35 weeks' gestation: An update with clarifications. Pediatrics. 2009;124:1193.
• American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297.
• Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. American Academy of Pediatrics. http://pediatrics.aappublications.org/content/114/1/297. Accessed April 2, 2018.
• Hay WW, et al., eds. The newborn infant. In: Current Diagnosis & Treatment: Pediatrics. 23rd ed. New York, N.Y.: McGraw-Hill Education; 2016. https://www.accessmedicine.mhmedical.com. Accessed April 2, 2018.
• Wong RJ, et al. Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants. https://www.uptodate.com/contents/search. Accessed April 2, 2018.
• Maisels MJ. Managing the jaundiced newborn: A persistent challenge. Canadian Medical Association Journal. 2015;187:335.
• Muchowski KE. Evaluation and treatment of neonatal hyperbilirubinemia. American Family Physician. 2014;89:87.
• Biliary atresia. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/liver-disease/biliary-atresia/all-content. Accessed Jan. 13, 2020.
• Wong RJ. Unconjugated hyperbilirubinemia in the newborn: Pathogenesis and etiology.https://www.uptodate.com/contents/search. Accessed Feb. 5, 2020.
• Picco MF (expert opinon). Mayo Clinic. Feb. 5, 2020.
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• Blood transfusion
• Photodynamic therapy

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Original Author(s): Dr Phil Jordan and Dr Umberto Piaggio Last updated: 16th February 2021 Revisions: 19

• 1 Introduction
• 2.1 Physiological jaundice
• 2.2 Pathological jaundice
• 3 Risk factors and history
• 4 Clinical Presentation
• 5.1 Bilirubin
• 5.2 Further investigations
• 5.3 As needed
• 6.1 Phototherapy
• 6.2 Fluid intake
• 6.3 Exchange Transfusion
• 6.4 IV Immunglobulin
• 7 Complications
• 8 Prognosis
• 9 References

Introduction

Jaundice is t he yellow colouring of skin and sclera caused by the accumulation of bilirubin in the skin and mucous membranes.

Neonatal jaundice  occurs in 60% of term infants and 80% of preterm infants [1] and is caused by hyperbilirubinaemia that is unconjugated (divided into physiological or pathological) or conjugated (always pathological).  High levels of unconjugated bilirubin have acute harmful effects as well as long term damage if left untreated, such as kernicterus .

10% of breast fed babies are jaundiced at 1 month.

Types of Jaundice

Physiological jaundice.

Jaundice in a healthy baby, born at term, is normal and may result from:

• Increased red blood cell breakdown: in utero the fetus has a high concentration of Hb (to maximise oxygen exchange and delivery to the fetus) that breaks down releasing bilirubin as high Hb is no longer needed
• Immature liver not able to process high bilirubin concentrations

Starts at day 2-3, peaks day 5 and usually resolved by day 10.   The baby remains well and does not require any intervention beyond routine neonatal care.

Physiological jaundice can progress to pathological jaundice if the baby is premature or there is increased red cell breakdown e.g. Extensive bruising or cephalohaematoma following instrumental delivery.

Pathological jaundice

Jaundice which requires treatment or further investigation.

• Onset less than 24 hours
• ?previous siblings treated for jaundice/family history/maternal rhesus status
• Maternal blood group (type O most likely to produce enough IgG antibodies to cause haemolysis)
• Requires investigation and treatment
• Onset after 24 hours
• likely dehydrated ?breast fed baby establishing feeding
• increased haemolysis due to bruising/cephalohaematoma
• Unwell neonate: jaundice as a sign of congenital or post-natal infection
• Metabolic: Hypothyroid/pituitarism, galactosaemia
• Breast milk jaundice: well baby, resolves between 1.5-4 months
• GI: biliary atresia, choledhocal cyst

Risk factors and history

Risk factors for pathological hyperbilirubinaemia: to be asked in history

• Prematurity, low birth weight, small for dates
• Previous sibling required phototherapy
• Exclusively breast fed
• Jaundice <24 hours
• Infant of diabetic mother

Clinical Presentation

• Colour: All babies should be checked for jaundice with the naked eye in bright, natural light (if possible). Examine the sclera, gums and blanche the skin. Do not rely on your visual inspection to estimate bilirubin levels, only to determine the presence or absence of jaundice.
• Drowsy: difficult to rouse, not waking for feeds, very short feeds
• Neurologically: altered muscle tone, seizures-needs immediate attention
• Other: signs of infection , poor urine output, abdominal mass/organomegaly, stool remains black/not changing colour

Investigations

• Transcutaneous bilirubinometer (TCB) can be used in >35/40 gestation and >24 hours old for first measurement. TCB can be used for all subsequent measurements, providing the level remains <250 µmol/L and the child has not required treatment
• Serum bilirubin to be measured if <35/40 gestation, <24 hours old or TCB >250 µmol/L
• Infants that are not jaundice to the naked eye do not need routine bilirubin checking.  
• Total and Conjugated Bilirubin is important if suspected; liver or biliary disorder, metabolic disorder, congenital infection or prolonged jaundice. Do not subtract conjugated from total to make management decisions for hyperbilirubinaemia.

Further investigations

• Serum bilirubin for all subsequent levels
• Blood group (Mother and Baby) and DCT
• FBC for haemoglobin and haematocrit
• U&Es if excessive weight loss/dehydrated
• Infection screen if unwell or <24 hours including Microbiological cultures if infection suspected: blood, urine, CSF. Consider TORCH screen.
• Glucose-6-phosphate dehydrogenase especially if Mediterranean or African origin
• LFTs if suspected hepatobiliary disorder

Phototherapy

Figure 1 – NICE treatment threshold graph [3]

• Above: If level is on or above the phototherapy line for their gestation and age (in days) phototherapy should be initiated and bilirubin monitored
• >50µmol/L below, clinically well with no risk factors for neonatal jaundice do not routinely repeat level
• <50µmol/L below, clinically well repeat level within 18 hours (risk factors present) to 24 hours (no risk factors present)
• Repeat bilirubin 4-6 hours post initiation to ensure not still rising, 6-12 hourly once level is stable or reducing.
• NB. Maximum skin coverage, eye protection for babies, breaks for breastfeeding/nappy changes/cuddles to be coordinated to maximise phototherapy
• Stop phototherapy once level >50µmol/L below treatment line on the threshold graphs
• Check for rebound of hyperbilirubinaemia 12-18 hours after stopping phototherapy

Fluid intake

Do not give additional fluids with phototherapy unless indicated and if possible expressed maternal milk is preferred. If phototherapy intensified or feeding poorly consider NGT feeding or IV fluids.

Give consideration to underlying cause i.e. infection, biliary obstruction

Exchange Transfusion

This is the simultaneous exchange of the baby’s blood (hyperbilirubinaemic) with donated blood or plasma (normal levels of bilirubin) to prevent further bilirubin increase and decrease circulating levels of bilirubin.

Performed via umbilical artery or vein and is indicated when there are clinical features and signs of acute bilirubin encephalopathy or the level/rate of rise (>8.5µmol/L/hour) of bilirubin indicates necessity based on threshold graphs. This will require admission to an intensive care bed.

IV Immunglobulin

IVIG can be used as adjunct to intensified phototherapy in rhesus haemolytic disease or ABO haemolytic disease.

Complications

Kernicterus , billirubin-induced brain dysfunction, can result from neonatal jaundice. Bilirubin is neurotoxic and at high levels can accumulate in the CNS gray matter causing irreversible neurological damage . Depending on level of exposure, effects can range from clinically undetectable damage to severe brain damage.

Depends on underlying cause but if correctly and promptly treated prognosis is excellent.

Always refer to local trust guidelines.

1st Author: Dr Phil Jordan

Senior Reviewer: Dr Umberto Piaggio

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Jaundice and the Breastfed Infant

What is jaundice.

Jaundice is a condition that causes your baby’s skin to turn yellow in the first few days after birth. You may also notice that the sclera (white parts) of the baby’s eyes are yellow.

The yellow color of the skin and sclera in newborns with jaundice comes from a build up of bilirubin. Small to medium increases in bilirubin are normal in newborns and will not hurt your baby.

Very high levels of bilirubin can cause hearing loss, seizures and brain damage.

Signs that bilirubin may be at a harmful level

• Yellow coloring of the skin, starting on the face and moving down the body
• Poor feeding
• Increased sleepiness

If your baby has jaundice, it is important that bilirubin levels are monitored closely. If your baby does not drink enough milk, this can lead to increased bilirubin. You should see a lactation consultant to get help with breastfeeding.

Two key factors  

• How much milk you are making?
• How much milk can your baby take from the breast?

Tips to help prevent jaundice in your baby

• Initiate breastfeeding as soon after birth as possible — preferably within one hour.
• Early, frequent, unrestricted breastfeeding helps to eliminate bilirubin from baby's body. Bilirubin exits the body in the infant's stools, and because your milk has a laxative effect, breastfeeding frequently will result in lots of soiled diapers and thus, lower bilirubin levels. Your newborn should breastfeed a minimum of eight times per day.
• Be sure that your baby is latched on well and is sucking efficiently. Seek assistance from a lactation consultant if there are any concerns your baby is not latching well.

What to do if your baby becomes jaundiced

• Provide frequent, unrestricted breastfeeding.
• Jaundice sometimes makes babies sleepy, so they breastfeed less enthusiastically. Waking your baby every two to three hours to feed is recommended.
• If your breasts still feel full after breastfeeding, pump or express your breasts. In addition, pumping after breastfeeding will help stimulate your milk production.
• Your baby’s healthcare provider may recommend supplementing your baby with bottles of expressed milk or formula in conjunction with breastfeeding.
• Some babies require phototherapy. Phototherapy (light treatment) is the process of using light to eliminate bilirubin in the blood. If your baby requires phototherapy, it is important to maximize the amount of time spent under the lights while still breastfeeding frequently.
• Seek the advice of a lactation consultant to assist you.

Contact the Breastfeeding and Lactation Program

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Risk of low levels of blood group antibodies mediating hemolysis in ABO-incompatible neonates with negative three hemolysis tests

Hongxing lin.

1 Department of Blood Transfusion, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, China

Pingxiang Luo

2 Department of Neonatology, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, China

Xiaosong Lin

3 Clinical Laboratory, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, China

Chengwen Que

Wenhui zhong.

Stacia Semple, Weill Cornell Medical Center, NewYork-Presbyterian, United States

Associated Data

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

To explore the risk of low-level blood group antibody-mediated hemolysis in ABO-incompatible newborns with negative three hemolysis tests, aiming to assist in the identification and management of neonatal jaundice.

A retrospective case-control study was performed in 892 children with jaundice. The patients were divided into three groups: group I, ABO compatible, negative three hemolysis tests; group II, ABO incompatible, negative three hemolysis tests; and group III, ABO incompatible, positive three hemolysis tests. We analyzed the differences in clinical data, blood routine and biochemical laboratory results.

(1) Patients in group II had higher levels of mean corpuscular volume (MCV), standard deviation of red blood cell volume distribution width (RDW-SD), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and bile acid (BA) than those in group I ( P  < 0.05). However, there were no statistically significant differences in the MCV, ALT, ALP and BA levels between groups II and III ( P  > 0.05). (2) Mean corpuscular hemoglobin concentration (MCHC) >359.5 g/L, cell volume distribution width (RDW-CV) >15.95%, and reticulocyte count (RET) >4.235% were identified as independent predictors of positive hemolysis test results ( P  < 0.001). The combination of MCHC, RDW-CV, and RET% yielded an AUC of 0.841.

Low-level blood group antibody-mediated hemolysis may occur in ABO-incompatible neonates even when three hemolysis tests are negative. Changes in liver function parameters must be monitored. The combination of MCHC, RDW-CV, and RET% can be used to improve the detection rate of HDN.

Introduction

Hemolytic disease of the newborn (HDN) is an immune hemolytic disease caused by differences in blood group antigens of the red blood cells of a mother and infant. During pregnancy, the maternal immune system is stimulated by fetal allogeneic red blood cell antigens to produce immunoglobulin G antibodies ( 1 ) that cross the placental barrier and destroy fetal red blood cells, resulting in fetal or newborn hemolytic anemia, jaundice, edema, and hyperbilirubinemia ( 2 ). The diagnostic criteria for ABO-HDN include ABO incompatibility between the mother and newborn, clinical manifestations of neonatal bilirubin abnormalities, and serological confirmation of the presence of hemolytic antibodies using three hemolysis tests ( 3 , 4 ). However, the three hemolysis tests are qualitative, and false-negative results may occur ( 5 ). It is not yet possible to identify which ABO-incompatible neonates with negative hemolysis test results have undetected low levels of blood group antibodies or determine if these low levels of antibodies cause severe hemolysis. Therefore, this study reviewed the clinical data and laboratory indicators related to ABO-HDN and explored the possibility of low-level blood group antibodies mediating hemolysis in ABO-incompatible neonates with negative hemolysis test results, aiming to assist in the identification and management of neonatal jaundice.

Materials and methods

Research objectives.

This study included 892 children with jaundice who were hospitalized in the Neonatology Department of Fujian Maternity and Child Health Hospital between June 2020 and May 2023. The children were full-term infants with a gestational age >37 weeks and a birth weight >2,500 g. Exclusion criteria for cases included (1) HDN caused by non-ABO blood group antibodies; (2) other causes of pathological jaundice, such as sepsis, G6PD deficiency, hemoglobinopathy, and cranial hematoma; (3) diseases of the liver and biliary system; and (4) other exclusion factors such as premature birth, low birth weight and incomplete clinical data. The data of 1,244 patients were collected, though 352 patients were excluded, resulting in the final analysis of the data of 892 patients.

All children underwent three hemolysis tests to investigate the cause of jaundice. Gender, gestational age, birth weight, mother's ABO blood type, length of hospitalization, age at the time of examination, and results of laboratory tests during hospitalization (including ABO blood type, three hemolysis tests, routine blood tests, and biochemical tests) were retrospectively collected and analyzed. The values of red cell indices were obtained to get the information regarding red cell destruction, such as red blood cell count (RBC), hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), coefficient of variation of red blood cell volume distribution width (RDW-CV), standard deviation of red blood cell volume distribution width (RDW-SD), reticulocyte count (RET), and reticulocyte percentage (RET%). Biochemical markers related to jaundice and liver function included total serum bilirubin (TSB), indirect bilirubin (IBIL), TSB/albumin ratio (B/A), alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT ratio, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), and bile acid (BA). The data were part of the daily diagnosis and treatment of the children during hospitalization, and the datasets were obtained from the hospital's information system.

Diagnostic criteria

• (1) The diagnostic criteria for ABO-HDN were ABO blood type incompatibility between mother and child, and among the results of three hemolysis tests, including direct anti-human ball test (DAT) and RBC antibody identification (containing free antibody test and antibody release test), any two positive tests or a single positive release test ( 6 ).
• (2) The diagnostic criterion for anemia was Hb < 145 g/L ( 7 ).
• (3) The diagnostic criterion for hyperbilirubinemia was TSB ≥ 256 umol/L in term infants ( 8 ).

Grouping method

The patients were divided into three groups based on the maternal and infant ABO blood type compatibility and the serological diagnosis of HDN: group I, ABO compatible, negative three hemolysis tests; group II, ABO incompatible, negative three hemolysis tests; and group III, ABO incompatible, positive three hemolysis tests.

Detection method

Blood type identification, free antibody experiments, and antibody release experiments were performed using the microcolumn gel method, and the direct anti-human sphere test was performed using the test tube method. Routine blood, biochemical, and other indicators were detected using fully-automated instrument analysis. The experimental sample requirements and testing operations were based on the “National Clinical Laboratory Procedures” ( 9 ).

Instruments and reagents

The blood type test card, anti-globulin card, and supporting WADiana automatic blood type tester were purchased from Beijing Banpers Technology and Trade Co. Ltd. Anti-globulin antibody reagents were purchased from Shanghai Blood Biomedicine Co., Ltd. A Sysmex XN-2000 automatic hematology analyzer was used for routine blood testing, and an Abbott CI16200 automatic biochemical analyzer was used for biochemical testing.

Statistical analysis

All statistical analyses were conducted using SPSS 22.0. Normally-distributed continuous data are expressed as mean and standard deviation while those with skewed distributions are expressed as median and interquartile range. The continuous data were compared using the rank sum test of multiple independent samples, and post-hoc multiple comparisons were made using the Kruskal-Wallis one-way analysis of variance. The chi-square test was used to compare categorical data. The correlation between each indicator and positive hemolysis test results were determined using correlation ratios. Receiver operating characteristic (ROC) curves were used to identify index and cutoff values for HDN screening. A binary logistic regression analysis was performed to test the significance of the cutoff values. Statistical significance was set at P  < 0.05.

Clinical and laboratory parameters

All results are presented in Table 1 . The gestational age and birth weight differed significantly between groups II and III ( P  < 0.05). Given that all children in the three groups were full-term infants with birth weights exceeding 2,500 g, the differences in gestational age and birth weight were considered negligible. The frequency of ABO incompatibility was higher in female children than in male patients (59.8% vs. 41.3%, P  < 0.05). However, the rate of positive hemolysis results did not differ between female and male patients with ABO incompatibility (63.3% vs. 56.8%, P  > 0.05). There was a significant difference in the age at the time of examination among the three groups ( P  < 0.05), with the oldest in group II and the youngest in group III.

Comparison of clinical and laboratory parameters.

The TSB, IBIL, and B/A levels did not show significant differences among the three groups ( P  > 0.05). The length of hospitalization, RBC, and Hb levels were similar between groups I and II ( P  > 0.05). However, the MCV, RDW-SD, ALT, LDH, ALP, and BA levels were increased in group II ( P  < 0.05). There were no statistically significant differences in the MCV, ALT, ALP and BA levels between groups II and III ( P  > 0.05).

The numbers of children with anemia and hyperbilirubinemia in group I were 41 and 140, respectively. In group II, the corresponding numbers were 41 and 135, respectively. The frequencies of anemia or hyperbilirubinemia were not significantly different between the patients in groups I and II (15.5% vs. 16.4% and 53.0% vs. 54.0%, respectively; P  > 0.05).

Correlations between indicators and positive hemolysis results

The RDW-SD, AST, AST/ALT ratio, and LDH showed weak correlations with positive hemolysis results ( P  < 0.001). Meanwhile, the RBC, Hb, MCH, MCHC, RDW-CV, RET, and RET% demonstrated moderate correlations with positive hemolysis test results ( P  < 0.001), as illustrated in Table 2 .

Correlations between indicators and positive hemolysis results.

ROC curve analysis of indicators for HDN screening

In both ABO-incompatible groups, the RBC, Hb, MCH, MCHC, RDW-CV, RET, and RET% proved valuable for screening HDN, with each index having an AUC greater than 0.600 ( P  < 0.001). The cutoff values for HDN screening are presented in Table 3 and Figure 1 .

ROC curve analysis of indicators for HDN screening.

ROC curve of MCHC, RDW-CV, and RET% for HDN screening. MCHC, mean corpuscular hemoglobin concentration; RDW-CV, coefficient of variation of red blood cell volume distribution width; RET%, reticullocyte percentage.

Effects of MCHC, RDW-CV, and RET% on HDN detection rate

Following logistic regression analysis, MCHC > 359.5 g/L, RDW-CV > 15.95%, and RET% > 4.235% emerged as independent predictors of positive hemolysis test results ( P  < 0.001), as illustrated in Table 4 . When combined, MCHC, RDW-CV, and RET% produced an AUC of 0.841, with both sensitivity and specificity surpassing those of each individual indicator ( Table 3 and Figure 1 ).

Effects of MCHC, RDW-CV, and RET% on HDN detection rate.

OR values were adjusted for age of Three Hemolysis Tests; R, references group.

HDN is an immune hemolytic disease, and it is the primary risk factor for neonatal pathological jaundice ( 10 ). ABO incompatibility is the main cause of hemolytic hyperbilirubinemia, and Clinical symptoms of jaundice appear between two and five days after birth ( 11 ). In China, prenatal examinations do not routinely screen for ABO-HDN-related antibodies. The laboratory diagnosis of ABO-HDN is typically based on three hemolysis tests performed after birth. False negative results are sometimes obtained due to weak erythrocyte antigens in newborns, untimely sample detection, the consumption of antibodies for blood type substances in the serum, limitations of the qualitative tests, and differences in result determination. Approximately 20% of newborns with ABO blood group incompatibility are diagnosed with HDN ( 12 ).

In this study, the bilirubin levels and B/A ratio, which was used to indicate the risk of hyperbilirubinemia, were not different between the groups, which is consistent with previously reported results ( 13 , 14 ). This may be due to the fact that the patients included in this study had clinical symptoms of jaundice and that the bilirubin level cannot be used to determine the cause of jaundice. Most patients in group II underwent laboratory testing at approximately five days of age, which was later than that in the other groups. It was observed that jaundice progressed slowly in group II. Therefore, the late monitoring of jaundice should not be overlooked in ABO-incompatible patients. In addition, there was no statistical difference in the length of hospitalization between groups I and II. The patients in the two groups had similar RBC, Hb levels, and frequencies of anemia and hyperbilirubinemia. Therefore, we believe that even if children in group II have a low level of blood group antibodies, it is unlikely to cause severe hemolysis. Moreover, the progression of hemolysis is slow and does not lead to significant abnormalities in bilirubin and hemoglobin levels.

As HDN may cause diffuse liver cell damage, laboratory indicators reflecting liver function were also analyzed in this study. Patients in group II had higher levels of ALT, LDH, ALP, and BA than those in group I. However, increased enzyme levels typically indicate liver injury and a reduced capacity of the liver to process bilirubin ( 15 – 18 ) . These findings suggest that the liver function differed between the two groups due to varying degrees of liver damage. The ALT, ALP, and BA levels did not differ between group II and group III, suggesting comparable liver function. Therefore, it is worth noting that even though patients in group II did not have severe hemolysis, their liver function and ability to metabolize bilirubin decreased.

The diagnosis of HDN includes serological tests to confirm the presence of hemolytic antibodies; however, low levels of antibodies may be missed, making it impossible to identify all patients with immune hemolysis. Immune hemolysis leads to the destruction and dissolution of red blood cells, which can cause abnormal volume and morphology of peripheral blood red blood cells. MCV and RDW are objective parameters that reflect the volume and volume heterogeneity, respectively. In this study, the MCV and RDW-SD in group II were higher than those in group I, though the RDW-CV was not significantly different. Additionally, the MCHC, RET, and RET% were higher in group II than in group I, and these indicators were correlated with positive hemolysis test results. This correlation was stronger than that between AST or LDH and positive hemolysis test results. Abnormal AST and LDH levels and their correlation with positive hemolysis results have been reported ( 19 , 20 ). These differences in erythrocyte compensatory changes after hemolysis suggests that the causes of hemolysis differ between the two groups of patients with negative hemolysis test. In addition, the RDW-CV and RDW-SD in group II were lower than in group III, while the MCV was similar between the groups, suggesting that the destruction and dissolution processes of red blood cells are comparable between group II and group III, but the intensity of hemolysis in group II was slightly weaker. Therefore, clinicians should be aware of hemolysis due to low levels of blood group antibodies in children in group II.

In this study, MCHC > 359.5 g/L, RDW-CV > 15.95%, and RET% > 4.235% were independent predictors of positive hemolysis test results. When maternal and infant ABO blood types are incompatible, these indicators are helpful in identifying patients who should undergo screening for HDN. The AUC, sensitivity, and specificity of the combination of these three indicators were greater of those of each individual indicator. Therefore, these indicators can be used to increase the detection rate of ABO-HDN, thereby helping determine the cause of jaundice in children with ABO incompatibility and improving the management of neonatal jaundice.

In reality, sometimes the same child's hemolysis test result is negative before admission, and reexamination after admission has a weakly positive result. During hospitalization, some patients experienced recurrent jaundice, but on repeat testing, the hemolysis test results were still negative. Female patients had a higher probability of ABO incompatibility in this study, though the ABO-HDN positivity rate did not differ between male and female patients. These results suggest that low-level blood group antibody-mediated hemolysis must be considered, especially in female patients.

Our study had certain limitations. Patients with multiple causes of jaundice were excluded in this study. The interaction between HDN and other causes lacked sufficient observation. Therefore, it is necessary to continue to expand the data to include cases with multiple jaundice etiologies for comparison and to raise further awareness to the application value of combining two of the three indicators (MCHC > 359.5 g/L, RDW-CV > 15.95%, and RET% > 4.235%). HDN-negative children with recurrent jaundice, especially those sent again for hemolysis three tests, will be in the focus of our follow-up observation. In addition, the indicators used in this study may change only after the immune hemolysis of red blood cells reaches a certain level, as they are indirect indicators and lag behind the development of ABO-HDN. Therefore, for children with ABO-incompatible hyperbilirubinemia, especially those with negative hemolysis test results and changes in liver function, more sensitive methods (such as flow cytometry) should be considered to qualitatively or quantitatively detect blood group antibodies.

Conclusions

In summary, ABO-incompatible newborns with negative three hemolysis tests may have low-level blood group antibody-mediated hemolysis. Red blood cells may undergo heterogeneous changes caused by immune hemolysis that is not severe. However, the changes in liver function caused by hemolysis must be monitored. MCHC > 359.5 g/L, RDW-CV > 15.95%, and RET% > 4.235% were identified as independent predictors of positive hemolysis test results. The combination of these predictors can help improve the detection of ABO-HDN and facilitate the management of jaundice.

Funding Statement

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Data availability statement

Ethics statement.

The studies involving humans were approved by Ethics Committee of Fujian Maternity and Child Health Hospital (approval number 2024KY018). The studies were conducted in accordance with the local legislation and institutional requirements. The Ethics Committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because a waiver of consent was obtained from the Ethics Committee as the data collection and analyses were retrospective.

Author contributions

HL: Conceptualization, Investigation, Formal Analysis, Methodology, Writing – original draft. PL: Conceptualization, Validation, Writing – review & editing. CL: Conceptualization, Data curation, Validation, Methodology, Writing – review & editing. XL: Investigation, Methodology, Writing – review & editing. CQ: Conceptualization, Data curation, Investigation, Methodology, Writing – review & editing. WZ: Conceptualization, Data curation, Visualization, Methodology, Supervision, Writing – review & editing.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

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