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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.
| Current hepatitis B infection | |
| Previous hepatotos B infection | |
| Previous hepatitis C infection |
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.
| Raised levels are seen in Wilson’s disease, a disease of copper metabolism | |
| Raised levels are suggestive of haemochromatosis, a disease of iron metabolism | |
| Poorly controlled diabetes is associated with liver disease | |
| Alpha-1 antitrypsin deficiency is a rare and inherited cause of liver cirrhosis |
Table 3 . Immunoglobulins
| Forms the majority of circulating immunoglobulins and is involved in the secondary immune response. Associated with autoimmune hepatitis. | |
| Forms around 10% of circulating immunoglobulins and is involved in the primary immune response. Associated with primary biliary cirrhosis. | |
| Involved in protecting mucous membranes, forms around 15% of total 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.
| Autoimmune hepatitis, , , , Sjorgren’s disease, Addison’s disease | |
| Autoimmune hepatitis | |
| Differentiates between type 1 and type 2 autoimmune hepatitis (AIH): associated with type 2 AIH | |
| Associated with primary biliary cirrhosis |
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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- Pathophysiology |
- Evaluation |
- Treatment |
- Geriatrics Essentials: Jaundice |
- Key Points |
Jaundice is a yellowish discoloration of the skin and mucous membranes caused by hyperbilirubinemia. Jaundice becomes visible when the bilirubin level is about 2 to 3 mg/dL (34 to 51 micromol/L).
(See also Liver Structure and Function and Evaluation of the Patient With a Liver Disorder .)
Pathophysiology of Jaundice
Most bilirubin is produced when hemoglobin (Hb) is broken down into unconjugated bilirubin (and other substances). Unconjugated bilirubin binds to albumin in the blood for transport to the liver, where it is taken up by hepatocytes and conjugated with glucuronic acid to make it water soluble. Conjugated bilirubin is excreted in bile into the duodenum. In the intestine, bacteria metabolize bilirubin to form urobilinogen. Some urobilinogen is eliminated in the feces, and some is reabsorbed, extracted by hepatocytes, reprocessed, and re-excreted in bile (enterohepatic circulation—see Overview of Bilirubin Metabolism ).
Mechanisms of hyperbilirubinemia
Hyperbilirubinemia may involve predominantly unconjugated or conjugated bilirubin.
Unconjugated hyperbilirubinemia is most often caused by ≥ 1 of the following:
Increased production
Decreased hepatic uptake
Decreased conjugation
Conjugated hyperbilirubinemia is most often caused by ≥ 1 of the following:
Dysfunction of hepatocytes (hepatocellular dysfunction)
Slowing of bile egress from the liver (intrahepatic cholestasis)
Obstruction of extrahepatic bile flow (extrahepatic cholestasis)
Consequences
Outcome is determined primarily by the cause of jaundice and the presence and severity of hepatic dysfunction. Hepatic dysfunction can result in coagulopathy, encephalopathy, and portal hypertension (which can lead to gastrointestinal bleeding).
Etiology of Jaundice
Although hyperbilirubinemia can be classified as predominantly unconjugated or conjugated, many hepatobiliary disorders cause both forms.
Many conditions (see table Mechanisms and Some Causes of Jaundice in Adults ), including use of certain drugs (see table Some Drugs and Toxins That Can Cause Jaundice ), can cause jaundice, but the most common causes overall are
Inflammatory hepatitis (viral hepatitis, autoimmune hepatitis, toxic hepatic injury)
Alcohol-related liver disease
Biliary obstruction
Mechanisms and Some Causes of Jaundice in Adults
Unconjugated hyperbilirubinemia | ||
Increased bilirubin production | Common: Less common: Resorption of large hematomas, ineffective erythropoiesis | Few or no clinical manifestations of hepatobiliary disease; sometimes anemia, ecchymoses Serum bilirubin level usually < 3.5 mg/dL (< 59 micromol/L), no bilirubin in urine, normal aminotransferase levels |
Decreased hepatic bilirubin uptake | Common: Less common: Drugs, fasting, portosystemic shunts | — |
Decreased hepatic conjugation | Common: , | — |
Conjugated hyperbilirubinemia† | ||
Hepatocellular dysfunction | Common: , , Less common: , , , , , | Aminotransferase levels usually > 500 U/L (8.35 microkat/L) |
Intrahepatic cholestasis | Common: , , , Less common: Infiltrative disorders (eg, , , , ), pregnancy, , | Gradual onset of jaundice, sometimes pruritus If severe, clay-colored stools, steatorrhea If long-standing, weight loss Alkaline phosphatase and GGT usually > 3 times normal Aminotransferase levels < 200 U/L (3.34 microkat/L) |
Extrahepatic cholestasis | Common: Common , Less common: , pancreatic pseudocyst, , common duct strictures caused by previous surgery, other tumors | Depending on cause, manifestations possibly similar to those of intrahepatic cholestasis or a more acute disorder (eg, abdominal pain or vomiting due to a common bile duct stone or acute pancreatitis) Alkaline phosphatase and GGT usually > 3 times normal Aminotransferase levels < 200 U/L (3.34 microkat/L) |
Other, less common mechanisms | Hereditary disorders (mainly and ) | Normal liver enzymes |
| = gamma-glutamyltransferase. | ||
Some Drugs and Toxins That Can Cause Jaundice
Increased bilirubin production | Drugs that cause (common among patients with |
Decreased hepatic uptake | |
Decreased conjugation | |
Hepatocellular dysfunction | , statins, many others, many drug combinations , carbon tetrachloride, phosphorus (see and ) |
Intrahepatic cholestasis | ), , phenothiazines |
Evaluation of Jaundice
History of present illness should include onset and duration of jaundice. Hyperbilirubinemia can cause urine to darken before jaundice is visible. Therefore, the onset of dark urine indicates onset of hyperbilirubinemia more accurately than onset of jaundice. Important associated symptoms include fever, prodromal symptoms (eg, fever, malaise, myalgias) before jaundice, changes in stool color, pruritus, steatorrhea, and abdominal pain (including location, severity, duration, and radiation). Important symptoms suggesting severe disease include nausea and vomiting, weight loss, and possible symptoms of coagulopathy (eg, easy bruising or bleeding, tarry or bloody stools).
Review of systems should seek symptoms of possible causes, including weight loss and abdominal pain (cancer); joint pain and swelling ( autoimmune or viral hepatitis , hemochromatosis , primary sclerosing cholangitis , sarcoidosis ); and missed menses (pregnancy).
Past medical history should identify known causative disorders, such as hepatobiliary disease (eg, gallstones , hepatitis , cirrhosis ); disorders that can cause hemolysis (eg, hemoglobinopathy , glucose-6-phosphate dehydrogenase [G6PD] deficiency ); and disorders associated with liver or biliary disease, including inflammatory bowel disease , infiltrative disorders (eg, amyloidosis , lymphoma , sarcoidosis , tuberculosis ), and HIV infection or AIDS .
Drug history should include questions about use of drugs or exposure to toxins known to affect the liver (see table Some Drugs and Toxins That Can Cause Jaundice ) and about vaccination against hepatitis.
Surgical history should include questions about previous surgery on the biliary tract (a potential cause of strictures).
Social history should include questions about risk factors for hepatitis (see table Some Risk Factors for Hepatitis ), amount and duration of alcohol use, injection drug use, and sexual history.
Family history should include questions about recurrent, mild jaundice in family members and diagnosed hereditary liver disorders. The patient’s history of recreational drug and alcohol use should be corroborated by friends or family members when possible.
Some Risk Factors for Hepatitis
| Day care attendance or employment Residence or employment in a closed institution Travel to an endemic area Oral-anal sex Ingestion of raw shellfish |
| Injection drug use
Sharing of razor blades or toothbrushes Tattooing Body piercing Absence of vaccination in health care workers High-risk sexual activity Birth in areas of high endemicity |
| Blood transfusion before 1992 Injection drug use
Exposure during health care work or sexual activity Date of birth between 1945 and 1965 |
Physical examination
Vital signs are reviewed for fever and signs of systemic toxicity (eg, hypotension, tachycardia).
General appearance is noted, particularly for cachexia and lethargy.
Head and neck examination includes inspection of the sclerae and tongue for icterus and the eyes for Kayser-Fleischer rings (best seen with slit lamp). Mild jaundice is best seen by examining the sclerae in natural light; it is usually detectable when serum bilirubin reaches 2 to 2.5 mg/dL (34 to 43 micromol/L). Breath odor should be noted (eg, for fetor hepaticus).
DR P. MARAZZI/SCIENCE PHOTO LIBRARY
The abdomen is inspected for collateral vasculature, ascites , and surgical scars. The liver is palpated for hepatomegaly, masses, nodularity, and tenderness. The spleen is palpated for splenomegaly. The abdomen is examined for umbilical hernia, shifting dullness, fluid wave, masses, and tenderness. The rectum is examined for gross or occult blood.
Men are checked for testicular atrophy and gynecomastia.
The upper extremities are examined for Dupuytren contractures .
Neurologic examination includes mental status assessment and evaluation for asterixis (a characteristic flapping tremor of the hands).
The skin is examined for jaundice, palmar erythema, needle tracks, vascular spiders, excoriations, xanthomas (consistent with primary biliary cholangitis ), paucity of axillary and pubic hair, hyperpigmentation, ecchymoses, petechiae, and purpura.
The following findings are of particular concern:
Marked abdominal pain and tenderness
Altered mental status
Gastrointestinal (GI) bleeding (occult or gross)
Ecchymoses, petechiae, or purpura
Interpretation of findings
Severity of illness is indicated mainly by the degree (if any) of hepatic dysfunction. Ascending cholangitis is a concern because it requires emergency treatment.
Severe hepatic dysfunction is indicated by encephalopathy (eg, mental status change, asterixis) or coagulopathy (eg, easy bleeding, purpura, tarry or heme-positive stool), particularly in patients with signs of portal hypertension (eg, abdominal collateral vasculature, ascites, splenomegaly). Massive upper GI bleeding suggests variceal bleeding due to portal hypertension (and possibly coagulopathy).
Ascending cholangitis is suggested by fever and marked, continuous right upper quadrant abdominal pain; acute pancreatitis with biliary obstruction (eg, due to a common duct stone or pancreatic pseudocyst) may manifest similarly.
Cause of jaundice may be suggested by the following:
Acute jaundice in the young and healthy suggests acute viral hepatitis , particularly when a viral prodrome, risk factors, or both are present; however, is also common.
Acute jaundice after acute drug or toxin exposure in healthy patients is likely to be due to that substance.
A long history of heavy alcohol use suggests alcohol-related liver disease , particularly when typical stigmata are present.
A personal or family history of recurrent, mild jaundice without findings of hepatobiliary dysfunction suggests a hereditary disorder, usually Gilbert syndrome .
Gradual onset of jaundice with pruritus, weight loss, and clay-colored stools suggests intrahepatic or extrahepatic cholestasis.
Painless jaundice in older patients with weight loss and a mass but with minimal pruritus suggests biliary obstruction caused by cancer.
Other examination findings can also be helpful (see table Findings Suggesting a Cause of Jaundice ).
Findings Suggesting a Cause of Jaundice
Risk factors | |
Alcohol use (heavy) | , including alcoholic hepatitis and cirrhosis |
Gastrointestinal cancer | Extrahepatic biliary obstruction |
Hypercoagulable state | Hepatic vein thrombosis ( ) |
Inflammatory bowel disease |
|
Pregnancy | Intrahepatic cholestasis, steatohepatitis ( ) |
Previous cholecystectomy | Biliary stricture Retained or recurrent common |
Recent surgery |
Benign postoperative intrahepatic cholestasis Lengthy cardiac bypass surgery |
Symptoms | |
Colicky right upper quadrant, right shoulder, or subscapular pain (current or previous) |
|
Constant right upper quadrant pain | or , acute |
Dark urine | Conjugated hyperbilirubinemia |
Joint pain, swelling, or both | (autoimmune or viral)
|
Nausea or vomiting before jaundice |
Common (particularly if accompanied by abdominal pain or rigors) |
Pruritus and clay-colored stools | Intrahepatic or extrahepatic cholestasis, possibly severe if stools are clay-colored |
Viral prodrome (eg, fever, malaise, myalgias) |
|
Physical examination | |
Abdominal collateral vasculature, , and splenomegaly | (eg, due to cirrhosis) |
Cachexia in a patient with a hard, lumpy liver | (common) |
Diffuse lymphadenopathy in a patient with acute jaundice |
|
Diffuse lymphadenopathy in a patient with chronic jaundice | , |
, palmar erythema, paucity of axillary and pubic hair, and vascular spiders |
|
Gynecomastia and testicular atrophy | , |
Hyperpigmentation | , |
|
|
Needle marks |
|
Resolving hematoma | Extravasation of blood into tissues |
Xanthomas |
|
The following are done:
Blood tests (bilirubin, aminotransferase, alkaline phosphatase)
Usually imaging
Sometimes biopsy (percutaneous or transjugular approaches)
Blood tests include measurement of total and direct bilirubin, aminotransferase, and alkaline phosphatase levels in all patients. Results help differentiate cholestasis from hepatocellular dysfunction (important because patients with cholestasis usually require imaging tests):
Hepatocellular dysfunction: Marked aminotransferase elevation ( > 500 U/L [8.35 microkat/L]) and moderate alkaline phosphatase elevation ( < 3 times normal)
Cholestasis: Moderate aminotransferase elevation ( < 200 U/L [3.34 microkat/L]) and marked alkaline phosphatase elevation ( > 3 times normal)
Also, patients with hepatocellular dysfunction or cholestasis have dark urine due to bilirubinuria because conjugated bilirubin is excreted in urine; unconjugated bilirubin is not. Bilirubin fractionation also differentiates conjugated from unconjugated forms. When aminotransferase and alkaline phosphatase levels are normal, fractionation of bilirubin can help suggest causes, such as Gilbert syndrome or hemolysis (unconjugated) vs Dubin-Johnson syndrome or Rotor syndrome (conjugated).
Other blood tests are done based on clinical suspicion and initial test findings, as for the following:
Signs of hepatic insufficiency (eg, encephalopathy , ascites , ecchymoses) or gastrointestinal (GI) bleeding: Coagulation profile (prothrombin time [PT]/partial thromboplastin time [PTT])
Hepatitis risk factors (see table Some Risk Factors for Hepatitis ) or a hepatocellular mechanism suggested by blood test results: Hepatitis viral and autoimmune serologic tests
Fever, abdominal pain, and tenderness: Complete blood count and, if patients appear ill, blood cultures
Suspicion of hemolysis can be confirmed by a peripheral blood smear.
Imaging is done if pain suggests extrahepatic obstruction or cholangitis or if blood test results suggest cholestasis.
Abdominal ultrasonography is usually done first; usually, it is highly accurate in detecting extrahepatic obstruction. CT and MRI are alternatives. Ultrasonography is usually more accurate for gallstones , and CT is more accurate for pancreatic lesions. All these tests can detect abnormalities in the biliary tree and focal liver lesions but are less accurate in detecting diffuse hepatocellular disorders (eg, hepatitis , cirrhosis ).
If ultrasonography shows extrahepatic cholestasis, other tests may be necessary to determine the cause; usually, magnetic resonance cholangiopancreatography (MRCP) , endoscopic ultrasonography (EUS), or endoscopic retrograde cholangiopancreatography (ERCP) is used. ERCP is more invasive but allows treatment of some obstructive lesions (eg, stone removal, stenting of strictures).
Liver biopsy is not commonly required but can help diagnose certain disorders (eg, disorders causing intrahepatic cholestasis, some kinds of hepatitis, some infiltrative disorders, Dubin-Johnson syndrome , hemochromatosis , Wilson disease ). Biopsy can also help when liver enzyme abnormalities are unexplained by other tests.
Laparoscopy (peritoneoscopy) allows direct inspection of the liver and gallbladder without the trauma of a full laparotomy. Unexplained cholestatic jaundice warrants laparoscopy occasionally and diagnostic laparotomy rarely.
Treatment of Jaundice
Treatment of causes and complications
The cause and any complications are treated. Jaundice itself requires no treatment in adults (unlike in neonates—see Neonatal Hyperbilirubinemia
Geriatrics Essentials: Jaundice
Symptoms may be attenuated or missed in the older patient; eg, abdominal pain may be mild or absent in acute viral hepatitis . A sleep disturbance or mild confusion resulting from portosystemic encephalopathy may be misattributed to dementia.
Suspect acute viral hepatitis in patients, particularly young and healthy patients, who have acute jaundice, particularly with a viral prodrome.
Suspect biliary obstruction due to cancer in older patients with painless jaundice, weight loss, an abdominal mass, and minimal pruritus.
Suspect hepatocellular dysfunction if aminotransferase levels are > 500 U/L and alkaline phosphatase elevation is < 3 times normal.
Suspect cholestasis if aminotransferase levels are < 200 U/L and alkaline phosphatase elevation is > 3 times normal.
Hepatic dysfunction is significant if mental status is altered and coagulopathy is present.
Copyright © 2024 Merck & Co., Inc., Rahway, NJ, USA and its affiliates. All rights reserved.
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MATTHEW V. FARGO, MD, MPH, SCOTT P. GROGAN, DO, MBA, AND AARON SAGUIL, MD, MPH
Am Fam Physician. 2017;95(3):164-168
Patient information : See related handout on jaundice in adults , written by the authors of this article.
Author disclosure: No relevant financial affiliations.
Jaundice in adults can be an indicator of significant underlying disease. It is caused by elevated serum bilirubin levels in the unconjugated or conjugated form. The evaluation of jaundice relies on the history and physical examination. The initial laboratory evaluation should include fractionated bilirubin, a complete blood count, alanine transaminase, aspartate transaminase, alkaline phosphatase, γ-glutamyltransferase, prothrombin time and/or international normalized ratio, albumin, and protein. Imaging with ultrasonography or computed tomography can differentiate between extrahepatic obstructive and intrahepatic parenchymal disorders. Ultrasonography is the least invasive and least expensive imaging method. A more extensive evaluation may include additional cancer screening, biliary imaging, autoimmune antibody assays, and liver biopsy. Unconjugated hyperbilirubinemia occurs with increased bilirubin production caused by red blood cell destruction, such as hemolytic disorders, and disorders of impaired bilirubin conjugation, such as Gilbert syndrome. Conjugated hyperbilirubinemia occurs in disorders of hepatocellular damage, such as viral and alcoholic hepatitis, and cholestatic disorders, such as choledocholithiasis and neoplastic obstruction of the biliary tree.
Jaundice occurs when the serum bilirubin level exceeds 3 mg per dL (51.3 μmol per L). It can be difficult to detect by physical examination alone. 1 Acute jaundice is often an indicator of significant underlying disease and occurs secondary to intra- and extrahepatic etiologies. A retrospective study of more than 700 individuals found that most cases (55%) of acute jaundice in adults are caused by intrahepatic disorders, including viral hepatitis, alcoholic liver disease, and drug-induced liver injury. The remaining 45% of acute jaundice cases are extrahepatic and include gallstone disease, hemolysis, and malignancy. 2 This article provides a systematic approach to the diagnosis of jaundice in adults and reviews common etiologies of hyperbilirubinemia. An algorithm for the evaluation of jaundice in adults is provided in Figure 1 . 3
| The initial laboratory evaluation of jaundice in adults should include fractionated bilirubin, complete blood count, alanine transaminase, aspartate transaminase, alkaline phosphatase, γ-glutamyltransferase, prothrombin time and/or international normalized ratio, albumin, and protein. | C | |
| Ultrasonography should be the first-line option for imaging in patients with jaundice because it is the least invasive and least expensive modality, and can effectively evaluate for obstructive disorders. | C | , |
| Visualization of the intra- and extrahepatic biliary tree should be evaluated by magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography. | C | , |
| Liver biopsy should be reserved for cases of jaundice where the diagnosis is unclear after the initial evaluation and if biopsy results will impact treatment and determine prognosis. | C |
Pathophysiology
Approximately 250 mg of bilirubin per day is produced by an average adult through the catabolism of the heme molecule. 4 Heme is released during red blood cell destruction. It is first converted to biliverdin and then to unconjugated bilirubin within macrophages in the reticular endothelial system. 5 Unconjugated bilirubin is lipid soluble and passes easily through cell membranes to bind to albumin in serum, whereas free (unbound) bilirubin is taken up by liver hepatocytes and converted to conjugated bilirubin. 4 , 6 Conjugated bilirubin is water soluble and is transported from liver hepatocytes into the biliary tract system where it passes to the intestines and is excreted into the stool. Some conjugated bilirubin is reabsorbed in the intestines and is excreted by the kidneys as urobilinogen. 4 , 6 Jaundice occurs when there are disruptions along this metabolic pathway, causing an increase in unconjugated bilirubin (e.g., from increased red blood cell destruction or impaired bilirubin conjugation) or conjugated bilirubin (e.g., from hepatocellular damage or biliary tract obstructions).
History and Physical Examination
The initial workup of jaundice should focus on the history and physical examination to help clarify the diagnosis. A detailed alcohol and drug use history can help identify intrahepatic disorders such as alcoholic liver disease, viral hepatitis, chronic liver disease, or drug-induced liver injury. A focused review of systems is important. For example, fever and prodromal viral symptoms can precede acute viral hepatitis, fever can be associated with underlying sepsis, and weight loss can be associated with underlying malignancy. The physical examination should include evaluation for underlying encephalopathy by testing for asterixis and mental status changes; evaluation of signs of chronic liver disease to include bruising, spider angiomas, palmar erythema, and gynecomastia; and a complete abdominal examination to evaluate for hepatomegaly, splenomegaly, right upper quadrant tenderness, and ascites. 3 , 7
Laboratory Evaluation
The laboratory evaluation to determine the etiology of jaundice should include fractionated bilirubin, a complete blood count, alanine transaminase, aspartate transaminase, γ-glutamyltransferase, alkaline phosphatase, prothrombin time and/or international normalized ratio, albumin, and protein. 7 Fractionated bilirubinemia is required to differentiate between conjugated and unconjugated hyperbilirubinemia. A complete blood count with a peripheral blood smear can help identify hemolysis and evaluate for anemia of chronic disease and thrombocytopenia, which is common in decompensated cirrhosis. Elevated alanine transaminase and aspartate transaminase levels can indicate hepatocellular damage. However, levels may be normal in chronic liver disease (e.g., cirrhosis). In such cases, there may not be enough normal liver parenchymal tissue to release elevated levels of these enzymes.
An elevated alkaline phosphatase level can be associated with biliary obstruction and parenchymal liver disease, but it is also associated with several other physiologic and nonbiliary pathologic processes in bone, kidney, intestine, and placenta. An elevated γ-glutamyltransferase level can be associated with biliary obstruction and hepatocellular damage, as well as pancreatic disorders, myocardial infarction, renal disease, and diabetes mellitus. 7 Protein, albumin, and prothrombin time or international normalized ratio are associated with liver synthetic function. Low levels of protein and albumin, or elevated prothrombin time or international normalized ratio, indicate decreased synthetic function and hepatic decompensation.
If the jaundice etiology is unknown after the initial laboratory evaluation, it is necessary to perform additional tests including hepatitis panels and autoimmune panels, such as antinuclear, smooth muscle, and liver-kidney microsomal antibodies. 3
Noninvasive imaging modalities in persons with jaundice include ultrasonography, computed tomography, and magnetic resonance cholangiopancreatography. Ultrasonography or computed tomography is usually the first-line option to evaluate for obstruction, cirrhosis, and vessel patency, with ultrasonography being the least invasive and least expensive modality. 3 , 7 Visualization of the intra- and extrahepatic biliary tree can be further evaluated using magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography, with the latter allowing for therapeutic options, such as biliary stent placement to relieve obstruction. 7 Endoscopic ultrasonography can be used in addition to endoscopic retrograde cholangiopancreatography for evaluation of common bile duct obstructions and can help determine if the obstruction is from a mass or stone. 8
Liver Biopsy
Liver biopsy should be reserved for cases of jaundice in which the diagnosis is unclear after the initial history and physical examination, laboratory studies, and imaging. It should be performed only if biopsy results are required to determine treatment and prognosis. Biopsy may alter care in only about one-third of cases. 7
Pseudojaundice
Skin color changes can occur in conditions other than hyperbilirubinemia, such as Addison disease, anorexia nervosa, ingestion of beta carotene–rich foods (carotenemia), or use of spray-tanning products.
Unconjugated Hyperbilirubinemia
Increased bilirubin production.
Unconjugated hyperbilirubinemia is usually a result of too much bilirubin presented to the conjugating machinery (from increased red blood cell destruction). Increased red blood cell breakdown may be caused by red blood cell membrane disorders, 9 red blood cell enzyme disorders, 10 hemoglobin disorders, 11 autoimmune red blood cell destruction, 12 or some cancers. The excess turnover of red blood cells results in increased heme metabolism, producing large amounts of bilirubin that overwhelm the conjugating machinery, leading to decreased excretion and clinical jaundice.
IMPAIRED BILIRUBIN CONJUGATION
Deficiencies in the same conjugating machinery may also lead to jaundice in individuals with normal red blood cell turnover. Gilbert syndrome involves a deficiency in uridine diphosphate-glucuronosyltransferase, and it affects 10% of the white population. 13 This is a benign condition that may be exacerbated by physical or emotional stress such as illness, strenuous exercise, or fasting. Crigler-Najjar syndrome is a more severe variant of the same enzyme deficiency. 13 Patients with impaired conjugation due to low levels of the bilirubin-UGT enzyme are particularly susceptible to jaundice from medications that inhibit this enzyme, such as protease inhibitors. 6 Table 1 lists the causes of unconjugated hyperbilirubinemia. 5 , 7 , 9 – 12
| Cold reactive |
| Drug induced (associated with approximately 150 drugs) |
| Mixed type |
| Warm reactive |
| Sickle cell anemia |
| Thalassemia |
| Crigler-Najjar syndrome |
| Gilbert syndrome |
| Glucose-6-phosphate dehydrogenase deficiency |
| Glucose-6-phosphate isomerase deficiency |
| Pyrimidine-5′-nucleotidase deficiency |
| Pyruvate kinase deficiency |
| Elliptocytosis |
| Ovalocytosis |
| Spherocytosis |
| Myeloproliferative neoplasms (especially polycythemia vera) |
Conjugated Hyperbilirubinemia
Intrahepatic disorders: hepatocellular damage and intrahepatic cholestasis.
The largest worldwide contributor to liver disease is viral hepatitis, mostly from hepatitis C. 14 Viral hepatitis causes increased oxidative stress within hepatocytes, leading to cell death, scarring, and diminished liver mass available for normal function. 4 , 15 Chronic alcohol consumption can cause various hepatic disorders, including steatosis or fatty liver disease with minimal symptoms and often no jaundice; alcoholic hepatitis with acute onset jaundice and more severe symptoms; and cirrhosis, which is often associated with decompensation and liver failure in the setting of jaundice. 3 Jaundice in persons with alcoholic liver disease can occur via multiple mechanisms, such as direct hepatocellular damage caused by ethanol metabolites or from alcohol's effect on bile acid uptake and secretion contributing to cholestasis. 3 , 16
Approximately 30% to 40% of patients with nonalcoholic fatty liver disease progress to nonalcoholic steatohepatitis, and approximately 40% to 50% of these patients develop fibrosis or cirrhosis that may lead to hyperbilirubinemia. 17 Although the exact mechanism is poorly understood, liver lipid deposition may trigger inflammation and fibrosis, particularly when coupled with type 2 diabetes. 17 Sepsis may also induce hyperbilirubinemia as circulating acute phase reactants and bacterial endotoxins disrupt bilirubin transport, leading to cholestasis and elevated bile salt levels. 18 , 19
Drug-induced liver injury has multiple potential mechanisms, including direct hepatocellular toxicity and activation of an immune response that advances the inflammatory cascade, inhibiting bilirubin transport into canaliculi, which causes cholestasis. 20 Wilson disease, a rare genetic disorder, is associated with a loss of function of a cellular transporter responsible for moving dietary copper into liver canaliculi. Elevated liver copper levels affect hepatic lipid metabolism, which leads to steatosis and cholestasis. 21 Additional causes of intrahepatic hyperbilirubinemia include autoimmune disorders, such as autoimmune hepatitis and the rare autoimmune condition primary biliary cirrhosis, which occurs most commonly in middle-aged women. Both conditions are associated with inflammation, which disrupts the transport of bilirubin within the liver. 3
EXTRAHEPATIC DISORDERS: CHOLESTASIS
Conjugated hyperbilirubinemia may also arise from extrahepatic obstruction. Patients with biliary obstruction may present with multiple signs and symptoms, including fever, pruritus, abdominal pain, weight loss, muscle wasting, dark urine, and pale stools. Choledocholithiasis is the most common non-neoplastic cause of biliary obstruction, accounting for 14% of all new cases of jaundice. 2 An estimated 20 million Americans have gallstones, and risk factors for choledocholithiasis include female sex, older age, increasing body mass index, and rapid weight loss. 22
Gallstones may cause jaundice by obstructing the biliary tree (typically the common bile duct) or by inducing a biliary stricture. 23 Less commonly, stones in the gallbladder or cystic duct may mechanically compress the common hepatic duct causing jaundice, and, rarely, stones may cause the formation of a biliary-vascular fistula with accompanying jaundice. 24 Biliary stricture causing postoperative jaundice is a rare complication of cholecystectomy (0.6% of cases). 7 , 23
Jaundice may be caused by surgeries such as liver transplantation and the Whipple and Billroth procedures, which both involve the creation of a choledochojejunostomy. Chronic pancreatitis may cause biliary strictures and jaundice, as may different forms of cholangitis. 7 , 25 In children, biliary atresia and choledochal cysts are the main causes of extrahepatic biliary obstruction. 26
Neoplasms are associated with 6.2% of new-onset cases of jaundice. 2 Cholangiocarcinoma may affect the proximal or distal portions of the biliary tree by causing biliary strictures. Five-year survival for persons who have resection is 20% to 40%; survival in unresectable disease is less than one year. 27 , 28 Primary sclerosing cholangitis confers a 1,500-fold increased risk of cholangiocarcinoma, but more than 80% of cases have no risk factors for disease. 27
Gallbladder cancer, although rare, is the most common biliary tract malignancy; risk factors include gallstones, infection ( Salmonella typhi ), and female sex. Median survival is six to 12 months, depending on the stage at diagnosis. 29 Ampullary cancers and bile duct compression from lymphadenopathy, or external tumors such as pancreatic cancer, may also cause obstruction.
Table 2 lists the causes of conjugated hyperbilirubinemia. 3 , 7 , 16 – 18 , 20 , 21 , 24 – 26
| Viral hepatitis (e.g., hepatitis A, B, C) |
| Alcoholic liver disease (e.g., alcoholic steatosis, alcoholic hepatitis, cirrhosis) |
| Nonalcoholic steatohepatitis |
| Drug-induced liver injury |
| Sepsis |
| Autoimmune disorders (e.g., primary biliary cirrhosis, autoimmune hepatitis) |
| Ischemic hepatitis |
| Genetic hepatic disease (e.g., Wilson disease, hemochromatosis) |
| Intrahepatic mass lesions (e.g., hepatocellular carcinoma, metastatic disease) |
| Choledocholithiasis |
| Biliary stricture |
| Biliary-vascular fistula |
| Biliary atresia |
| Cholangitis (bacterial, primary sclerosing, secondary sclerosing) |
| Choledochal cysts |
| Chronic pancreatitis |
| Gallbladder carcinoma |
| Cholangiocarcinoma |
| Pancreatic tumors (e.g., pancreatic adenocarcinoma) |
| Infections (e.g., human immunodeficiency virus/AIDS, cytomegalovirus) |
This article updates a previous article on this topic by Roche and Kobos. 3
Data Sources: A PubMed search was completed using the keyword and medical subject heading (MeSH) jaundice. The search included randomized controlled trials, meta-analyses, clinical trials, systematic reviews, clinical practice guidelines, and review articles. Also searched were Essential Evidence Plus, the National Guideline Clearinghouse, and the Cochrane Database of Systematic Reviews. Search dates: January through August 2015, and November 2016.
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army Medical Department, the U.S. Army, the Uniformed Services University of the Health Sciences, or the Department of Defense.
Hung OL, Kwon NS, Cole AE, et al. Evaluation of the physician's ability to recognize the presence or absence of anemia, fever, and jaundice. Acad Emerg Med. 2000;7(2):146-156.
Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States?. Am J Gastroenterol. 2007;102(3):558-562.
Roche SP, Kobos R. Jaundice in the adult patient. Am Fam Physician. 2004;69(2):299-304.
Levitt DG, Levitt MD. Quantitative assessment of the multiple processes responsible for bilirubin homeostasis in health and disease. Clin Exp Gastroenterol. 2014;7:307-328.
Korolnek T, Hamza I. Macrophages and iron trafficking at the birth and death of red cells. Blood. 2015;125(19):2893-2897.
Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology. 2014;146(7):1625-1638.
Winger J, Michelfelder A. Diagnostic approach to the patient with jaundice. Prim Care. 2011;38(3):469-482:, viii.
American College of Radiology. ACR Appropriateness Criteria. Jaundice. 2012. https://acsearch.acr.org/list . Accessed Novemer 11, 2016.
Gallagher PG. Abnormalities of the erythrocyte membrane. Pediatr Clin North Am. 2013;60(6):1349-1362.
Koralkova P, van Solinge WW, van Wijk R. Rare hereditary red blood cell enzymopathies associated with hemolytic anemia - pathophysiology, clinical aspects, and laboratory diagnosis. Int J Lab Hematol. 2014;36(3):388-397.
Martin A, Thompson AA. Thalassemias. Pediatr Clin North Am. 2013;60(6):1383-1391.
Bass GF, Tuscano ET, Tuscano JM. Diagnosis and classification of auto-immune hemolytic anemia. Autoimmun Rev. 2014;13(4–5):560-564.
Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol. 2010;24(5):555-571.
Sun S, Song Z, Cotler SJ, Cho M. Biomechanics and functionality of hepatocytes in liver cirrhosis. J Biomech. 2014;47(9):2205-2210.
Suhail M, Abdel-Hafiz H, Ali A, et al. Potential mechanisms of hepatitis B virus induced liver injury. World J Gastroenterol. 2014;20(35):12462-12472.
Rocco A, Compare D, Angrisani D, Sanduzzi Zamparelli M, Nardone G. Alcoholic disease: liver and beyond. World J Gastroenterol. 2014;20(40):14652-14659.
Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62(1 suppl):S47-S64.
Bauer M, Press AT, Trauner M. The liver in sepsis: patterns of response and injury. Curr Opin Crit Care. 2013;19(2):123-127.
Kosters A, Karpen SJ. The role of inflammation in cholestasis: clinical and basic aspects. Semin Liver Dis. 2010;30(2):186-194.
Chen M, Suzuki A, Borlak J, Andrade RJ, Lucena MI. Drug-induced liver injury: Interactions between drug properties and host factors. J Hepatol. 2015;63(2):503-514.
Wooton-Kee CR, Jain AK, Wagner M, et al. Elevated copper impairs hepatic nuclear receptor function in Wilson's disease. J Clin Invest. 2015;125(9):3449-3460.
Cafasso DE, Smith RR. Symptomatic cholelithiasis and functional disorders of the biliary tract. Surg Clin North Am. 2014;94(2):233-256.
Fang Y, Gurusamy KS, Wang Q, et al. Pre-operative biliary drainage for obstructive jaundice. Cochrane Database Syst Rev. 2012;9:CD005444.
Luu MB, Deziel DJ. Unusual complications of gallstones. Surg Clin North Am. 2014;94(2):377-394.
Mortelé KJ, Wiesner W, Cantisani V, Silverman SG, Ros PR. Usual and unusual causes of extrahepatic cholestasis: assessment with magnetic resonance cholangiography and fast MRI. Abdom Imaging. 2004;29(1):87-99.
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| Case Study: Neonatal Jaundice | |||
Neonatal Jaundice
Case Presentation
Martin and Kim were both twenty-five when they had Michael, their first child. Kim remained very healthy during her pregnancy and went into labor at 9:00 a.m., just 3 days after her due date. Delivery went quite smoothly, and that evening, mother and child rested comfortably. Two days later, Kim and Michael were released from the hospital. That evening at feeding time, Kim noticed that the whites of Michael's eyes seemed just slightly yellow, a condition that worsened noticeably by the next morning. Kim called the pediatrician and made an appointment for that morning.
Upon examining Michael, the pediatrician informed Martin and Kim that the infant had neonatal jaundice, a condition quite common in newborns and one that need not cause them too much concern. The physician explained that neonatal jaundice was the result of the normal destruction of old or worn fetal red blood cells and the inability of the newborn's liver to effectively process bilirubin, a chemical produced when red blood cells are destroyed. The physician told the parents he would like to see Michael every other day in order to monitor blood bilirubin concentration until the bilirubin concentration dropped into the normal range. He recommended that Kim feed Michael frequently and instructed them to place Michael in sunlight whenever possible.
Case Background
Neonatal jaundice in a disorder that affects nearly 50% of all newborns to at least a small degree. The yellow coloration of the skin and sclera of the eyes is due to the accumulation of bilirubin in adipose tissue and its adherence to collagen fibers. In neonatal jaundice, the excess bilirubin is not due to an abnormal level of red blood cell destruction. It is due to the inability of the young liver cells to conjugate bilirubin, or make it soluble in bile, so that it can be excreted and removed from the body by the digestive tract. This inability is corrected, usually within one week, as the liver cells synthesize the conjugation enzymes. If uncorrected, sufficiently high bilirubin concentrations can cause brain damage. Frequent feedings of a newborn with jaundice increase gastrointestinal tract motility and decrease the likelihood of reabsorbing significant amounts of bilirubin in the small intestine. Radiation from sunlight alters the chemical form of bilirubin, making is easier for the liver to excrete.
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Presentation of Case Dr. Akash Gupta (Pediatrics): A 16-year-old boy was admitted to this hospital in autumn because of jaundice and abnormal results on liver-function tests.
A 2-day-old, 2.68-kg term male neonate is brought to the emergency department with lethargy, poor feeding, and significant generalized jaundice. He was born via spontaneous vaginal delivery at home to a gravida 4, para 3 Amish woman under the supervision of a midwife, at an estimated gestational age of 39 weeks after an uncomplicated pregnancy with scant prenatal care. Jaundice was noticed 7 ...
This clinical case maps to the following UKMLA presentations: Jaundice. You might also be interested in our premium collection of 1,300+ ready-made OSCE Stations, including a range of history taking, clinical examination and data interpretation stations.
Jaundice, also known as hyperbilirubinemia,[1] is a yellow discoloration of the body tissue resulting from the accumulation of an excess of bilirubin. Deposition of bilirubin happens only when there is an excess of bilirubin, a sign of increased production or impaired excretion. The normal serum levels of bilirubin are less than 1mg/dl; however, the clinical presentation of jaundice as scleral ...
Neonatal jaundice is a clinical manifestation of elevated total serum bilirubin (TSB), termed neonatal hyperbilirubinemia, which results from bilirubin that is deposited into an infant's skin. The characteristic features of neonatal jaundice include yellowish skin, sclerae, and mucous membranes. Jaundice derives from the French word jaune, meaning yellow. Neonatal jaundice is the most ...
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.
Reviewed/Revised Sept 2023. Jaundice is a yellowish discoloration of the skin and mucous membranes caused by hyperbilirubinemia. Jaundice becomes visible when the bilirubin level is about 2 to 3 mg/dL (34 to 51 micromol/L). (See also Liver Structure and Function and Evaluation of the Patient With a Liver Disorder.)
Choledocholithiasis is the most common non-neoplastic cause of biliary obstruction, accounting for 14% of all new cases of jaundice. 2 An estimated 20 million Americans have gallstones, and risk ...
Neonatal Jaundice. Case Presentation. Martin and Kim were both twenty-five when they had Michael, their first child. Kim remained very healthy during her pregnancy and went into labor at 9:00 a.m., just 3 days after her due date. Delivery went quite smoothly, and that evening, mother and child rested comfortably. Two days later, Kim and Michael ...
Introduction. Jaundice is the 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 ...
Presentation of Case. Dr. Joseph D. Planer (Medicine): A 55-year-old man with a history of opioid use disorder and hepatitis C virus (HCV) infection presented to this hospital with jaundice. Four ...
Obstructive jaundice has many common etiologies, which might cause us to overlook diagnoses that are far worse. This is a case of a Hispanic male who presented with jaundice and worsening liver function. During his hospitalization, he was erroneously diagnosed before being diagnosed with gastric cancer.
This is a format for case presentation and clinical examination in a child presenting with features of jaundice. The article is written in the same way as if the case is presented to the examiner. Introduction / Opening the consultation. XYZ, an 8 months old girl baby, 1st born to non-consanguineously married parents, xxx by religion, resident of xxx, presented to the outpatient department ...
An appropriate-for-gestational age (AGA) African American female infant is born at term via elective, repeat cesarean section at 39 weeks' gestation to a gravida 2, para 2 woman. The mother's pregnancy had been complicated only by gestational hypertension, and maternal antenatal testing results were unremarkable. Maternal blood type is O positive with a negative antibody screen during ...
The theme is neonatal jaundice, a condition that happens to babies when their bilirubin level in the blood is too high. This can cause the newborn's skin or eyes to appear yellow. However, it goes away within days and is not a cause for concern. Thus, if you want to continue sharing knowledge on the subject, a clinical case like the one you can ...
In most cases, jaundice in babies does not require medical attention. Jaundice that is mild usually goes away on its own as the baby's liver develops further. This may require a week or two. Frequent feedings (10-12 times a day) may promote bowel motions in the infant. This aids in the baby's body's removal of extra bilirubin.
CASE SUMMARY. This study describes a female IDCT patient with bile duct lesions. The strong mimicry of IDCT lesions confused doctors, and consequently, this patient, who had no skin lesions, was first diagnosed with cholangiocarcinoma. Then, she presented with persistent abdominal distension without jaundice.
Most travel-associated hepatitis E cases have occurred among travelers returning from the Indian subcontinent. When traveling in countries where HEV-3 is found, eating raw or inadequately cooked boar, deer, or pig meat, or food products derived from any of these, can increase the risk for HEV infection. Clinical Presentation
Nonvertex presentation after 38 weeks of gestation. 10. Hyperemesis or significant dehydration. 11. Isoimmunization, Rh-negative sensitized, positive titers, or any other positive antibody titer that may have a detrimental effect on mother or fetus. ... Jaundice occurring before 24 hours or outside of normal range. (10) Failure to urinate ...
"HFpEF accounts for nearly half of all heart failure cases, ... of gallbladder problems, which may include pain in your upper stomach (abdomen), fever, yellowing of skin or eyes (jaundice), and clay-colored stools. ... and obesity and the timeline for future readouts, presentations, and other milestones relating to tirzepatide and its clinical ...
Viral hepatitis is the main cause of infectious liver disease. During pregnancy, a risk of vertical transmission exists both during gestation and at birth. HAV, HBV, and HCV might progress similarly in pregnant and non-pregnant women. In this study, we found a prevalence of 0.22% of viral hepatitis in pregnant women, with a light preponderance of HCV over HAV and HBV.