Aetiology
Bilirubin is a waste product from the breakdown of the haem molecule in red blood cells. Macrophages in the reticuloendothelial system break down haem and produce unconjugated bilirubin. This lipid-soluble molecule easily crosses cell membranes and enters the blood.
Unconjugated bilirubin is taken up by hepatocytes and conjugated with glucuronic acid. The conjugated bilirubin is water-soluble, allowing excretion in bile. Gut bacteria convert conjugated bilirubin into urobilinogen and stercobilinogen, which are excreted in the urine and stool.[Figure caption and citation for the preceding image starts]: Bilirubin metabolismCreated by the BMJ Knowledge Centre [Citation ends].
Increased red blood cell destruction or impaired bilirubin conjugation causes elevated unconjugated (indirect) bilirubin levels, whereas hepatocellular damage or biliary tract obstruction causes elevated conjugated (direct) bilirubin levels.[1]
Jaundice can be classified according to the site of bilirubin metabolism dysfunction (prehepatic, hepatocellular, and cholestatic) or according to type of bilirubin accumulation (increased direct or indirect bilirubin levels).
Prehepatic causes
A rise in unconjugated (indirect) serum bilirubin indicates either increased bilirubin production from red blood cell destruction or a dysfunction in bilirubin conjugation. Referred to as prehepatic because the pathological process occurs before the bilirubin is metabolised by the liver.
Prehepatic causes: haemolysis
Hereditary haemolytic anaemias
Haemolysis of red blood cells (RBCs) leads to elevation of serum unconjugated bilirubin levels.
Causes fall into three broad categories:
RBC membrane defects (e.g., hereditary spherocytosis, elliptocytosis, pyropoikilocytosis)
enzyme deficiencies (e.g., glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency)
abnormal haemoglobin production (e.g., sickle cell anaemia, thalassaemia).
Acquired haemolytic anaemias
Haemolysis of RBCs leads to elevation of serum unconjugated bilirubin levels.
Autoimmune haemolytic anaemia occurs when RBCs are attacked by autoantibodies and targeted for extravascular destruction. This usually occurs as part of other autoimmune conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, or scleroderma), or in relation to a lymphoproliferative disorder (usually non-Hodgkin's lymphoma or chronic lymphocytic leukemia).
Alloimmune haemolytic anaemia can be caused by transfusion reactions, usually due to ABO blood group incompatibility.
Many drugs are associated with haemolysis.
Infectious causes include cytomegalovirus, infectious mononucleosis, toxoplasmosis, and leishmaniasis.
Microangiopathic haemolytic anaemias are serious anaemias caused by disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, haemolytic uremic syndrome, and eclampsia.
Paroxysmal nocturnal haemoglobinuria is a rare disorder resulting in an acquired RBC membrane defect and subsequent haemolysis.
Prehepatic causes: impaired bilirubin conjugation
Gilbert's syndrome
An inherited condition with no serious consequences, which affects 2% to 10% of white people in developed countries.[2] It is characterised by intermittent jaundice due to unconjugated bilirubin in the absence of haemolysis or underlying liver disease.
Caused by a defect in the UGT1A1 gene, which encodes the hepatic conjugation enzyme uridine-diphosphoglucuronate glucuronosyltransferase.
Most inheritance is autosomal-recessive, but autosomal-dominant transmission can occur if there is a missense mutation in the UGT1A1 gene.
Jaundice may be precipitated by dehydration, fasting, menstrual periods, or stress, such as an intercurrent illness or vigorous exercise.
With the exception of unconjugated hyperbilirubinaemia, standard serum liver function test results are normal. No further investigations are required.
Episodes resolve spontaneously.
Hepatocellular causes
Conditions that damage the structure and/or function of hepatocytes give rise to hepatocellular jaundice. Such conditions include infections, toxin, cancer, autoimmune conditions, and genetic conditions.
Hepatocellular causes: infections
The viral hepatitides A, B, C, D, and E may all cause jaundice.
Hepatitis A
The most common cause of acute viral hepatitis, particularly among children and young adults. In some countries, >75% of adults have been exposed. It does not cause chronic liver disease.
Over 70% of newly infected older children and adults develop jaundice.[3] Children aged under 6 years are less likely to develop jaundice with hepatitis A infection.
It spreads primarily by faecal-oral contact and thus may occur in areas of poor hygiene. Sporadic cases are also common, usually as a result of person-to-person contact. Water-borne and food-borne epidemics occur, especially in developing countries. Eating contaminated raw shellfish is sometimes the cause.
May cause acute liver failure, which is characterised by jaundice, coagulopathy (international normalised ratio [INR] >1.5), and hepatic encephalopathy in a patient who does not have pre-existing liver disease.
Relative frequency has decreased in developed countries. Improvements in hygiene, public health policies, and sanitation have had the greatest impact on hepatitis A. Vaccination programmes and passive immunisation have successfully led to some reduction in illness in high-risk groups.
Hepatitis B
Jaundice in patients with hepatitis B may be due to acute infection or decompensation of cirrhosis caused by chronic infection.
Hepatitis B virus (HBV) is transmitted hematogenously and sexually. Routine screening of donor blood for hepatitis B surface antigen (HBsAg) has nearly eliminated the previously common post-transfusion transmission, but transmission through needles shared by drug users remains common. Vertical transmission from mother to infant is common.
Most acute infections are asymptomatic. Approximately 30% to 50% of patients develop symptoms, including jaundice, vomiting, fatigue, and abdominal pain.[3][4]
Infection may result in a self-limiting disease requiring no treatment, particularly for immunocompetent adults where the risk of chronicity is 5%. If acquired perinatally or in early childhood, it may result in a high rate of chronic disease. Ninety percent of infants who acquire the infection perinatally develop chronic hepatitis B. Between 25% and 50% of children who are infected between ages 1 and 5 years develop chronic infection.[3]
May cause acute liver failure, which is characterised by jaundice, coagulopathy (INR >1.5), and hepatic encephalopathy in a patient who does not have pre-existing liver disease.
Antiviral therapy is effective in suppressing viral replication, as defined by undetectable HBV DNA in approximately 95% of patients who are treated with oral antiviral therapy.
Universal hepatitis B vaccination has been implemented in most countries worldwide.[5]
Hepatitis C
Most newly infected patients are asymptomatic; a minority develop symptoms of acute hepatitis (including jaundice).[3]
Infection with hepatitis C virus (HCV) is rarely self-limiting. Chronic infection develops in over 50% of patients infected with HCV. Cirrhosis develops within 20 years of disease onset in 10% to 20% of people with chronic HCV infection.[6][7]
Infection is most commonly transmitted through blood, primarily when parenteral drug users share needles, but also through tattoos or body piercing. Sexual transmission and vertical transmission from mother to infant are relatively rare. Transmission through blood transfusion has become very rare since the advent of screening tests for donated blood.
Direct-acting antivirals can achieve a sustained virological response or cure in >95% of patients and have few adverse events. Sustained virological response, when HCV viral load is undetectable 12 weeks after completing treatment, leads to substantial reductions in all-cause and liver-related mortality, liver transplantation, and hepatocellular carcinoma.[8]
The US Preventive Services Task Force recommends annual HCV screening in adults aged 18-79 years.[9]
Hepatitis D
A defective virus that requires HBV to cause clinically recognisable disease.
Hepatitis D virus-HBV co-infection is considered the most severe form of chronic viral hepatitis because it progresses more rapidly to cirrhosis and hepatocellular carcinoma.
Immunisation against HBV can prevent hepatitis D infection.
Hepatitis E
Jaundice occurs in about 40% of patients.
Epidemiological and clinical patterns of hepatitis E virus (HEV) infection differ between developing and developed countries.[10]
In developing countries, outbreaks of acute HEV (HEV1 and HEV2) infection are often water-borne and linked to faecal contamination of the water supply. It represents an acute, self-limiting illness that usually requires either no treatment, or supportive treatment only. In developed countries, HEV3 and HEV4 are transmitted zoonotically from animal reservoirs.
Increased mortality is seen in pregnant women, with mortality rates of 20% to 25% reported, particularly during the third trimester.[11]
HEV may cause acute liver failure, which is characterised by jaundice, coagulopathy (INR >1.5), and hepatic encephalopathy in a patient who does not have pre-existing liver disease.
Chronic infection is more common in the developed world, with rapid progression to cirrhosis in organ transplant recipients, patients with haematological malignancy requiring chemotherapy, and individuals with HIV.
In addition to classic hepatic manifestation, HEV has been associated with extrahepatic manifestation of disease, including neurological syndromes, renal injury, pancreatitis, and haematological disorders.
HIV infection
Patients with known HIV disease represent a unique population with a multitude of possible aetiologies for jaundice.[12]
Highly active antiretroviral therapy may cause drug-induced hepatitis.
Opportunistic infections and malignancy can cause hepatobiliary pathology in HIV-infected patients. Frequently, there is co-infection with HBV or HCV, as well as complications related to other viruses (cytomegalovirus, Epstein-Barr virus, or herpes simplex virus). Autopsy studies have shown a 33% to 78% rate of infection or malignancy in HIV-infected patients.[12]
Parasitic infections
Parasitic infections that cause jaundice include ascariasis (caused by Ascaris lumbricoides), hydatidosis (caused byEchinococcus granulosus), Clonorchis sinensis, and Fasciola hepatica.
Jaundice may occur in patients with Plasmodium falciparum malaria and is a risk factor for more severe disease.[13]
Jaundice usually occurs as a result of haemolysis of infected red blood cells, although direct infection of hepatocytes by the malaria parasite can also cause jaundice.
Amoebic liver abscess is a rare complication of infection with the protozoan parasite Entamoeba haemolytica. Entamoeba infections most commonly occur in tropical and subtropical regions. Mature parasitic cysts are ingested in contaminated water. Trophozoites penetrate the colon wall, causing colitis, and travel to the liver through the portal veins. There, an inflammatory reaction and cell necrosis form an abscess. Patients present acutely with right upper quadrant pain and fever in addition to jaundice.[14]
Leptospirosis
A zoonosis with worldwide distribution, caused by motile spirochetes from the genus Leptospiraand maintained in nature by chronic renal infection of carrier animals.[15]
There are over 1 million cases and 58,000 deaths worldwide each year.[15]
People who work outdoors or with animals are at risk. Leptospirosis has been associated with swimming or water sports in contaminated lakes and rivers.[16]
There are two phases of the disease: an acute/initial phase followed 5 to 7 days later by the immune phase.
Symptoms during the acute/initial phase include high fevers, chills or rigors, headache, myalgia (often localised in the calves), abdominal pain, diarrhoea, nausea and vomiting, asthenia, anorexia, photophobia, and conjunctival suffusion.
After 5 to 7 days, fever resolves and the patient develops immune phase symptoms including severe eye pain, headache, photophobia, pulmonary symptoms (cough, dyspnoea, chest pain, haemoptysis), palpitations, conjunctival suffusion, muscle tenderness, mental status changes (delirium, coma), and focal neurological deficit.
Hepatosplenomegaly, abdominal tenderness, and jaundice may be elicited in both the acute/initial phase and immune phase of the disease.
The immune phase is associated with severe disease and may manifest as renal failure, hepatic failure, and/or pulmonary haemorrhages.[17]
Weil's disease, the most severe form of leptospirosis, is characterised by jaundice, haemorrhage, and renal failure.
Hepatocellular causes: toxins
Alcohol
Jaundice may be caused by acute alcoholic hepatitis, or as a manifestation of advanced cirrhosis.[18]
About 40 to 80 g/day in men and 20 to 40 g/day in women for 10-12 years is sufficient to cause liver damage in the absence of other liver diseases. Ten percent to 20% of patients with chronic heavy alcohol use develop alcoholic hepatitis or cirrhosis.[19]
The progression of fibrosis in patients with alcoholic liver disease is faster in those who smoke and have other metabolic liver diseases, including non-alcoholic fatty liver disease, hereditary haemochromatosis, alpha-1 antitrypsin deficiency, and Wilson's disease.
Alcoholic hepatitis can occur at any stage of alcohol-related liver disease. In addition to new or worsening jaundice, patients might have constitutional symptoms such as fatigue and other symptoms of advanced liver disease (e.g., oedema, pruritus, asterixis, confusion, ascites, splenomegaly, portal hypertension, and variceal bleeding).[18]
Drug-induced liver injury
Approximately 2000 cases per year in the US.[20] The associated mortality is approximately 10%.[21]
Many medications may result in acute and chronic elevation of liver tests. Some effects are due to direct (dose-dependent, intrinsic, and predictable) hepatotoxicity; others may be idiosyncratic drug reactions (largely dose-independent, and unpredictable).[22][23][24] Idiosyncratic drug-induced liver injury (DILI) is uncommon, occurring in only 1 in 1000 to 1 in a million individuals exposed to an approved drug.[23][25][26] Another mechanism of hepatotoxicity, indirect DILI, arises when the biological action of the drug affects the host immune system, leading to a secondary form of liver injury.[23]
Pre-existing liver disease, diabetes, and obesity are associated with increased incidence and severity of DILI.[23] European guidelines list age, female sex, and ethnicity as risk factors for DILI; US guidelines, however, report that there is insufficient data to consider these as reliable risk factors.[27]
Paracetamol-induced hepatotoxicity (46%) and idiosyncratic DILI (11%) are the most common causes of acute liver failure in the US.[28] Antimicrobials, central nervous system agents, and anti-inflammatory agents are the most commonly implicated agents in the DILI series and registries worldwide.[23][29]
Liver injury associated with herbal and dietary supplements is increasing in frequency worldwide.[23] In one prospective study, herbal and dietary supplements accounted for 16% of cases of DILI overall.[30] The most commonly reported product was bodybuilding supplements, with a phenotype suggestive of injury from anabolic steroids.
The Livertox database summarises the causes, diagnosis, incidence, and management of drug-induced injury for many different drugs and is free to access. LiverTox Database Opens in new window It includes herbal and dietary supplements.
Hepatocellular causes: neoplasia
Primary neoplasms and liver metastases may cause jaundice through the destruction of healthy liver tissue, reducing the capacity of the liver to conjugate bilirubin, or through the compression of the intrahepatic bile ducts, causing cholestasis.[31]
Hepatocellular carcinoma
This is the most common primary liver cancer. Worldwide, its prevalence is increasing, because of the increasing burden of chronic hepatitis B and C infection. Both infections increase the risk of hepatocellular carcinoma. Older age, male sex, obesity, diabetes, alcohol use, and family history also increase the risk.[32]
Lymphoma
Jaundice occurs in 3% to 10% of lymphoma patients. Lymphoma may cause a mass lesion or diffusely infiltrate the liver. Liver involvement is more common in non-Hodgkin’s lymphoma.[33]
Liver metastases
The liver is a common site of metastases from cancers affecting other organs, particularly colorectal cancer, where 25% of patients develop liver metastases.
Pancreatic cancer and cholangiocarcinoma predominantly cause cholestatic jaundice, and are discussed in the Cholestatic causes section below.
Hepatocellular causes: autoimmune
Autoimmune hepatitis
A chronic inflammatory liver disease of unknown aetiology. The pathogenesis is believed to involve a complex interplay between genetic predisposition, environmental triggers (several viruses, drugs, or herbal agents have been proposed to be triggers), autoantigens, and dysfunction of immunoregulatory mechanisms.
Characterised by the presence of circulating autoantibodies with a high serum globulin concentration, inflammatory changes on liver histology, and a favourable response to immunosuppressive treatment.
Patients may develop fluctuating jaundice, but more commonly the condition is detected on investigation of abnormal serum liver function tests.
Primary biliary cholangitis
Previously known as primary biliary cirrhosis.
Chronic autoimmune liver disease resulting from progressive destruction of the intrahepatic bile ducts that can lead to liver fibrosis and cirrhosis.
Common symptoms are tiredness, itching, and - in more advanced cases - jaundice. In early cases, there may only be changes in blood tests.[34]
Primary biliary cholangitis is a relatively rare disease, with a prevalence of less than 1 in 2000 people. It is much more common in women, with a female:male ratio of at least 9:1.[35]
Primary sclerosing cholangitis
A chronic progressive cholestatic liver disease, characterised by inflammation and fibrosis of the intrahepatic and/or extrahepatic bile ducts, resulting in diffuse, multifocal stricture formation.
Affects males more frequently than females, with a median age of onset between 30 and 40 years. One systematic review and meta-analysis of studies conducted in North America and Europe reported a pooled incidence rate of 0.77 per 100,000 person years.[36] Incidence and prevalence in Northern Europe has subsequently been reported to be 1 per 100,000, and 1 per 10,000 per year, respectively.[37] Rates in Southern Europe are suspected to be lower.
Often associated with inflammatory bowel disease (up to two-thirds of patients with primary sclerosing cholangitis have inflammatory bowel disease).[38]
Presentation is insidious. Symptoms are rare in early disease. As the condition progresses, right upper quadrant pain, pruritus, fatigue, jaundice, fever, and weight loss may occur.[39]
Hepatocellular causes: genetic
Wilson's disease
A rare autosomal recessive inherited disorder of copper metabolism characterised by excessive deposition of copper in the liver, brain, and other tissues.[40]
Fewer than 50% of patients develop jaundice before diagnosis.[41]
Patients usually present with liver disease during the first decade of life or with neuropsychiatric illness during the third decade.
The diagnosis is confirmed by measurement of serum ceruloplasmin and urinary copper excretion.
Hereditary haemochromatosis
One of the most common genetic disorders found in Northern Europeans, with a prevalence of 1 in 200 to 1 in 400 people.[42]
An autosomal recessive inherited disorder caused by continued absorption of iron from the upper small intestine, despite normal total body iron.
In advanced disease, iron accumulation causes widespread tissue damage, including diabetes mellitus, arthritis and arthralgia, cardiomyopathies and arrhythmias, and cirrhosis.[42]
Alpha-1 antitrypsin deficiency
An autosomal codominant condition caused by mutations in the SERPINA1 gene encoding alpha-1 antitrypsin (AAT), a key serum protease inhibitor.
Patients with the Z variant or other rare variants have an increased risk of developing liver disease, owing to protein accumulation in hepatocytes.
Pulmonary and hepatic manifestations include emphysema and cirrhosis.
In the most severe form of AAT deficiency, the clinical features consist of early-onset emphysema, neonatal hepatitis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. However, phenotypic expression throughout life is extremely variable.
Patients may report a family history of liver or lung disease below the age of 40 years.
Cholestatic causes
Cholestatic jaundice (sometimes called post-hepatic jaundice) results from obstruction of bile drainage. Causes may be benign or malignant.
Cholestatic causes: benign
Choledocholithiasis
Jaundice due to choledocholithiasis occurs as a result of either the primary formation of stones in the common bile duct (CBD) or the passage of gallstones from the gallbladder through the cystic duct into the CBD.
Bile stasis, bactibilia, chemical imbalances, pH imbalances, increased bilirubin excretion, and the formation of sludge are among the principal factors thought to lead to the formation of stones.
Gallstones are differentiated by their chemical composition. Cholesterol stones are composed mainly of cholesterol, black pigment stones are mainly pigment, and brown pigment stones are made up of a mix of pigment and bile lipids.
Obstruction of the CBD by gallstones leads to symptoms and complications that include pain, jaundice, cholangitis, pancreatitis, and sepsis.
Postoperative stricture
Iatrogenic biliary duct injury during surgery may cause strictures and subsequent obstruction.
Ascending cholangitis
An infection of the biliary tree, most commonly caused by obstruction. The most common underlying causes are choledocholithiasis and strictures due to surgery, chronic pancreatitis, radiotherapy, or chemotherapy.
In its less severe form, there is biliary obstruction with inflammation and bacterial seeding and growth in the biliary tree. Sludge also forms, providing a growth medium for the bacteria. As the obstruction progresses, the bile duct pressure increases. This forms a pressure gradient that promotes extravasation of bacteria into the bloodstream and, ultimately, sepsis.
In the more severe, life-threatening form, patients have purulent biliary tree contents, as well as evidence of sepsis, hypotension, multi-organ failure, and mental status changes.
Immunoglobulin G4 (IgG4) cholangiopathy
IgG4 cholangiopathy is a hepatobiliary fibro-inflammatory condition that affects the large bile ducts and gallbladder and, less commonly, the intrahepatic small ducts. It is characterised by increased serum levels of IgG4.
Patients are typically men aged 50-60 years, and more than 75% will present with common bile duct obstruction and jaundice.[43]
Corticosteroids are the initial treatment and may be needed for maintenance.
Parasitic infection
Biliary obstruction is a rare complication of strongyloidiasis. The presence of Strongyloides stercoralis in the duodenal mucosa can result in papillary stenosis.
Treatment of strongyloidiasis usually resolves the biliary obstruction.
Cholestatic causes: malignant
Pancreatic cancer
Carcinoma of the head of the pancreas results in obstruction of the distal common bile duct and the development of obstructive jaundice. One systematic review found that 30% of people with pancreatic cancer reported having jaundice.[44] Jaundice had a positive predictive value for pancreatic cancer of 4% in people over 40 years of age.[44]
In 2020, 57,600 new cases of pancreatic cancer were expected in the US, where it is the third most common cause of cancer death.[45][46]
Cancer of the exocrine pancreas is rarely curable and has an overall survival rate of <4%. The highest cure rate occurs if the tumour is truly localised to the pancreas; however, this stage of the disease accounts for less than 20% of cases.
Cholangiocarcinoma
Cholangiocarcinoma arises from the intrahepatic or extrahepatic biliary epithelium. More than 90% are adenocarcinomas, and the remainder are squamous cell tumours. As the tumour grows, it obstructs the drainage of bile.
A strong relationship exists between cholangiocarcinoma and primary sclerosing cholangitis (PSC). Cholangiocarcinoma generally develops in patients with long-standing ulcerative colitis and PSC. The lifetime risk of developing this cancer in the setting of PSC is 10% to 20%.
Patients with ulcerative colitis without symptomatic PSC are also at increased risk.
Certain chemical exposures have been implicated in the development of bile duct cancers, primarily in workers in the printing, aircraft, rubber, and wood-finishing industries.[47][48] Cholangiocarcinoma has occasionally developed years after administration of the radiopaque medium thorium dioxide.
Metastases
Metastatic deposits in the liver and surrounding lymph nodes can compress the biliary tree, causing cholestatic jaundice.
Lymphoma
Lymphoma affecting the lymph nodes at the porta hepatis can compress the extrahepatic bile duct, causing cholestasis and jaundice.[33]
Pregnancy
An evaluation of data from consecutive deliveries in a maternity department at one US hospital found that 397 pregnant women, out of a total of 80,857 (0.5%), had elevated bilirubin. The most common causes were gallstones (25%), pre-eclampsia/eclampsia/HELLP (haemolysis, elevated liver enzymes, low platelets; 24%), and intrahepatic cholestasis of pregnancy (13%).[49]
End-stage liver disease
End-stage liver disease can occur due to any liver-related aetiology. Patients with advanced liver disease may be receiving active treatment (including referral to a liver transplant unit and placement on the waiting list) or have a limited life expectancy approaching the last days of life.
Signs may include progressive jaundice and symptoms can include variceal haemorrhage, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, and hepatorenal or hepatopulmonary syndrome.
Decompensated cirrhosis requiring admission to hospital is associated with a 50% mortality rate at 12 months. It is, therefore, recommended that any patient who has decompensated cirrhosis is managed comprehensively, including an assessment of their supportive care needs. This may include referral to the local specialist palliative care team if complex physical, psychosocial, or spiritual needs are identified.[50]
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