Gastroenterology & Hepatology
This was previously featured in an exam
This was previously featured in an exam
Question 109 of 180
A 28 year old woman presents to ED complaining of fatigue, nausea and right upper quadrant (RUQ) abdominal pain. She has no previous medical history. On examination you note RUQ tenderness and yellowing of her skin and sclera. Her observations are: BP 125/86, HR 95 bpm, RR 16, SpO2 97% OA, temp 36.8°C. Her blood results include:
- Alkaline phosphatase (ALP): 124 IU/L
- Alanine aminotransferase (ALT): 556 IU/L
- Aspartate aminotransferase (AST): 428 IU/L
- Bilirubin: 108 mmol/L
- International normalised ratio (INR): 1.1
- Albumin: 23 g/L
What is the most likely diagnosis?
Answer:
- Hepatitic picture
- A predominant rise in ALT is the most marked abnormality.
- Acute viral hepatitis can cause ALT to rise to several thousand units per litre (U/L).
- Acute liver injury from drugs (such as paracetamol overdose) or ischaemia can produce ALT levels greater than 10,000 U/L.
- Acute alcoholic hepatitis can cause AST and ALT to rise to several hundred U/L.
- Alcohol-induced hepatocyte damage usually produces a ratio of AST to ALT greater than 1, whereas infection cause ALT to rise more than AST.
- The transaminases (AST, ALT) are not usually raised in obstructive jaundice unless complicated by cholangitis.
- ALP may also be raised.
Jaundice
Gastroenterology & Hepatology
Last Updated: 12th February 2021
Jaundice describes the yellow pigmentation of the skin, sclera, and mucous membranes, resulting from raised plasma bilirubin. Normal bilirubin levels range between 5 – 19 micromol/L. Clinical jaundice may not become apparent until serum bilirubin is greater than 51 micromol/L.
Pathophysiology
The causes of jaundice can be broadly classified by the stages of bilirubin metabolism, although there may be some overlap between categories. Dysfunction at any of these 3 phases can lead to jaundice:
- Pre-hepatic: Haem molecules are degraded in macrophages via biliverdin to bilirubin. This occurs mainly in the spleen and liver but also in other tissues such as the skin and kidneys. On release from macrophages, bilirubin is bound to plasma albumin and transported to the liver for conjugation and excretion. Unconjugated bilirubin is insoluble in water.
- Intra-hepatic: Once in the liver, unconjugated bilirubin is selectively removed from the blood by hepatocytes. It is then conjugated in the hepatocytes with glucuronic acid, becomes water soluble and can be excreted in bile.
- Post-hepatic: Soluble bilirubin is transported through the liver and cystic ducts in bile and then stored in the gallbladder or passes into the duodenum. In the intestine, some bilirubin is excreted in the stool and the rest is metabolised by gut flora into urobilinogens which are reabsorbed and excreted by the kidneys.
The categories of pre-hepatic, intra-hepatic and post-hepatic (obstructive) jaundice are not mutually exclusive and more than one mechanism leading to jaundice can be present at one time.
Causes
- Causes of pre-hepatic jaundice:
- Haemolytic anaemias
- Haemolytic anaemias result from increased haemolysis of abnormal red blood cells due to conditions such as: homozygous sickle cell disease, thalassaemia major, hereditary spherocytosis, glucose-6-phosphate dehydrogenase deficiency, vitamin B12 deficiency, autoimmune disorders.
- Drugs
- Malaria
- Malaria infection can lead to jaundice through several mechanisms including intravascular haemolysis, disseminated intravascular coagulation and rarely malarial hepatitis.
- Gilbert's syndrome
- Gilbert’s syndrome is an inherited metabolic disorder that causes excess unconjugated bilirubin due to defective conjugating enzymes in the hepatocytes. Typically it presents as an incidental finding on blood tests, with slightly raised serum bilirubin levels, while other routine liver function tests and reticulocyte count remain within normal limits. Plasma bilirubin concentrations can rise in people with Gilbert’s syndrome during intercurrent illness, periods of stress, or when fasting, and frank jaundice may occur. No treatment is required.
- Crigler-Najjar syndrome
- Crigler-Najjar syndrome is a rare inherited disorder causing defects in the hepatic bilirubin conjugating enzyme leading to unconjugated hyperbilirubinaemia.
- Haemolytic anaemias
- Causes of intra-hepatic jaundice:
- Viral infection
- Viral hepatitis (hepatitis A, B, C, D, and E) can cause jaundice through intra-hepatic inflammation leading to disruption in the transport of conjugated bilirubin. Epstein-Barr virus infection occasionally causes transient hepatitis and jaundice. HIV infection can cause jaundice through extra-hepatic obstruction due to AIDS cholangiopathy.
- Alcohol
- Jaundice in alcohol-related liver disease can be caused through alcoholic hepatitis, disruption of bile uptake and secretion resulting in cholestasis and development of fatty liver (steatosis) and cirrhosis with jaundice from chronic alcohol misuse.
- Non-alcoholic fatty liver disease (NAFLD)
- Non-alcoholic fatty liver disease refers to excessive fat accumulation (steatosis) in the hepatocytes. Steatosis can be associated with hepatocellular injury, inflammation, and may progress to advanced liver fibrosis and cirrhosis.
- Autoimmune liver disorders
- Primary biliary cirrhosis (PBC) is a rare progressive liver disorder typically presenting in middle-aged women. Symptoms include fatigue and itch. Jaundice develops as the disease progresses. 95% of people with PBC have high titres of anti-mitochondrial antibodies.
- Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory condition which affects the intra and extra-hepatic bile ducts leading to fibrosis and stricture formation. PSC is more common in men. Nearly 70% of people with PSC also have inflammatory bowel disease and it can lead to cholangiocarcinoma. Antinuclear cytoplasmic antibody is present in 30% of people with PSC.
- Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which can lead to cirrhosis, liver failure, and death if untreated. Most cases have no identifiable precipitant. AIH may present as an ‘acute hepatitis’ with jaundice preceded by anorexia, nausea, and flu-like symptoms, or more insidiously with fatigue, malaise, anorexia, and weight loss. Acute liver failure, nausea, amenorrhoea, and joint pains may also occur. About 25% of people with AIH are asymptomatic at diagnosis. Bloods tests may reveal raised serum aminotransferases (especially if alkaline phosphatase is normal), immunoglobulins and autoantibodies (70% have smooth muscle antibody, 60% have antinuclear antibody) in the absence of viral hepatitis.
- Metabolic causes of intra-hepatic jaundice
- Dubin-Johnson and Rotor’s syndromes are rare hereditary metabolic conditions that disrupt transport of conjugated bilirubin from the liver cells.
- Haemochromatosis is the most common inherited liver disease in the UK, affecting 1 in 200 of the population. It leads to iron overload, and people usually present with skin pigmentation (80%), cirrhosis (70%), or diabetes (55%) due to excessive iron deposits in the liver and pancreas.
- Wilson’s disease is a rare autosomal recessive disorder which causes liver disease through excess deposition of copper in the hepatocytes. It also affects the basal ganglia and eyes.
- Drugs
- Malignancy of the biliary system
- Hepatocellular carcinoma causes approximately 1500 deaths per year in the UK. Risk is increased in men, with advancing age, and in people with cirrhosis - especially due to hepatitis B and C infection.
- Cholangiocarcinoma is the second most common primary liver tumour worldwide after hepatocellular carcinoma. Primary sclerosing cholangitis is the most common known predisposing factor for cholangiocarcinoma in the Western world but most cases are sporadic. Cholangiocarcinoma is usually advanced at presentation and typically presents with features of jaundice, pale stools, dark urine, itch, weight loss, and abdominal pain.
- Gallbladder cancer typically presents with jaundice, hepatomegaly, and a mass in the right upper quadrant (Courvoisier's sign).
- Viral infection
- Causes of post-hepatic or obstructive jaundice:
- Gallstones
- Most people with gallstone disease are asymptomatic but gallstones can cause obstruction of the flow of bile within the biliary duct system and lead to complications such as: jaundice, biliary colic, cholecystitis, cholangitis and pancreatitis.
- Surgical strictures
- Biliary strictures and infection should be considered in people with post-operative jaundice. Biliary strictures can occur following liver transplantation or cholecystectomy. Complications associated with biliary strictures include chronic cholestasis, recurrent cholangitis, and secondary biliary cirrhosis.
- Extra-hepatic malignancy
- Pancreatic cancer can present with jaundice due to obstruction of the lower common bile duct. Incidence increases with age, in particular, over the age of 50 years. Features associated with pancreatic cancer include: jaundice, abdominal pain, nausea or vomiting, constipation, diarrhoea, weight loss, malaise, and new-onset diabetes mellitus.
- Jaundice associated with lymphoma or metastatic cancers such as breast or bowel cancer can be due to intra-hepatic cholestasis from infiltration of the liver, or obstruction of the biliary ductal system.
- Pancreatitis
- Pancreatitis typically presents with sudden onset of severe pain in the epigastrium or left upper quadrant radiating into the back. The most common causes of pancreatitis are alcohol misuse and gallstones. Pancreatitis can lead to jaundice from pancreatic oedema.
- Parasitic infection
- In addition to malaria, infection with other parasites such Fasciola and Clonorchis can cause jaundice.
- Gallstones
Drug-induced liver injury:
- Antibiotics and anti-epileptics are the most commonly reported drugs causing drug-induced liver injury (DILI).
- Drugs can cause jaundice through:
- Haemolysis of red blood cells (for example, methyldopa, and sulphasalazine).
- Hepatitis (for example, paracetamol overdose, pyrazinamide, rifampicin, and isoniazid).
- Cholestasis (for example, co-amoxiclav, flucloxacillin, oral contraceptives, hormone replacement therapy, chlorpromazine, and corticosteroids).
- Hepatic idiosyncratic reactions (for example, aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], amiodarone, sodium valproate, and minocycline).
Assessment
- Take a history including:
- Duration and previous episodes of jaundice.
- Colour of urine and stools, including any evidence of tarry/bloody stools suggesting melaena.
- Pain including the site, severity, and radiation.
- Itching (pruritus).
- Systemic features such as anorexia, weight loss, fever, rigors, arthralgia, myalgia, rash, fatigue, nausea, and vomiting.
- Alcohol intake in units.
- Travel abroad to areas endemic for viral hepatitis and parasites that can cause jaundice.
- Other risk factors for viral hepatitis — intravenous drug use, tattoos, body piercings, blood transfusion, multiple sexual partners, sex between men or with sex workers.
- Past medical history of biliary surgery, gallstones, hepatitis, autoimmune liver disease, thyroid disease, or non-alcoholic fatty liver disease.
- Drugs — prescribed and over-the-counter, including herbal medications and dietary supplements. Always ask about potential paracetamol overdose.
- Occupation — exposure to viral hepatitis, HIV, or hepatotoxic chemicals.
- Family history of inherited anaemias or haemoglobinopathies.
- Possibility of pregnancy — jaundice associated with pregnancy is an obstetric emergency.
- Carry out an examination looking for:
- Signs of sepsis — fever, tachycardia, and hypotension.
- Signs of chronic liver disease:
- Palmar erythema and spider naevi
- Finger nail clubbing
- Leukonychia (white nails)
- Dupuytren’s contractures (contracture of the palmar fascia)
- Gynaecomastia, with loss of body hair and testicular atrophy
- Caput medusae (collateral vessels on the skin of the abdomen, such as around the umbilicus)
- Signs of liver failure:
- Altered neuromuscular function such as ataxia, nystagmus, or asterixis (coarse flapping tremor) can occur with hepatic encephalopathy
- Altered mental state such as drowsiness, confusion, disorientation, or coma
- Bruising, petechiae, or purpura
- Lymphadenopathy:
- Enlargement of the left supraclavicular lymph nodes (Troisier’s sign) can be caused by malignancy including metastatic pancreatic and gastric cancer
- More widespread lymphadenopathy with hepatosplenomegaly can indicate lymphoma
- Masses such as:
- Hepatomegaly can be due to many causes including chronic parenchymal liver disease such as alcoholic liver disease or viral hepatitis; malignancy such as primary hepatocellular cancer or secondary metastatic cancer; or haematological disease such as lymphoma or myelofibrosis
- Splenomegaly can be due to haematological disorders such as lymphoma or haemolytic anaemia, portal hypertension, infections such as glandular fever, or rheumatological conditions such as systemic lupus erythematosus
- Palpable gallbladder (Courvoisier’s sign) — a palpable gallbladder in a jaundiced person is likely to be due to extra-hepatic obstruction such as from pancreatic cancer
- Abdominal tenderness:
- Localised tenderness in the right upper quadrant below the costal margin on deep inspiration (Murphy’s sign) may indicate acute cholecystitis.
- Widespread abdominal tenderness may indicate pancreatitis or peritonitis
- Ascites indicates underlying causes such as intra-abdominal malignancy, chronic liver disease, or severe heart failure.
Red flags in jaundice
- Same-day emergency assessment should be arranged for people presenting with jaundice and the following symptoms or signs:
- Signs associated with hepatic encephalopathy such as:
- Confusion or alteration in mental state.
- Altered neuromuscular function such as poor coordination, ataxia, asterixis, and nystagmus.
- Signs associated with severe hepatic dysfunction such as:
- Bruising, purpura, or petechiae.
- Signs of gastrointestinal blood loss such as:
- Haematemesis or melaena.
- Signs associated with sepsis such as:
- Fever, hypotension, and tachycardia.
- Marked abdominal tenderness or pain.
- Vomiting.
- Suspected paracetamol overdose.
- Signs associated with hepatic encephalopathy such as:
- Urgent referral should be made for people presenting with jaundice and weight loss which may indicate:
- Underlying malignancy — refer using a suspected cancer pathway, for an appointment within 2 weeks.
- Chronic disease (such as alcoholic cirrhosis) — refer to an appropriate specialist, the urgency depending on clinical judgement.
Investigations
- Initial bloods
- FBC – haemolysis, infection, anaemia, thrombocytopenia
- U&Es – renal impairment, hyponatraemia
- Clotting – prolonged prothrombin time
- Amylase – pancreatitis
- LFTs – liver dysfunction/cholestasis
- Urine dipstick – if positive for bilirubin this indicates increased levels of conjugated bilirubin in the serum
- Full liver screen if LFTs show a non-obstructive pattern
- Viral serology - hepatitis A, B and C
- Autoantibody profile - ANA and SMA for autoimmune hepatitis, AMA for PBC
- Ferritin and transferrin saturation – hereditary haemochromatosis
- Alpha1-antitrypsin - alpha1-antitrypsin deficiency
- Alpha-fetoprotein – hepatocellular carcinoma
- Caeruloplasmin – Wilson’s disease
- Thyroid function tests
- Abdominal ultrasound scan – gallstones, dilated bile ducts (indicating extra-hepatic obstruction), liver cysts and tumours, pancreatic masses (visualisation can be impaired by overlying bowel gas and body habitus)
- Abdominal CT scan – particularly helpful for identifying small lesions in the liver or pancreas
Interpretation of liver function tests
- Isolated raised bilirubin
- This is most often due to Gilbert's syndrome.
- Cholestatic picture
- Alkaline phosphatase (ALP) is raised more than alanine transferase (ALT) in intra-hepatic cholestasis, cholangitis, or extra-hepatic obstruction.
- Bony disease such as Paget's disease can also cause raised ALP and complicate interpretation of LFTs. Gamma-glutamyl transferase (GGT) is not significantly present in bone, such that concomitant elevated GGT and alkaline phosphatase (ALP) indicates the liver as the source of the ALP.
- Hepatitic picture
- A predominant rise in ALT is the most marked abnormality.
- Acute viral hepatitis can cause ALT to rise to several thousand units per litre (U/L).
- Acute liver injury from drugs (such as paracetamol overdose) or ischaemia can produce ALT levels greater than 10,000 U/L.
- Acute alcoholic hepatitis can cause AST and ALT to rise to several hundred U/L.
- Alcohol-induced hepatocyte damage usually produces a ratio of AST to ALT greater than 1, whereas infection cause ALT to rise more than AST.
- The transaminases (AST, ALT) are not usually raised in obstructive jaundice unless complicated by cholangitis.
- ALP may also be raised.
- Mixed picture
- Occasionally LFTs may indicate both cholestasis and hepatocyte damage, and this is usually due to cholangitis associated with stones in the common bile duct.
- Albumin
- Low serum albumin suggests chronic liver disease.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
