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Jaundice By MedRx Jaundice is a medical condition characterized by the yellowing of the skin, mucous membranes, and the whites of the eyes (sclera). It occurs when there is an excess of bilirubin in the body. Therefore, it is a presentation medical students should be aware of! In this handout, we will go through the differential diagnosis of jaundice, the important aspects of a history and the important investigations related to jaundice. Wewillthencoverthreeimportantconditionswhichcause jaundice: Hereditary Spherocytosis, Alcoholic Hepatitis and Pancreatic Cancer Contents Using this handout 1. Bilirubin metabolism and the Differential diagnosis of jaundice The content in this handout is quite b. Hepaticatic detailed. The most important aspects c. Post-hepatic are the differential diagnosis (section 2. How to take a jaundice history 1), the ‘essential advice’ and any a. HPC writing in bold - prioritize these first! b. PMH At the same time, the content is not c. DH exhaustive and should not be seen as d. FH covering every detail but instead the e. SH most important ones. This handout is 3. Jaundice investigations for purely educational purposes and a. LFTs should not be used when treating b. Imaging patients. 4. Jaundice conditions a. Hereditary Spherocytosis (Pre- b. Alcoholic Hepatitis (Hepatic) c. Pancreatic Cancer (Post-Hepatic) Bilirubin metabolism and the Differential diagnosis of jaundice Bilirubin is a yellow pigment that forms during the normal breakdown of red blood cells. It is processed by the liver and eventually excreted from the body. However, if there is an issue with the liver's ability to process bilirubin, or if there is an excessive breakdown of red blood cells, bilirubin levels can rise, leading to jaundice. Clinically, jaundice is not noticeable until the bilirubin level is > 20mg/L and it is best seen in the sclera and oral mucous membranes (e.g. under the tongue). To begin to build a differential of jaundice, we need to consider the steps in bilirubin metabolsim. Using this, we can split the causes of jaundice into the following: • Pre-hepatic • Hepatic • Post-hepatic Pre-Hepatic 1. Hemolysis: Bilirubin is derived from the breakdown of heme, a component of hemoglobin found in red blood cells. When red blood cells reach the end of their lifespan (about 120 days), they are removed from circulation in a process called hemolysis. This occurs primarily in the spleen and, to a lesser extent, in the liver. 2. Unconjugated Bilirubin: The released heme is converted into unconjugated bilirubin in the reticuloendothelial cells (specialized cells involved in immune responses) of the spleen and liver. 3. Binding to Albumin: Unconjugated bilirubin is not soluble in water and needs to be bound to a protein called albumin to be transported through the bloodstream to the liver. What can cause Pre-Hepatic Jaundice? Prehepatic jaundice, also known as hemolytic jaundice, occurs when there is an excessive breakdown of red blood cells (hemolysis), leading to an increased production of bilirubin. This excess bilirubin overwhelms the liver's capacity to process it, resulting in elevated bilirubin levels in the blood. Here are some common causes of prehepatic jaundice: - Hemolytic Anemias: Conditions like hereditary spherocytosis, thalassemia, and sickle cell anemia cause abnormal red blood cells that have a shorter lifespan. This leads to increased breakdown and bilirubin production. - Transfusion Reactions: Incompatible blood transfusions can lead to the rapid destruction of transfused red blood cells, causing a surge in bilirubin levels. - Autoimmune Hemolytic Anemia: This condition occurs when the immune system mistakenly targets and destroys its own red blood cells, leading to hemolysis. - Malaria: The malaria parasite (Plasmodium) infects red blood cells, causing them to rupture and release bilirubin. - Drug-Induced Hemolysis: Certain medications can trigger an immune response against red blood cells, leading to their destruction. This can occur as a rare side effect of certain drugs. - G6PD Deficiency: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited enzyme deficiency that makes red blood cells vulnerable to oxidative stress, leading to hemolysis. - Hemolytic Disease of the Newborn (HDN): This occurs when a mother's immune system reacts against red blood cells in a fetus, usually due to Rh or ABO blood group incompatibility. Hepatic 4. Uptake by the Liver: The bilirubin-albumin complex enters the liver through the bloodstream. Once inside the liver, bilirubin is taken up by hepatocytes, the main cells of the liver. 5. Conjugation in the Liver: Inside the hepatocytes, unconjugated bilirubin is enzymatically converted into conjugated bilirubin through a process called conjugation. This involves the addition of a sugar molecule (glucuronic acid) to bilirubin, making it water-soluble. What can cause Hepatic Jaundice? Hepatic jaundice, also known as hepatocellular jaundice, occurs when there is a dysfunction or damage to the liver that impairs its ability to process and excrete bilirubin. This leads to an accumulation of bilirubin in the bloodstream, causing yellowing of the skin and eyes. Here are some common causes of hepatic jaundice: - Hepatitis: Viral hepatitis (e.g., Hepatitis A, B, C) can lead to inflammation and damage to liver cells, impairing their ability to process bilirubin. - Alcoholic Liver Disease: Chronic alcohol consumption can lead to liver damage, including fatty liver, alcoholic hepatitis, and cirrhosis, all of which can cause hepatic jaundice. - Drug-Induced Liver Injury: Certain medications, especially in high doses or with prolonged use, can lead to liver damage. This includes drugs like paracetamol, certain antibiotics, and some antifungal medications. - Cirrhosis: Cirrhosis is advanced scarring of the liver tissue, often resulting from long-term liver damage due to conditions like chronic alcoholism, chronic hepatitis, or nonalcoholic fatty liver disease (NAFLD). - Liver Cancer (Hepatocellular Carcinoma): Primary liver cancer can directly affect liver function, leading to impaired bilirubin processing. - Autoimmune Hepatitis: This is an immune-mediated inflammatory condition where the body's immune system mistakenly attacks liver cells, leading to liver damage. - Wilson’s Disease, Hemochromatosis, Alpha-1-Antitrypsin Deficieny, Budd-Chiarai, Reye’s syndrome Post-Hepatic 6. Excretion into Bile: Conjugated bilirubin is then secreted into bile canaliculi, tiny ducts within the liver, and eventually into the bile ducts. From there, it is transported to the gallbladder for storage and eventual release into the digestive system. 7. Intestinal Processing: In the intestines, bilirubin undergoes further chemical changes by gut bacteria, converting it into urobilinogen. Some urobilinogen is absorbed back into the bloodstream and eventually excreted by the kidneys (giving urine its yellow color). The rest is excreted in feces, giving them their characteristic brown color. 8. Excretion: Bilirubin is eliminated from the body via feces and urine. The yellow color of urine is a result of the presence of urobilinogen. What can cause Post-Hepatic Jaundice? Post-hepatic jaundice, also known as obstructive jaundice, occurs when there is an obstruction in the bile ducts that prevents the normal flow of bile from the liver to the intestine. This obstruction leads to a buildup of bilirubin in the bloodstream, causing yellowing of the skin and eyes. Here are some common causes of post-hepatic jaundice: - Gallstones: Small, hard deposits of cholesterol or bilirubin can form in the gallbladder or bile ducts, obstructing the flow of bile. - Bile Duct Strictures: Narrowing or strictures in the bile ducts can result from inflammation, scarring, or tumors, leading to an obstruction. - Pancreatic Cancer: Tumors in the pancreas can grow and press on the bile duct, causing an obstruction. - Biliary Tract Cancer: Cancerous growths in the bile ducts, gallbladder, or ampulla of Vater can obstruct the flow of bile. - Cholangitis: This is an inflammation of the bile ducts, often caused by a bacterial infection. It can lead to strictures and obstructions. - Choledocholithiasis: Large gallstones can migrate from the gallbladder into the common bile duct, causing an obstruction. - Biliary Atresia, Primary Scleorising Cholangitis, Parastic Infections, Pancreatitis, Gallbladder Cancer, Inflammatory Bowel Disease Taking a Jaundice history SH HPC Excessive Alcohol - Acute or chronic? - Right upper quadrant discomfort, nausea, vomiting, and Consumption pruritus (itch) are all features of hepatitis of any cause (virus, Quantify exactly how many units autoimmune, drugs, alcohol). a week the patient consumes and - Fever or diarrhoea may additionally be present if the liver is remember that recommended infected (e.g. viral hepatitis, abscess). levels are <14 units / week for - Steatorrhoea (pale, floating, foul-smelling faeces), dark urine, and females and <21 units/week for pruritus are seen in obstruction to biliary flow. males. Levels above 35 - Weight loss, fever, and night sweats could indicate a units/week for females or 50 malignancy of the liver, bile duct, or pancreas. units/week for males are very - Bronzed skin and signs of diabetes mellitus (polyuria, weight loss, infections) are suggestive of haemochromatosis. This condition dangerous. is hereditary so check for family history. - Exposure to outdoor water/sewage (that may be contaminated IV Drug User or by rat urine and faeces) is a risk factor for Weil’s disease. Unprotected sex? Risk of Hepatitis! PMH Foreign - Gallstones? Consider obstructive jaundice due to gallstones or ascending cholangitis blocking the common bile duct. Travel? - Liver disease? ‘Fatty liver’ (steatohepatitis due to chronic alcohol You must consider the possibility abuse or dyslipidaemia), hepatitis B and C, haemochromatosis, of malaria, hepatitis A, and, if Wilson’s disease, α1-antitrypsin deficiency, PBC, and PSC are all they have been to the Far East, causes of jaundice per se and also significant risk factors for liver hepatitis E. cirrhosis. - Haemophilia? Such patients may have received blood products Tattoos? contaminated with hepatitis C, a scenario which was tragically the The unsterile case up until the 1980s. conditions under - Recent blood transfusion or surgery? This may suggest a blood which some group incompatibility, although this is thankfully rare in hospitals tattoos are today. created, - Ulcerative colitis? This makes PSC more likely, as there is a strong particularly those association between these conditions. acquired abroad, - Diabetes mellitus? As mentioned above, this is seen in increases the risk of blood-borne haemochromatosis. transmission (e.g. - Emphysema? Suggests α1-antitrypsin defi ciency. viral hepatitis). - Psychosis? May suggest Wilson’s disease (rare!). DH FH Anything which can cause hemolysis – there are 4 main mechanisms: 1. Intravascular hemolysis (e.g. sulphonamides, aspirin in G6PDH- 1. Gilbert’s deficient patients). 2. Wilson’s disease 2. Autoimmune, extravascular haemolysis (e.g. methyldopa). 3. Hereditary 3. Hepatitis (e.g. paracetamol overdose). spherocytosis 4. Cholestasis (e.g. co-amoxiclav). 4. Any of above conditions (under PMH) Jaundice Investigations Bloods and Imaging are useful to investigate jaundice and differentiate between different types of jaundice (prehepatic, hepatic, or post-hepatic). Liver Screen A liver screen, also known as a liver function test (LFT) panel or liver panel, is a set of blood tests designed to assess the health and function of the liver. It provides valuable information about how well the liver is performing its various functions, including processing bilirubin, producing proteins, and metabolizing substances. A typical liver screen includes the following components: Component Total bilirubin Measures the total amount of bilirubin in the blood, which includes both direct (conjugated) and indirect (unconjugated) bilirubin. Direct bilirubin Specifically measures the conjugated form of bilirubin, which is water-soluble and excreted in the bile. Indirect bilirubin Measures the unconjugated form of bilirubin, which is not water- soluble and needs to be processed by the liver. ALT An enzyme found primarily in the liver. Elevated levels can indicate liver damage or disease. AST Another enzyme found in the liver, as well as in other tissues like the heart and muscles. Elevated levels can indicate liver damage or injury. ALP An enzyme produced in the liver and other organs, particularly the bones and bile ducts. Elevated levels may suggest liver or bone disease. GGT An enzyme found in the liver, bile ducts, and pancreas. Elevated levels may indicate liver disease or bile duct obstruction. Albumin A protein produced by the liver. It helps maintain blood volume and pressure, and it plays a role in transporting substances in the blood. Total Protein Measures the total amount of protein in the blood, including albumin and globulins. PT Assesses the blood's ability to clot. Abnormal results may indicate liver dysfunction. PTT Another test to evaluate blood clotting, often used in conjunction with PT.Imaging The choice of imaging modality depends on various factors, including the suspected cause of jaundice and the patient's clinical condition. Here are some of the main types of imaging used to investigate jaundice. Ultrasound (US): - Purpose: Provides initial imaging of the liver, gallbladder, bile ducts, and surrounding structures. - Advantages: Non-invasive, widely available, cost-effective, and can be performed quickly. - Findings: Detects gallstones, liver size, dilated bile ducts, tumors, cysts, and other structural abnormalities. Computed Tomography (CT) Scan: - Purpose: Offers more detailed cross-sectional images of the liver and surrounding organs. - Advantages: Provides high-resolution images, useful for detecting tumors, abscesses, and identifying vascular abnormalities. - Contrast Enhancement: Often performed with intravenous contrast to enhance visibility of blood vessels and tissue structures. Magnetic Resonance Imaging (MRI): - Purpose: Provides detailed images of the liver and associated structures. - Advantages: Excellent soft tissue contrast, helpful for evaluating liver lesions, bile ducts, and identifying structural abnormalities. - MRCP (Magnetic Resonance Cholangiopancreatography): Specifically focuses on imaging the bile ducts and pancreatic duct. Endoscopic Retrograde Cholangiopancreatography (ERCP): - Purpose: Combines endoscopy with X-ray imaging to directly visualize and diagnose issues in the bile ducts and pancreas. - Advantages: Can both diagnose and treat certain biliary conditions (e.g., remove stones, place stents). Percutaneous Transhepatic Cholangiography (PTC): - Purpose: Involves the injection of contrast material directly into the bile ducts via a needle inserted through the skin and liver. - Advantages: Provides detailed images of the bile ducts, helpful for identifying obstructions or strictures. Oesophageal cancer – risk factors and symptoms What is it? Investigations Hereditary Spherocytosis (HS) is a Complete Blood Count (CBC): genetic disorder characterized by Reveals anemia, with a lower than abnormal red blood cells (erythrocytes) normal red blood cell count and that are spherical in shape rather than hemoglobin levels. Additionally, the the normal biconcave disc shape. mean corpuscular volume (MCV) may These misshapen red blood cells are be decreased. less flexible and more prone to hemolysis (breakdown), leading to Peripheral Blood Smear: Shows anemia. HS is primarily an inherited the characteristic spherical shape of condition, often passed down in an red blood cells in HS. autosomal dominant pattern. The British Journal of Haematology (BJH) guidelines state that 'patients with a family history of HS, typical clinical features and laboratory investigations (spherocytes, raised mean corpuscular haemoglobin concentration [MCHC], increase in reticulocytes) do not require any additional tests’ If the diagnosis is equivocal the BJH recommend the EMA binding test and the cryohaemolysis test Presentation Anemia: Due to the premature Management destruction of red blood cells (hemolysis), Folate Supplementation: Since red blood cells individuals with HS often have anemia. are being destroyed at a faster rate, individuals This can lead to symptoms such as fatigue, with HS may benefit from folic acid supplements weakness, and pallor. to support red blood cell production. Jaundice: Excess bilirubin, a breakdown Splenectomy: In severe cases or when the product of red blood cells, can accumulate, spleen is significantly enlarged, surgical removal causing yellowing of the skin and eyes (splenectomy) may be recommended to reduce (jaundice). hemolysis. However, this can increase the risk of certain infections and necessitates lifelong Splenomegaly: The spleen may become vaccinations and prophylactic antibiotics. enlarged as it works harder to filter and remove the abnormal red blood cells from Blood Transfusions: In severe cases of anemia, circulation. or during acute hemolytic crises, blood transfusions may be necessary. Gallstones: High levels of bilirubin can lead to the formation of gallstones in the gallbladder. Alcoholic Hepatitis clotting, a common finding in severe alcoholic What is it? hepatitis. Alcoholic hepatitis is a condition Complete Blood Count (CBC): May show characterized by inflammation of the liver due anemia and elevated white blood cell count. to heavy and prolonged alcohol consumption. It is considered a serious and potentially life- Serum Albumin: Levels may be low due to threatening condition. reduced liver function. Imaging Studies: Ultrasound, CT scan, or Presentation MRI can help assess liver size and detect any Jaundice: One of the hallmark signs of complications like ascites or liver abscesses. alcoholic hepatitis is the yellowing of the skin and eyes (jaundice) due to elevated bilirubin levels. Scoring Systems MELD Score (Model for End-Stage Liver Disease): Predicts short-term Abdominal Pain: Many individuals with mortality in people with liver disease, alcoholic hepatitis experience pain or including alcoholic hepatitis. It considers tenderness in the upper right quadrant of the bilirubin levels, creatinine, and INR. abdomen. Child-Pugh Score: Assesses the severity of Enlarged Liver (Hepatomegaly): The liver disease based on factors like bilirubin liver may be enlarged and tender to the touch. levels, albumin levels, PT/INR, presence of Ascites: In severe cases, fluid can accumulate in the abdominal cavity, causing ascites, and hepatic encephalopathy. abdominal swelling (ascites). Management Fever and Malaise: Some individuals may Alcohol Cessation: The most crucial step in have a fever and generally feel unwell. managing alcoholic hepatitis is complete Nausea and Vomiting: Digestive symptoms abstinence from alcohol. such as nausea and vomiting can occur. Medications: Hepatic Encephalopathy: In advanced cases, there may be confusion, altered mental Corticosteroids (e.g., prednisolone): In some cases, corticosteroids may be status, and even coma due to liver's impaired prescribed to reduce inflammation and ability to filter toxins. improve liver function. Investigations Liver Function Tests (LFTs): Elevated Pentoxifylline: Can be used in severe levels of liver enzymes like ALT and AST cases to help reduce inflammation. indicate liver inflammation and damage. Vitamin Supplementation: Particularly thiamine (vitamin B1) to prevent Wernicke- Bilirubin Levels: Elevated bilirubin levels Korsakoff syndrome. contribute to jaundice. Liver Transplantation: In severe cases Prothrombin Time (PT) or with liver failure, transplantation may be International Normalized Ratio (INR): considered. Prolonged PT/INR reflects impaired blood Pancreatic Cancer Endoscopic Ultrasound (EUS): Combines endoscopy with ultrasound to obtain detailed images of the pancreas and surrounding structures. CA 19-9: A tumor marker that may be elevated in pancreatic cancer. However, it is not specific and can be elevated in other conditions. LFTs: To assess liver function, as What is it? pancreatic cancer can affect the bile ducts and liver. Pancreatic cancer is a malignant tumor that arises in the pancreas, an organ Management located behind the stomach. It is often detected at an advanced stage, making Surgery: Surgical removal of the it one of the most challenging cancers tumor (resection) is the primary to treat. One of the most common treatment if the cancer is localized and operable. This may involve a Whipple forms is adenocarcinoma of the procedure (pancreaticoduodenectomy) pancreatic head. or distal pancreatectomy. Presentation Abdominal Pain: Typically, individuals with pancreatic cancer experience pain in the upper abdomen or back. This pain may become more severe as the cancer progresses. Jaundice: When the tumor obstructs the bile duct, it can lead to yellowing of the skin and eyes (jaundice). This occurs due to the buildup of bilirubin in the bloodstream. Weight Loss and Loss of Appetite: These are common symptoms, often attributed to the metabolic changes induced by the Chemotherapy: Often used in cancer. combination with surgery (neoadjuvant) or after surgery Investigation (adjuvant) to kill cancer cells and prevent recurrence. CT Scan: Provides detailed images of the pancreas, surrounding organs, and Palliative Care: Focuses on blood vessels. It's crucial for staging providing relief from symptoms, the cancer. improving quality of life, and offering support for individuals with advanced or incurable pancreatic cancer. References 1. Oxford Cases in Medicine and Surgery – Jaundice [BOOK] 2. https://teachmephysiology.com/gastrointestinal-system/liver/bilirubin-metabolism/ 3. https://manualofmedicine.com/topics/gastroenterology/evaluation-of-jaundice/ 4. https://app.pulsenotes.com/presentations/gastrointestinal/notes/jaundice 5. https://bestpractice.bmj.com/topics/en-gb/1143 6. https://www.passmedicine.com/v7/menu.php? – Alcoholic Liver Disease 7. https://bestpractice.bmj.com/topics/en-gb/265?q=Pancreatic%20cancer&c=suggested