CCCS5 GI HE Bilirubin Metabolism and Neonatal Hyperbilirubinemia Case Study PDF

Clinical chemistry case study GI History and Examination Bilirubin metabolism and a case study on “Neonatal Hyperbilirubinemia” Gastrointestinal system: history The most common complaints resulting from disorders involving the GI tract include pain and alterat...

Clinical chemistry case study GI History and Examination Bilirubin metabolism and a case study on “Neonatal Hyperbilirubinemia” Gastrointestinal system: history The most common complaints resulting from disorders involving the GI tract include pain and alterations in bowel habit, especially diarrhea or constipation. Of these complaints, abdominal pain is the most frequent and variable and may reflect a broad spectrum of problems, from the least threatening to the most urgent. Gastrointestinal system: history Acute abdomen: a sudden, severe abdominal pain. It is in many cases a medical emergency, requiring urgent and specific diagnosis. Causes include: Peritonitis Appendicitis Bowel, gastric or gallbladder perforation Intestinal obstruction Ruptured ectopic pregnancy Biliary or renal colic Gastrointestinal system: history Common causes of abdominal pain based on site Epigastric: e.g. pancreatitis, gastritis/duodenitis, peptic ulcer Left upper quadrant: Peptic ulcer, gastric or colonic cancer, abscess, renal (colic, pyelonephritis). Right upper quadrant: Cholecystitis, biliary colic, hepatitis, peptic ulcer, renal (colic, pyelonephritis). Loin: Renal colic, pyelonephritis, renal Gastrointestinal system: history Common causes of abdominal pain based on site Left iliac fossa: inflammatory bowel disease, colon ca, pelvic abscess, renal colic, UTI, Gynaecological: Torsion of ovarian cyst, salpingitis, ectopic pregnancy. Right iliac fossa pain All causes of left iliac fossa pain plus appendicitis and Crohn’s ileitis, Pelvic: Urological: UTI, retention, stones. Gastrointestinal system: history Common causes of abdominal pain based on site Generalized: Gastroenteritis, irritable bowel syndrome, peritonitis, constipation. Central: Mesenteric ischemia, abdominal aneurysm, pancreatitis. Remember referred pain: Myocardial infarct referred to epigastrium; pleural pathology. Gastrointestinal system: history Other Gastrointestinal symptoms Vomiting: Causes include: GI: Gastroenteritis, peptic ulceration, intestinal obstruction, acute cholecystitis, acute pancreatitis. Other causes: CNS: meningitis, migraine, increased Intracranial pressure, motion sickness. Drugs: AB, Opiates, Cytotoxics, Digoxin. Metabolic: uraemia, hypercalcaemia, hyponatraemia, pregnancy, DKA, Gastrointestinal system: history Other Gastrointestinal symptoms Nausea: an unpleasant, diffuse sensation of unease and discomfort, often perceived as an urge to vomit. Non-specific symptom. Some common causes: motion sickness, migraine, low blood sugar, gastroenteritis, food poisoning, drugs (e.g. erythromycin, ergotamine, nifedipine, chemotherapy) or morning sickness Gastrointestinal system: history Other Gastrointestinal symptoms Dysphagia (difficult swallowing), odynophagia (painful swallowing) Indigestion (also known as dyspepsia): a term refers to a group of symptoms that often include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain frequently caused by GERD or gastritis. In a small minority of cases it may be the first symptom of peptic ulcer disease (an Gastrointestinal system: history Other Gastrointestinal symptoms Hematemesis (vomiting blood) Abdominal distension: fat, fluid (ascites), faeces, flatus, and fetus Melena: blood stools (altered blood): Upper GI bleeding Hematochezia: fresh blood through the anus, usually in or with stools: lower GI bleeding Tenesmus: feeling of incomplete evacuation of the bowels due to e.g. a Gastrointestinal system: history Other Gastrointestinal symptoms Diarrhea causes include: Infection, poorly absorbed sugars, inflammatory bowel disease, functional bowel disorder, pancreatic insufficiency, celiac disease, medications (PPIs, Antibiotics) Constipation causes include: normal transit (most common), medications (e.g. opioids, atropine, amitriptyline, verapamil), obstruction (e.g. cancer), metabolic (e.g. hypothyroidism, Gastrointestinal system: history Other Gastrointestinal symptoms Steatorrhea: pale stools difficult to flush, caused by malabsorption of fat in the small intestine and hence greater fat content in the stool. Causes: Ileal disease (eg Crohn’s), pancreatic disease, and obstructive jaundice (due to decreased excretion of bile salts from the gallbladder). Jaundice: will be discussed later Gastrointestinal system: examination General exam: general state (ill/well/cachexic) colour: pale, jaundiced (see later) Scars on the abdomen? Stomas? Hands exam: Inspection: clubbing, koilonychia, palmar erythema, pigmentation of the palmer creases Asterixis: Gastrointestinal system: examination Face exam: Skin and eyes: jaundice, conjunctival pallor, Kayser–Fleischer rings, xanthelasma, sunken eyes (dehydration) Mouth: angular stomatitis (Fissuring of the mouth’s corners is caused by denture problems, candidiasis, or deficiency of iron or riboflavin (vitamin B2)), glossitis (a smooth, red, sore tongue) eg caused by iron, folate, or angular stomatitis B12 deficiency glossitis; Gastrointestinal system: examination Abdominal exam: Inspection Scars—previous surgery, transplant, stoma Visible masses, hernias or pulsation of AAA Visible veins suggesting portal hypertension Gynaecomastia, hair loss Gastrointestinal system: examination Abdominal exam: Palpation: masses, hepatomegaly, splenomegaly, renomegaly, tenderness, guarding (involuntary tensing of abdominal muscles—pain or fear of it), or rebound tenderness (greater pain on removing hand than on gently depressing abdomen— peritoneal inflammation); Percussion: If this induces pain, there may be peritoneal inflammation below Gastrointestinal system: examination Abdominal exam: Auscultation: Bowel sounds: absence implies ileus; they are enhanced and tinkling in bowel obstruction.  Heme degradation and Bilirubin Metabolism The human body produces about 4 mg per kg of bilirubin per day from the metabolism of heme. Approximately 80 percent of the heme moiety comes from catabolism of red blood cells, with the remaining 20 percent resulting from ineffective erythropoiesis and breakdown of muscle myoglobin and cytochromes. Bilirubin is transported from the plasma to the liver for conjugation and excretion.”1 1 Roche and Kobos, “Jaundice in the Adult Patient.”, Am Fam Physician. 2004 Jan 15;69(2):299-304.  Bilirubin Metabolism1 Formation and transport of Bilirubin1: Bilirubin is formed in macrophages of the reticuloendothelial system. The initial substrate is predominantly hemoglobin. Heme group biliverdin bilirubin Bilirubin is only slightly soluble in plasma and, therefore, is transported to the liver by binding noncovalently to albumin. Bilirubin circulates in the blood before uptake by the liver. Uptake of bilirubin by the liver1 Bilirubin dissociates from the carrier albumin molecule and enters a Bilirubin Metabolism Formation of bilirubin diglucuronide In hepatocytes two molecules of glucuronic acid are added to bilirubin, producing bilirubin diglucuronide. This process is referred to as conjugation. catalyzed by microsomal bilirubin UDP- glucuronosyltransferase (bilirubin UGT) using UDP- glucuronic acid as the glucuronate donor. Bilirubin Metabolism Secretion of bilirubin diglucuronide into the bile The conjugated bilirubin is water soluble and is excreted into bile. Excretion occurs into the bile canaliculus by carrier-mediated transport. active transport of conjugated bilirubin against a concentration gradient into the bile canaliculi and then into the bile. energy-dependent rate-limiting step susceptible to impairment in liver disease Unconjugated bilirubin (UCB) is normally not secreted into bile. Dubin-Johnson syndrome: rare deficiency in the protein required for transport of CB out of the liver  Bilirubin Metabolism Formation of urobilins in the intestine: Bilirubin diglucuronide is hydrolyzed and reduced by bacteria in the gut to yield urobilinogen, a colorless compound. Most of the urobilinogen is oxidized by intestinal bacteria to stercobilin, which gives feces the characteristic brown color. Some of the urobilinogen is reabsorbed from the gut and enters the portal blood A portion of the reabsorbed urobilinogen is taken up by the liver and then re-secreted into the bile (enterohepatic urobilinogen cycle) The remainder of the urobilinogen is transported by the blood to the kidney1, where some is excreted as urobilinogen2 and the remainder is converted to yellow urobilin and excreted, giving urine its characteristic color. Lack of urobilinogen in the urine and feces indicates biliary obstruction; stools are whitish (“clay-colored”) owing to Lippincott's Illustrated Reviews: Biochemistry, Sixth Edition Denise R. Ferrier, Page 282 – 284 1 the absence of bile pigment. Urinary and fecal Bhagavan and Ha “Metabolism of Iron and Heme” in Essentials of Medical Biochemistry, 2011 2 Hereditary Disorders of Bilirubin Metabolism and Transport Hyperbilirubinemia Bilirubin is found in the blood in two fractions: Unconjugated (indirect) fraction: is insoluble in water and is bound to albumin in the blood. Conjugated (direct) fraction, is water soluble and can therefore be excreted by the kidney. The normal values of total serum bilirubin are reported between 1 and 1.5 mg/dL with 95% of a normal population falling between 0.2 and 0.9 mg/dL. The most frequently reported upper limit of normal for conjugated bilirubin is 0.3 mg/dL. 1 If the direct fraction is less than 15% of the total, the bilirubin can be considered to all be indirect. Dennis Kasper et al, Harrison's Principles of Internal Medicine, 19 edition, 1 Hyperbilirubinemia Elevated levels of serum bilirubin (direct or indirect) Hyperbilirubinemia occurs as a result of1 1. Overproduction; 2. Impaired uptake, conjugation, or excretion of bilirubin; 3. Regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts1 Fauci et al, Harrison's manual of Medicine, 17 edition, Page 269 1 Unconjugated Hyperbilirubinemia1 Elevation is rarely due to liver disease. Isolated (i.e. with normal liver enzymes) unconjugated hyperbilirubinemia (bilirubin elevated but