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H. pylori infection It is a gram-negative bacterium that causes peptic Ulcers Diagnosis: Serology test (will remain positive in 50% after eradication)Urea breath test (Expensive, false-negative with recenttherapy) Stool antigen test (cheap and specific) Rapid urease test (simple, false-negative with recent therapy) Histology by biopsy (most accurate of all tests) Culture (time-consuming, expensive, determines the antibiotic susceptibifity) H. pylori test Serology test Urea breath test Stool antigen test Rapid urease test Histology Sensitivity > 80% > 90% 80Specificity > 90% > 90% > 90% 95-100% Table 7 J: Different types of H. pylori tests Treatment: Triple therapy: o The first line treatment o PPI bid, amoxicillin lg bid, and clarithromycin 500 mg bid for 7— 14 days Quadruple therapy: o PPI + metronidazole + tetracycline + bismuth. o Indicated in the probability of clarithromycin resistance or penicillin allergy Levofloxacin-based therapy: PPI bid + amoxicillin lg bid + levofloxacin 500 mg qday for 10 14 days. Follow-up: Test for the cure of H. pylori after treatment with stool or breath tests (not serology test) Testing should be done 4 weeks after completion of the therapy Upper endoscopy is indicated if the patient is still symptomatic after treatment or if the cause is uncertain page 1138 | INTERNAL1-17AFEEF-MERGED-1.pdf |
complications of peptic Ulcer disease include perforation, chronicity, bleeding. anemia, outlet malignant obstructiontransformation, and gastric pain relation to food Prevalence Risk of malignancy Routine biopsy Healing confirmation by endoscopy The most common location Gastric ulcer Aggravated Less common 4% Needed Needed Incisura angularis Duodenal ulcer Relieved More common No risk Not needed Not needed unless complicated The first part (first 2 cm) Anterior duodenal wall Table 72: Gastric vs. Duodenal ulcer Wes: 25% of gastric cancers will ulcerate To avoid false-negative results for H. pylori, stop antibiotics for 28 days and strop PPI for 2 weeks before testing (or do histological testing by biopsy) Selective COX 2 inhibitors NSAl Ds provides NO better protection than non-selective NSAl Ds + PPI Gastroparesis Defective gastric emptying but without obstruction. Can be inherited or acquired disorder of the gastric pacemaker or autonomic disorder Causes: Longstanding diabetes leads to gastric dysmotility Systemic sclerosis Hypothyroidism Antichofinergic drugs and narcoticsuagnosis: Mainly clinical diagnosis For acute symptoms: upper endoscopy is indicated to ruleout gastric outlet obstruction For chronic symptoms: Nuclear gastric emptying study Page 1189 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Symptoms: abdominal fullness, vomiting, weight loss, bloating, andearly satiety. Treatment: Erythromycin (for acute gastroparesis) Metoclopramide (for chronic gastroparesis) Notes: During testing for gastric emptying, RBS should be < 275(high glucose can acutely impair gastric emptying) Dystonia and tardive dyskinesia are extrapyramidal side effects of metoclopramide; stop it if any of them appear to avoid the irreversibility of these side effects. Upper GI bleeding (UGIB) Basic anatomy: ligament of Treitz: the suspensory ligament of the duodenum Upper Gl bleeding: is a bleeding proximal to the ligament of Treitz (75% of Gl bleedings) Causes: Duodenal ulcer (the most common cause) Gastric Ulcer, gastritis, gastric cancer Esophagogastric varices, Esophagitis, Esophageal cancer Mallory-Weiss tear Aortoenteric fistula Coagulopathy (drugs, renal disease, liver disease, DIC) Epistaxis Eso ha us Right crus of diaphragm /'-m The aorta ment of Treit Z Duodenum Flgure 38: The suspensory Ligament of Treitz page1190 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Clinical features: Occult blood in the stool (less severity) Melena (Black stool) Coffee ground vomiting Hematemesis Hematocheia (the most severe) Hemodynamic instability (according to severity) o Orthostasis (less severity) o Tachycardia o Hypotension (the most severity) When going from lying down to a standing position, More than a 10 bpm increase in heart rate is called orthostatic tachycardia More than 20 mm Hg drop in systolic BP or > 10 mm Hg drop in diastolic BP is called orthostatic hypotension Management: Stabifize patient (ABC): intravenous lines, fluid resuscitation, blood, and platelet transfusion, and keep the patient NPO NC tube insertion (this will determine UGIB vs. LGIB) Intravenous proton pump inhibitors Serial HB, KFT, electrolytes, vitals monitoring. Upper endoscopy (the best diagnostic and therapeutic) Surgery may have a rule if endoscopy fails to stop the bleeding Treatment of the cause:o Coagulation problems: Vitamin K, FEP, cryoprecipitate o Thrombocytopenia: platelet transfusiono Esophageal varices: Octreotide decreases Portal BP Page 1191 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Rockall Score: Points Age < 60 Shock SBP > 100 Comorbidities60-79 HR > 100 SBP> 10023 280 SBP< 100 HF, IHD CKD, CID, malignancy Score O and no further evidence of bleeding: discharge home Score > O: Refer for urgent upper endoscopy Table 73: Rockall Score for risk of death in upper Gl bleeding Notes: Platelet transfusion indicated if the platelet count is < 50,000 with active bleeding Metoclopramide and erythromycin have an action of increasing gastric emptying; they are useful before endoscopy to remove clots Diseases of Malabsorption Celiac disease (gluten-sensitive enteropathy) It is an autoimmune disease due to exposure to gliadin (gliadin is a product of gluten breakdown) associated with HLA-DQ2 (chromosome 6) found in 80-90%, HLA-DQ8 It usually starts at age 6 months when adding food other than milk (It never manifests at birth) Pathogenesis: Gluten is a protein present in (Rye, Barley, Oats, and Wheat) Gluten exposure can cause characteristic changes in the lining of the small intestine, resulting in malabsorption (Rapid response and reversible if a gluten-free diet has been taken) The proximal part of the small bowel is more affected than the distal part page 1192 | INTERNAL1-17AFEEF-MERGED-1.pdf |
celiac disease may be associated with other autoimmune conditions like TOM, thyroid diseases, primary biliary cirrhosis, lg A deficiency, pernicious anemia, IBD, and myasthenia gravis. Clinical picture: (These symptoms are reversible when a gluten-free det is administrated) Bloating and abdominal pain Chronic diarrhea (greasy, smelly stool) Weight loss, failure to thrive (malabsorption) Anemia (folate, BIZ and iron malabsorption) Symptoms of vitamin deficiency Skin manifestation (Dermatitis herpetiformis) (10%) Diagnosis: Anti-gfiadin, anti-endomysial, and anti-tissue transglutaminase antibodies (best initial tests) Perform Anti-t TG lg G for patients with lg A deficiency Small bowel biopsy (most accurate) (diagnosis of celiac disease and exclude bowel lymphoma) Improvement of symptoms on a gluten-free diet Stool fat > 7% Measure bone density for all patients diagnosed with Celiac disease Notes: Cefiac disease is usually misdiagnosed as IBS, so if a patientpresents with a history of IBS and anemia, do Anti-t TG, biopsy ifpositive, and then order a gluten-free diet. However, all patientsshould be treated with a gluten-free diet regardless of symptoms,including those with isolated dermatitis herpetiformis Treatment: Gluten-free diet Monitor response by measuring Anti-t TG Ig A antibody or by repeating bowel biopsy Vitamin D and calcium for patients with Osteomalacia complications: malnutrition, anemia, vitamin deficiency, bleedingtendency, and small bowel lymphoma or adenocarcinoma. Page 1193 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Sites for absorption of nutrients The site for absorption of different nutrients: Stomach: Alcohol. Duodenum: Cat Mg, iron, Vitamins A and D, glucose. Jejunum: Fat, sucrose, lactose, fat-soluble vitamins A and D, water-soluble vitamins, proteins, amino acids, glucose. Ileum: Proteins and amino acids, vitamin B12. Colon: Water, potassium, sodium chloride, fatty acids fromfiber digestion. Table 74: The sites for absorption of different nutrients Diseases of vitamin deficiencies Beriberi: It is caused by thiamin (vitamin Bl) deficiency Wet beriberi: SOB, lower limb edema, heart failure Dry beriberi: (Wernicke's encephalopathy): Paralysis, confusion, and nystagmus Pellagra: It is caused by vitamin B3 (Niacin) deficiency Features: Dementia, diarrhea, dermatitis, depression, and death (5Ds) Scurvy: It is caused by vitamin C (ascorbic acid) deficiency Features: Gum bleeding, sore legs and arms Osteomalacia: It is caused by vitamin d deficiency In pediatrics, it is called Rickets This will lead to bone deformities, bone pains, and pathological fractures Vitamin K deficiency: Vitamin K is also known as phytonadione Vitamin K-dependent clotting factors are (X, IX, Vll, Il, protein c, and protein S) Its deficiency will lead to bleeding tendency and elevated INR Vitamin A deficiency: Vitamin A is also known as retinoic acid Its deficiency will lead to night blindness, dry hyperkeratofic skin, conjunctival dryness, and corneal ulceration. page 1194 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Diarrhea Diarrhea is an increase in stool frequency or loose stool Diarrhea classification: Can be Acute < 14 days vs. Chronic > 14 days Inflammatory vs. Non-inflammatory Secretory (persist with fasting) vs. Osmotic (stop with fasting) Bloody diarrhea vs. Watery diarrhea stool electrolytes: Stool osmolality = 2(Na + K) If stool osmolality is less than 250 m Osm, the cause is: Factitious diarrhea (Laxative use, Adding water to stool) Stool osmotic gap = 290 2(Na + K): If > 100 m Osm, osmotic diarrhea is the cause If < 50 m Osm, secretory diarrhea is the cause Osmotic diarrhea: Stool osmotic gap > 100 m Osm Stops with fasting and never awake patient during sleep Usually not leading to dehydration Secretory diarrhea: Stool osmotic gap < 50 m Osm Occurs at fasting or during sleep Usually high volume > I L/day Causes of infectious diarrhea:The most common cause of diarrhea is infection Viral (rotavirus is the most common cause)Toxin-mediated (Staph. aureus, Clostridium) Bacteria (Shigella, Campylobacter, c. difficile, salmonella) Protozoa (Giardia, Cryptosporidium, amoebic dysentery) Systemic (diverticulitis, sepsis, PID, meningitis, atypical pneumonia, malaria) causes of non-infectious diarrhea: 01: (IBD, malignancy, Zollinger-Ellison syndrome) Metabolic: (DKA, DM. thyrotoxicosis, uremia, VIPoma)Drugs and toxins: (NSAl Ds, PPIs, cytotoxic agents, Antibiotics,Carcinoid syndrome Page 1195 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Causes of bloody diarrhea: Infectious: o Bacterial: Enterohemorrhagic E. Coli, Salmonella, Shigella, Campylobacter, Yersinia, C. difficile (lessoften bloody), o Viruses: CMV o Parasites: Entamoeba histolytica, Schistosorrüasis Inflammatory Bowel Disease Medications: NSAl Ds, chemotherapy Gl bleeding (AVMs, diverticulosis, brisk UGI bleeds, etc. ) Others: Ischemic Colitis, Diverticulitis, Cancer, Radiation Causes bloody diarrhea Campylobacter jejuni Enteroinvasive E. coli Entameba histolytica Salmonella Shigella (dysentery type) Yersinia enterolitica Enterohemorrhagic E. coli (Shigella toxin-producing)Causes of non-bloody darrhea Shigella (diarrhea type) Enteropathogenic E. coli Enterotoxigenic E. coli Vibrio cholera Most viral diarrhea Toxin-mediated (Staph aureus, clostridium botulinum) Table 75: Causes of bloody vs. non-bloody diarrhea Clinical picture: Fever and Bloody diarrhea indicate colitis History < 18 hours indicates toxin-mediated History > 5 days indicate protozoal infection Symptoms of the systemic causes Dehydration may be present (need further assessment) Diagnosis: Stool culture and microscopy (do not order stool culture for diarrhea less than I-week duration) Colonoscopy (used for most patients with chronic diarrhea) 24 hours stool collection for fat (if colonoscopy is not diagnostic) | INTERNAL1-17AFEEF-MERGED-1.pdf |
Treatment: Fluid and electrolytes replacement (oral is the best, IV if Antibiotics (rarely indicated) Indications for antibiotics use: If a bacterial cause is identified or strongly suspected (Shigella, Vibrio cholera, C. difficile, Traveller's diarrhea) Associated bacterial infection (Otitis, pneumonia) Prolonged fever with fecal blood or leukocytes Melanosis coli: is a benign pigmentation of the colon mucosa; it results from chronic laxative use Campylobacteriosis Campylobacter is the rnost common bacterial cause of infectious intestinal disease Diagnosis is made by a positive stool culture but requiresspecial media and handing Clinical features: Prodrome: headache, myalgia, and fevers (as high as 400C)Abdominal pain Watery offensive diarrhea 2 —4 days, then become bloody Treatment: Usually, supportive treatment is adequate Erythromycin or aithromycin can be used when there is arisk of complications Traveler's diarrhea Traveler's diarrhea occurs within 2 weeks of a visit to a tropical area Usually, mild self-limiting diarrhea for less than 72 hours Causes: E. coli is the most common cause Other causes: Shigella, Salmonella, Campylobacter, Giardia Treatment: Fluoroquinolseverity of traveler's diarrhea ones significantly when given reduce for 1-3 the days. duration and Page 1197 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Giardiasis It is an infection with the parasite Giardia lamblia Giardia lamblia is a flagellate protozoan Transmitted through contaminated water, food, surfaces, orobjects. (oral-fecal transmission) Pathogenesis: Giardia parasite causes non-inflammatory diarrhea(it does not invade the intestinal mucosa but only covers itpreventing absorption) Clinical features: Giardiasis presents as traveler's diarrhea with symptomslasting more than 10 days It can cause both acute or chronic diarrhea (Chronic diarrhea is most likely to be associated with weight loss)Symptoms: bloating, flatulence, abdominal pain, loose stool,explosive watery diarrhea, weight loss Symptoms begin after returning from a travel Treatment: Metronidazole (the most commonly used drug) Tinidazole Pseudomembranous colitis Clostridium difficile are gram-positive bacilli Clostridium difficile antibiotic-associated colitis is produced by two toxins, A and B Pathogenesis: Pseudomembranous colitis is diarrhea that OCCUß as a result of antibiotic use The eradication of the normal flora in the intestine leads to excessive growth of clostridium difficile that will release toxins leading to bloody or watery diarrhea Possible complications are (toxic megacolon and sepsis) The most common antibiotics implicated in Clostridium difficile infections are Clindamycin, Cephalosporins (second and third generations), Quinolones, Amoxicillin, and Ampicillin) Page 1198 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Diagnosis: Clinical presentation of diarrhea following antibiotics use Cytotoxin assay of the stool is the best test to order; it is sensitive and highly specific Colonoscopy would show the classic Pseudomembranes Treatment: If this is the first episode of Clostridium difficile infection o Oral vancomycin for 10 days (the first-line treatment) o Oral fidaxomicin (the second line) o Oral vancomycin and IV metronidazole (the third line) If the patient has recurrent episodes: o Oral vancomycin and IV metronidazole o Consider surgery o Consider fecal microbiota transplant (if > 2 episodes) If fulminant or complicated disease is not responsive to the previous treatment, perform a colectomy. Severe C. diffcile infection is defined by any one of the following: WBC count > 15,000/ul Serum creatinine > I. 5 times the baseline Age of more than 60-year-old Page 1199 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Disorders of the large intestine Inflammatory Bowel Diseases (IBD) The two main types of inflammatory bowel disease are Crohn's disease (CD) and Ulcerative colitis (UC). They are HLA B27-associated diseases They are best diagnosed with endoscopy and biopsy. Features Male: female Most common site non-caseating granuloma Smoking relation Serum marker Crohn's disease Equal for both Terminal ileum Present Increased by smoking ASCA Microscopic involvement of CD and UC:Ulcerative colitis Male more affected The Rectum. Not present Decreased by smoking p ANCA Features Site Thickness Character Goblet cells Gross feature Crohn's disease Any site from mouth to anus Transmural Skip lesions Increased Cobble-stone appearance Ulcerative colitis It starts at the rectum and never spreads beyond the ileocecal valve Mucosa and submucosa Continuous disease Depleted Pseudopolyps Table 76: differences between IBD types Page 1200 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Clinical features of CD and Crohn's UC: disease Features Diarrhea Weight loss Malabsorption Mouth and anus presentation Crypt abscess Relapsing-remitting Abdominal pain Usually, non-bloody More Present May be involved RIF mass Less common Present Present Ulcerative colitis Bloody Less Absent Not involved LIF pain More common Present Present Table 77: Clinical features of CD vs. UC E)åraintestinal manifestations in CD and UC: System involved Eye Cutaneous Hepatobiliary Pancreas Genitourinary Pulmonary Musculoskeletal Hematology Manifestation Uveitis, Scleritis, Episcleritis Erythema nodosum Pyoderma gangrenosum Primary sclerosing cholangitis Liver cirrhosis Gallstones (Bile acid malabsorption in CD) Pancreatitis Nephrolithiasis Chronic bronchitis Bronchiectasis Seronegative arthritis Anemia Increased thromboembolic events Table 78: Extraintestinal manifestations in CD and UC Page 1201 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Complications of CD and UC: Features Complications Crohn's disease Stricture Obstruction Fistula Malabsorption Colorectal cancer Less risk Ulcerative colitis Toxic megacolon Cholangitis More risk Table 79: Complications of CD vs. UC Toxic megacolon: a severe life-threatening compfication of IBDseen more commonly in UC, characterized by dilatation of colon with a risk of rupture The drugs used in the treatment of CD and UC: 5-Aminosalicylic acid (5 ASA): o E. g., mesalaine, olsalazine o Mild to moderate relapses in UC o Long-term treatment to maintain remission o Side effects include: rash, infertility, agranulocytosis, headache, diarrhea, and renal failure Steroids: o The main treatment for active disease o Given as a short tapering dose to induce remission Immunosuppressants: o E. g., azathioprine, mercaptopurine o Used in steroid-refractory cases, or those requiring frequent steroid courses o Side effects: Bone marrow suppression and hepatotoxicity Methotrexate: Used in patients with CD but not effective in UC Metronidazole and ciprofloxacin: Used for isolated perianal Crohn's disease Anti-turner necrosis factor-alpha (Anti-TNF) fn Mmab, adalimumab o Used in active Crohn's disease refractory to conventional therapy o Screen for TB and HBV for all patients before starting Anti-TNF éage1202 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Nutritional support for malnourished patients Surgery: o Curative for UC o Symptomatic relief for CD o Used for treatment of complications. Treatment of Ulcerative colitis: Mild UC (< 4 bowel movements/ day) Moderate UC Severe UC (> 6 bowel movements/ day)5 ASA (maintenance) Steroid for remission 5 ASA a ent maintenance I. V glucocorticoids; then Anti-TNF antibody Surgery for refractory cases (curative) Table 80: Treatment of UC Treatment of Crohn's disease: Mild to moderate CD No fever, no tendemess, < 10% weight loss Moderate to severe CD Fever, abdominal pain, > 10% weight loss Severe fulminant CDFever, severe tenderness, and weight loss despite steroids. Fistula Budesonide or mesalamine (remission) 6-MP, azathioprine, or methotrexate (for maintenance) Prednisolone for remission 6-MP, azathioprine, or methotrexate (for maintenance) Anti-TNF for refractory cases I. V glucocorticoids (for remission) Anti-TNF antibodies Surgery for refractory disease (not curative) Azathioprine, 6-MP, Anti-TNF Table 8 1 : treatment of CD Page 1203 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Microscopic Colitis Chronic diarrhea, no abdominal pain, no weight loss More common in women 45 60 years old No increased risk of colon cancer Causes: NSAl Ds, PPI, and SSRls have been implicated as causativeagents Colonoscopy: Gross examination of the mucosa is normal, but microscopic examination shows colitis (collagenous or lymphocytic) Treatment: Loperamide, Bismuth Stop NSAID, PPI, or SSRI (if possible) Budesonide (the best efficacy — used for severe cases) Irritable bowel syndrome (IBS) It is a functional disorder of the large bowel, not explained by investigations. IBS is the most common cause of Gl referral More in young adults, more in females than males 10-15% of the population Cause is unknown Pathogenesis: abnormal uncoordinated contractions of bowels Types according to Symptoms: Pain-predominant Diarrhea-predominant (IBS-D) Constipation-predominant (IBS-C) Mixed types (IBS-M) Diagnosis: Rome IV criteria for IBS diagnosis: Abdominal pain for at least 1 day per week, for at least 3 monthsin the past 6 months with 2 out of the following: Relieved with defecation Associated with a change in consistency Associated with a change in frequency | INTERNAL1-17AFEEF-MERGED-1.pdf |
Investigations: Usually not needed (Apply criteria) CBC, TSH, tissue transglutaminase, CRP, stool analysis and Culture, and sigmoidoscopy are only indicated if there is an alarming sign to rule out celiac disease, anemia, infection, IBD, and thyroid disease. Treatment: Diet modification Antispasmodics for pain in all types of IBS For IBS-D o TCA for pain o Loperamide, cholestyramine for diarrhea o Eluxadoline (for both pain and diarrhea) o Rifaximin (an antibiotic used for global symptoms) For IBS-C: o SSRls for pain o Lubiprostone (for women) o Linaclotide Red Hag for IBS (Alarming symptoms): Age of onset 2 50 years A family history of IBC) Weight loss, Anemia, Fever Blood or pus in the stool Nocturnal defecation Abnormal gross findings on flexible sigmoidoscopy If red flags present, consider a diagnosis other than IBS Table 82: Alarm symptoms for IBS Page 1205 | INTERNAL1-17AFEEF-MERGED-1.pdf |
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Hepatology CHAPTER 6 AM JAD K. ALAFEEF Phone number: +962798843824 E-mail: Afeeef. 2005@gmail. com Page 1207 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Introduction to hepatology The normal Liver functions General facts: The liver is the second largest organ of the human bodyafter the skin Located at the right upper quadrant (RUQ) of the abdomen It has two lobes (right and left lobe) The function of the liver. Metabolism of nutrients (carbohydrates, proteins, lipids)Metabolism of drugs and hormones (e. g., estrogen)Storage of (Iron, copper, vitamin A, vitamin B12, and D3)Protein synthesis (albumin, complement, clotting factors,ceruloplasmin, transferring and protease inhibitor-Alpha-l-antitrypsin) Bile formation and excretion Removal of ammonia from the portal blood 10 Figure 39: The liver and biliary tree (l) Right hepatic duct (2) Left hepatic duct (3) Common hepatic duct (4) Cystic duct (5) Pancreas (6) Common bile duct (7) Pancreatic duct (8) Sphincter of O" (9) Duodenum (10) Gall bladder page 12Ø | INTERNAL1-17AFEEF-MERGED-1.pdf |
Liver function test (LFT) PT, INR: It reflects the ability of the liver to synthesize proteins Caused by decreased vitamin K-dependent clotting factors. prolonged INR and Low serum albumin imply severe hepatocellular dysfunction. Serum albumin level: Could be deficient in liver disease, Nephrotic syndrome, Gl loss This is a marker of liver capacity to synthesize proteins. If decreased, ascites and edema can present Serum bilirubin: Bilirubin has two types (direct and indirect) Can be increased in pre-hepatic, intrahepatic, or post-hepatic conditions Indirect hyperbilirubinemia indicates a pre-hepatic cause (e. g., hemolysis) or impaired uptake (e. g., Gilbert syndrome) Direct hyperbilirubinemia can result from obstructive (post-hepatic) or hepatocyte dysfunction (intrahepatic). AST and ALT They are liver enzymes that, if elevated, indicate damage in hepatocytes. ALT More specific than AST ALT > 5000 u/l indicates acetaminophen hepatotoxicity or hepatic ischemia If AST > ALT and AST/ALT ratio > 2, alcoholic liver disease The most common cause of minimal elevation of ALT and AST is a non-alcoholic fatty liver disease Alkaline phosphatase (ALP) It is an indicator of obstructive liver disease if very high with less prominent elevated AST and ALT (Confirm obstructive liver disease by elevated GCT)If isolated high ALP, consider a bone disease ALP can be produced by the placenta and is elevated inthe case of pregnancy. Page 1209 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Jaundice Jaundice is a yellowish discoloration of the skin and mucous It manifests clinically when plasma bilirubin > 2. 5 mg/dl The indirect (unconjugated) bilirubin is fat-soluble, while the direct (conjugated) type is water-soluble RBC Destruction Release of Hemoglobin Globin Heme Biliverdin mino Acid In intestine Deconjugated Stercobilinoge Urobilinogen Unconjugated Bilirubin Conjugate Bilirubin UDP-glocoronosyl-Stool transferase enzyme Urine Figure 40: Bilirubin metabolism and excretion Terms: Conjugated hyperbilirubinemia: total bilirubin above normal with conjugated (direct) fraction > 20% of total bilirubin Unconjugated hyperbilirubinemia: total bilirubin above normal with conjugated (direct) fraction <15% of total bilirubin Table 83: Bilirubin metabolism page 1210 | INTERNAL1-17AFEEF-MERGED-1.pdf |
s of Jaundice: Pre-hepatic jaundice: o Isolated raised bilirubin with normal other LFTs Due to the destruction of RBC (hemolysis) Elevated unconjugated bilirubin Intra-hepatic jaundice: o The inability of the liver to uptake, conjugate, or secretion bilirubin by hepatocytes Both direct and indirect bilirubin are increased Post-hepatic jaundice: o Impaired secretion due to mechanical obstruction Alkaline phosphatase is significantly elevated o Increased conjugated bilirubin levels Gilbert syndrome: An autosomal dominant familial condition The mutation results in a decreased UDP-glucuronosyl-transferase enzyme The patient will exhibit mild jaundice (< 3 mg/dl unconjugated hyperbilirubinemia) The jaundice is more prominent in dehydration and stress Normal AST and ALT and absence of hemolysis along with indirect hyperbilirubinemia are enough for diagnosis (without extensive testing) Patient otherwise asymptomatic No need for treatment Page 1211 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Acute liver diseases Viral Hepatitis It is the viral infection and inflammation of the parenchyrrnof the liver If hepatitis persists for more than 6 months, it is called chronichepatitis (acute hepatitis is less than 6 months) Virus A, B, C, D, and E are causes of viral hepatitis Other causes are called non-A-E hepatitis (hepatitis X), rare HDV is preventable by HBV vaccine (HDV requiring HBs Agfor entry into hepatocyte) Hepatitis A & B have vaccinations, buf C and Edo not HBV and HCV are associated wifh an increased (6k of Hepatocellular carcinoma and glomerulonephrifis. Clinical features of hepatitis: Most cases are asymptomatic Prodrome for 1-2 weeks followed by jaundice Jaundice Enlargement of (liver, spleen, and lymph nodes) Right upper quadrant pain and fever Rash and arthritis (more in HBV and HCV) Lab results expected in hepatitis: Elevated AST and ALT (do not correlate with the disease progression) Elevated Alkaline phosphatase (hepatitis leads fo a degree of cholestasis) Abnormal protein synthesis by the liver (prolonged PT. high JNR, and low serum albumin) Metabofic disturbances (hypoglycemia, lactic acidosis, and hyperammonemia) Virus Incubation period HAV 15— 19 days HBV 60-180 days HCV14— 160 days HDV 21 — 42 days HEV 21-63 days Transmission Oral fecal Parenteral Parenteral Parenteral Oral fecal Chronlcity Wusfype Never Yes Yes Yes Never RNA DNA RNA RNA RNA Table 84: General information about hepatitis vtwes Page 1212 | INTERNAL1-17AFEEF-MERGED-1.pdf |
ction transmitted by infected needle sticks The most common infe is hepatitis B (30%), followed by hepatitis C (3%), and HIV (0. 3%) Hepatitis A virus HAV is the most common hepatotropic virus It can only cause acute hepatitis (no chronicity) Usually infectious before the appearance of jaundice Infection with HAV provides lifelong immunity Clinical features: HAV is associated with abrupt onset of fatigue, nausea, vomiting, fever, jaundice, and abdominal pain. In small children, especially less than 5 years old, it may present without jaundice (Anicteric HAV infection) Symptoms are more severe in adults than children. Diagnosis: Cfinical suspicion is important for diagnosis Elevated ALT and AST (usually > 1000 u/l) lg M Anti-HAV (the most accurate) Prevention of HAV: HAV Inactivated (Killed vaccine) provides 10 — 20 years of immunity HAV immunoglobulins (intramuscular injection) provide protection for 3 months Indications of HAV vaccine: It was added to the Jordanian routine vaccination program for pediatrics on 2020 Travelers to endemic areas IV drug users Homosexual men Patients with chronic liver disease and clotting factors deficiency. Treatment: (only supportive) Intravenous hydration Fat-soluble vitamin supplementation (for prolonged cholestasis) If an acute liver failure occurs, refer for liver transplantation Page 1213 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Hepatitis B virus HBV is strongly associated with polyarteritis nodosa andassociated with an increased risk of hepatocellular cancer as well as hepatoma HBV, HDV transmitted by blood transfusion, saliva, sex,vertical transmission (from mother to fetus) HDV is preventable by HBV vaccine (HDV requiring HBs Ag for entry into hepatocyte) HBV marker The meaning HBs Ag Infection HBe Ag Active infection Anti-HBs Immunity Anti-HBc lg MAcute Anti HBc lg G Chronic Acute active HBV Infection + HBs Ag + HBe Ag + Anti-HBc lg M Vaccinated + Anti-HBS-Anti-HBc Chronic active HBV Infection + HBs Ag + HBe Ag + Anti-HBc lg G Recovered + Anti-HBs + Anti-HBC-Anti-Hbe Chronic inactive HBV Infection + HBs Ag-HBe Ag + Anti-HBc lg G Recovering + Anti-HBS + Anti-HBC + Anti-Hbe Table 85: HBV markers interpretation Prevention: HBV vaccine is a part of a routine immunization program in Jordan HBV vaccine should be provided at 3 doses (O, I, 6 months) for all healthcare providers Needlestick patients and infants born to hepatitis B-positive mothers should receive the first dose of HBV vaccine and HBV immunoglobulin at 2 different sites within 12 hours after exposure. page 1214 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Treatmen?, Supportive measures No need to treat inactive HBV infection Interferon-a2b (IFN-a2b): o It has immunomodulatory and antiviral effects The treatment duration is 24 weeks o Side effects are: flu-like symptoms, marrow suppression, depression, retinal changes, autoimmune disorders Other antiviral agents (Lamivudine, Tenofovir) Complications: Acute liver failure (coagulopathy and encephalopathy) Hepatocellular carcinoma Membranous glomerulonephritis (due to Hbe Ag deposition in the glomerulus) Hepatitis C virus HCV is the most common hepatitis that transmitted by a blood transfusion Acute HCV is asymptomatic, and patients usually present with signs and symptoms of chronic liver disease HCV transmission is like HBV but less likely to be transmitted by sex Testing: ALT and AST are normal in 40% of HCV infection cases Order Anti-HCV to diagnose its presence Order HCV RNA (if positive, indicates active disease) HCV genotyping should be performed at the time of diagnosis to help to choose the treatment regimen Treatment: Peginterferon and ribavirin are approved by the FDA for usein children older than 3 years of age with HCV hepatitis Sofosbuvir and simeprevir are newer treatments Page 1215 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Fulminant Hepatic Failure (FHF) Fulminant hepatic failure: Severe hepatic failure withdevelopment of hepatic encephalopathy and coagulopathy within 8 weeks after onset of acute liverdisease in the absence of evidence of pre-existing liverdisease, its major cause of death is cerebral edema Sub-fulminant hepatic failure: 8 weeks to 6 months Chronic hepatic failure: more than 6 months Causes: Acute viral hepatitis (most common cause 70%). The mostcommon virus is HBV (50%). Drugs (e. g., paracetamol, amoxicillin-clavulanate, Valproate, phenytoin) Malignancy (most commonly lymphoma) Shock, ischemia Herpes infection Mushroom poisoning Wilsons disease Acute fatty liver of pregnancy Clinical picture: Jaundice Hepatic encephalopathy No hepatomegaly Investigations: Deterioration in LFT Toxicology screen Hepatitis profile Wilsons disease workup Autoimmune hepatitis workup (ANA, ASMA, Anti-LKM) Treatment: Supportive therapy Treatment of hepatic encephalopathy (lactulose) Treatment of the cause o Chelation with penicillamine or trientine for Wilson's disease o N-acetylcysteine for paracetamol poisoning o Penicillin G or silymarin for Mushroom poisoning Liver transplant for candidate patients page | INTERNAL1-17AFEEF-MERGED-1.pdf |
poor prognostic factors of non-paracetamol related FHF: Drug or Non-A-E-hepatitis båreme age (< 10 or > 40 years) The interval from onset of jaundice to encephalopathy > 7 days Serum bl Ttrubin > 18 mg/dl > 50 seconds Table 86: Poor prognostic factors of FHF Paracetamol poisoning Also called acetaminophen poisoning Acute overdose > 140 mg/kg or 7 grams in adults In alcohofic patients, a lower dose of paracetamol can cause fiver failure Paracetamol is metabolized by glucuronidation and sulfation, with a small amount by the cytochrome P4S0 enzyme system Cünical picture: Early 24 48 hours: Nausea, vomiting, pallor After 48 hours: Hepatotoxicity, RUQ tenderness, hepatomegaly, deteriorating KFT and LET, and Hepatic failure Diagnosis: Serum paracetamol level Gastric lavage (as soon as possible) Activated charcoal (within 4 hours) N-acetylcysteine administration if: o Paracetamol concentration of 2 100 mg/d L at 4 hours o Paracetamol concentration of? 15 mg/d Lat 15 hours o When the ingestion time is not known, regardless of the paracetamol concentration Liver transplantation: o If arterial PH < 7. 3, 24 hours after ingestion, or o Serum creatinine > 300 umol/l, PT > 100 sec, and Grade Ill-IV encephalopathy Poor factors of paracetamol-induced liver failure: PH < 7. 3 (regardless of the grade of encephalopathy)PT > 100 second, creatinin > 300umol/l, and grade Ill to IV encephalopathy. Table 87: Poor prognostic factors of paracetamo Mnduced liver fa Nwe Page 1217 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Chronic liver diseases Liver Cirrhosis Liver cirrhosis is a fibrosis and nodule formation of liver tissue Causes: Chronic hepatitis (B, C, B+D) but not hepatitis A and EAlcoholic and Non-alcoholic fatty liver disease Autoimmune hepatitis Alpha-I-antitrypsin deficiency (10% cause liver disease)Drug-induced liver cirrhosis. Right side Heart failure (chronic liver congestion will result incardiac cirrhosis) Symptoms: The patient may remain asymptomatic for 20 years/stage Iliver cirrhosis, but if stage 2 starts, symptoms will manifest. Loss of appetite, low energy, weakness, and weight loss Signs: Ascites (the most common symptom) Coagulopathy Asterixis and encephalopathy Clubbing Feminization (scanty pubic hair, testicular atrophy, gynecomastia) Hypoalbuminemia and edema Skin (Palmer erythema, jaundice, Itching, spider nevi) Portal HTN and varices Fetor hepaticus (breath with bad smell seen in portal HTN with a portosystemic shunt) Thrombocytopenia, anemia, or pancytopenia Hepatorenal syndrome Hepatopulmonary syndrome Diagnosis: CBC: the first sign is low platelets PT. INR (the second sign is elevated INR) Serum albumin: low albumin Serum bilirubin: high bilirubin Hypoglycemia (indicate terminal condition) Liver biopsy is the most accurate test page 1218 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Treatment: Treatment of the cause Avoid hepatotoxic agents (alcohol, drugs) Treatment and prevention of complications: o Upper endoscopy for all new patients (to evaluate for varices) Ultrasound to diagnose ascites o Paracentesis for all new patients to: Determine SAAG and diagnose the cause Cytology and culture to rule out SBP o Vaccination for HAV, HBV, and other routine vaccinations. The definite treatment is a liver transplant Child-Pugh score for liver cirrhosis: 1 point Ascites None Encephalopathy None Bilirubin mg/dl Albumin g/dl PT (sec) INR> 3. 5 < 1. 72 points Slight Grade 1 or 2 2-3 2. 8-3. 5 1. 7-2. 33 points Moderate Grade 3 or 4 < 2. 8 > 2. 3 Class A (5 — 6 points): I-year survival is 100% Class B (7— 9 points): I-year survival 80% Class C (10— 15 points) I-year survival 45% Table 88: Child-Pugh score for liver cmosis Complications of cirrhosis: Causes of death in cirrhosis: Renal failure (hepatorenatsyndrome), Sepsis. Gl bleeding, and Hepatocellular Carcinoma. Other complications: o Low PLT, WBC, Hb (pancytopenia)o Bleeding tendencyo Infections o Peptic ulcers Page 1219 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Alcoholic liver diseases Requires regular drinking rather than binge drinking No clear relationship between the dose and liver damage Women are at higher risk than men Clinical features: Alcoholic fatty liver: (hepatomegaly, good prognosis, disappear 3 months of abstinence) Alcoholic hepatitis (jaundice, malnutrition, hepafomegaly,portal HTN) Alcoholic cirrhosis (in chronic alcohol intake, same featuresas mentioned in liver cirrhosis) Lab test: High AST and ALT (usually < 300 and almost always < 500) AST: ALT ration 2 High GCT High Ferritin level (acute phase reactant) AST is higher than ALT in alcoholic hepatitis due to hepatic deficiency of pyridoxal 5'-phosphate, an ALT enzyme co-factor. Management: Stop alcohol Good nutrition Steroids for acute alcoholic hepatitis (contraindicated in sepsis, varices, pancreatitis, and kidney disease) Liver transplant (End-stage liver disease) page 1220 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Non-alcoholic fatty liver diseases (NAFLD) prevalence increased with obesity, Dyslipidemia, insulin resistance, and T2DM Hepatomegaly is often present Classifications: Simple fatty infiltration (steatosis): No morbidity Fat and inflammation: non-alcoholic steatohepatitis (NASH). It may progress to fibrosis, cirrhosis, or cancer Liver cirrhosis Clinical picture: Most commonly asymptomatic abnormal LFT (especially high ALT, AST, GCT) A clinical picture of cirrhosis Investigations: ALT higher than AST (best initial test) Abdominal U/S (high echogenicity of the liver indicates NASH) Liver biopsy (gold standard) Treatment: Modify risk factors Treat complications Avoid hepatotoxic drugs Primary biliary cholangitis (PBC) Autoimmune condition: the interlobular bile ducts become damaged by a chronic inflammatory process leading to progressive cholestasis and liver cirrhosis It is more common in women 40 — 60-year-old Clinical features: 50% are asymptomatic Pruritus, fatigue, weight loss, jaundice The complications of portal hypertension Features of fat-soluble vitamin deficiency. Usually associated with other autoimmune diseases (E. g., Sjögren's syndrome, autoimmune hepatitis) Diagnosis: LFT (high direct bilirubin, Alkaline phosphatase, and GCT) Anti-mitochondrial antibodies (AMA) (highly specific) Anti-smooth muscle antibodies (ASMA) in 30% of patients Raised serum lg M Page 1221 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Treatment: Cholestyramine (treatment of pruritus) Fat-soluble vitamin supplementation Ursodeoxycholic acid (UDCA): o Used early, even in asymptomatic patients. o A hydrophilic bile acid that decreases the bile injury by the more hydrophobic bile acid o It increases the biliary secretion o It has an anti-inflammatory and immunomodulatory effect o UDCA delays the histologic progression of PBC Liver transplantation for candidate patients Primary sclerosing cholangitis (PSC) IBD (especially ulcerative colitis) is present in 80% of PSC It is characterized by autoimmune damage for both intralobular and extralobular biliary tree. Males are affected more than females Clinically presents with itching and features of hyperbifirubinemia Diagnosis: High direct bilirubin level High alkaline phosphatase level ERCP or MRCP (beading of the biliary system) ASMA, ANCA Liver biopsy shows onion skin fibrosis (the most accurate) Treatment: Endoscopic therapy for extrahepatic strictures Liver transplant Patients with PSC are at risk of developing gallbladder cancer, cholangiocarcinoma, or colon cancer (when associated with IBD) Age group Affected ducts Association Diagnosis Treatment PBC Women 40 60 years Small bile ducts Autoimmune diseases Anti-mitochondrial ab. UDCAPSC Men 20 30 years Medium/large ducts IBD ERCP or MRCP Endoscopic therapy Table 89: PBC vs. PSC Page 1222 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Autoimmune hepatitis Autoantibodies against liver tissue More common in women Clinical picture: Consider autoimmune hepatitis in a young woman with hepatitis or hepatic failure who is serology negative to hepatitis viruses and has other associated autoimmune conditions Signs of acute hepatitis (fever, jaundice, fatigue, RUQ pain) Signs of chronic hepatitis Associated autoimmune diseases: Thyrotoxicosis Myxoedema Ulcerative colitis Hemolytic anemia Glomerulonephritis Nephrotic syndrome Vitiligo Investigations: LFT (Liver function test) ANA (sensitive but not specific) ASMA (anti-smooth muscle antibody) ALKM (Anti-liver kidney microsomal antibody) ASLA (Anti-soluble liver antigen) (most specific, not sensitive) BIOPSY (the most accurate test) Treatment: Steroids Azathioprine (started once LFT returns to normal) Page 1223 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Complications of liver cirrhosis Ascites Ascites is an accumulation of fluids in the peritoneal cavity Paracentesis should be done if (new-onset ascites, fever, orabdominal pain and tenderness) Symptoms: Asymptomatic if less than 1 liter of fluid Abdominal distension starts if more than 1 liter Shifting dullness and fluid thrill on examination Signs and symptoms of the cause Pathogenesis: Ascites occurs due to increase permeabifity in intestinal capillaries due to splanchnic vasodilatation, which also activates the renin-angiotensin system and causes sodium water retention Investigations: Abdominal U/S is best to detect ascites Paracentesis to determine the cause Ascitic protein < 2. 5 g/dl Ascitic protein 2 2. 5 g/dl Treatment:SAAG < 1. 1 SAAG 21. 1 Nephrotic syndrome Cirrhosis Malignancy, TB, or CHF, or Budd-Chiari pancreatitis syndrome Table 90: Differential diagnosis of ascites Stop ACEI, ARB, and NSAl Ds in patients with ascites Treatment of the cause Sodium restriction Diuretics (spironolactone is the best but furosemide may be used) Paracentesis TIPSS (Trans-jugular intrahepatic portosystemic shunt) SAAG is the serum ascites albumin gradient TIPSS can increase the risk of hepatic encephalopathy Paracentesis is diagnostic and symptomatic treatment Treatment of ascites is symptomatic and does not prolong the life F age1224 | INTERNAL1-17AFEEF-MERGED-1.pdf |
spontaneous Bacterial Peritonitis (SBP) Bacterial infection in a patient with ascites but without perforation of the bowel E. coli (most common) More common in patients with Gl bleeding Symptoms: Maybe asymptomatic in 30% of cases Abdominal pain, fever, chills, hypotension May worsen encephalopathy Diagnosis All patients with ascites should have paracentesis to rule out SBP (30% of patients are asymptomatic) High ANC (Absolute neutrophil count) in ascites (best initial test) Culture 80% sensitivity (usually not needed for diagnosis) (most accurate test) Prophylaxis Indications: Cirrhosis or Gl bleeding: IV ceftriaxone daily or norfloxacin bid * 7d Previous episode of SBP: Long-term prophylaxis with daily norftoxacin or TMP/SMX Treatment: Antibiotics: (Cefotaxime or ceftriaxone) Albumin: Decreases mortality and the risk of renal failure Complications: Acute kidney injury Encephalopathy Page 1225 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Portal HTN and esophageal varices The normal Portal vein pressure gradient is 5 mm Hg Portal hypertension is defined as the portal pressure ofthan 10 mm Hg If the portal pressure exceeds 12 mm Hg, there will be a high risk of esophageal variceal bleeding When portal pressure is high, collaterals will appear fo shuntblood to the systemic circulation, esophageal Variceal,Caput medusa, rectal varices Manifestations of portal HTN: Splenomegaly (high sensitivity to portal HTN)Caput medusa (collaterals at the abdominal wall)Esophageal varices Rectal varices Investigations: Periodic upper endoscopy (for esophageal varices)Abdominal U/S (splenomegaly, ascites, etc. )CT /MRI angiography to detest portal patency CBC: anemia of chronic disease and low platelets (due to hypersplenism) Portal pressure measurement (the most accurate)o Transjugular approach o Percutaneous transhepatic approach Treatment of portal HTN without Gl bleeding: Propranolol (80-160 mg/day), Nadolol Treatment of the cause and complications Treatment of esophageal variceal bleeding: The priority, in this case, is to restore circulation with I. V fluids, Blood, and plasma The hemoglobin transfusion goal is 7 g/dl (increasing Hb more than 7 will lead to increased portal pressure and thus more bleeding) All should receive prophylactic antibiotics "ciprofloxacin" to prevent hepatic encephalopathy and SBP. Terlipressin or Octreotide: o Vasopressin analog that reduces the portal pressure o Terlipressin reduces mortality in Variceal bleeding Endoscopy: o Diagnostic and therapeutic o Banding can be used to stop bleeding éage122å | INTERNAL1-17AFEEF-MERGED-1.pdf |
Balloon tamponade: o Sengstaken-Blakemore tube can be inserted and inflated to stop bleeding. It should be deflated 10 minutes every 3 hours to avoid esophageal necrosis Transjugular intrahepatic portosystemic shunt (TIPSS): o A stent inserted between the portal and hepatic vein o It increases the risk of hepatic encephalopathy Hepatic encephalopathy Hepatic encephalopathy is a neuropsychiatric manifestation of liver disease Measuring the plasma ammonia level can be helpful (but monitoring serial ammonia value is not helpful). Pathogenesis: Nitrogenous substances produced by gut bacteria (Ammonia or Gamma-aminobutyric acid) are usually metabolized by the liver and do not cause harm If there is liver failure or the blood is bypassing the liver, ammonia will accumulate in the brain and cause a decreased level of consciousness. EEG will show a diffuse slowing in alpha waves Clinical grading of hepatic encephalopathy: Grade l: poor concentration, slurred speech, slow mentation, disordered sleep rhythm Grade 2: drowsy, aggressive behavior Grade 3: marked confusion, sleepy, response to pain Grade 4: coma, unresponsive Precipitating factors of hepatic encephalopathy are trauma,infection, heavy protein meals, GI bleeding, hepatoxic drugs, or constipation Prophylaxis: Give lactulose (titrated to 3 stools per day)Do not use protein restriction as prophylaxis for hepaticencephalopathy Page 1227 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Treatment: Treatment of the precipitating cause Lactulose (laxative): decreases colon PH and the proteincontent of the Gl tract; thus, ammonia absorption Rifaximin 400 mg TID: Non-absorbable antibiotics to reducethe gut bacteria Neomycin is no longer recommended for hepatic encephalopathy due to its significant side effects. Liver storage diseases Hemochromatosis Increase total body iron and iron deposition in the liver leading to damaged hepatocytes and other organs Normal body iron: 4-5 grams Hereditary Hemochromatosis is an autosomal recessive disorder; HFE gene mutation leads to increased iron absorption from the intestine Secondary hemochromatosis results from iatrogenic iron overload from repeated blood transfusions or maybe dietary Affected organs in hemochromatosis are the liver, heart, skin, pancreas, testes, and endocrine glands. Symptoms: At 40 years old, they present with: Fatigue and Arthropathy (early symptoms) DM, HF, arrhythmias, Impotence, loss of libido, testicular atrophy Destructive Arthropathy of the second MCP joints with Hook-like osteophytes Unusual sites Osteoarthritis (e. g., ankle, shoulder) Liver cirrhosis that may progress to Hepatocellular cancer Gray skin pigmentation (bronzed diabetes) Investigations: The most appropriate screening test is fasting serum transferrin saturation High serum ferritin and Plasma iron Liver biopsy (best to confirm the diagnosis) Genetic testing to identify the mutation page 1228 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Treatment: For hereditary hemochromatosis: o Venesection weekly 500 ml (250 mg iron) — until serum iron is normal, then as required (liver and heart will improve BUT not DM) Screening for the first-degree relatives For secondary hemochromatosis: o Hydroxyurea to reduce the need for blood transfusion o Deferoxamine (iron-chelating agent) Wilson's disease Copper is normally absorbed in the stomach and proximal small intestine, taken to the liver for storage, and then incorporated into ceruloplasmin Wilson's disease is an autosomal recessive disorder of copper metabolism on chromosome 13, reducing ceruloplasmin synthesis and copper accumulation. The affected organs are the liver, basal ganglia of the brain, eyes, kidneys, and skeleton. Clinical picture: at age 5 — 45 years Acute hepatitis (may progress to fulminant hepatic failure) Chronic hepatitis and liver cirrhosis Neurological (extrapyramidal, parkinsonism, dementia) Eye (Kayser-Fleischer ring) Investigations: Low serum ceruloplasmin (best lab for diagnosis)High free serum copper High urine copper Very high hepatic copper (biopsy) (the best)Treatment: Low copper diet A chelating agent (penicillamine for life)Liver transplant, if indicated Page 1229 | INTERNAL1-17AFEEF-MERGED-1.pdf |
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Hematology CHAPTER 7 AM JAD K. ALAFEEF Phone number: +962798843824 E-mail: Afeeef. 2005@gmail. com Page 1231 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Introduction to Hematology The normal Hemostasis Hemostasis: is a process that causes bleeding to stop; ifdepends upon the interaction between vessel wall,platelets, and clotting factors. Hemostasis is triggered by injuries resulting in damagedvessels and collagen exposure Phases of hemostasis: Phase I (Primary hemostasis): o Vasoconstriction (first response in hemostasis)o Platelets aggregation and formation of the plugo The platelet adhesion is mediated by v WFPhase Il (Secondary hemostasis): o The plasma proteins normally circulate in the plasmain their inactive form. o Activation of coagulation cascade and formation ofa cross-linked fibrin clot Phase Ill: o Natural inhibitors of the coagulation system inhibit excessive coagulation o Anti-thrombin destroys the activated factors Xa, >Ga, and thrombin (lla). INTRINSIC PATHWAY EXTRINSIC PATHWAY Contact activator TISSUe damage Vill Traumax Xla Illa Vila TISSUe factor Xa lla Stable fibrin clot la Figure 4 1: The coagulation cascade in secondary hemostasis page 1232 | INTERNAL1-17AFEEF-MERGED-1.pdf |
screening assays: PT (Prothrombin time): Assess the function of factors l, Il, V, Vll, and X It measures the time for clot Normally 1 1 —14 sec International normalized ratio (INR): (PT patient/ PT normal) Normally 0. 9-1. 2 partial thromboplastin time (PTT): Assesses the intrinsic and the common pathways It assesses factors l, Il, V, Vlll, IX, X, Xl, and Xll. Normally 60 70 sec Table 91: the laboratory tests used in assessing hemostasis a PTT Vill Vil Xl x Xll Table 92: The clotting factors affecting PT and PTT Clotting factor name fibrinogen Vill Il Prothrombin IX Ill Thromboplastin (tissue factor) X VI Ionized calcium Xl VProaccelerin Xll Vll Proconvertin Xlll Clotting factor name Antihemophilic factor Christmas factor Stuart-Prower factor Plasma thromboplastin antecedent Hageman factor fibrin-stabilizing factor Table 93: Clotting factors names and numbers Factor Vll has the shortest half-life Vitamin K-dependent clotting factors are (X, IX, Vll, Il,proteins C and S)Factor 13 deficiency causes bleeding tendency withoutincreasing in PT or PTTFactor 12 deficiency causes an increase in PTT but withouta bleedin tendency. Page 1233 | INTERNAL1-17AFEEF-MERGED-1.pdf |
The normal hematopoiesis Hematopoiesis is a process of blood formation Erythropoietin is a hormone secreted by kidneys in response to hypoxia to activate hematopoiesis Sites of hematopoiesis: Embryo: Yolk sac Children: spleen, Liver, and Lymph nodes Adults: pelvis, sternum, and vertebral bodies Megakaryocytes Hematopoietic stem cell Myeloid Blasts Lymphoid blasts @ o 0 0000 Erythroblast Megakaryocytes Mast cells T cell B cell NK cel Eosinophil Monocyte Neutrophil &ythrocytes platelets Basophil Dendritic cell Plasma cell Figure 42: The normal hematopoiesis Blood products life span: RBC: 120 days usually removed by spleen (reticuloendothelial system) Platelets: 7 to 10 days WBC: hours page 1234 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Lymphocytes: They are a type of WBC that is a part of the immune system B cells: produce antibodies T cells: destroy infected cells All lymphocytes are formed in the spleen and enter the circulation via lymphatic circulation Differentiated in the thymus (T cells) and Lymph nodes (B cells) Lymphocytes will be elevated in viral infection, some malignancies, and low in case of immunodeficiency or viral infections. Hematologic investigations Complete Blood Count (CBC) Also known as CP (complete picture), FBC (Full blood count) Terms: RBC count: number of R3Cs per mm3 of blood Hb: Amount of hemoglobin in each liter of blood HCT: Hematocrit usually equals Hb*3 MCV: Mean corpuscular volume, RBC size o Normally (80-100 fl): Normocytic o If < 80 fl: Microcytosis o If > 100 fl: Macrocytosis RDW: RBC distribution width (RBC size variation) WBC count: number of WBC per mm3 of blood PLT count: number of platelets in mm3 of blood WBC differentials: number and percentage of each type of WBCs in blood Reticulocytes count: number of immature RBCs in circulation Blood film Also known as peripheral smear Blood film is used to diagnose hematological disorders and isroutinely employed to look for blood parasites, such asmalaria and filariasis. RBCs do not have nucleus reticulocytes have one Blood film will show the following:RBCs size: (microcytic, normocytic, or macrocytic) RBCs color: (hypochromic, normochromic or Polychromasia)RBCs Shape: Poikilocytosis: increased proportion of RBCs ofabnormal shape Page 1235 | INTERNAL1-17AFEEF-MERGED-1.pdf |
target cells SCA/Thalassemia IDA Hyposplenlsm Liver disease basophlllc stippling Lead poisoning Thalassemia Sideroblastic anemia Schistocytes (helmet cells) Intravascular hemolysis MAHATear-drop Polkllocytes Myeloflbrosls Howell-Jolly bodies Hyposplenism Pencil Polkllocytes b O(. b Spherocytes coo bofü00, Hereditary spherocytosls AHA Heinz bodes G6PD deficiency Alpha-thalassemia Burr cells (echinocyte) Uremia Iron deficiency anemia Pyruvate kinase deficiency Table 94: Blood film Interpretation page 1236 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Bone Marrow examination A sample of Bone marrow taken from the posterior iliac crest or stemum Bone marrow aspiration: taking a fluid marrow sample Bone marrow Biopsy: a sample of intact bone marrow Anticoagulants Heparin There are two types of heparin, Unfractionated heparin (UH) and low molecular weight heparin (LMWH) Heparin prevents the activation of factors Il, IX, X, and Xl Molecular weight Dosing Half-life used as outpatient Response Risk of bleeding Risk of osteoporosis Risk of HIT syndrome Monitoring In renal failure patients UH 15 kilodalton IV high dose 90 minutes inpatient Unpredictable Higher Higher Higher Needed (PTT) Better than LMWH Response to antidote Better LMWH 4. 5 kilodalton Subcutaneous 4— 5 hours In or outpatient use Predictable Less Less Less No need Contraindicated when unfractionated, heparin can be used safely poor Table 95: Unfractjonated vs. LMWH Page 1237 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Warfarin Warfarin has been used for many years as a first-line intreating venous thrombosis and reducing the risk of stroke in atrial fibrillation and valvular replacement patients. Monitoring of the warfarin effect is best done by the INRMechanism of action: Warfarin is a vitamin K antagonist (VKA) It inhibits clotting factors Il, Vll, IX, X, and protein C Indications of warfarin: It prevents thrombosis in mechanical heart valves As second-line treatment after direct oral anticoagulants for DVT, PE, AF The target INR in patients on warfarin: Unprovoked DVT/PE: 2 — 3 for 6 months Provoked DVT/PE: 2 — 3 for 3 months Recurrent DVT/PE: 2 —3 for life Atrial fibrillation with high CHA2DS2VAS score: 2— 3 lifelong Aortic valve replacement: 2 — 3 lifelong Mitral valve replacement: 2. 5 — 3. 5 lifelong Side effects: Bleeding Teratogenic effects in pregnancy Skin necrosis (paradoxical thrombosis) Warfarin-induced skin necrosis: It is a rare condition due to acquired protein C deficiency following treatment with anti-vitamin K anticoagulants. This condition is treated by Fresh Frozen Plasma (FEP) or pure activated protein C Surgical management of the necrotic area may be needed. Table 96: warfarin-induced skin necrosis page 1238 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Reduce warfarin effect potentiate watfarin effect Rifampicin Amiodaron Antithyroid drugs Erythromycin Carbamazepine Fluconazole Fluoxetine Cholestyramine Metronidazole Sucralfate Furosemide High dose salicylate Tamoxifen Green tea TMP/SMXGinseng Thyroxine Ribavirin Hi h Alcohol dose Table 97: Warfarin drug interactions Warfarin overdose An INR level of more than 5 in a patient who is taking warfarin is considered an overdose This condition carries a high risk of bleeding, including major and life-threatening. Treatment of warfarin overdose if there is no bleeding: INR 5-8: o Hold warfarin for 2 doses o Restart warfarin in a lower dose when INR < 5 INR > 8: o Hold warfarin o Vitamin K 1 —5 mg PO o Repeat Vitamin K dose if INR still > 8 for > 24 hourso Restart warfarin in a lower dose when INR < 5Treatment of warfarin overdose with minor bleeding: Hold warfarin Vitamin K I — 3 mg intravenously Repeat Vitamin K dose if INR still > 8 for > 24 hours Restart warfarin in a lower dose when INR < 5Treatment of warfarin overdose with major bleeding:Hold warfarin Vitamin K 5 mg intravenously Provide Prothrombin complex concentrate Provide FFP is Prothrombin complex concentrate is notavailable Page 1239 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Vitamin K administration in valve replacement patients will leavethem un-anticoagulated for several days. Therefore, you mayneed to provide heparin after vitamin K administration Until thetarget INR is achieved again. Avoid vitamin K in valve replacement patients unless necessary Action Factors affected Half-life Monitoring Side effects Antidote Heparin vs. warfarin Warfarin Heparin Antagonize vitamin K Agonize antithrombin Ill Vitamin K dependent Factors 9, 10, 1 1, 12 2—3 days INR Skin necrosis Osteoporosis Bleeding Vitamin K, FFP, and Prothrombin complex concentrate90 minutes PTT High liver enzymes Hyperkalemia Bleeding Thrombocytopenia Osteoporosis Protamine sulfate Table 98: Heparin vs. Warfarin Page 1240 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Direct oral anticoaqulants (DOAC) Indcations for DOAC: Non-valvular AF with high CHA2DS2VAS score prevention of thromboembolism in hip or knee surgeries Treatment of DVT and PE Dabigatran (Pradaxa): It is a direct thrombin inhibitor Excreted mainly by kidneys; doses adjustment in chronic Edney disease is required Dose and renal adjustment: ocra > 30 m L/min. 150 mg PO BID cra 15-30 m L/min. 75 mg PO BID o Cr Cl < 30 m L/min or dialysis: It should never be prescribed The antidote: Idarucizumab capsules Evaroxaban (Xaretto): It is a direct factor Xa inhibitor Excreted mainly by the liver Dosage and renal adjustment: o If Cr Cl > 50 m L/min, 20 mg PO daily with evening meal o If Cr Cl < 50 m L/min 15 mg PO daily The antidote: Andexanet alpha Apixaban (Eliquis): It is a direct factor Xa inhibitor Excreted mainly by the stool Dosage and renal adjustment0 Normal KFT. 5 mg PO BIDo Serum creatinine > 1. 5 mg/d L: 2. 5 mg PO BID 0 ESRD on dialysis: 5 mg PO BIDo ESRD on dialysis plus age 80 years: 2. 5 mg PO BID o ESRD on dialysis plus weights 60 kg: 2. 5 mg PO BIDThe antidote: Andexanet alpha Edoxaban (Savaysa) It is a direct factor Xa inhibitor Excreted mainly by the stool No authorized antidote Dosage and renal adjustmento Cr Cl >95 m L/min: Do not use (increase ischemic stroke risk) o Cr Cl >50 to 95 m L/min: 60 mg PO dailyo Cr Cl 15-50 m L/min: 30 mg PO Daily Page 1241 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Blood products and transfusion Blood compositions Blood is composed of cells, Plasma, and proteins The cells: The cells are RBCs, platelets, and WBCs The life-span for blood cells: o RBCs: 90-120 days o Platelets: 7— 10 days o WBCs: several hours The plasma: Plasma is a yellowish fluid that holds cells and clotting factors Serum: is the same as plasma but without clotting factorsand fibrinogen (collected by centrifuge of blood) Blood Proteins: The main blood proteins are albumin, globulin, immunoglobulins, prothrombin, and fibrinogen. They are responsible for transport, immunity, coagulation,and oncotic pressure maintenance. Blood grouping systems ABO blood grouping system: The first blood grouping system recognized in 1900 was the ABO system The major blood groups in this system are A, B, AB, and O. Group A blood contains A antigen and anti-B antibodies, while group B contains B antigen and anti-A antibodies. The possibility of RBC or plasma transfusion is linked to the fact that antibodies should not meet the antigens. Rh blood grouping system: It is the second most important grouping system after the ABO system Rh antigen is a protein that, if found on the RBC membranes, is considered Rh-positive and vice versa Unless sensitized, Rh-negative patients usually do not have anti-D antibodies in their plasma. Ignoring the ABO blood group, Rh-negative blood can be transfused to the Rh-positive one. However, Rh-positive blood can cause sensitization in Rh-negative patients. pagepu | INTERNAL1-17AFEEF-MERGED-1.pdf |
Blood products p RBC (packed Red Blood Cells) It contains red blood cells Each unit contains 450 ml and increases Hb by 1 g/dl Stored at — 6 co for 35 days maximum Need a crossmatch Not used as a volume expander Platelets: Contains platelets Each unit (300 cc) increases PLT count by 5000-10000 Stored at 22-24 co degree (room temperature) for 5 days maximum No need for crossmatch It has the highest infection rate FFP (Fresh Frozen Plasma): All clotting factors but low levels of factor 8 and v WF Each unit = 300 cc Stored at-25 c degree for 36 months maximum Use lg A deficient donor FFP for lg A deficient recipient Need a crossmatch Cryoprecipitate: Rich in factors l, Vill, Xlll, v WF Each unit = 50 cc Stored at-25 c degree for 36 months maximum Better to do a crossmatch Blood Transfusion and transfusion reactions Indications of blood products transfusion: Whole blood: acute active bleeding PRBC transfusion: o Hb of less than 7 g/dlo Hb of less than 8 g/dl in patients with IHD. o Acute bleeding with significant Hb drop Platelet transfusion: low platelet counts with a major bleeding FFP and cryoprecipitate:o Warfarin overdose, Vitamin K deficiency0 DIC o Hepatic failure Page 1243 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Immediate hemolytic transfusion reaction: It occurs due to ABO incompatibility Intravascular, fatal hemolysis Clerical error is the most common cause Symptoms: fever, chills, chest pain, back pain, loin pain, anddark urine (hemoglobinuria). Diagnosis: o Positive Coomb's test (best) o Increased free Hb o Hemoglobinuria o Decreased haptoglobin < 5 mg/dl Treatment: stop transfusion, send sample again to cross-match, I. V fluids, osmotic diuresis (mannitol), alkalinization ofurine Delayed hemolytic transfusion reaction Extravascular hemolysis up to 7 days post-transfusion Caused by Rh or minor blood group incompatibifry Not detected by the crossmatch Not fatal Treated by steroids and supportive care Non-hemolytic febrile reaction Due to the presence of WBC It can be decreased by giving filtered blood without WBCs Treatment: paracetamol Urticaria and anaphylactic reaction Most common in lg A deficient patients Maybe mild to fatal To avoid this complication, use blood from lg A deficient donor Transfusion infection The most common infection is CMV Others: HBV, HCV, HIV, malaria More with platelet and plasma Iron overload: Repeated transfusion after about 20 units Each unit PRBCs contains 250 mg of iron Electrolyte disturbances Hyperkalemia (hemolyzed RBCs) Hypocalcemia (from citrate) page 1244 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Other blood transfusion reactions: Thrombophlebitis: In the used vein Air embolism: Usually need 50 cc of air to manifest Dilatational thrombocytopenia: Most common complication after massive transfusion Clotting factor deficiency: Most commonly, factors V and Vlll Volume overload (Pulmonary edema) Metabolic acidosis Hypothermia Anemia of reduced RBC production Introduction to anemia The normal Hb is W18 g/dl in males and 12-16 g/dl in females. Anemia is defined as a hemoglobin concentration of less than 13 g/dl for men or less than 12 g/dl for women Whatever the cause of anemia, the symptoms will be thesame, but symptoms vary with severity and chronicity. General symptoms of anemia: Fatigue, Headache, Faintness Breathlessness, Palpitation, angina Typical exertional chest pain Intermittent claudication General signs of anemia: Pallor Heart murmur (Flow murmur)Signs related to the causes: (splenomegaly, hepatomegaly,CKD, hematuria, Koilonychia (IDA), Rectal piles, varices, oranal fissure) Classification of anemia: according to MCV: Microcytic anemia: MCV < 80 femtoliter/cell Normocytic anemia: MCV 80-100 fl Macrocytic anemia: MCV > 100 fl Page 1245 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Microcytic IDA (most common) Thalassemia Lead poisoning Sideroblastic anemia Chronic disease (30%)Normocytic Acute bleeding Acute hemolysis Chronic diseases (70%) Liver disease Aplastic anemia Myelofibrosis Leukemia Macrocytic B12 deficiency Folate deficiency Methotrexate Alcoholism Liver disease Hypothyroidism MDs Table 99: Causes of anemia according to the MCV Iron metabolism Normal body total iron is 4-5 grams. Of this, about 2. 5 g is contained in the hemoglobin neededto carry oxygen through the blood, and most of the rest is contained in ferritin complexes that are present in all cells but most common in bone marrow, liver, and spleen Two major iron forms are ferrous (Fe+2) and ferric iron (Fe*3) The site for absorption is the proximal duodenum To be absorbed, it is reduced from ferric (Fe+3) to ferrous form (Fe+2) by an enzyme called ferric reductase enzyme (secreted by enterocyte of the duodenum) Factors that increase iron absorption: Increased acidity Alcohol Use of vitamin C supplement When iron is complemented with lactose The iron of animal source (ferrous) is more absorbable than plant source (ferric) Factors that decrease iron absorption: Tea drinking (converts ferrous to ferric) Use of PPIs or any acid suppressant Plant-source iron (ferric type) Normal dietary allowance of iron: In adults: 8-11 mg/day In premenopausal women: 18 mg/day In pregnant women: 27 mg/day Table 100: The normal dietary allowance of ion page 1246 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Iron Deficiency Anemia (IDA) IDA is the most common type of anemia causes: Poor intake Decrease absorption (e. g., celiac disease, gastrectomy) Increased Iron demands (pregnancy, adolescence) Chronic Blood loss (most common cause) Gl bleeding (Most common blood loss in men and postmenopausal women) Excessive menstruation (The most common cause of IDA in young females) Signs and Symptoms: Signs and symptoms of anemia (mentioned above) Brittle nails and nail cracking Koilonychia (flattening or concavity of the nails) Angular stomatitis Sore tongue Pica (eating unusual substances like soil and ice) Plummer-Vinson syndrome (esophageal web, dysphagia + IDA) Diagnosis: Cfinical impression by the presence of signs, symptoms, and maybe the source of blood loss Hypochromic, microcytic anemia Blood film: o Poikilocytosis (Variable RBC shapes)o Anisocytosis (Variable RBC sizes) o Target cells Investigations for the cause:o Stool for occult bloodo Urinalysis for RBC in urineo Upper and lower endoscopy may be needed Low values High values Hemoglobin RDW MCV, MCH Transferrin level Serum ferritin and iron TIBC Transferrin saturation Table 101: Expected lab tests in IDA Page 1247 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Treatment: Treatment of the cause Iron replacement (oral is the first line, 1M, or IV) Blood transfusion may be needed for severe caseso HB less than 7 g/dl o HB less than 8 g/dl in a patient with Heart disease Iron needed = Body weight Hb) + 500 mg (for store) Anemia of chronic disease Present in chronic infections, chronic inflammations, and neoplasia (TB, Osteomyelitis, endocarditis, IBD, Chronic rend failure, SLE, RA, Malignancy) Usually Mild and asymptomatic (chronic process) Mostly associated with normal MCV (60-70%) but may present with low MCV (30-40%) (initially normal MCV then decreased) Pathophysiology of anemia of chronic disease: Decreased release of iron from Bone marrow to developing erythroblast Decreased erythropoietin production and response Decreased RBC survival (less than 120 days) Diagnosis: Signs and symptoms of anemia Signs and symptoms of chronic disease CBC: Normocytic anemia (maybe microcytic) Low serum Iron, Normal Ferritin level, and low TIBC Treatment: Treatment of the underlying cause Erythropoietin (EPO) injection Rarely need a Blood transfusion (usually mild anemia) EPO will not be effective if the serum ferritin is low and ferrous treatment will not beeffective if the serum ferritin is high or normal. The tar et Hb should not exceed 11 /d L. page1248 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Sideroblastic anemia In this type of anemia, Iron inside the cells is inadequately utilized to form normal hemoglobin levels Causes of sideroblastic anemia: Congenital sideroblastic anemia: X-Iinked or can be autosomal recessive Alcohol abuse B6 deficiency Lead toxicity Drugs (INH, phenacetin, chloramphenicol) MDs (the only type associated with high MCV) Myeloid Leukemias Pathogenesis: Normally heme is composed of Iron plus protoporphyrin A defect in protoporphyrin leads to Failure of iron utilization in Bone marrow (enzyme defect) Iron overload and accumulation of iron in mitochondria (Ring sideroblasts) Clinical features: Only symptoms of anemia with no specific other symptoms Suspect diagnosis when Microcytic anemia present but other causes of Microcytic anemia excluded Hepatosplenomegaly and signs of organ damage due to iron overload. Diagnosis: Microcytic anemia High iron and ferritin level Peripheral smear: basophilic stippling, target cells Prussian blue stain of bone marrow: iron granules around the nucleus (ring sideroblasts) (most accurate test) Genetic study Treatment: Anemia usually responds to pyridoxine (Vitamin B6)If there is severe anemia, provide a blood transfusion Iron chelating agent (deferoxamine)Forc acid can improve iron utilization If there is a secondary cause, stop the causative agent MDs usually do not respond to pyridoxine Page 1249 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Lead poisoning Lead poisoning is a known cause of sideroblastic anemia inwhich it inhibits the heme synthesis enzymes leading tomicrocytic anemia The classic presentation: Microcytic anemia Autonomic neuropathy Motor neuropathy Abdominal pain Diagnosis: History of exposure (occupational, living in old houses) The classic presentation (anemia, neuropathy, abdominal pain) Ferritin level is normal or high Blood film shows basophilic stippling Treatment: Treatment of anemia (may need PRBC transfusion) Edetate Di-sodium (Chelating agent) Aplastic anemia Pancytopenia in CBC Bone marrow will show Hypocellularity Causes: Congenital (Fanconi anemia) Primary aplastic anemia (autoimmune) — most common cause Secondary aplastic anemia: o Viral infection (parvovirus 59) o Toxic (drugs, chemicals) o Radiation o Pregnancy, SLE, PNH Clinical features: Signs and symptoms Anemia-low Hb Infection-low WBC Bleeding-Low PLT Treatment: Supportive Bone marrow transplantation if < 50 years Immunosuppressant if autoimmune (cyclosporine, anti-thymocyte globulin)p-åge1250 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Macrocytic anemias Introduction and causes Macrocytic anemia is anemia with high MCV > 100 fl It can be macrocytic megaloblastic or macrocytic non-megaloblastic Non-megaloblastic anemia Megaloblastic anemia B12 deficiency Alcohol excess Fofic acid deficiency Liver disease Methotrexate (anti-folate) Hypothyroidism MDs Facts about Cobalamin (vitamin B12): The liver stores B12 enough for 3 years (B12 deficiency takes years to manifest) Vegetarian or strict vegan persons are more prone to B12deficiency because it is present in animal sources. Absorption of vitamin B12 takes place by the intrinsic factor terminal ilium pathway or by the passive diffusion at higher doses. Pancreatic enzymes are needed to remove B12from R-protein so it can bind to the intrinsic factor. Parietal cells produce intrinsic factor (IF) that binds to the ingested in the stomach. When they reach the terminal ileum, B12 is absorbed there. Facts about Folic acid (Vitamin B'): Folate sources are leafy vegetables, liver, and kidney. Folate deficiency can be caused by psoriasis, skin loss, and turnover. Vitamin B12 Type Water soluble Source Animal source Daily requirements 1 microgram Table 102: Vitamins Folic acid (B') Water soluble Animal and plant 400 IU vs. folate Page 1251 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Meqaloblastic anemia It is an anemia characterized by megaloblasts (distinctivemorphologic appearances of the developing RBCs) in the It is caused mainly by either B120r folate deficiency The MCV in this condition will be high (>IOO fl) Etiology: Vegetarians and vegans have a high risk of B12 deficiency Pemicious anemia is a known cause of B12 deficiency Folate deficiency is the most common cause of anemia withmegaloblasts in chronic alcoholics Pemicious anemia is an autoimmune disease that leads togastric mucosal atrophy, failure of the intrinsic factorsecretion, and B12 malabsorption. Intrinsic factor antibodies in 50% or Anti-parietal cellantibodies can be detected It is associated with other autoimmune diseases Clke thyroid diseases, Addison's disease, and vitiligo Clinical features: Hematologic features: o Varying degrees of anemia with high MCV o Reduced platelet and WBC may present o High LDH and high bilirubin (due to intramedullary hemolysis) o Blood film will show oval macrocytes and hypersegmented Neutrophils (>6 lobes) o Bone marrow examination will show hypercellularity Neurological manifestations: o Gloves and stockings neuropathy o Subacute combined degeneration of the spinal cord and ataxia o Dementia o Optic atrophy Other blood tests: o Low serum B120r folate levels o High methylmalonic acid level (the most sensitive test for B12 deficiency) o High homocysteine and normal methylmalonic acid are associated with folate deficiency. page 1252 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Treatment: High dose oral B12 1000 — 2000 micrograms daily Intramuscular B12 indications: Severe anemia not responsive to oral treatment Neurological dysfunction not responsive to oral B12 Malabsorption syndromes For folic acid deficiency, oral folic acid of 1 —5 mg per day Notes: Replacement of folate and leads to Hypokalemia (due to rapid cell production) Replacement of folate in a patient with B12 deficiency before correcting 312 will aggravate neuropathy Schillinq test This test is used to differentiate the causes of B12 malabsorption All steps of the schilling test should be done after filling the B12binding sites by administration of 1000 mcg intramuscular B12 injection. The possible causes of B12 malabsorption: Pernicious anemia Ileal resection or ilea! disease Bacterial overgrowth Chronic pancreatitis Steps of schilling test: Step 1: radiolabeled B12 is administrated orally, and 24-h urine collection is done to check for radiolabeled B12 excretion Step 2: same as step 1, but now it is combined with intrinsic factor (IF) Step 3: same as step 1, but now it is combined with intrinsic factor (IF), pancreatic enzymes, and a 5-day course of antibiotics (often tetracycline) Page 1253 | INTERNAL1-17AFEEF-MERGED-1.pdf |
The Schilling test results interpretation: Pernicious anemia Chronic pancreatitis Bacterial overgrowth Radiolabeled With cobalamin intrinsic factor Low Normal Low Low Low Low Ileal disease Low Low With pancreatic enzymes Low Normal Low Low With 5-day antibiotic course Low Low Normal Low Table 103: schilling test interpretation (Low: < 3%, Normal: > 7%) Anemia of high RBC destruction Hemolytic anemia introduction It is defined as increased RBCs destruction that will lead tobone marrow hypercellularity and reticulocytosis Causes: Extravascular: RBC removed by liver and spleen prematurely Intravascular: RBC lysis in circulation Intravascular hemolysis Extravascular hemotysis Immediate transfusion reaction Delayed transfusion reaction G6PD deficiency Sickle cell anemia MAHA Thalassemia PNHHereditary spherocytosis Cold agglutinin AIHA Hemolytic disease of newbom DIC Warm autoimmune AIHA Table 104: Causes of Intravascular and Extravascular hemolysis page 1254 | INTERNAL1-17AFEEF-MERGED-1.pdf |
classifications according to the cause: Congenital defects in: o RBC membrane (Spherocytosis, Elliptocytosis) o RBC hemoglobin (thalassemia, sickle cell disease) o Enzymes (G6PD deficiency) Acquired: o Alloimmune: Hemolytic transfusion reaction o Autoimmune: cold and warm antibodies o Paroxysmal nocturnal hemoglobinuria (PNH) o Microangiopathic hemolytic anemia (MAHA) o Mechanical (prosthetic valve, burn) o Hypersplenism o March hemoglobinuria o Infections (malaria, sepsis) o Drugs and chemicals Clinical features: Features of anemia (fatigue, pallor, etc. ) Jaundice (high bilirubin from RBCs destruction) Red urine (from hemoglobinuria) Gall stones (manifest in chronic hemolysis) Diagnosis: CBC, blood film, bilirubin level, LDH, and coombs test shouldbe done when hemolytic anemia is suspected Fragmented RBCs may present in blood film Positive Coombs test in immune cases only. Elevated Reticulocytes LDH Indirect bilirubin Reduced Hemoglobin Serum haptoglobin RBCs survival Urinary urobilinogen and Hb Urine hemosiderin In hemolytic anemia, there is a slight increase in MCV since reticulocytes are larger than normal RBCs Table 105: Expected lab results in hemolytic anemia Page 1255 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Coombs test There are two types of Coombs test (Direct and indirect)Direct Coombs test detects antibodies bound to RBCs The indirect Coombs test detects the presence of Anti-RBCsantibodies in plasma Direct antiglobulin test (DAT): It will be positive in case of autoimmune Hemolytic anemia,transfusion reaction, and hemolytic disease of the newborn Blood sample mixed with antibodies to human globufin:o If agglutinated, Positive DAT (immune cause) o If no agglutinated, negative DAT (nonimmune cause)Indirect Antiglobulin Test (IAT): Stage l: Plasma mixed with RBCs with known antigen Stage 2: then mixed with antibodies to human globufin: o If agglutinated, Plasma contains RBCs antibodies o If no agglutinated, no RBCs antibodies in the plasma Hereditary Spherocytosis (HS) Autosomal dominant diseases The most common abnormality is a deficiency of membrane proteins (Beta-spectrin or ankyrin), leading to loss of RBCs elasticity and RBCs destruction when passing through the spleen. Clinical picture: Maybe asymptomatic compensated hemolytic anemia Recurrent episodes of hemolysis and intermittent jaundice A family history of anemia is usually present. 50% have gall-stones (which may lead to cholecystitis) Clinical course may be complicated by a crisis: o Hemolytic crisis (associated with infection) o Megatoblastic crisis (associated with folate o Aplastic crisis (associated with parvovirus B19 infection) e 1256 pa g | INTERNAL1-17AFEEF-MERGED-1.pdf |
Diagnosis:I-lb.. 6-10 g/d L (depends on the degree of compensation) Reticulocytosis (usually 6 — 20%) High indirect bilirubin and LDH Blood film: Spherocytes (small round hyperchromic RBCs without central pallor) Negative Coombs test The osmotic fragility test is no longer recommended flow cytometric EMA (eosin-5-maleimide) binding test (the most accurate test) The presence of positive family history, typical clinical features, spherocytes, high MCHC, and high reticulocytes do not require any additional tests. If the diagnosis is not certain, an EMA test should be done Treatment: Fofic acid supplement (5 mg/week for life) May need a transfusion in hemotytic crisis Screening for first-degree relatives Splenectomy in moderate to severe cases: 2 weeks before Splenectomy, the patient should receive: o Pneumococcal vaccine o Meningococcal C vaccine o H. influenza B vaccine o Then regular H. influenza and pneumococcal Hereditary Elliptocytosis It is an autosomal dominant disorder If is the same as spherocytosis, but blood film shows Elfiptocyte The disease is milder and usually requires no treatment. If more severe, treatment is the same as spherocytosis. Page 1257 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Hemoglobinopathies Thalassemia Syndromes It is a group of genetic disorders of globin chain production Abnormal hemoglobin leads to cell membrane damage anddecreased RBC survival Types of Hemoglobin: Adult Hb (Hb A): o Composed of 2 alpha and 2 ß chains o It has a good ability to carry oxygen and the beststability o By the 24th week of GA, Hb A constitutes 5% of Hb o At term, it becomes 30% of the total Hb o At 6th — 12th months of age, it rises to 98% Fetal Hb (Hb F): o Composed of 2 alpha and 2 gamma chains (major Hb in fetal life but adult comprises less than 1% of total o It has a better abifity to carry oxygen than Hb A bufis less stable. o After the 8th week, Hb F is the predominant hemoglobin o At birth, 70% of the hemoglobin's are Hb F o After 6— 12 months, only a trace is present Hb A2: composed of 2 alpha and 2 sigma chains (normally presents in about 1 —2% of total Hb) Hb S: Substitution of valine amino acid for glutamine amino acid in the 6th position of ß-chain of hemoglobin (sickle cell anemia) Types of thalassemia: ß-Thalassemia: reduced chains synthesis Alpha-Thalassemia: reduced Alpha chains synthesis ß-thalassemia It is the most common type of thalassemias due to a failure Of synthesis of ß chains In ß-Thalassemia, there is a decreased or absent Hb A, and an increase in Hb F and Hb A2 page 1258 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Types of P-thalassemia: Homozygote: p-Thalassemia Major (Cooley's anemia) o Inability to produce Hb A After 6 months of life, they develop profound anemia Heterozygote: ß-Thalassemia Minor (trait) o Reduced alpha chain production leads to reduced but not absent Hb A. o Usually, patients have asymptomatic mild microcytic hypochromic anemia, with little or no symptoms and normal ferritin level Features of Thalassemia major: Severe anemia requiring transfusion in the first year of life Recurrent infections Bone marrow hyperplasia causing bossing of the head and prominent malar eminence Splenomegaly (early), hepatomegaly (slow) Iron overload in a transfusion-dependent patient (usually after 20 units of blood transfusion)results in features of Hemochromatosis Investigations: CBC: Microcytic hypochromic anemia o Severe in thalassemia majoro Mild in thalassemia minor Peripheral blood film: o Hypochromic Microcytic anemiao Poikilocytosis (abnormally shaped RBCs)o Basophilic stippling Hb electrophoresis: (most accurate test)o Thalassemia minor (Hb A: 80-95%, Hb A2 4-8% and Hb F: 1-5%) o Thalassemia major (Hb A: 0%, Hb A2. 4-10%, and Hb F: 90-96%) Skull X-ray shows hair on end appearance. Page 1259 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Treatment: Thalassemia minor usually requires no treatment. Blood transfusion to keep Hb > 10 g/dl (some may needrepeated transfusion while Thalassemia minor may need no treatment) Chelating agent to prevent iron overload (start after bloodtransfusion of > 100ml/kg) Folic acid supplement 5mg daily is indicated Hydroxyurea: increases the production and concentration offetal hemoglobin (Hb F), which reduces transfusion requirements. A possibility of a cure in selected children using HSCT Alpha-Thalassemia Occurs due to reduction or absence of alpha chain synthesis Normally there are 4 alpha genes Pathology: I-alpha gene deletion: no clinical effect 2-alpha gene deletion: alpha thalassemia minor (trait) 3-alpha gene mutation: Hb H disease o Hb H is useless o There are moderate anemia and splenomegaly All the 4-alpha gene deletion: o Stillbirth at (28-40 weeks gestation, or die shortly after birth (They are pale, oedematous, Hydrops fetalis) Diagnosis: Genetic study (most accurate test) Alpha thalassemia minor (trait): o Mild Microcytic hypochromic anemia o Electrophoresis: Normal Hb A2 and Hb F and NO Hb H o It is a diagnosis of exclusion Hb H disease: o Microcytic hypochromic anemia of variable severity o Electrophoresis shows Hb H (10-40% of total Hb) Management: For alpha thalassemia trait, no treatment For Hb H disease: o Folic acid o Avoid oxidative drugs o Suppodive treatment if needed o Blood transfusion as needed page 1260 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Sickle cell anemia (SCA) SCA is usually well compensated with reticulocytes count that is always high More common in African American origin pathogenesis: SCA is an autosomal recessive disorder that leads to the substitution of valine amino acid for glutamine amino acid in the 6th position of the #hain of hemoglobin resulting in Hb S formation Hb S can crystallize if the patient has dehydration or infection, giving RBC a sickle shape. These RBCs are vulnerable to destruction anemia Bone marrow hypercellularity as compensation —+ bone marrow hyperplasia —+ Bone deformity (Skull bossing) The abnormal charge of these sickle cells leads to adherence to endothelium and vasoocclusion that may lead to splenic infarction (called autospienectomy) Clinical picture: Features of hemolytic anemia Gall stones due to chronically elevated bilirubin Recurrent infection: due to autosplenectomy (especially encapsulated organisms) Bone deformities (skull bossing) Tissue infarction due to Vaso-occlusion: o Chronic skin ulcers o Avascular necrosis of the femoral head o Renal impairment o Bfindness: due to retinal detachment or proliferative retinopathy o Stroke Acute crises: Hemolytic crisis Aplastic crisis (parvovirus B19 infection can precipitate that) Vaso-occlusive crises:o Bone pain, painful infarction of the spleen, strokeo Papillary necrosis and renal impairmento Mesenteric infarctiono Chest Pain (Bone involvement or pulmonary infarction) o Penile involvement (Priapism: persistent painful erection of the penis) Page 1261 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Diagnosis: Low hemoglobin (7-10 g/dl) High Reticulocytes count (USUal Iy 10-25%) High WBC and platelets High bilirubin Hb electrophoresis: (Hb S: 85-98%, Hb A: 0%, Hb F: variable)(most accurate test) Salmonella is the most common cause of osteomyelitis in SCApatients (as twice as staph aureus) Treatment: An allogenic Bone marrow transplant Hydroxyurea (Increase level of Hb F and Reduce frequency of painful crisis) Iron chelating agent to prevent iron overload Supportive treatment o Folic acid to prevent megaloblastic crisis o Treatment of infections to avoid crises o Avoid dehydration and hypoxia to avoid sequestration Management of crises: o Pain crisis: IV fluids, opioid analgesia, 02 therapy o Hemolytic crisis: Blood transfusion, supportive o Vaso-occlusive crisis: IV fluids, Analgesia, Exchange transfusion Siclde cell trait: Sickle cells < 40% in electrophoresis Asymptomatic, no treatment Genetic counseling is required page 1262 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Autoimmune hemolytic anemia (AIHA) RBCs Autoantibodies Divided into warm and cold types (according to which temperature the antibodies best cause hemolysis) Characterized by a positive DAT (Coomb's test) Causes of warm AIHA include: 50% are idiopathic, SLE, Neoplasia (lymphoma, CLL. lung cancer), Drugs (Quinidine, NSAl Ds, Methyldopa, Penicillin's, Cephalosporins, ciprofloxacin, Rifampicin, Phenytoin) Causes of cold AIHA include: Neoplasms (CLL Myeloma, Lymphoma, Waldenström macroglobulinemia), and Infections (Mycoplasma pneumonia, EBV, CMV, HIV, Hepatitis C malaria, E. coli) Antibody type temperature Hemolysis site Management Evan's syndrome:Warm AIHA lg G Room temp. Extravascular Steroids,Cold AIHA lg M Intravascular Avoid cold splenectomy, IVIG exposure Table 106: Warm vs. cold AIHA Itis an autoimmune thrombocytopenia present in 10% of patients with AIHA Page 1263 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Non-immune hemolytic anemia Parox smal nocturnal hemo lobinuria PNH Stem cell disorder that can progress to Aplastic anemia,Myelodysplasia, Or AML In acquired hemolysis (intravascular hemolysis), RBCs become sensitive to lysis by complement in acidosis. Deficiency of complement regulatory proteins CD55 and CD59During sleep, there is hypoventilation and mildly increased COZ which do not affect the normal population but causehemolysis in patients with PNH Clinical picture: Hemolysis and hemoglobinuria (may present in first-moming urine but can be in all urine samples in severe cases) Anemia (also IDA due to an iron loss in the urine) Patients are more prone to venous thromboembofism (thrombosis is the most common cause of death in PNH) Diagnosis: High urine hemosiderin IDA, pancytopenia Hypoplastic bone marrow Flow cytometry: absent CD55, CD59 (most accurate test) Treatment: Supportive (Iron replacement, folic acid replacement, blood transfusion as needed) Eculizumab (inhibits complement activation) BMT (the only way to cure) Microangiopathic hemolytic anemia (MAHA) It is defined as intravascular destruction of RBCs that leads to hemoglobinemia, hemoglobinuria, and schistocytes in blood film (fragmented RBCs) It can be caused by TTP, ITP, DIC, HUS, prosthetic heart valve, or vasculitis March hemoglobinuria: Damage of RBCs in feet, associated with prolonged marching or running page 1264 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Disorders of primary hemostasis Idiopathic thrombocytopenic purpura (ITP) Autoantibodies against platelets leading to platelet destruction, thrombocytopenia, and bleeding If platelets < 20,000 u/l, patients are at risk of spontaneous bleeding Typically preceded by a viral infection, especially in children Symptoms: Easy bruising, epistaxis, menorrhagia, petechial rash Look for a healthy person with isolated thrombocytopenia Diagnosis: ITP is a diagnosis of exclusion If the patient is elderly, think about B-cell malignancy and perform a bone marrow biopsy If connective tissue diseases are suspected, perform autoantibodies If Viral infection is suspected, hepatitis profile, HIV testing, CMV testing, etc. Treatment: If no bleeding and Platelet count > 30,000: No treatment Mild bleeding or platelet count < 30,000: Steroids Severe bleeding or platelet count < 10000: IVIG Recurrent episodes, steroid-dependent: splenectomy If splenectomy and steroids are not effective: rituximab, azathioprine, cyclosporine, mycophenolate Platelet transfusion is only indicated if there is life-threatening bleeding and the platelet count is less than 20*10A9/L/ Bleeding from platelet disorders is superficial in the form of epistaxis, gum bleeding, petechiat purpura, or vaginal bleeding Bleeding from clotting factors deficiency is usually deep in the form of hemarthrosis (bleeding in joints) or bleeding inside muscles. Brain hemorrhage and Gl bleeding can result from both platelet and factor disorders Despite that the platelet is destructed in the spleen by the macropha es, there is no splenomegaly in ITP patients Page 1265 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Thrombotic Thrombocytopenic Purpura (TTP) Both TTP and HUS are different versions of the same basicdisease (deficiency of metalloproteinase ADAMTS 13)Hemolytic Uremic Syndrome (HUS) is associated with E. coli0157:H7 (more frequent in children) Pathogenesis: TTP patient has an ADAMTS 13 (v WF-cleaving protease)deficiency TTP can occur in patients with cancer, transplant recipients,HIV, SLE, and those who receive quinine, clopidogrel, ticlopidine, or cyclosporine. Platelets and fibrin are deposited in the arteriolar walls,leading to the destruction of RBCs when passing through these arterioles (Microangiopathic hemolytic anemia-MAHA). Clinical presentation and diagnosis: Fever Neurological manifestations (headache, confusion, ataxia, seizures, and mental status and focal abnormaüties) Microangiopathic hemolytic anemia Fragmented RBCs (schistocytes) High reticulocytes and LDH levels Indirect hyperbilirubinemia Other features of intravascular hemolysis Coombs test is negative Thrombocytopenia Renal impairment Treatment: Immediate discontinuation of the causative drug. Emergency plasma exchange Platelet transfusion in TIP-HUS can exacerbate the microvascular occlusion. PT, a PTT, D-dimer, and fibrinogen levels are normal in TTP-page 1266 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Heparin-Induced Thrombocytopenia (HIT) It is a drop of platelet count 2 50% after starting heparin This condition is not dose-dependent (can OCCUr after administration of any amount of heparin) Both types of heparin can cause HIT syndrome, but in LMWH, it is less likely Clinical features: The onset is 5 15 days after starting heparin but can occur within hours if there was previous exposure. Thrombosis is the most common manifestation Venous thrombosis (3 times more common than arterial): DVT, PE, Cerebral sinus thrombosis... Arterial thrombosis: Ml, CVA, Acute limb ischemia, Organ infarction, Skin necrosis Diagnosis: Platelet factor 4 (PF4) antibodies Heparin-induced antiplatelet antibodies > 50% decrease in platelet after heparin administration Treatment: Stop heparin and use a direct thrombin inhibitor (such as argatroban or lepirudin) Because of 90% cross-reactivity, LMWH should not be substituted HIT type I Onset1 —4 days Pathogenesis Heparin-induced aggregation Thrombosis Not present Treatment No need to stop heparin HIT type Il 5— 15 days Antibodies to PF4 Present Mandatory to Stop heparin Table 107: Types of HIT syndrome Page 1267 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Von Willebrand disease (v WD) VWD is the most common inherited bleeding disorder It is an autosomal dominant disease Decreased level of functioning v WF Clinical picture: Bleeding tendency: easy bruising, epistaxis, menorrhagia, GIbleeding Family history of bleeding tendency v WF is a protein that has two functions: o Carrier for factor Vlll (if deficient v WF, factor Vlllwill be decreased) o Binding platelets to sub-endothelial collagen (primary hemostasis) The nature of bleeding due to v WF deficiency is sirrilar tobleeding from platelet disorders (superficial) Diagnosis: Symptoms and Family history suggestive of the disease High bleeding time (BT) Normal PT, normal platelet count High PTT in 50% of patients Low plasma factor Vlll LOW v WF Treatment: Mild bleeding: Tranexamic acid Desmopressin (DDAVP) increases the level of v WF Severe bleeding: Cryoprecipitate or Factor Vlll Page 1268 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Platelet dysfunction Uremia-induced platelet dysfunction: Uremia prevents the normal function of platelets Look for a patient with uremia and platelet type bleeding BT is prolonged, v WF is normal Treatment: DDAVP, dialysis, and estrogen The platelet dysfunction here is reversible by dialysis Aspirin and clopidogrel mediated platelet dysfunction: They permanently cause the platelet to lose their function The bleeding time will be elevated until the platelet is replaced by new ones Glanzmann's thrombasthenia: It is an autosomal recessive rare disorder leading to an absence of the platelet Gp Ilb/llla receptor (defective aggregation) The difference between ITP and Glanzmann's is that in ITP, there are antibodies against GP 11b/llla receptors Page 1269 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Disorders of secondary hemostasis Hemophilia An X-Iinkod rocossivo disease that has fwo types (almost oxclusivoly in malos) Typo A'. Factor Vill deficiency Typo B: Factor IX deficiency, also known as Chisfmas disease Clinical picture: Usually, diagnosis at fhe age of 6 months (pafienf becomes more mobile and susceptible fo injuies) Symptoms vary according to the seve(lfy of the disease Hemarfhrosis, muscle hematomas, prolonged bleeding The severity of hemophilia: Mild: factor level > 0. 05 — 0. 4 u/J Moderate: factor level 0. 01-0. 05 u/l Severe: factor level < 0. 01 U/l Diagnosis: Clinical picture and family History suggestive of hemophi6a Normal Bleeding time (Normal BT) Normal PT and High PTr Low factor VIJI or factor IX (most accurate fest) Normal v WF Treatment: Desmopressin (DDAVP) I. V or intranasal (For mild bleeding to cover minor surgeries)-(not effective in severe hemophilia A or B) I. V factor Vlll for severe bleeding (for hemophifia A) Factor IX concentrate (for hemophilia B) Anti-factor Vlll antibody can develop in 30% of cases; this wil make treatment ineffective (in this case, activated factor Vlj should be provided) page1210 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Disseminated intravascular coagulation (DIC) DIC is a consumptive coagulopathy that leads to thrombocytopenia, elevated PT and PTT, and schistocytes DIC never occurs in healthy people without risk factors Risk factors: Sepsis, malignancy, drug toxicity Burns, snake bites Cancer Obstetric problems (placental abruption, missed abortion, amniotic fluid embolism) Types: Chronic DIC: o It causes venous thromboembolic manifestations o PT, PTT may be normal or high (well-compensated) Acute DIC (Rapidly evolving): o Coagulation: Tissue factor released from destructed tissues causes widespread activation of coagulation o Bleeding: The consumption of the coagulation factors and platelets witl lead to Thrombocytopenia, elevated PT, PIT, and INR, and low fibrinogen o MAHA: Delayed dissolution of fibrin polymers by fibrinolysis may result in the mechanical disruption of RBCs, producing schistocytes. Investigations: Thrombocytopenia Prolonged PT. PTT, and INR Normal to Low fibrinogen (at least 50% reduction from the baseline) Elevated D-dimer (the most sensitive) Blood film: Schistocytes in 50% of cases. Treatment: Treatment of the underlying cause If there is no serious bleeding or thrombosis, no specific treatment Platelet transfusion to maintain platelet count > 50,000 FFP: to correct coagulation factors Cryoprecipitate: to maintain fibrinogen > 150 mg/dl (if FFP failed to control bleeding)Correct dehydration, Renal failure, Acidosis, and treat shock For slowly evolving chronic DIC, heparin is the choice Page 1271 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Hemophilia v WD ITP Warfarin Aspirin DICNormal Normal Normal High Normal Higha PTT High High Normal Normal Normal High Normal High High Normal High High Platelet Normal Normal Low Normal Normal Low Table 108: Interpretation of the blood test results Venous thromboembolism (VTE) Deep vein thrombosis (DVT) The lower limb is the most common site for DVT, but axillary DVT presents in 2 — 3% of cases The major concern about DVT is the risk of PE development The risk factors of DVT are the same as that of PE Virchow's Triad (Risk factors for DVT/PE): Venous stasis: (major surgery, prolonged travel, pregnancy, lower limb injury) Endothelial damage (i. e., trauma) Hypercoagulabifity state: 0 History of DVT/PE o Hormone replacement therapy (e. g., estrogen) o Malignancy (of any kind) o Nephrotic syndrome (due to antithrombin Ill loss) o Coagulopathies (e. g., factor V Leiden) Table 109: Virchow's triad (the risk factors for hypercoagulability) Clinical features: Some patients may be asymptomatic Pain, swelling, and erythema of the affected limb A palpable cord and low-grade fever (less common) Patient may present with complications page 1272 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Complications of DVT: Pulmonary embolism (the most important) phlegmasia alba dolens: severe arterial spasm due to massive iliofemoral DVT (pale, swollen limb with absent peripheral pulses) Phlegmasia cerula dolens: severe congestion and cyanosis due to a massive iliofemoral DVT (swollen blue limb with a high risk of gangrene) Venous gangrene Investigations: D-Dimer: high sensitivity, done for low probability cases Doppler UIS: accuracy is 80-85% Duplex scan: sensitivity and specificity are 90-100% Enhanced Helical CT scan: shows thrombus in small veins Ascending venography Normal veins Vein diameter Normal Blood flow Spontaneous Echogenic material None Distal compression Augments blood flow Blood flow Phasic flow DVT Dilated Poor Present Poor augmentation Loss of phasic flow Table 1 10: Difference between normal and thrombosed veins Treatment: DOAC (Apixaban or Rivaroxban): o It should be started once the diagnosis is suspected o The first-line treatment for patients who do not have contraindications o In the active malignancy patients, DOAC became preferred over LMWH Warfarin: o The second line treatment after DOAC o Used in severe renal impairment (GER < 15 m L/min) o Used as first-line if the patient has antiphospholipid syndrome. LMWH: o Used as a bridge for warfarin (to prevent skin necrosis) o Used as monotherapy for 6 months in malignancy or pregnant patients (second line after DOAC) Page 1273 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Inferior vena cava filter indications: o Contraindications to anticoagulants o Recurrent emboli while on adequate anticoagulationo Right ventricular heart failure Length of anticoagulation: 3 months: for provoked DVT/PE (known risk factor) 6 months: for unprovoked cases (unknown risk factor) 3 — 6 months: for people with active cancer Lifelong: for recurrent DVT/PE Pulmonary Embolism (PE) PE is an occlusion of the pulmonary artery or its branches byan embolus Clot migration from DVT site to lodge in the pulmonary artery Less than 30% have clinical evidence of DVT Clinical features: Symptoms: o Sudden dyspnea (the most common symptom) Pleuritic chest pain (the 2nd most common symptom) Lungs should be clear, and chest x-ray should be normal Signs: Tachypnea (most common sign) Pleural rub (the second most common sign) o Accentuated S2 Tachycardia, cough, and hemoptysis Signs of DVT are not always present Low Oxygen saturation /hypoxia Hypotension (a sign of massive PE) Diagnosis: Apply wells criteria: o Score > 4 (high probability): CTPA (Best investigation) o score 4(low probability): Perform D-dimer, then do CTPA (if positive) o If CTPA is contraindicated, VQ scan is the next step page 1214 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Well's Criteria for PE: 3Clinical signs and symptoms of DVT 3No alternative diagnosis 1. 5Heart rate > 100 bpm Immobilization 2 3 days or surgery in the past 4 weeks 1. 5 Previous DVT or PE 1. 5 Hemoptysis Malignancy Table I l: Well's Criteria, A scoring system for the diagnosis of PE Chest X-Ray The most common finding is a normal chest x-ray The most common abnormality is Atelectasis Wedge shape infarction, Pleural-based lesion (Hampton hump) Oligemia (Westermark sign) ECG o Sinus tachycardia (the most common) Nonspecific ST-T changes (2nd most common) Sl Q3T3 (The classic ECG changes in PE) Other changes include (RBBB, right ventricular strain, and Right axis deviation) Venous Doppler U/S for DVT detection ABCs: hypoxia with respiratory alkalosis. Treatment: Admission to hospital Thrombolysis is the first-line treatment for massive PE (hypotensive patients)The same treatment approach for DVT Treatment of complications (effusion, respiratory failure, etc. ) Page 1275 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Myeloproliferative disorders These are chronic conditions characterized by clonalproliferation of marrow precursor cells Most patients have one disorder, but these disorders canoverlap in one patient They include: Polycythemia Vera (PV) Myelofibrosis Essential thrombocythemia (ET) Chronic myeloid leukemia (CML) Polycythemia Rubra Vera (PV) Increase in bone marrow erythropoiesis despite low erythropoietin level It is a genetic problem caused by JAK2 mutation Usually, in the age above 40 years Clinical features: Maybe asymptomatic with an incidental finding of high Hb. Splenomegaly is common Symptoms of Hyperviscosity: o Headache, blurred vision, tinnitus, HTN o Dizziness o Pruritus, especially after a hot bath (histamine-mediated) Erythromelalgia (painful erythema on the hand refieved by aspirin) Diagnostic criteria: (ABC or ABD are diagnostic) Major criteria: (A) Hb > 16. 5 for males or > 16 form females (B) Hypercellular bone marrow on biopsy (C) Positive JAK2 mutation The minor criterion: (D) Subnormal Erythropoietin level Secondary polycythemia should always be excluded first page 1276 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Other laboratory findings: Low serum iron (iron consumption) High vitamin B12 level (unknown etiology) Platelets and WBCs may be elevated as wel Treatmen Y. Aspirin; to prevent peripheral arterial or cerebrovscu W diseases Venesection; to maintain Hb less than 15 g/dl, decrease symptoms of Hyperviscosity Hydroxyurea, interferon-alpha to suppress myeloprofiferation Radioactive phosphate for the older patient (decrease transformation to acute leukemias) Antihistamine (symptomatic treatment) Allopurinol (protect against high uric acid) Complications: In 25% of cases, this disorder can transform into acute leukemia or Myelofibrosis Peripheral arterial diseases or CVA's Venous thromboembo!isrn Peptic ulcer disease and upper Gl bleeding Myelofibrosis Bone marrow fibrosis, due to increased production of fibroblasts Usually, in patients > 50 years Clinical features: Weight loss. night sweat Hepatomegaly, Massive splenomegaly Features of anemia In myelofibrosis, hematopoiesis shifts to the spleen and liver that cause hepatosplenomegaly (it is called extramedullary erythropoiesis) Page 1277 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Lab tests: Pancytopenia (Platelets and WBC can be high early in thedisease) Teardrop poikilocytosis in blood film Bone marrow aspiration and biopsy (replacement of normaltissue with fibrous tissue) JAK-2 mutation Others: Folate deficiency, High uric acid level Treatment: Supportive: blood transfusion, folic acid Hydroxyurea: reduce splenomegaly and reduce WBC Splenectomy may be required (reduce the risk of splenic rupture) HSCT (definitive treatment) Essential thrombocythemia (ET) It is a myeloproliferative disease of the megakaryocytes in the bone marrow, leading to increased platelet production. It is more common in females aged 50 — 60 years Clinical picture: It can be an incidental finding in CBC (asymptomatic) Unusual site venous thrombosis (mesenteric, hepatic, or portal veins) Erythromelalgia may present Splenomegaly in 25% of cases Bleeding may present (abnormal quality of platelets) Diagnosis: CBC shows thrombocytosis Blood smear shows large size platelets Bone marrow: shows a large number of megakaryocytes Treatment: Hydroxyurea Aspirin Plateletpheresis in case of severe bleeding Reactive thrombocytosis: Platelets count is high but does not exceed 1,000,000, usually secondary to another disorder (e. g., RA, IBD, TB, or Vascufifis) Page 1278 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Malignant white cell disorders Acute leukemias It is a disorder in the hematopoietic tissue maturation leading to the accumulation of blast cells in the bone marrow and peripheral circulation. Heredity factors, radiation, chemicals, and drug exposures may be implicated in the development of leukemia. Classification: Acute leukemia is classified into myelogenous and lymphocytic types (refers to the type of blast that build up in bone marrow and blood) ALL is the most common in children, but AML is 8 times more common than ALL in adults Blast cells can be differentiated into: Lymphoblasts: are positive for Td T nuclear staining Myeloblasts: are positive for myeloperoxidase enzyme and Auer rods (a crystallized version of the enzyme) Clinical features: Bone pain Symptoms of pancytopenia (fatigue, bleeding, infection) Organ infiltration (hepatomegaly, splenomegaly, gum hypertrophy, L. N enlargement, etc. ) Diagnosis: Cytopenia on CBC and blast cells in peripheral smear Bone marrow examination showing blast cells of > 20% DIC workup (PT, PTT, D-dimer, fibrinogen) Tumor lysis workup (I-JA, LDH, potassium, Cr, Phosphorus, Calcium) Leukemoid reaction: This is not leukemia; in some infections, there will be a very high leukocyte count of> 40,000. It can be differentiated from leukemia by having a high LAP score (high leukocyte alkaline Phosphatase that is high in Leukemoid reaction and low in leukemia). Page 1279 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Blasts in circulation: usually give us a high leukocyte count, but notall leukemias have high leukocytes count. Subteukemic leukemia o Normal leukocyte count o High blood blast cells o High bone marrow blasts Aleukemic leukemia o Normal leukocyte count o No blood blast cells o High bone morrow blast Acute lymphoblastic leukemia (ALL) In 75% of cases, it is B-cell in origin Philadelphia chromosome t(9;22) is common and indicates a poor prognosis in ALL patients. Treatment: Intensive combination chemotherapy often followed by allogeneic HSCT Intrathecal chemotherapy with or without radiation for CNS prophylaxis Tyrosine kinase inhibitor dasatinib for Philadelphia-positive patients Acute myeloqenous leukemia (AML) It is more common than ALL in adults It is further classified into (MO to M7) Lymphadenopathy or hepatosplenomegaly indicates another diagnosis as they are rarely present in AML. Diagnosis: Bone marrow biopsy showing > 20% blast cells is diagnostic Auer rods may be seen on a peripheral blood smear Treatment: Platelet transfusion whenever platelet count < 10,000 Chemotherapy for non-promyelocytic leukemia Allogeneic and autologous HSCT page 120 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Acute Promyelocytic Leukemia (APML): It is the M3 subtype of AML It occurs due to t(15;17) mutation A high number of Auer rods and increased risk of coagulation; can present with DIC Treatment by vitamin A Chronic leukemias Chronic Myeloid Leukemia (CML) A myeloproliferative disorder resulting from malignant transformation of hematopoietic stem cells About 90% of CML patients have gene mutation t(9;22) called Philadelphia chromosome (it indicates a good prognosis in CML) Philadelphia chromosome leads to the production of BCR-ABL gene, which encodes for BCR-ABL protein with a tyrosine kinase activity responsible for abnormal cell differentiation. Clinical features: Chronic phase: o The patient will have non-specific symptoms like night sweating, weight loss, abdominal fullness (due to massive splenomegaly) o Can present as an incidental finding of high WBC count o Responsive to treatment and easily controlled Accelerated phase: o Fever, bone pain, splenomegaly o More difficult to control disease Blast crisis phase: o Transformation to acute leukemia o Present as bone marrow failure o Not responsive to treatment Diagnosis: Persistently high WBC: > 150,000 all are neutrophils in CML Usually, no anemia or thrombocytopenia at the presentation Bone marrow biopsy with cytogenetics and genetic study for Philadelphia chromosome are confirmatory tests. Page 1281 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Treatment: Hydroxyurea (alleviates leukocytosis and splenomegaly) Tyrosine kinase inhibitor (imatinib, dasatinib, or nilotinib) isused for disease control for lifelong treatment Allogenic HSCT for accelerated phase and blast crisis Causes of massive splenomegaly (> 1 kg): CML Myelofibrosis lymphoma Kala-azar (visceral leishmaniasis) Malaria (chronic) Gaucher's syndrome Table 1 12: Causes of massive splenomegaly Chronic lymphoblastic leukemia (CLL) CLL is the most common leukemia in adults Clinical features: Most patients diagnosed when having asymptomatic lymphocytosis Lymphadenopathy 80%, hepatosplenomegaly 50% Autoimmune hemolytic anemia (warm lg G antibodies) Anemia, thrombocytopenia, high WBC > 20,000 Diagnosis: High WBC count > 20,000 in CLL (predominantly lymphocytes) 50% of patients have hypogammaglobulinemia Smudge cells: lab artifact (the fragile nucleus is crushed by the coverslip) Bone marrow biopsy Rai staging system of CLL: Stage O: lymphocytosis alone Stage 1: lymphocytosis and lymphadenopathy Stage Il: lymphocytosis and hepatosplenomegaly Stage Ill: lymphocytosis and anemia Stage IV: lymphocytosis and thrombocytopenia page 1282 | INTERNAL1-17AFEEF-MERGED-1.pdf |
For stage O and stage 1, no treatment For stages Il, Ill, and IV, Chemotherapy (fludarabine) For refractory cases, cyclophospharride (more efficacy but more toxic) For severe infections, IVIG For autoimmune hemolytic anemia, prednisolone Supportive treatment BMT if the disease is not controlled *tier phenomenon: Conversion of CLL to high-grade lymphoma occurs in 5% of patients Myelodysplastic syndrome (MDs) A pre-leukemic disorder presents in older patients (> 60 years) Fall-re of maturation of blast cells and accumulation of blast cells in the bone marrow of less than 20% Can progress to AML, causing Pancytopenia (but usually death OCCUß due to infection or bleeding before transformation to leukemia) Caused by radiation, chemotherapy or can be a primary process Corßder a diagnosis of MDs in a patient with Macrocytic anerria and pancytopenia in a patient with normal B12 and Folate It is the only case in which sideroblasfic anemia presents with macrocytosis Prussian blue stain shows ring sideroblasts Page 1283 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Lymphomas It is a malignant tumor of lymphoid tissue, characterized by abnormal T and B cells proliferation They are most commonly B-cell in origin Classified according to biopsy findings into 2 types Types are: Hodgkin's lymphoma (HL) Non-Hodgkin's lymphoma (NHL) Non-Hodqkin's lymphoma (NHL) B cell origin in 70% and T cell in 30% There will be a proliferation of lymphocytes in lymph nodesand spleen Usually widespread at presentation and can affect any lymphoid tissue (e. g., Tonsils, Adenoid, Gut, Nasopharyngealglands, Skin) NHL and CLL are similar, but NHL is solid mass while CLL is circulating in the blood. Clinical features: Painless L. N enlargement It may involve pelvic, retroperitoneal, or mesenteric structures B symptoms Tiredness, weight loss, fever Lower limb weakness: metastasis to extradural space compressing the spinal cord Bone pain Types according to the rate of cell division: Low grade (incurable with conventional therapy) Intermediate grade High grade (curable with conventional therapy) page 1284 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Ann-Arbor staging of lymphoma: Four major stages: l: single lymph node (LN) Il: 2 LN/regions on the same side of the diaphragm Ill: involvement is at both sides of the diaphragm IV: widespread disease Each stage may be subdivided Into A or B: A: No systemic symptoms other than pruritus B: A presence of B symptoms Table 13: Ann-Arbor staging of lymphoma Diagnosis: Excisional L. N biopsy (best initial test) CBC is normal in most cases LDH (if high indicates worse severity) Bone marrow biopsy, Abdominal, chest, and pelvic CT (for staging) Treatment: For stages la and lla, local radiation with a small dose of chemotherapy For stage Ill or IV or the presence of B symptoms: rituximab and CHOP (Cyclophosphamide, Hydroxydaunorubicin, Oncovin (vincristine), Prednisolone) Hodgkin's lymphoma (HL) Same as NHL in presentation, diagnosis, B symptoms, and staging Associated with biopsy finding of large binucleated cells of B cell origin called Reed Sternberg cells. Maybe Associated with a previous infection with infectious mononucleosis B cell in origin Occur usually at age 20 —35, a second peak at 50— 70 years Subtypes: Nodular sclerosing (NSCHL) (Most common type) Lymphocyte predominant (the best prognosis) Mixed cellularity (good prognosis, associated with a large number of Reed Sternberg cells) Lymph Ocyte depleted (the worst prognosis) Page 1285 | INTERNAL1-17AFEEF-MERGED-1.pdf |
Treatment: For stages la and lla, local radiation with a small dose ofchemotherapy For stage Ill or IV or the presence of B symptoms, ABVD(Adriamycin (doxorubicin), Bleomycin, Mnblastine, Dacarbazine) Relapse after radiotherapy is treated by chemotherapy, but relapse after chemotherapy is treated with extra high dose chemotherapy and BMT Presenting stage Usual site Reed-Sternberg cells E*ra-nodal disease Best prognosis Worst prognosis Hodgldn stage I or Il (80%) Cervical area Present Less common Lymphocyte predominant Lymphocyte depleted Non-Hodgkin stage Ill or IV in (80%) Disseminated Not present More common Low-grade type High-grade type Table 1 14: Hodgkin vs. Non-Hodgkin lymphoma The drug Doxorubicin Bleomycin Vincristine Cyclophosphamide Table 1 15: Common side effect Cardiomyopathy Lung fibrosis Neuropathy Hemorrhagic cystitis effects of the lymphomas drugs pa-ge128b | INTERNAL1-17AFEEF-MERGED-1.pdf |
Burkitt's lymphoma It is a high-grade B cell lymphoma It is associated with the c-myc gene translocation t(8: 14). Microscopy finding is starry sky appearance The Epstein-Barr virus (EBV) is strongly implicated in the development of the African type of Burkitt's lymphoma and, to a lesser extent, the sporadic type Types: Sporadic type: abdominal (e. g., ileocecal) tumors are the most common (more common in HIV patients) Endemic (African) type: typically involves maxilla or mandible Treatment: Chemotherapy: tends to produce a rapid response which may cause tumor lysis syndrome. Tumor lysis syndrome (TLS) is a side effect of chemotherapy due to the rapid destruction of a large number of cells Features of TLS include: hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and acute renal failure TLS should be treated by IV fluids, Mannitol, urinary alkalization, and correct electrolytes. Mutation The associated disease Philadelphia chromosome (CML and ALL) Acute promyelocytic leukemia C-myc gene in Burkitt's lymphoma to 4; 18) Follicular lymphoma Table 1 16: Common gene translocations in hematology Page 1287 | INTERNAL1-17AFEEF-MERGED-1.pdf |