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Autoimmune hepatitisDiagnosis: piecemeal necrosis on liver biopsy, also correlate with serology Treatment: steroids +/- azathioprine, cyclosporine, tacrolimus, MMF, liver transplant Type 1 “classic” autoimmune hepatitis – ANA, ASMA, AMA (rarely) Type 2 –LKM-1, ASMA (occasional), Type 3 – generally seronegative, ASMA (occasional), AMA (rarely) Type 4 (PBC) – ANA, ASMA, AMA (rarely) Primary biliary cirrhosis (PBC) autoimmune destruction of small intrahepatic bile ducts / females 35-60 / cholestasis late / Presentation: usu. begins with pruritis Labs: high AMA (>1:40), elevated alkaline phosphatase (2-5x ↑) Diagnosis: liver biopsy shows lymphocytic destruction of bile ducts Associations: ⅔ have Sjogren’s / 20% have CREST / 17% with autoimmune thyroiditis / can get various lung disease (IPF, granulomatous, lymphocytic interstitial pneumonitis, pulmonary HTN, pulmonary hemorrhage) Secondary biliary cirrhosis obstruction / edema, inflammation / portal tract lesions, but hepatocytes intact AMA (-), lower alkaline phosphatase Sclerosing Cholangitis Primary: 5% of ulcerative colitis Secondary: many causes / in AIDS pts – CMV, cryptosporidium, PCP, MAI (some)
men (70%), 75% of PSC and cholangiocarcinoma occur in IBD patients (UC >> Crohn’s) / 3 per 100,000 (1:100 as much as alcoholic cirrhosis) / 4th leading indications for liver transplant Mechanisms (speculated): chronic portal bacteria, toxic bacterial metabolites of bile, ischemic damage, genetic/immunological Location: mostly intra/extrahepatic ducts (15% with gall bladder/cystic duct too) Presentation: asymptomatic until obstructive liver disease signs develop, episodes of acute bacterial cholangitis (fever, chills, lab abnormalities) / steatorrhea, vitamin A deficiency Course: may evolve over many years / mean age at diagnosis 40 yrs, survival 12 yrs from diagnosis Labs: hypergammaglobulinemia in 30% (elevated IgM 50%), pANCA (65%), ASMA (10%), ANA (20%), elevated obstructive liver enzymes, elevated urinary copper and serum ceruloplasmin Ulcerative Colitis: more with early age onset of UC / may precede symptoms of UC by many years (diagnosed with ERCP) / some say some degree of UC exists in all PSC / PSC does not correlate with activity of UC Other associations: thyroiditis, type I DM Complications: liver failure, cholangiocarcinoma (20% of PSC patients, even 20 yrs after colectomy, smoking and presence of IBD increases risk), vitamin K deficiency (rare, but happens with chronic jaundice, cholestyramine use), vitamin D deficiency (osteoporosis) Diagnosis: ERCP (fine ulcerations, dilatation, narrowing) with cholangiogram [pic] [pic] / transhepatic cholangiogram is the 2nd choice / percutaneous liver biopsy will probably miss lesions (concentric fibrosis around bile ducts) but can be used to follow disease Ddx: stricture/obstruction from previous surgery, cholangitis, bile duct neoplasms, choledocholithiasis, congenital biliary tree abnormalities Treatment: ursodiol is of debatable utility, steroids are not helpful (other immunosuppressives under investigation), ERCP may diagnose and treat complications, liver transplant only proven cure (cholangiocarcinoma is relative contraindication to transplant); may experience sclerosing cholangitis (recurrence vs. rejection vs. bacteria from roux-en-Y) Pruritis: cholestyramine, colestipol binds bile acids / naloxone (elevated endogenous opiates implicated) / ursodiol, odansetron, m-testosterone, rifampin, phenobarbital, antihistamines, UV light, plasmapheresis Recurrent cholangitis: optimal antibiotic choice and use of preventative abx under investigation Alpha-1-antitrypsin (see lungs) cholestatic liver disease in infancy, cirrhosis and/or portal hypertension / chronic liver disease / MM normal / ZZ abnormal Hemochromatosis [NEJM] Primary: inherited disorder / 5-10% frequency of gene in population [most common mutation can be tested, small minority have other mutations] / AR / most are homozygote for the C282Y mutation of the HFE gene increased iron absorption, progressive iron overload Pathology: increased Fe uptake (normal 3 g, increased to 20-40 g) / women lose 20-30 mg at menses / hemosiderin deposition (causes direct damage to liver, pancreas) Secondary: increased absorption (chronic liver disease, iron-loading anemias, porphyria cutanea tarda, dietary overload) or parenteral administration (multiple blood transfusions) of iron / secondary has much less total iron build-up (ferritin) Presentation: often diagnosed early with fatigue, arthralgias (25-50%) or increased AST/ALT’s or fatigue, arthralgias (frequent), skin pigmentation (90%, gray or bronze color), liver disease (RUQ pain, hepatomegaly, cirrhosis, HCC), and diabetes Complications: micronodular cirrhosis, diabetes, skin pigmentation, restrictive cardiac failure, arthritis (may have CPPD, often 2nd and 3rd MCP (1st most-asked pimp question in history of mankind), impotence / 200 x risk of HCC (30% incidence) Labs: ferritin increased (proportional to iron burden), transferrin increased (Fe %sat) Diagnosis: liver biopsy can be useful to quantify iron overload and assess liver fibrosis (can also use genetic testing to risk stratify patients for development of fibrosis/cirrhosis (look for presence of the C282Y or H63D mutation) Ddx: can have falsely high ferritin levels from other diseases Treatment: phlebotomy, deferoxamine Course: life expectancy goes to normal if treated before cirrhosis Wilson’s disease AR mutation in ATP7B gene / onset in 10s to 20s Mechanism: abnormal copper transport causes increased GI absorption and decreased clearance
2-5 months after travel to endemic area / occurs in 3-25% of intestinal amebiasis (especially with HIV) /most common presentation: RUQ abdominal pain Diagnosis: positive antibodies in 98% of cases (indirect hemagglutinin test) / ultrasound 75-85% sensitivity Treatment: metronidazole usually works +/- chloroquine, but drain if rupture is imminent Parasitic: echinococcus Diagnosis: U/S or CT (90% sensitive and direct aspiration may seed peritoneum), eosinophilia, positive heme agglutination Treatment: open resection (do not spill), instillation ethanol or 20% NaCl Liver Neoplasia 5% of liver tumors are benign Hemangioma most common benign liver tumor / incidence of 7% of population / usually clinically unimportant but can cause consumptive coagulopathy Presentation: pain (can rupture), jaundice (can obstruct) Diagnosis: do NOT biopsy (risk of bleeding) / peripheral enhancement on CT, arteriography Focal Nodular Hyperplasia central stellate scar / unencapsulated, but well-defined / central blood supply, not likely to rupture / 2 cells thick / females 2:1 / not related to OCPs / any age / 20% symptomatic from mass effects / not precursor to HCC
1 per million / risk factors: females, reproductive years, birth control pills (40 x risk) Pathology: peripheral blood supply, may rupture (1/4 present with circulatory collapse) causing necrosis (increased ALT and CT findings) / portal tracts absent
very common worldwide / 3 per 100,000 in US (and rising) / males > female / 95% liver tumors are malignant Risk Factors: HBV, HCV (major cause in US), alcoholic cirrhosis, hemochromatosis, smoking?, vinyl chloride, OCPs Pathology: large mass with satellite lesions / may be green with bile / 50% with mets to regional nodes, lung Presentation: weight loss, RUQ, shoulder pain, weakness Physical Signs: hepatomegaly, portal hypertension, ascites, jaundice (50%) Diagnosis: often positive AFP (elevated in germ cell tumors; >500 suggestive, >1000 almost diagnostic) Ultrasound: cystic v. solid / radiography: benign v. malignant / CT or MRI: multiplicity and anatomical / hepatic arteriography to diagnose hemangioma Treatment: wedge resection (often difficult due to underlying liver disease) / entire lobectomy does not improve survival transplant can be curative in selected patients (must have single lesion < 5 cm or 3 or fewer < 3 cm) Prognosis: no treatment 3 month survival / with resection 3 yr survival / 5 yr survival rate is 10-50% / with successful transplant survival same as nonmalignant liver transplant patient Liver metastases most common malignant liver tumor / one source colon > stomach > pancreas > breast > lung / another source lung > colon > pancreas > breast > stomach Treatment: liver mets from colon cancer (up to 3 lesions) should be resected (some say 4-5) Liver Transplant [NEJM] Child-Pugh rating system: must have >= 7 to qualify for liver transplant / get points for INR, low albumin, ascites, hepatic encephalopathy Must demonstrate (in rehab) no alcohol/drugs for 6 months Malignancy develops in 2%-7% of transplant recipients (from immunosuppression) (100 fold > than normal) / transitional cell Ca of UG tract and renal cell Ca, skin and lips, lymphomas (esp. CNS), cervical, lung, head and neck, colon / onset time 1-158 months (avg. 40) / lymphomas develop faster Hematology [onc] [transfusion medicine] Anemia (work up) [Ddx] hemolytic anemia, HELLP, aplastic anemia Hemoglobinopathy sickle cell, thalassemia Thrombocytopenia [Ddx] HIT, TTP, ITP, APA Coagulation Bleeding disorders Hemophilia, Von Willebrand’s Hypercoagulability APA, factor V, G20210 Thromboembolic DIC, HELLP, TTP, HUS, HSP Leukemia Lymphoblastic ALL, AML, CLL, Hairy Cell Myeloproliferative CML, myelofibrosis, thrombocythemia, PRV, leukemoid reaction Plasma cell dyscrasias MM, WM, heavy chain disease, benign monoclonal gammopathy Histiocytoses Lymphoma Hodgkin’s NHL B-cell small lymphocytic, cleaved cell, diffuse large cell, Burkitt’s T-cell adult T-cell, lymphoblastic, Sezary Basic Principles Clotting Cascade [diagram][diagram] [hematology lab slides] Hb conc. in whole blood RBC count hematocrit Male 14-18 g/dL male 4.7-6.1 e6/ul male .42 - .52 Female 12-16g/dL female 4.2-5.4 e6/ul female .37 - .47
hematocrit/RBC count (use fudge factor) normal 80-94 fL (normocytic may include high degree of variation - anisocytosis) false elevation with cold agglutinins Mean corpuscular Hb Hb/RBC count (fudge factor) MCHC Hb/hematocrit (normo, hyper or hypochromic) Neutrophils Dohle bodies (vague, blue cytoplasmic inclusions) blacks may have lower low end (1160 vs. 1700)
plasma cells, endothelial cells, histiocytes, nucleated RBC’s, myeloblasts Anemia [causes of anemia] Hb < 12 Hb < 15 in neonate Hct < 37 Hct is 50 in neonate, then drops to 30 and gradually increases to puberty levels Physiology anemia in tissue produces more 2,3-DPG, shifts Hb curve to the right redistribution of blood flow away from kidneys and skin increased cardiac output (in severe anemia) physiologic anemia in young infant – 2o shift in oxygen dissociation curve
clinical signs of acute anemia: syncope, orthostatic hypotension, orthostatic tachycardia very acute hemorrhage normal Hct and Hb (corrects with fluid intake) clinical signs of ongoing anemia: tachycardia, pallor (conjunctiva, lips, oral mucosal, nail beds [pic], palmar creases), jaundice, petechiae, purpura (TTP), glossitis (pernicious anemia, iron deficiency), systolic ejection murmur, S3, splenomegaly (hemolysis, neoplasia, infiltration), LAD Anemia Work-Up Consider: age, sex, color, ethnic, neonatal, nutrition/diet, drugs, diarrhea, inflammation, infection, pica, prosthetic valves, guaiac status, Initial workup: reticulocyte count iron studies (TIBC, ferritin, %sat) haptoglobin, LDH, direct/indirect Bilirubin serum or RBC folate, B12 More workup: peripheral smear, Coomb’s, Hgb electrophoresis, bone marrow Classification of Anemia Normochromic, Normocytic Marrow hypoplasia (drugs, radiation) Aplastic anemia Marrow infiltration (myeloma, lymphoma, leukemia) Myelofibrosis Renal insufficiency Hemolytic anemia Acute hemorrhage Anemia chronic disease
Sideroblastic anemia (lead, INH, EtOH, congenital) Anemia of chronic disease (?rarely)
Folate, Vitamin B12 Drugs (AZT, TMP, pentamidine, phenytoin, primidone, phenobarbital [mild], chronic nitrous oxide) Myelodysplasia Liver disease
reticulocytes live about 1-1.5 days then circulate 120 days absolute reticulocyte count (normal 50-70,000/mm3)
reticulocyte x [patient’s Hct / normal Hct] x [1/RBC maturation time] <1 % is inadequate production, > 4% RBC destruction corrected reticulocyte count accounts for any anemia Peripheral Smear Cell Types Spherocytes hereditary/secondary (autoimmune-mediated hemolysis) Tear drop cells (extramedullary hematopoeisis) myeloproliferative disease (e.g. myelofibrosis), pernicious anemia, thalassemia Helmet cells – microangiopathic hemolysis, severe iron deficiency Schistocytes – microangiopathic hemolysis [pic] Sickle cell – HbSS Findings Hypochromic – lead, iron deficiency Hyperchromic – B12, Folate, spherocytosis Basophilic stippling – lead, hemolysis, thalassemia Pappenheimer bodies – postsplenectomy, hemolytic, sideroblastic, megaloblastic Rouleaux formation – multiple myeloma, Waldenstrom’s, other conditions Parasites – Malaria, Babesiosis Nucleated RBC’s – extramedullary hematopoeisis, hypoxia, hemolysis Target cells – hemoglobinopathies, iron deficiency, liver disease Heinz bodies (denatured Hgb) (requires supravital stain) unstable hemoglobinopathies, some hemolytic anemias Howell-Jolly Bodies (nuclear fragments) - hemolytic, megaloblastic, asplenia Cabot ring (nuclear remnants) – megaloblastic
myeloid/erythroid or M:E ratio / hyporegenerative, aplastic anemia / diagnosis of leukemia aspirate Wright smear / more painful core biopsy stained biopsy (and aspirate clot) for neoplasm, granuloma Dx Ineffective Hematopoeisis Causes: metabolic deficiency, primary stem cell defect (e.g. MDS), abnormal bone marrow microenvironment (autoimmune, infections—HIV, Tb, histoplasmosis) Pathology: hypercellular marrow with thrombocytopenia, anemia, low reticulocyte count
There is no excretory pathway for iron (only through skin and GI loss) menstruating women may lose 7 mg/day (30 mg/month) vs. 1 mg/day other males/females Fe2+ absorbed in duodenum (1-2 mg of 15 mg total intake), transferrin takes Fe3+ in cell and blood, stored as ferritin (Fe3+/apoprotein) in equilibrium between blood and marrow histiocytes hemosiderin in histiocytes in erythron (iron > apoprotein) Iron deficiency anemia (IDA) [NEJM] Epidemiology: black females have slightly decreased Hgb in general / women > 50 (2%), < 50 (5%), men (~1%) Causes: Blood loss (GI bleeds): ulcer, cancer, angiodysplasia, IBD, hookworm Uterine blood loss: menstruation, fibroids Malabsorption: gastrectomy, celiac disease, IBD Intake problem: bovine milk-fed infants (not enough Fe), pregnancy, vegetarian diet Clinical: fatigue, shortness of breath, may have cravings for dirt or paint (pica) or ice (pagophagia), glossitis, cheilosis, koilonychias / rare/advanced cases: postcricoid esophageal web (Plummer-Vinson syndrome) Labs: TIBC and FEP increase, decreased Fe saturation (<10%) decreases may precede other findings / low RPI, increased TIBC (transferrin), decreased ferritin, absent iron stores in marrow, increased protoporphyrin and zinc-protoporphyrin / may have elevated RPI and thrombocytosis due to bleeding (caused by iron deficiency) Peripheral smear: hypochromic, microcytic [pic] / anisocytosis, poikilocytosis when severe Note: peripheral smear may distinguish from thalassemia minor / RDW > 15 supports Fe deficiency (because marrow is producing a lot of erythrocytes; lower RDW suggests stable thalassemia) 2-3 months minimum age of onset Treatment: oral ferrous sulfate / parenteral iron (use cautiously because of increased risk of anaphylaxis) / transfusion (see other) Anemia of chronic disease (new term is anemia of chronic inflammation) inflammatory cytokines (hepatic synthesis of hepcidin) decreased RBC lifespan, impaired iron metabolism (including absorption), refractoriness to erythropoietin / slightly decreased MCHC / normo/macrocytic Labs: decreased TIBC and Fe saturation (10-20%) but increased ferritin (usually) and Fe in macrophages [note: ACD may co-exist with IDA and make these labs difficult to interpret]
Lead (Pb), alcohol, INH toxicity / congenital form (sex-linked) Labs: increased Fe, increased Fe saturation, increased ferritin
Other: precursor to leukemia, autoimmune (SLE, RA), thymoma, lymphoma, hereditary, pregnancy Labs: giant pronormoblasts on peripheral smear, ↑ erythropoietin
Labs: BUN > 36, Cr 3-5, Hg may be < 7 / Fe labs are normal (may become Fe deficient following hemodialysis losses) Exceptions: HUS (increased erythropoiesis), polycystic (normal erythropoiesis), diabetes mellitus (decreased erythropoiesis relative to state of renal failure)
problems making DNA, so precursors get held up in marrow, macrocytic Folate made into THF by DHF reductase / FIGlu (histidine metabolite) is a marker for folate deficiency / malnourished, milk-fed, pregnant, drugs (phenytoin, isoniazid, phenobarbital, primidone, cycloserine) B12 Molecular: important in reversing the “folate trap” / methylmalonic acid is a urine marker for folate deficiency (folate helps metabolize odd-chain fatty acids) Diagnosis: > 2 hypersegmented PMNs/HPF [pic], macrocytic anemia, decreased WBC, decreased platelets / direct B12 / Schilling test (not needed now) / consider doing one EGD to r/o adenocarcinoma Presentation: you can have CNS Sx without hematological findings Causes: pernicious anemia (see below) dietary deficiency - only in vegans because body stores last several years malabsorption – IF not produced by parietal cells (gastrectomy) terminal ileum lesions - Crohn’s, celiac disease, etc. bacterial overgrowth or D. latum (fish tapeworm) Pernicious anemia [NEJM] B12 deficiency / Ab to IF or gastric mucosa (anti-parietal Ab positive in 90%) / young blacks, old whites / 20-30% with family history disease Presentation: jaundice (hemolysis), cheilitis, glossitis (burning tongue, atrophy of papillae, deep/red mucosa, cobblestone appearance) Neuropathy – paresthesias, weakness (demyelination in posterior columns) CNS: “megaloblastic madness” - constellation of symptoms Associations (autoimmune): vitiligo, thyroid Treatment: 1 mg SC x 3 d and check reticulocyte count Pediatric Anemias birth – 12 months Blackfan-Diamond Syndrome 12 mo – 5 yrs transient erythroblastopenia of childhood (TEC) follows viral infection, like childhood ITP, usually self-limited any age transient erythroid aplasia in hemolytic disease follows viral infection, exacerbates underlying hemolytic disease late childhood – on pure red cell aplasia Blackfan-Diamond Syndrome congenital macrocytic anemia due to (lack erythropoietin receptors?) / presents within months of birth / associated with Turner’s and thumb abnormalities / may see urinary, cardiac, skeletal anomalies / Treatment: corticosteroids may help Transient Erythroblastopenia of Childhood (TEC) normocytic / 6 months – 4 yrs / usually only one episode per life / may require transfusion Hemolytic anemia Dx RPI to establish bone marrow response / look for erythrocyte detritus / increased unconjugated bilirubin, increased urobilinogen in urine (dark urine), free serum decreased haptoglobin / can measure haptoglobin, free serum Hb, urine Hb, hemopexin, methemalbumin / Note: haptoglobin, serum and urine Hb not as altered with extravascular hemolysis Mechanical Intravascular artificial heart valves, DIC, TTP, malignant HTN (microangiopathic) produces hemosiderin in urine, Hb in serum/urine, and schistocytes (broken cells)
RES enlargement produces spherocytes/chopped cells (could be considered immune-mediated by macrophages eating RBCs) Autoimmune mechanisms Warm agglutinins (occurs at any temperature) IgG against certain universal Rh component (more extravascular, i.e. RES plucks RBC’s out of circulation, gives spherocytes, not schistocytes) [pic] may be drug-induced (methyldopa), autoimmune (SLE et al) or alloimmune (erythroblastosis fetalis, transfusion reaction) Treatment: remove offending agent and/or steroids / also consider cyclophosphamide, azathioprine, danazol, IVIG, rituximab) / splenectomy in refractory cases Cold agglutinins IgM against I antigen on RBC / paroxysmal cold hemoglobinuria - anti-P antigen Causes: Mycoplasma pneumoniae and (rarely) EBV Labs: same as other hemolytic anemias (↓ haptoglobin, ↑ MCV, erythroid hyperplasia) Treatment: steroids, splenectomy, replacement, other? Infectious C. perfringens sepsis (and other GP/GN sepsis), malaria (and other protozoa), Bartonella, Tb (local and disseminated), Borrelia, Leptospirosis, malaria, mumps Chemical Agents, Drugs, and Venoms Oxidant Drugs and Chemicals Oxygen (high pressure) / Vitamin E deficiency in infants
Dapsone and phenazopyridine (Pyridium) also are associated with Heinz body hemolysis triamterene, methyldopa, rifampin Nonoxidant Mechanisms PTU arsine (metal industry, transistor, gold refining) – give exchange transfusions Trimellitic Anhydride (plastic industry) lead
copper (see Wilson’s disease) Water (drowning with entry of > 0.6 L) Hemodialysis (contaminants) Other Agents Venoms
Physical Agents Thermal Injury, ionizing irradiation (debatable)
NADPH from hexose monophosphate shunt (first step is G-6-PD) neonatal hemolysis and jaundice only in premature infants / also less severe in blacks because young RBC’s have more enzyme function and are not susceptible to drug-induced attacks, so the hematocrit does not fall as much Causes (of acute attacks): Drugs: many antibiotics (sulfamethoxazole, nitrofurantoin), anti-malarials, phenacetin, vitamin K, seizure meds, chemotherapy agents, HIV meds infection favism (severe Mediterranean variant) due to fava beans Labs: Heinz bodies / can have false negative G6PD levels during crisis (because decreased levels occur in older RBCs, not new ones being produced) Diagnosis: measure decreased levels of GPI anchors or GPI-linked surface proteins CD55 or CD59 Treatment: usually self-limited once offending agent removed Pyruvate kinase deficiency autosomal recessive / RBCs have impaired glycolysis, reduced ATP, and lyse Download 3.95 Mb. Share with your friends:
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