PATH POST MT11

Autosplenectomy

prone to infections by encapsulated bacteria, such as Hemophilus influenzae and Streptococcus

β+ Thalassemia

reduced β chains produced (mutations in promotor region of gene -- transcription defect)

Spherocytosis

(autosomal dominant) form of spherocytosis, an auto-hemolytic anemia characterized by the production of red blood cells that are sphere-shaped rather than bi-concave disk shaped (donut-shaped), and therefore more prone to hemolysis. *Howell-Jolly bodies* may be seen within red blood cells. molecular defects in the genes that code for spectrin (alpha and beta), *ankyrin* (most common) or band 3 protein

*Diffuse/signet ring type* gastric adenocarcinoma

->*No gland* formation, ->single cells/sheets/clusters -> signet ring cells, ->*no intestinal metaplasia*, ->*E-cadherin* implicated - *CDH1 MUTATION* -> more common in *familial types* with ->*young female* predominance -> *linitis plastica* appearance (infiltrative) DOESN'T FORM GLANDS (VS INTESTINAL TYPE)

HPylori associated atrophy

->*antral predominant*, ->patchy, ->multifocal, ->normal serum gastrin, ->no ECL cell hyperplasia (Enterochromaffin-like), ->generally not anemic, ->no increase in carcinoid tumors

B- Thalassemias

*Diminished synthesis of structurally normal β- globin chains*, with *unimpaired α-chain production*. • β+ Thalassemia: reduced β chains produced (mutations in promotor region of gene)

B- Thalassemias

*Hypochromic microcytic anemia.* • Reduced survival of RBCs & RBC precursors, due to cell membrane damage by precipitated α chains. 75% of precursor RBC normoblasts die in the hyperplastic bone marrow (ineffective erythropoiesis). • Extramedullary hematopoiesis, if severe (endometrial polyp - RBC synthesis outside medullary bone) • Excessive absorption of dietary iron. *Secondary Hemochromatosis*

Hemolytic Anemia (usually acquired - most common immune mediated) *extrinsic RBC defect*

*Immune mediated* - autoimmune, drugs *Nonimmune* - mechanical trauma, infections, chemicals Sequestration - due to hypersplenism

Thalassemia Syndromes -disorder of genetic LESIONS

*Low levels of normal Hb ( hypochromic, microcytic RBCs).* • Relative excess of the unimpaired chain aggregates insoluble inclusions leading to extravascular hemolysis (spleen, BM).

Diagnosis of H pylori

*endoscopy based invasive tests* -> rapid urease test (positive = red), -> histopathology culture ~*silver stain* ~ seen in mucous layer of stomach ->PCR; *Non invasive tests* -> urea breath test, -> serology (IgG, IgA), ->PCR in saliva and feces

Chronic gastritis pathology

*endoscopy* -> patchy/diffuse erythema -> +/- hemorrhage -> to boggy appearing mucosa with thick mucosal folds; *Microscopy* -> inflammatory infiltrate ~lymphocytes, ~plasma cells in lamina propria), ->PMNs in surface epithelium and glandular lumen (activity), -> lymphoid aggregates (marker for H. pylori infection), ->intestinal metaplasia and ->glandular atrophy

Hemolytic Anemia *Intrinsic RBC Defect* -generally hereditary

*membrane defect* = Hereditary Spherocytosis (auto dom North Europe) *enzyme defect* = G6PD + PNH (GPI def) *Hemoglobin defect* = Sickle Cell, Thalessemaia

Pappenheimer bodies

- Aggregate in small cluster near periphery - Stain with Prussian blue

Heinz bodies

- Composed of denatured hemoglobin - Precipitate on RBC membrane - Well stained with supravital stains found in G-6-PD deficiency Stain: brilliant cresyl fast violet

Howell jolly bodies

- Post-splenectomy - Hemolytic anemia - Megaloblastic anemia

Stages of erythropoiesis

- Proeryhthroblast - Basophilic normoblast - Polychromatic normoblast (Hb appears) - Orthochromatic normoblast - Reticulocyte - Erythrocyte

Peptic ulcer disease CHRONIC DEEP

-> 50% < 2 cm, -> round to oval, -> punched out with relatively straight walls -> sharp raised margins but not everted, -> depth varies but may penetrate entire wall -> smooth clean base, -> radiating surrounding mucosal folds

Etiopathogenesis of peptic ulcer disease

-> H pylori (70% of gastric and 90% of duodenal ulcers), ->*NSAIDS* (inhibit prostaglandin synthesis), -> smoking (impairs mucosal blood flow), ->alcohol, ->psychological stress, ->ZE syndrome - Zollinger Ellison syndrome (multiple ulcers)

Acute gastritis

-> acute often *transient inflammation *of the mucosa -> NSAIDS, ->excessive alcohol consumption, ->heavy smoking, ->ischemia and shock, ->severe stress (burns, surgery), ->cancer chemotherapy, ->systemic infections, ->uremia -> may be asymptomatic, ->may have epigastric pain, ->nausea, ->vomiting, ->hematemesis and melena (if capillaries are exposed), ->bleeding can be fatal

Early gastric adenocarcinoma

-> confined to mucosa and submucosa, -> regardless of involvement of regional lymph nodes -> better prognosis because depth is not as extensive

Acute erosive gastritis

-> loss of surface epithelium -> erosions along with hemorrhage -> hyperemia, punctate areas of hemorrhage -> edema and congestion of lamina propria, ->neutrophils in the surface epithelium and lumina of the glands

Chronic gastritis NON EROSIVE

-> mucosal inflammatory changes leading eventually to *mucosal atrophy and/or epithelial metaplasia* Etiology: ~most common is chronic infection with *H. pylori* (95%), ~autoimmune (atrophic), PERNICIOUS ANEMIA ~alcohol and smoking; less common causes are: ~post surgical after antrectomy, ~radiation, ~granulomatous conditions (Crohn's, sarcoidosis) -> asymptomatic -> nausea, vomiting, ->epigastric discomfort, ->dyspepsia and ->indigestion -> DIFFUSE ATROPHY OF GLANDS IN LP- SEE LESS GLAND CELLS -> GET LYMPHOID FOLLICLES

Peptic ulcer disease CHRONIC DEEP

-> often solitary lesions -> occur in any part of the GIT exposed to aggressive action of gastric acid peptic juices ~duodenum, ~stomach, ~gastro-esophageal junction, ~margins of gastrojejunostomy, ~Meckel's diverticulum, ->stomach/duodenum/jejunum in Zollinger Ellison syndrome

Mechanism of duodenal ulcers

->H.pylori causes duodenitis and gastric metaplasia, ->gastritis (which increases cytokines to cause duodenitis and gastric metaplasia), ->*increased post-prandial gastrin* -> and *reduced somatostatin* ~which increases basal gastric acid secretion ~ leads to hyperacidity of duodenal bulb ~ causes duodenitis and gastric metaplasia ->and increased basal gastric acid secretion (via histamine metabolites) ~ leads to hyperacidity of duodenal bulb ~ causes duodenitis ~ and gastric metaplasia

B- Thalassemia

->Note that the hallmark of the disease, aggregates of unpaired a-globin chains, are not visible in routinely stained blood smears. ->Blood transfusions are a double-edged sword ~diminishing the anemia and its attendant complications, ~but also adding to the systemic iron overload.

Look for elevated serum gastrin levels (autoimmune gastritis)

->Young female, ->Sjogren syndrome, ->epigastric pain, ->nausea, ->weakness and easy fatigue -> anemia with high MCV of RBCs -> atrophic gastric mucosa seen on endoscopy -> what test to use?

Autoimmune gastritis

->auto-antibodies against *parietal cells* and/or intrinsic factor (IF) -> causes gland destruction, ->ECL hyperplasia [Enterochromaffin-like] (due to increased gastrin), -> pyloric metaplasia - GET GOBLET CELLS IN BODY AND FUNDUS (USUALLY ONLY AT ANTRUM AND CARDIA) -> leads to *GASTRIC atrophy* -> causes loss of acid production (achlorhydria) ->and loss of intrinsic factor ~vitamin B12 deficiency ~pernicious anemia -> *increased gastrin levels* (antrum not inhibited by acid) -> endoscopic biopsy, ->INCREASED risk of *gastric carcinoma*, ->AND *carcinoid tumors* (from ECL hyperplasia) PARIETAL CELLS ONLY IN *BODY AND FUNDUS* (ANTRUM HAS G CELLS - H.PYLORI GASTRITIS HERE)

Peptic ulcers - complications

->bleeding, ->perforation, ->gastric outlet obstruction, ->malignant transformation (unknown in duodenal and exceedingly rare in gastric -> possibly malignant initially rather than transformation) USUALLY BENIGN STAYS BENIGN

Peptic ulcers - clinical

->burning epigastric pain 1-3 hours after meals, ->relieved by food and alkali -> worse at night, -> associated weight loss, -> gastric outlet obstruction

Pyloric stenosis

->can be *congenital* ~most common in *first male child*, ~*M*: F is 3:1 ~ concentric hypertrophy THICKENING of circular muscle coat -> or *acquired* ~chronic antral gastritis, ~peptic ulcers, ~malignancy -> get regurgitation, ->projectile vomiting, ->and palpable epigastric mass, ->visible peristalsis -> treated by surgery (myotomy)

Acute gastric ulcers

->can present with massive upper GI bleed, ->usually multiple circular and small -> asymptomatic, -> 5-10% of patients admitted in ICU -> gastric rugae are normal, -> base is not indurated -> *adjacent gastric mucosa normal* SO NOT MALIGNANT

H. Pylori

->gram negative curvilinear, motile (flagella), ->non-invasive and urease positive bacillus -> associated with 2 patterns of gastritis -> predominant* antral* inflammation ->and *multifocal* leading to multifocal gastric atrophy -> other diseases assist ~peptic ulcers, ~gastric CA, ~gastric lymphoma)

H Pylori

->has enzymes ~proteases, ~ureases and ~phospholipases) that cause damage to mucosa; ->attracts PMNs and other inflammatory cells ->that also cause damage to mucosa ->and uncontrolled proliferation of B cells ->leading to lymphoma; ->damage to mucosa leads to chronic gastritis and peptic ulcers

*Intestinal type* gastric adenocarcinoma

->in setting of *chronic gastritis*, ->*neoplastic glands resemble intestinal epithelium* (colon), ->associated with H pylori, ->intestinal metaplasia is precursor lesion -> more common in high risk populations DOES FORM GLANDS (VS DIFFUSE TYPE)

Gastric ulcers

->loss of mucosa that extends through muscularis mucosae or deeper -> healing time greater than with erosions -> commonly gastric and duodenal -> peptic type is caused by exposure to aggressive action of acidic peptic juices -> chronic and often *solitary lesions*

Gastrointestinal stromal tumor (GIST)

->mesenchymal tumor derived from *cells of Cajal* - GUT PACEMAKER CELLS (pacemaker of the GI system) -> anywhere in GIT -> can be benign or malignant (based on size and mitoses) -> usually *submucosal* -> *whorls* and *bundles of spindle shaped cells* -> *C-kit (CD-117)* is the tumor marker (stains around myenteric plexus) -> use *GLEEVEC/Imatinib Mesylate* to treat FLESHY FIRM APPEARING

Gastric adenocarcinoma -> clinical

->mostly asymptomatic in early stages, ->non-specific symptoms first ~weight loss, ~anorexia, ~abdominal pain), ->pyloric obstruction, ->Krukenberg tumor, ->*Virchow's LN*, ->prognosis depends on depth of invasion and nodal status

Gastric adenocarcinoma

->pylorus/antrum 50-60%, ->cardia 25%, INCREASING HERE ->body and fundus less common -> can be exophytic, flat or excavated -> can spread ~regionally, ~trancelomic (UMBILICAL) = SISTER MARY JOSEPH LYMPH NODE, ~lymphatic, ~*hematogenous* EXCEPTION

Microcytic Hypochromic cells

-Iron deficiency anemia - Thalassemia -Anemia of chronic disorder -Sideroblastic anemia

Natural Selection of Sickle Cell

10% of black Americans are heterozygotes. (Natural selection occurred in W. Africa, where 10-30% of people are heterozygous, because HbS has had a protective effect against severe falciparum malaria infection).

Beta Globin Genes

2 on Chromosome 11

Alpha Globin Genes

4 on Chromosome 16

Peptic ulcer disease CHRONIC DEEP

4 zones 1) necrotic fibrinoid debris in middle 2) non-specific inflammatory infiltrate (predominantly Neutrophilic), 3) granulation tissue, 4) fibrosis and collagenous scar -> typically GET features of chronic gastritis in adjacent mucosa BENIGN STAYS BENIGN

G6PD Deficiency: Pathophysiology

Abnormal enzyme variants misfolded, thus susceptible to proteolytic degradation. Since mature RBCs have no nucleus and do not form new proteins, enzyme activities fall rapidly as RBCs age (half-life of G6PD A- is moderately reduced, that of G6PD Mediterranean is severely reduced). As a result, older RBCs are not protected against oxidant stresses

a1-antitrypsin gene

Chromosome 14

Sickle Cell Disease

Clinical findings, including family history. Peripheral blood smear - sickled cells. Laboratory tests for sickled hemoglobin: • Mixing blood with an oxygen-consuming agent (e.g. metabisulfite) induces sickling. • Hemoglobin electrophoresis. • Prenatal diagnosis - DNA screening.

Sickle Cell Disease: Pathogenesis

Deoxygenated HbS molecules aggregate and polymerize. Further deoxygenation results in formation of long needle-like structures that produce sickling. Sickling is initially reversible, but with repeated episodes, membrane damage leads to irreversible sickling, and RBC "stickiness" (thus prone to small vessel thrombosis)

Bone Marrow in Hemolytic Anemia

Erythroid hyperplasia

Normal erythropoiesis

Erythroid precursors mature through various stages of nucleated cells (normoblasts), lose their nucleus, then are released into the circulation as reticulocytes (5 - 7 days) -Reticulocytes give rise to mature RBCs (1-2 days) - Depends upon erythropoietin (EPO) - Average life span of RBCs - 120 days

β-Thalassemia Major: Clinicopathological Features

Expansion of hematopoietic marrow prominent facial bones, erosion of bony cortex and new bone formation. • Huge spleen & liver (due to extravascular hemolysis & extramedullary hematopoiesis) • Hemosiderosis and 2º hemochromatosis, due to iron overload (affects heart, liver, pancreas).

Anisocytosis with macrocytosis -

Folate or vitamin B12 defeciency, autoimmune hemolytic anemia, cytotoxic chemotherapy, Chronic liver disease, Myelodysplastic syndrome

Intrinsic RBC defect leading to Hemolytic Anemia *Enzyme defect*

G-6-PD deficiency, *Paroxysmal nocturnal hemoglobinuria (PNH)*

While not clinically significant the most common G6PD

G6PD*B*

Sickling in Sickle Cell

HbA & HbF ↓sickling; HbC ↑sickling Dehydration ↑ sickling Coexisting α-thalassemia ↓sickling (less globin, therefore less Hemoglobin present). lower pH and low O2 tension ↑sickling. Hyperbilirubinemia (jaundice), *gallstones*

Intrinsic Hemolytic Anemia due to hemoglobin defects

Hemoglobinopathies RBC diseases mostly characterized by *mutations in globin genes* leading to defective hemoglobins -Sickle Cell Disease -Hb C disease

Intrinsic RBC Defect leading to hemolytic Anemia *membrane defect*

Hereditary spherocytosis.

Sickle Cell Disease

Homozygotes have almost 100% HbS, referred to as SS. Heterozygotes (Sickle cell trait) have about 40% HbS, referred to as AS.

Extrinsic RBC Defect leading to Hemolytic Anemia *Sequestration*

Hypersplenism

B-Thalassemia Major Syndrome

Mediterranean, parts of Africa, S.E. Asia, and immigrants from these areas. *Presents 6-9 months after birth, when HbF naturally starts to fall* * Hb levels = 3-6 g/dl.* • HbF remains elevated, and may become the major Hb in these individuals. HbA2 may be normal, low or high.

Clinical features of Hereditary Spherocytosis

Most commonly mild to moderate chronic hemolytic anemia (25% are asymptomatic, and a minority are severely affected from birth). • Intercurrent infections can induce aplastic or hemolytic crises. *Treatment: Splenectomy - anemia corrects, spherocytosis persists*

Normocytic RBC

Normal diameter is about 7.2 μm - Size is comparable to nucleus of a mature lymphocyte - Central pallor around one third (Normochromic

Lab findings in Hemolytic Anemia

Polychromatophilia, increased retics, erythroid hyperplasia, increase in unconjugated bilirubin seen in both intravascular and extravascular intravascular--higher plasma hemoglobin, higher LDH (variable), hemosiderin seen in urine, sometimes hemoglobin seen in urine

Intrinsic Hemolytic Anemia due to Thalssemia Syndromes

RBC disease caused by *lesions in globin genes* leading to decreased synthesis of globin chains of HbA

G6PD

Recessive X-linked -in males *Acute Hemolysis* 2-3 days after exposure to oxidant stress like infections, sulfa drugs, fava beans *Neonatal Jaundice*

Intrinsic RBC defect leading to Hemolytic Anemia *Hemoglobin defect*

Sickle cell disease, Thalassemias.

Normal Peripheral Blood Smear

Stained with Wright Giemsa stain

Sickle Cell Treatment

Support measures for crises -analgesics, rehydration, exchange transfusions. • Folic acid supplementation. • Penicillin prophylaxis. • Hydroxyurea: increases amount of HbF in RBCs inhibits polymerization of HbS. • Bone marrow transplantation.

Intravascular Hemolysis

Urine: Hemosiderinuria, +/- Hemoglobinuria. (Due to using up all Haptoglobin)

Poikilocytosis

Variation in shape of RBCs

Anisocytosis

Variation in size of RBCs

Sickle Cell Outcome

With SS (homozygous) disease, 90% survive to age 20, and about 50% survive to age 50. *Infection is the major cause of death in children <5 years.* • *Acute chest syndrome, stroke and kidney damage are very serious vaso-occlusive complications*, especially if recurrent. Adults → organ failure (kidney).

Sickle Cell Crises Aplastic crises

acute viral infection, due to parvovirus B19 (infects red cell precursors).

Basophilic stippling

aggregation of ribosomes - Lead poisoning, - Thalassemia - Megaloblastic anemia

*haptoglobin*

an α2-globulin that binds free hemoglobin and prevents its excretion in the urine but produces a complex that is rapidly cleared by mononuclear phagocytes (catabolized to bilirubin -->jaundice) -decreased in small amounts in extravascular hemolysis, large amounts in intravascular hemolysis -When depleted, free hemoglobin oxidizes to methemoglobin, which is brown in color. The renal proximal tubular cells reabsorb and catabolize much of the filtered hemoglobin and methemoglobin, but some passes out in the urine, imparting a red-brown color.

Extrinsic RBC Defect leading to Hemolytic Anemia *immune mediated*

autoimmune, drugs.

Howell- Jolly Bodies

basophilic nuclear remnants (clusters of DNA) in circulating erythrocytes -- normally pitted out by the spleen during erythrocyte circulation, but will persist in individuals with functional hyposplenia or asplenia.

Acute gastric ulcers

caused by ->severe trauma, ->major surgeries, ->extensive burns (*Curling ulcers*), ->head injuries and other intracranial lesions (*Cushing ulcers*) -> pathogenesis is related to systemic acidosis and hypoxia (severe trauma and burns) ->OR vagal stimulation (intra cranial lesions)

intravascular hemolysis

complement fixation, intracellular parasites (falciparum malaria), or exogenous toxic factors (clostridium perfingens sepsis), or mechanical injury. Causes of mechanical injury include trauma caused by cardiac valves, thrombotic narrowing of the microcirculation, or repetitive physical trauma (e.g., marathon running and bongo drum beating). *Hemoglobinema, hemoglobinuria, hemosiderinuria, jaundice but Spenomegaly generally not seen!*

hemosiderosis

due to phagocytosis of RBCS most pronounced in the spleen, liver, and bone marrow

chronic hemolysis, elevated biliary excretion of bilirubin leads to...

formation of pigment gallstones (cholelithiasis)

Schistocytes

fragmented RBCs - from damaged RBCs Seen in -Microangiopathic hemolytic anemia (MAHA) - DIC - Thrombotic thrombocytopenic purpura -Hemolytic uremic syndrome -Prosthetic heart valves

Gastric adenocarcinoma

highest occurrence in Japan and South Korea -> decreasing occurrence in most places -> unfavorable prognosis, ->2 subtypes ~*intestinal* and ~*diffuse/signet ring* type

Nucleated red blood cells (NRBCs, normoblasts)

immature red blood cells. - indicate markedly accelerated erythropoiesis and/or severe bone marrow stress. - Seen in acute bleeding, severe hemolysis myelofibrosis, leukemia

Sickle Cell Crises Vaso-occlusive/ painful crises

ischemic events, infections, due to microvascular occlusions - in bones, lungs, brain, retina, kidneys (kids/young adults), leg ulcers (adults).

Sickle Cell Crises Sequestration crises

kids/young adults, rapid pooling of blood in the spleen.

Macrocytes

large red blood cells (> 8.5 mm) with an elevated MCV (> 100) - Important causes include: o Vitamin B12 or folic acid deficiency o Liver diseases o Alcoholism o Myeloproliferative disorders o Myelodysplastic disorders

Peripheral blood smear of Hemolytic Anemia

macrocytic anemia with polychromasia, due to increased reticulocytes In intravascular hemolysis only: • Urine: Hemosiderinuria, +/- Hemoglobinuria.

Extrinsic RBC Defect leading to Hemolytic Anemia *nonimmune mediated*

mechanical trauma, infections,

β-Thalassemia minor/trait (β+/β or β°/β)

mild asymptomatic anemia.

β-Thalassemia intermedia

milder variants of B- thal major severe variants of B- thal minor or B-thal major combined the a-thal

β° Thalassemia

no β chains, in homozygote (mutations in splicing or chain termination translation defect).

Sickle Cell Disease

point mutation atposition 6 in the β globin gene --> glutamic acid replaced by valine, in the translated region of the β globin chain --> HbS.

Supravital staining

reveals Heinz bodies in G6PD def

β-Thalassemia major (β+/β+, β+/β°, β°/β°) notice no normal B

severe transfusion-dependant anemia.

Spherocytes

small (less than 6.5um) dense spheroidal RBCs with normal or decreased MCV and absent central pallor. *increased mean corpuscular hemoglobin concentration* (MCHC) *a measure of the concentration of hemoglobin in a given volume of packed red blood cells* Seen in: -Hereditary spherocytosis - Autoimmune hemolytic anemia -Burns

G6PD

when RBCs are exposed to oxidants ->they oxidate the SH groups on globin chains ->causing preciptation of denatured globins on the RBC membrane ->leading to *HEINZ BODIES* if less severe = Hemolysis spleen macrophages form ->*bite cells and ->spherocytes* ->which are later removed by spleen

Glucose-6-Phosphate Dehydrogenase Deficiency

• Abnormality in the Hexose Monophosphate Shunt (Glutathione metabolism) due to impaired enzyme function, leaves *RBCs prone to oxidative injuries* -cannot form NADPH G6PD A- (American Blacks) G6PD Mediterranean (middle eastern) -due to natural selection from malaria

Sickle Cell kids

• Hyperplastic BM skull bone changes • Hypersplenism - repeated infarction and fibrosis autosplenectomy (by early adulthood)

Diagnosis of Spherocytosis

• ↑ MCHC in most patients. • Osmotic Fragility Test: In 65% HS patients, RBCs lyse prematurely (compared to normal RBCs), when exposed to increasingly hypotonic salt solutions due to shape not allowing for expansion *use family history + hemolytic evidence + peripheral blood findings

Plasma/serum in hemolytic anemia

↑ Bilirubin (unconjugated), free hemoglobin (more so in intravascular hemolysis), ↑ LDH, ↓ or absent Haptoglobin.