Pathogenesis of type II DM.

(1) insulin resistance and

(2) β-cell dysfunction: inadequate insulin secretion in the face of insulin resistance and hyperglycemia

Sedentary lifestyle, obesity and insulin resistance

Among identical twins, the concordance rate is 50% to 90%, showing some genetic component also.

Loss-of-function abnormalities of either the insulin receptor or its down-stream signaling molecules cause insulin resistance

β cell dysfunction

hyperinsulinemic state is a compensation for peripheral resistance and can often maintain normal plasma glucose for years, but after some years the β cells are overwhelmed and can no longer secrete adequate insulin

adverse effects of high circulating FFAs ("lipotoxicity") or chronic hyperglycemia ("glucotoxicity") on β cells

decrease in β-cell mass, islet degeneration, and deposition of islet amyloid.

Pathogenesis of type I DM.

chronic autoimmune attack on β cells

manifestations of the disease (hyperglycemia and ketosis) occur late in its course, after more than 90% of the β cells have been destroyed

T lymphocytes react against β-cell antigens and cause cell damage: include CD4+ TH1 subset, which activates macrophages, and CD8+ cytotoxic T lymphocytes, which directly kill β cells

cellular necrosis and lymphocytic infiltration. This lesion is called insulitis

IFN-γ, produced by T cells, and tumor necrosis factor and interleukin-1

Autoantibodies against a variety of β-cell antigens, including insulin and glutamic acid decarboxylase( GAD) can be found

Associated with HLA-DR3, or DR4 type of MHC II antigens

some viral antigens are antigenically similar to β cell antigens (molecular minicry),

Classification of Diabetes Mellitus.

Type 1 diabetes (β-cell destruction): Immune-mediated, Idiopathic

Type 2 diabetes (insulin resistance with relative insulin deficiency)

Maturity-onset diabetes of the young (MODY), caused by mutations in:

Hepatocyte nuclear factor (MODY1)

Glucokinase (MODY2)

Genetic defects in insulin processing or insulin action

Defects in proinsulin conversion

Insulin gene mutations

Insulin receptor mutations

Exocrine pancreatic defects

Chronic pancreatitis

Pancreatectomy

Neoplasia

Cystic fibrosis

Hemachromatosis

Endocrinopathies

Acromegaly

Cushing syndrome

Hyperthyroidism

Pheochromocytoma

Glucagonoma

Infections

Cytomegalovirus

Coxsackie virus B

Drugs: Glucocorticoids, Thyroid hormone, Protease inhibitors, b-adrenergic agonists, Thiazides, Nicotinic acid, Phenytoin

Genetic syndromes associated with diabetes

Down syndrome

Kleinfelter syndrome

Turner syndrome

Gestational diabetes mellitus.

Dx of DM:(diagnosis of Diabetes Mellitus)

A random blood glucose concentration of 200 mg/dL or higher, with classical signs and symptoms

A fasting glucose concentration of 126 mg/dL or higher on more than one occasion, or

An abnormal oral glucose tolerance test (OGTT), in which the glucose concentration is 200 mg/dL or higher 2 hours after a standard carbohydrate load (75 gm of glucose.

Pt with impaired glucose tolerance have a significant risk of progressing to overt diabetes.

Comparison of Type 1 DM and Type 2 DM

Secretory Diarrhea.

Infectious: viral damage to mucosal epithelium

Rotavirus

Caliciviruses

Enteric adenoviruses

Astroviruses

Infectious: enterotoxin mediated

Vibrio cholerae

Escherichia coli

Bacillus cereus

Clostridium perfringens

Infectious: damage to mucosal epithelium

Shigella

Salmonella

Campylobacter

Entamoeba histolytica

Neoplastic

Tumor elaboration of peptides, serotonin, prostaglandins

Villous adenoma in distal colon (nonhormone mediated)

Excess laxative use.

Etiological classification of Diarrhea.

Malabsorption

Defective intraluminal digestion

Primary mucosal cell abnormalities

Reduced small intestinal surface area

Lymphatic obstruction

Infectious: impaired mucosal cell absorption, eg Giardia

Decreased intestinal transit time

Surgical reduction of gut length

Neural dysfunction, including irritable bowel syndrome

Hyperthyroidism

Diabetic neuropathy

Carcinoid syndrome

Decreased motility (increased intestinal transit time)

Small intestinal diverticula

Surgical creation of a "blind" intestinal loop

Bacterial overgrowth in the small intestine

Osmotic Diarrhea.

Disaccharidase (lactase) deficiencies

Lactulose therapy (for hepatic encephalopathy, constipation)

Prescribed gut lavage for diagnostic procedures

Antacids (MgSO4 and other magnesium salts)

Primary bile acid malabsorption

Exudative Diseases

Idiopathic inflammatory bowel disease.

Typhlitis (neutropenic colitis in the immunosuppressed).

Diseases of the Intestine.

Hernia - Inguinal

Hernia - Opened.

Intestinal Obstruction:

Intussusception:

Volvulus:

Diverticula:

Comparison between Crohn Disease and Ulcerative Colitis.

Ulcerative colitis.

limited to the mucosa and submucosa

begins in the rectum and extends proximally in a continuous fashion

migratory polyarthritis, sacroiliitis, ankylosing spondylitis, uveitis, erythema nodosum, and hepatic involvement (pericholangitis and primary sclerosing cholangitis

Differences from Crohn’s disease

Well-formed granulomas are absent.

There are no skip lesions.

The mucosal ulcers rarely extend below the submucosa.

Mural thickening does not occur

high risk of carcinoma development

Morphology of UC:

rectum and sigmoid are invariably involved and may involve the entire colon-pancolitis

hyperemia, edema, and granularity with friability and easy bleeding

islands of regenerating mucosa bulge upward to create pseudopolyps

pericolonic abscess formation

Exposure of the muscularis propria and neural plexus to fecal material also may lead to complete shutdown of neuromuscular function-toxic megacolon

M/E

A diffuse, predominantly mononuclear inflammatory infiltrate in the lamina propria

crypt abscesses due to neutrophils

In late stages, granulation tissue fills in the ulcer craters, followed by regeneration of the mucosal epithelium

Submucosal fibrosis and mucosal architectural disarray and atrophy remain

Clinical features and complications:

mucoid diarrhea that may persist for days, weeks, or months and then subside, only to recur

Complications

severe diarrhea and electrolyte derangements

massive hemorrhage

severe colonic dilation (toxic megacolon) with potential rupture

perforation with peritonitis

Inflammatory strictures of the colorectum-must be differentiated from cancer.

sequential mucosal changes from dysplasia to invasive carcinoma- surveillance with repeated colonoscopies and multiple biopsies aimed at detecting dysplasia for possible prophylactic colectomy.

Crypt Abscess

Toxic Megacolon

Crohn’s disease.

Used to be called "terminal ileitis" or "regional enteritis”

extra-intestinal complications of immune origin, such as uveitis, sacroiliitis, migratory polyarthritis, erythema nodosum, primary biliary cirrhosis, and obstructive uropathy due to excess formation of calcium oxalate stones

Hallmarks are

Sharply limited transmural involvement of the bowel by an inflammatory process with mucosal damage

Presence of noncaseating granulomas

Fistula formation

Gross morphology:

sharply delimited and transmural inflammation of the bowel with mucosal damage

The intestinal wall is rubbery and thick, due to edema, inflammation, fibrosis, and hypertrophy of the muscularis propria

lumen is almost always narrowed, seen radiographically as the "string sign,"

When several bowel segments are involved, the intervening bowel is essentially normal ("skip" lesions).

ulcers coalesce into long, serpentine linear ulcers, which tend to be oriented along the axis of the bowel- giving cobblestone appearance

adhesions with adjacent loops of bowel, fistula or sinus tract and abscess formation

Microscopic feature:

inflammation, with neutrophilic infiltration into the epithelial layer and accumulation within crypts to form crypt abscesses

Ulceration

chronic mucosal damage in the form of architectural distortion, atrophy, and metaplasia

the muscularis mucosae and muscularis propria are usually markedly thickened, and fibrosis

Lymphoid aggregates

dysplastic changes in long standing cases- predictors of adenocarcinoma

Clinical feature and complications:

chronic relapsing inflammatory disorders with recurrent episodes of diarrhea, crampy abdominal pain, and fever lasting days to weeks

Complications

fistula formation to other loops of bowel, the urinary bladder, vagina, or perianal skin

abdominal abscesses or peritonitis

intestinal stricture or obstruction,

massive intestinal bleeding,

toxic dilation of the colon, or

carcinoma of the colon or small intestine.

Inflammatory Bowel disease.

result from an abnormal local immune response against the normal flora of the gut, and probably against some self antigens, in genetically susceptible individuals

Crohn disease may affect from esophagus to anus but most often involves the ileum; about half of cases exhibit noncaseating granulomatous

Ulcerative colitis is a nongranulomatous disease limited to the colon

First-degree relatives are 3 to 20 times more likely

Pathogenesis include imbalance between 2 factors

(1) factors that activate the host immune system, such as luminal microbes, dietary antigens, and endogenous inflammatory stimuli; and

(2) host defenses that down-regulate inflammation and maintain the integrity of the mucosa

Genetic Predisposition:

Ulcerative colitis has been associated with HLA-DRB1, whereas

HLA-DR7 and DQ4 alleles are associated with approximately 30% of Crohn disease

Immunologic Factors

predominant class of T-cell response.The inflammatory cytokine TNF may play an important role and TNF antagonist are used in the treatment

neutrophils initially and mononuclear cells later in the course

perinuclear antineutrophil cytoplasmic antibodies, which are present in about 75% of persons with ulcerative colitis

End results:

(1) impaired integrity of the mucosal epithelial barrier, and

(2) loss of surface epithelial cell absorptive function

Papillary Carcinoma.

previous exposure to ionizing radiation

they may be well circumscribed and even encapsulated; in other instances, they infiltrate the adjacent parenchyma with ill-defined margins

areas of fibrosis and calcification and are often cystic

Gross papillary foci may be present

Unlike hyperplastic papillary lesions, the neoplastic papillae have dense fibrovascular cores. Concentrically calcified structures termed psammoma bodies are often present within the papillae

nuclear features even in the absence of a papillary architecture are diagnostic of papillary Ca- finely dispersed chromatin, which imparts an optically clear appearance, giving rise to the designation "ground-glass" or "Orphan Annie eye" nuclei

Invaginations of the cytoplasm may give the appearance of intranuclear inclusions (hence the term pseudo-inclusions)

Metastases to adjacent cervical lymph nodes common- might be the only presentation of the neoplasm.

Follicular Carcinoma.

nodular goiter may predispose

RAS mutations in follicular adenomas and carcinomas suggests that they may be related tumors

Hürthle cell variants of follicular carcinomas may be seen

extensive histologic sampling of the tumor-capsule-thyroid interface is needed, to exclude capsular and/or vascular invasion

follicular lesions in which the nuclear features are typical of papillary carcinomas should be regarded as papillary cancers.

metastasize through the bloodstream to the lungs, bone, and liver

Well-differentiated metastases may take up radioactive iodine, so can be used for therapy

Because better differentiated lesions may be stimulated by TSH, exogenous thyroxine is given to supress the TSH in the body .

Medullary Carcinoma.

Like normal C cells, medullary carcinomas secrete calcitonin, the measurement of which plays an important role

Neuroendocrine cells may secrete VIP, causing diarrhoea

Cases associated with MEN-2A or MEN-2B, in contrast, occur in younger patients and may even arise in children- all MEN-2 positive people carrying RET mutations are offered prophylactic thyroidectomies

Multicentricity is particularly common in familial cases

polygonal to spindle-shaped cells, which may form nests, trabeculae, and even follicles

Acellular amyloid deposits, derived from altered calcitonin- which can be demonstrated by immunohistochemical methods

multicentric C-cell hyperplasia in the surrounding thyroid parenchyma is a characterstic finding in familial .

Anaplastic Carcinoma.

multinodular goiter, or other differentiated carcinoma are usually present

bulky masses that typically grow rapidly beyond the thyroid capsule into adjacent neck structures

Any of the following pictures may be found in microscope

(1) large, pleomorphic giant cells;

(2) spindle cells with a sarcomatous appearance

(3) mixed spindle and giant-cell lesions

(4) small cells, resembling those seen in small-cell carcinomas

Foci of papillary or follicular differentiation may be present in some tumors, suggesting origin from a better differentiated carcinoma.

Molecular steps in carcinogenesis of Thyroid.

Papillary carcinoma: (75% to 85%): novel fusion genes, known as ret/PTC , which constitutively activate RET and the downstream MAP kinase signaling pathway

Follicular carcinoma: mutations in the RAS family of oncogenes (HRAS, NRAS, and KRAS), PAX8-PPARγ1 fusion gene.

Medullary carcinoma: associated with MEN 2

Anaplastic carcinomas: "dedifferentiation" of a well-differentiated papillary or follicular carcinoma; Inactivating point mutations in the p53 .

Thyroid adenoma.

Although the vast majority of adenomas are nonfunctional, a small proportion produces thyroid hormones ("toxic adenomas")

Activating ("gain of function") somatic mutations in the TSH receptor itself

well-defined, intact capsule

cells are arranged in uniform follicles that contain colloid

Variant: brightly eosinophilic granular cytoplasm (oxyphil or Hürthle cell change)

exhibit focal nuclear pleomorphism, atypia, and prominent nucleoli (endocrine atypia)

Careful evaluation of the integrity of the capsule is critical in the distinction of follicular adenomas from follicular carcinomas, that’s why FNAC is useless in differentiating between the two.

On radionuclide scanning, adenomas appear as "cold" nodules relative to the adjacent normal thyroid gland. Toxic adenomas, however, will appear as "warm" or "hot" nodules

malignancy is virtually nonexistent in "hot" nodules.

Thyroid neoplasm.

Solitary nodules, in general, are more likely to be neoplastic than are multiple nodules.

Nodules in younger patients are more likely to be neoplastic than are those in older patients.

Nodules in males are more likely to be neoplastic than are those in females.

A history of radiation treatment to the head and neck region is associated with an increased incidence of thyroid malignancy.

Nodules that take up radioactive iodine in imaging studies (hot nodules) are more likely to be benign than malignant.

GIANT CELL ARTERITIS, TEMPORAL ARTERITIS.

Giant cell /temporal arteritis - the most common of the vasculitides. It is a granulomatous inflammation of arteries of large to small size. It affects principally the arteries in the head-especially the temporal arteries but also the vertebral and ophthalmic arteries. Also affection of aorta leads to giant cell aortitis

Pathology : Giant cells present in the wall the involved artery. Thrombus found in lumen of the artery – which is composed of a granulomatous infiltrate. Association with HLA – DR antigen and presence of clonal T cells at multiple affected sites.

Clinical Features :

Occurs in older population, at least 50 yrs old.

Patient presents with headache and temporal pain. Visual symptoms are common, and blindness is a complication in 50% of cases.

Temporal Artery will feel firm and nodular. Pain on palpation of artery is common finding.

Treatment: responds well to steroids.

TAKAYASU ARTERITIS.

An inflammatory disorder of the aortic arch and its major branches, with localized stenosis or occlusion

An auto-immune basis has been proposed. It is most common in young women, similar to other auto-immune disorders. Presence of giant cells in the lesion makes the diagnosis difficult but the clinical presentation helps to differentiate.

Pathogenesis : Also known as PULSELESS DISEASE.

There is irregular thickening of the aortic arch or branch vessel wall with intimal wrinkling.

When the aortic arch is involved, the orifices of the major arteries to the upper portion of the body may be markedly narrowed or even obliterated by intimal thickening – which leads to weakness of pulse in upper extremity – pulseless disease.

POLYARTERITIS NODOSA.

Systemic vasculitis affecting medium and small muscular arteries- kidneys 85%, heart 75%, liver 65%, GI 50%

Morphology - acute (fibrinoid necrosis with infiltrate), healed (fibrosis, calcification and infiltrate)

PATHOLOGY: Multiple organs involved, but the lungs are characteristically not involved.

CLINICAL FEATURES:

fever, malaise, weakness, leukocytosis and specific organ involvement

Condition is associated with Hepatitis-B in about 30% of cases.

Treatment: steroids, cyclophosphamide

WEGENER'S GRANULOMATOSIS.

Systemic vasculitis of small arteries and veins.

Granulomatous inflammation of nose, sinuses, lung, kidney

Anti Cytoplasmic Neutrophil Antibodies (ANCA) are found in serum.

CLINICAL FEATURES: Patient may have persistent sinusitis, pneumonitis, hematuria, proteinuria.

Coagulation disorders.

Deficiencies of Clotting factors

Onset - delayed after trauma

Deep bleeding

Into joints - Hemarthroses

Into deep tissues – Hematoma

large skin bleed – Ecchymoses

Common disease :

Hemophilia A

Hemophilia B

Vitamin K deficency

Von Willebrand Disease – Coagulation + platelet

Factor VIII Deficiency:

Classic hemophilia (hemophilia A)

X-linked disorder (affects 1º males)

Most common - severe bleeding

Severity of disease -less than 1,2- 5, 5- 60%

Abnormal aPTT – Intrinsic path.

Diagnosis - factor VIII assay

Treatment - factor VIII concentrate

Cryoprecipitate

Recombinant factor VIII

Factor IX Deficiency:

Christmas disease (Hemophilia B)

X-linked recessive disorder

Indistinguishable from classic hemophilia (F VIII)

Requires evaluation of factor VIII and IX activity levels to diagnose

Treatment - factor IX concentrate

Cryoprecipitate if factor IX unavailable

Acquired coagulation disorder:

Vitamin K deficiency

- neonates - decreased intestinal

flora and dietary intake

- oral anticoagulants

- fat malabsorption syndromes

Required for factors II, VII, IX, X

Prolonged PT and aPTT

Laboratory findings in coagulation disorder:

Normal bleeding time & Platelet count

Prolonged prothrombin time (PT)

deficiencies of II, V, VII, X

Prolonged time (aPTT)

all factors except VII, XIII.

Major Disorders Associated with Disseminated Intravascular Coagulation.

Obstetric Complications

Abruptio placentae

Retained dead fetus

Septic abortion

Amniotic fluid embolism

Toxemia

Infections

Gram-negative sepsis

Meningococcemia

Rocky Mountain spotted fever

Histoplasmosis

Aspergillosis

Malaria

Neoplasms

Carcinomas of pancreas, prostate, lung, and stomach

Acute promyelocytic leukemia

Massive Tissue Injury

Traumatic

Burns

Extensive surgery

Miscellaneous

Acute intravascular hemolysis, snakebite, giant hemangioma, shock, heat stroke, vasculitis, aortic aneurysm, liver disease

Clinical Course:

1)Acute DIC – mainly presents as a bleeding diathesis. shock, with acute renal failure, dyspnea, cyanosis, convulsions, and coma. Hypotension is characteristic. petechiae and ecchymoses on the skin. severe hemorrhage into the gut or urinary tract.

Waterhouse-Friderichsen syndrome – microthrombi in glomeruli may lead to microinfarct in renal cortex – in severe cases can cause renal cortical necrosis, and involvement of adrenal glands in severe cases is known as WF syndrome.

Microinfarcts in the brain may give rise to bizarre neurologic signs.

2) Chronic DIC - tends to present as thrombotic complications.

Laboratory evaluation

Thrombocytopenia

PT and PTT – prolonged

Fibrin split products are increased in the plasma.

Thrombocytopenia.

Decreased platelet count.

Is characterized by spontaneous bleeding which is evident at platelet count below 20,000/μL, 20,000 to 50,000 may lead to post-traumatic bleeding.

a prolonged bleeding time

normal PT and PTT.

Sites of bleeding in thrombocytopenia – following are common sites but bleeding can occur from any site though.

Skin and mucous membranes

Petechie

Ecchymosis

Hemorrhagic vesicles

Gingival bleeding and epistaxis

Menorrhagia

Gastrointestinal bleeding

Intracranial bleeding

Spontaneous bleeding after trauma

Thrombocytopenia is one of the most common hematological manifestations of AIDS.

Causes of Thrombocytopenia:

Decreased production of platelets

Generalized diseases of bone marrow

Aplastic anemia: congenital and acquired

Marrow infiltration: leukemia, disseminated cancer

Selective impairment of platelet production

Drug-induced: alcohol, thiazides, cytotoxic drugs

Infections: measles, human immunodeficiency virus (HIV)

Ineffective megakaryopoiesis

Megaloblastic anemia

Myelodysplastic syndromes

Decreased platelet survival

Immunologic destruction:

Autoimmune: idiopathic thrombocytopenic purpura, systemic lupus erythematosus

Isoimmune: post-transfusion and neonatal

Drug-associated: quinidine, heparin, sulfa compounds

Infections: infectious mononucleosis, HIV infection, cytomegalovirus

Nonimmunologic destruction:

Disseminated intravascular coagulation

Thrombotic thrombocytopenic purpura

Giant hemangiomas

Microangiopathic hemolytic anemias

Sequestration: Hypersplenism

Dilutional.

Idiopathic Thrombocytopenic Purpuras.

Autoimmune in origin.

may occur in isolation or in association with an underlying condition such as lymphoma or collagen vascular disease like SLE.

Autoantibodies to platelets against platelet membrane glycoprotein IIb/IIIa, Major site of production of autoantibodies is spleen.

Acute - children (post infection)

Chronic - adults (increase in females, 20-40 yrs)

The spleen usually appears remarkably normal or mild enlargement.

No splenomegaly or lymphadenopathy.

Bone marrow aspiration – normocellular/increased numbers of megakaryocytes.

Diagnosis is by clinical picture, marrow examination, and exclusion of other causes of thrombocytopenia

In more than two thirds of patients, splenectomy is followed by the return of normal platelet counts and complete remission of the disease

Basic pathogenesis in TTP is widespread formation of hyaline thrombi in the microcirculation that are composed primarily of dense aggregates of platelets surrounded by fibrin.

Deficiency of enzymes - tissue metalloproteases that normally degrades very-high-molecular-weight von Willebrand factor (vWF), there is accumulation of vWF in plasma - promote platelet microaggregate formation throughout the microcirculation.

Formation of myriads of platelet aggregates causes thrombocytopenia, and the narrowing of blood vessels by the thrombi results in microangiopathic hemolytic anemia.

Heparin Induced Thrombocytopenia.

Heparin – binds to AT III – inactivation of factors IIa, IXa, Xa, XIa, XIIa. – used as anticoagulant. Large molecular weight substance.

On long term adminstration it will bind to a factor ie. Platelet factor 4 present on the membrane of platlets. There by making the platelets antigenic. So destruction by immune reaction. Decreased platelets in circulation.

Polycythemia.

Relative:

Reduced plasma volume (hemoconcentration)

Primary:

Abnormal proliferation of myeloid stem cells, normal or low erythropoietin levels (polycythemia vera);

inherited activating mutations in the erythropoietin receptor (rare)

Secondary: Increased erythropoietin levels

Appropriate: lung disease, high-altitude living, cyanotic heart disease

Inappropriate: erythropoietin-secreting tumors (e.g., renal cell carcinoma, hepatoma, cerebellar hemangioblastoma);

surreptitious erythropoietin use (e.g., in endurance athletes).

Aplastic Anemia.

Aplastic anemia is a disorder characterized by the suppression of multipotent myeloid stem cells, with resultant anemia, thrombocytopenia, and neutropenia (pancytopenia).

A form of anemia where there is selective suppression of erythroid stem cells reffered to pure red cell aplasia – diamond blackfan syndrome, in which anemia is the only manifestation.

Immunohemolytic Anemias.

caused by antibodies that react against normal or altered RBC membranes.

Immunohemolytic anemias are classified on the basis of the nature of the antibody involved:

Warm Antibody Immunohemolytic Anemias :

These are characterized by the presence of immunoglobulin G (IgG) antibodies usually against Rh antigen which are active at 37°C.

Cold Antibody Immunohemolytic Anemias :

These anemias are characterized by the presence of low-affinity immunoglobulin M (IgM) antibodies, which bind to RBC membranes at temperatures 0-4°C, as may be encountered in distal body parts (e.g., hands, toes). Fixaton of C3b can cause intravascular Hemolysis. But C3b is active at 37°C. When such antibody- and complement-coated cells travel to warmer areas, the weakly bound IgM antibody is released, and the cell is left with a coating of C3b. So RBC coated with C3b is phagocytosed - extravascular hemolysis .

Microangiopathic Hemolytic Anemia.

MHA is the form of intravascular hemolysis

These disorders is characterized by the presence of vascular lesions that predispose the circulating RBCs to mechanical injury.

RBCs may be disrupted by physical trauma in a following circumstances:

1) Patients with valve replacement – Trauma to the RBC due to sheer forces from the prosthetic valve.

2) Disseminated intravascular coagulation DIC - widespread deposition of fibrin in the small vessels leads to mechanical damage to the RBCs as they squeeze through abnormally narrowed vessels.

3) Malignant hypertension

4) thrombotic thrombocytopenic purpura

5) hemolytic-uremic syndrome

Disseminated cancer

Peripheral Smear – shows injured RBCs – schistocytes i.e. red cell fragments also called as "burr cells," "helmet cells," and "triangle cells" due to different shapes.

Glucose 6 Phosphate dehydrogenase deficiency.

G6PD – is a rate limiting enzyme in HMP shunt pathway. This pathway is responsible for production of NADPH which is required in number of metabolic reactions. Of which one most important is reduction of Glutathione to GSH. It is antioxidant which protects cell membranes from free radical damage.

RBCs are sensitive to injury by oxidative stresses, so deficiency of GSH leads to hemolysis.

Defective production of GSH leads to

accumulation of Hydrogen peroxide,

which in turn denatures

Globin chains, it damages RBC membrane

to cause hemolysis.

Clinical Manifestation –

Males are affected more than females – X linked Disease

Asymtomatic unless RBC subjected to oxidative stress as follows:

Drugs - primaquine , sulfonamides, nitrofurantoin, aspirin (in large doses), and vitamin K derivatives.

Infections that trigger release of free radicals from phagocytes Fava beans

Symptoms can present with symptoms of

Intravascular as well as extravascular hemolysis.

IV hemolysis – because of denaturation of Hb, and cell membrane damage in blood vessel initially.

Extravascular hemolysis – the cells which escpaes IV hemolysis, are bearing inclusion bodies (denatured Hb), so it becomes less deformable and sequestered in spleen leading to EV hemolysis.

Lab findings :

Peripheral Smear

Heniz bodies - Denatured Hb is precipitated within the RBCs in the form of inclusions called Heinz bodies.

Bite cells - the inclusion-bearing RBCs are less deformable, and their cell membranes are further damaged when splenic phagocytes attempt to "pluck out" the inclusions, creating so-called bite cells

Other findings of IV or EV hemolysis Depanding on stage of disease.

Hereditary Spherocytosis.

Autosomal dominant / Autosomal recessive (25% more severe) pattern of inheritance

Spherodial RBCs – which makes RBC less deformable and more vulnerable to splenic destruction.

Intrinsic defect in the RBC membrane.

Normally the biconcave shape of RBCs is function of RBC membrane proteins, specially spectrin and ankyrin, this proteins forms a meashlike network in intracellular face of membrane, this stabilize the membranes and is responsible of normal shape, strength and flexibility of RBC.

Mutations in this proteins leads to loosening of the membrane fragments as they are not stable, so the biconcave shape is disturbed, there by the surface area decreases, but the volume is not lost, so to maintain the ratio of surface area to volume, the RBC takes shape of sphere.

The spleen plays a major role in the destruction of spherocytes.

Cords of billroth -------splenic sinusoids.

The abnormal RBCs are sequestered and eventually destroyed by macrophages, which are plentiful in the splenic cords.

MORPHOLOGY

Microscopic - On smears, the RBCs lack the central zone of pallor because of their spheroidal shape. Increased erythropoiesis in the marrow is stimulated.

Peripheral smear shows – reticulocytosis.

Gross - Splenomegaly.

Autosplenectomy.

Microvasuclar Ischemia.

Autosplenectomy - Intially there is moderate splenomegaly caused by congestion of the red pulp with masses of RBCs sickled and jammed together. Which is followed by hypoxia, leading to ischemia and infraction – leading to shruken and fibrotic spleen - This process, referred to as autosplenectomy. Autosplenectomy patients shows presence of Howell jolly bodies in peripheral smears

Increased chances of infection – encapsulated bacteria.

Vascular congestion, thrombosis, and infarction may affect any organ, including bones, liver, kidney, retina, and skin. retinal detachment, chronic leg ulcers , renal infraction, necrosis of head of long bones – AVN of femoral head , can be seen in chronic cases.

Priapism due to obstruction of penile venous outflow that may lead to fibrosis and eventual erectile dysfunction – impotence.

Sickle cell Anemia.

Sickle cell Anemia is hemoglobinopathie , where substitution of valine for glutamic acid at the sixth position of the β-chain produces HbS.

Autosomal recessive pattern of inheritance – most commonly found in African American – natural selection. Most common cause of familial hemolytic anemia in Asian countries.

Sickle cell exist is 2 forms in population – sickle cell disease – HbS and sickle cell trait HbS + HbA.

Patients with disease are homozygous for the mutation, where as with trait are heterozygous.

So under normal conditions sickle cell trait is asymptomatic. As it has nearly 40 – 50% of Hb A , so the RBC of heterozygote have little tendency to sickle.

Another trait is HbSC – here there is presence of HB C, this HB has greater tendency to aggregate than HbA. So this patient lies in spectrum between trait and disease.Hb F has protective effect as it inhibits polymerisation of Hb S. Donot manifests in newborn till 5 to 6 months.

Clinical consequences of Sickling:

Increased RBC destruction – severe hemolytic anemia.

Erytropoesis is activated in bone marrow - Erythroid hyperplasia in bone marrow ,bone resorption and appositional new bone formation giving crew –cut appearance on radiograph.

Extramedullary erythropoiesis – splenomegaly and hepatomegaly

Jaundice

Pigmented gallstones formation.

The sickling of RBCs produces widespread microvascular obstructions and capillary stasis resulting ischemia and infarction.

Obstruction of small capillaries of hand and foot leads to ischemic damage to hand and foot, such patients presents with swelling of hand and foot – this is referred to as hand foot syndrome.

Microvascular ischemia is responsible for vasooclusive crisis and autosplenectomy.

Hemolytic anemias

Anemia that are associated with decreased RBC life span.

Hemolytic anemias are characterized by an increased rate of RBC destruction, a compensatory increase in erythropoiesis reticulocytosis and retention of iron ,marked erythroid hyperplasia within the marrow and an increased reticulocyte count in peripheral blood

in severe hemolytic anemias, extramedullary hematopoiesis may develop in the spleen, liver, and lymph nodes.

The causes are - Intracorpuscular and Extracorpuscular hemolytic anemia.

According to mechanism of RBC destruction hemolytic anemia can be intravacular or extravacular.

Because extreme alterations of shape are necessary for RBCs to successfully navigate the splenic sinusoids, reduced flexibility makes this passage difficult and leads to splenic sequestration, followed by phagocytosis.

Schematic of splenic sinus (electron micrograph). A red cell is in the process of squeezing from the red pulp cords into the sinus lumen. Note the degree of deformability required for red cells to pass through the wall of the sinus.

Thalassemia.

Thalassemia syndromes are a heterogenous group of inherited disorders caused by genetic lesions leading to decreased synthesis of either alpha or beta globin chain of Hb A.

β Thalassemia

The β-globin mutations associated with β-thalassemia fall into two categories:

(1) β0, in which no β-globin chains are produced; and

(2) β+, in which there is reduced (but detectable) β-globin synthesis

Individuals inheriting one abnormal allele have thalassemia minor or thalassemia trait, which is asymptomatic or mildly symptomatic.

Most individuals inheriting any two β0 and β+ alleles have β-thalassemia major;

occasionally, individuals inheriting two β+ alleles have a milder disease termed β-thalassemia intermedia

The reduced synthesis of β-globin leads to inadequate HbA formation, so that the MCHC is low, and the cells appear hypochromic and microcytic.

more important is red cell hemolysis, which results from the unbalanced rates of β-globin and α-globin chain synthesis.

Unpaired α chains form insoluble aggregates that precipitate within the red cells and cause membrane damage that is severe enough to provoke extravascular hemolysis

intramedullary destruction of erythroid precursors (ineffective erythropoiesis) causes inappropriate increase in the absorption of dietary iron, which often leads to iron overload.

α Thalassemias

Most of the α-thalassemias are caused by deletions that remove one or more of the α-globin gene loci. The severity of the disease that results from these lesions is directly proportional to the number of α-globin genes that are missing

For example, the loss of a single α-globin gene is associated with a silent-carrier state, whereas

the deletion of all four α-globin genes is associated with fetal death in utero, because the blood has virtually no oxygen-delivering capacity.

With loss of three α-globin genes there is a relative excess of β-globin or chains other than α-globin. Excess β-globin forms relatively stable β4 tetramers known as HbH that cause less membrane damage than do free α-globin chains.

In all gene deletions, gamma4 tetramer is present known as Hb Bart.

The hemolytic anemia and ineffective erythropoiesis tend be less severe in α-thalassemia than in β-thalassemia.

Unfortunately, both HbH and Hb Bart have an abnormally high affinity for oxygen, which renders them ineffective at delivering oxygen to the tissues.

Clinical features :

mainly for thalassemia majors:

(microcytic), pale (hypochromic), Target cells , poikilocytosis, anisocytosis, and reticulocytosis. Nucleated red cells (normoblasts)

hyperplasia of erythroid progenitors, with a shift toward early forms.

The expanded erythropoietic marrow may completely fill the intramedullary space of the

skeleton, invade the bony cortex, impair bone growth, and produce skeletal deformities – skull X-ray film shows crew cut appearence

splenomegaly, hepatomegaly, and lymphadenopathy

produce growth retardation and a degree of cachexia

Affected children fail to develop normally, and their growth is retarded from shortly after birth. They are sustained only by repeated blood transfusions, but gradually systemic iron overload develops

Unless steps are taken to prevent iron overload, over the span of years severe hemosiderosis develops, Unless patients are treated aggressively with iron chelators, cardiac failure

When feasible, bone marrow transplantation at an early age is the treatment of choice.

Disorders Associated with Splenomegaly.

I. Infections

Nonspecific splenitis of various blood-borne infections (particularly infective endocarditis)

Infectious mononucleosis

Tuberculosis

Typhoid fever

Brucellosis

Cytomegalovirus

Syphilis

Malaria

Histoplasmosis

Toxoplasmosis

Kala-azar

Trypanosomiasis

Schistosomiasis

Leishmaniasis

Echinococcosis

II. Congestive States Related to Portal Hypertension

Cirrhosis of the liver

Portal or splenic vein thrombosis

Cardiac failure

III. Lymphohematogenous Disorders

Hodgkin lymphoma

Non-Hodgkin lymphomas and lymphocytic leukemias

Multiple myeloma

Myeloproliferative disorders

Hemolytic anemias

Thromobocytopenic purpura

IV. Immunologic-Inflammatory Conditions

Rheumatoid arthritis

Systemic lupus erythematosus

V. Storage Diseases

Gaucher disease

Niemann-Pick disease

Mucopolysaccharidoses

VI. Miscellaneous

Amyloidosis

Primary neoplasms and cysts

Secondary neoplasm and metastasis.

Pernicious Anemia.

Vitamin B12 (Cobalamin) Deficiency Anemia:

can also cause a demyelinating disorder involving the peripheral nerves and, ultimately and most importantly, the spinal cord

Vitamin B12 is abundant in all animal foods, including eggs and dairy products, and is resistant to cooking and boiling.

Even bacterial contamination of water and nonanimal foods can provide adequate amounts.

It is stored in the liver, which normally contains reserves that are sufficient to support bodily needs for 5 to 20 years

As a result, deficiencies due to diet are rare and are virtually confined to strict vegans

Metabolism of vitamin B12:

Peptic digestion releases dietary vitamin B12, which then binds to salivary B12-binding proteins called cobalophilins, or R binders.

R-B12 complexes are transported to the duodenum and processed by pancreatic proteases; this releases B12, which attaches to intrinsic factor secreted from the parietal cells of the gastric fundic mucosa.

The intrinsic factor-B12 complex passes to the distal ileum and attaches to the epithelial intrinsic factor receptors, which leads to absorption of vitamin B12.

The absorbed B12 is bound to transport proteins called transcobalamins, which then deliver it to the liver and other cells of the body.

Pathogenesis of B12 deficiency:

Three types of antibodies have been found in pernicious anemia

parietal canalicular antibodies, which bind to the mucosal parietal cells;

blocking antibodies, which block the binding of vitamin B12 to intrinsic factor; and

binding antibodies that react with intrinsic factor-B12 complex and prevent it from binding to the ileal receptor.

An occurrence of pernicious anemia with other autoimmune diseases such as Hashimoto thyroiditis, Addison disease, and type I diabetes mellitus is well documented

gastrectomy (which leads to loss of cells producing intrinsic factor) or

resection of ileum (which prevents absorption of intrinsic factor-B12 complex), and in

disorders that involve the distal ileum (such as Crohn disease, tropical sprue, and Whipple disease

In individuals older than 70 years of age, gastric atrophy and achlorhydria can interfere with the production of acid and pepsin, which are needed to release the vitamin from its bound form in the diet.

Vitamin B12 is required for recycling of tetrahydrofolate

pallor, easy fatigability, and, in severe cases, dyspnea and even congestive heart failure. The increased destruction of erythroid progenitors may give rise to mild jaundice. Gastrointestinal symptoms

The principal neurologic lesions associated with vitamin B12 deficiency are demyelination of the posterior and lateral columns of the spinal cord, sometimes beginning in the peripheral nerves. In time, axonal degeneration

spinal cord disease begins with symmetric numbness, tingling, and burning in feet or hands, followed by unsteadiness of gait and loss of position sense, particularly in the toes

Diagnosis is made by

(1) low serum vitamin B12 levels,

(2) normal or elevated serum folate levels,

(3) serum antibodies to intrinsic factor,

(4) moderate to severe megaloblastic anemia,

(5) leukopenia with hypersegmented granulocytes, and

(6) a dramatic reticulocytic response (within 2-3 days) to parenteral administration of vitamin B12.

Megaloblastic Anemia (a)

Folic Acid Deficiency

Decreased intake

Inadequate diet—alcoholism, infancy

Impaired absorption

Malabsorption states

Intrinsic intestinal disease

Increased metabolism

Anticonvulsants, oral contraceptives

Increased loss

Hemodialysis

Increased requirement

Pregnancy, infancy, disseminated cancer, markedly increased hematopoiesis

Impaired use

Folic acid antagonists

Metabolic inhibitors of DNA synthesis and/or folate metabolism, e.g., methotrexate.

Folate metabolism:

the best sources of folate are fresh uncooked vegetables and fruits. Food folates are predominantly in polyglutamate form and must be split into monoglutamates

Phenytoin and a few other drugs inhibit folate absorption, while others, such as methotrexate, inhibit folate metabolism

The principal site of intestinal absorption is the upper third of the small intestine; thus, malabsorptive disorders that affect this level of the gut, such as celiac disease and tropical sprue, can impair folate uptake

conversion from dihydrofolate to tetrahydrofolate by the enzyme dihydrofolate reductase is particularly important.

Tetrahydrofolate acts as an acceptor and donor of one-carbon units in a variety of steps involved in the synthesis of purines and thymidylate, the building blocks of DNA, and its deficiency accounts for the inadequate DNA synthesis

measuring serum and red cell folate

symptoms referable to the alimentary tract are common and often severe. These include sore tongue and cheilosis.