general pathology

General Pathology Cellular and Organ Pathology

Disorders of Glycogen Degradation.

Pathology of Calcification.

Jaroslava Dušková

Inst. Pathol. ,1st Med. Faculty, Charles Univ. Prague

Glycogen– morphology, function, regulation– pathology states

inborn - glycogenoses acquired

– hyperglycemia – DM I, DM II, MODY– hypoglycemia – insulinoma– hyperglycemia – glucagonoma– glycogen storage in the neoplasms (clear cell kidney ca,

seminoma, Ewing sarcoma… Calcification

– dystrophic– metastatic

Disorders of Glycogen Degradation. Pathology of Calcification. Table of contents

clinical manifestationscomplications

Glycogen linear and branched polymer cca 60 000 - D-glucose

molecules– monoparticles (beta) - muscle– complex particles (alpha) -

hepatocyte

Main Hormones in Glycogen Metabolism

insulin

glucagon

The Actions of Insulin on Cells Increased glycogen synthesis –in liver (and

muscle) cells. Reducing high blood glucose levels in diabetes.

Forces adipose tissue to make fats; lack of insulin causes the reverse.

Decreased proteolysis Decreased lipolysis Decreased gluconeogenesis Increased amino acid uptake Increased potassium uptake Arterial muscle tone – forces arterial wall muscle

to relax, increasing blood flow, especially in micro arteries; lack of insulin reduces flow by allowing these muscles to contract

Glucagon -physiologic effects

increase in blood concentration of glucose. Neurons can not utilize alternative energy sources like fatty acids

Glucagon stimulates breakdown of glycogen stored in the liver.

Glucagon activates hepatic gluconeogenesis. Non-hexose substrates such as amino acids are converted to glucose.

Glucagon also appears to have a minor effect of enhancing lipolysis of triglyceride in adipose tissue.

Control of Glucagon Secretion

Secreted in response to hypoglycemia Two other conditions :

– Elevated blood levels of amino acids, after consumption of a protein-rich meal . Since high blood levels of amino acids also stimulate insulin release both insulin and glucagon are active.

– Exercise: not clear whether the actual stimulus is exercise per se, or the accompanying exercise-induced depletion of glucose.

Negative control - glucagon secretion is inhibited by – high levels of blood glucose

– insulin

– somatostatin

Glycogen Metabolism Diseases diabetes mellitus type I (& LADA – late autoimmune diabetes of

adults) - polygenic HLA-DR 3, 4

diabetes mellitus type II - polygenic

MODY - more than 10 types described – monogenic

insulinoma

glucagonoma

insulin resistance in :

– metabolic syndrome (=obesity, glucose intolerance, hypertension,

hyperlipemia… )

– insulin receptor mutations

– polycystic ovary syndrome

– hypercortisolism…….

Complications of Diabetes

glucotoxicity due to: formation of Advanced Glycation E productsrelease of pro-inflammatory cytokines and growth factorsgeneration of ROS (free radicals) in endothelia

Complications of Diabetes

macroangiopathy microangiopathy retinopathy nephropathy neuropathy infections…..

diabetic gangrene

EnzymesInvolved in Glycogen Metabolism

g.-synthase - brancher phophorylase kinase - debrancher g-6-phosphatase -glucosidase

Glucokinase role in maintenance of glucose homeostasis

glucose

pancreas – B cell

hepatocyte

GKA

GLUT2

GLUT2

GKB

GKh

glucose – G6P

ATP/ADP

K+

Ca2+

M

insulin

IR

glucose G6P

glycogen

Storage DiseasesDef.:

inborn errors of metabolism (mostly single gene abnormality) leading to an enzyme defect with subsequent accumulation of the substrate (& lack of

the product) in tissues or organs „thesaurismoses“

E defect - gl-6 - phosphatase

Organ damage - liver, kidney

Glycogenosis I – von Gierke

E -defect - alfa1, 4 - glycosidase Organ damage - heart

Glycogenosis II – Pompe

Glycogen Storage Diseases -1.

Disease E- def Severity of Disease

Tissues Involved

von Gierke

Glucose-6

phosphatase

Severe Liver,kidney, gut

Pompe 1,4 glucosidase

Lethal Heart (+systemic)

Cori Amylo-1,6 Glucosidase (debrancher)

Lethal Liver (+systemic)

Glycogen Storage Diseases -2.

Disease E- def Severity of Disease

Tissues Involved

Andersen Amylo-1,4-1,6 transglucosidase (brancher)

Lethal Liver (+systemic)

Mc Ardle Muscle phosphorylase

Mild Skeletal muscle

Hers Liver

phosphorylaseMild Liver

Clear Intracellular Vacuoles & adjunct techniques

accumulations of water neg. lipides SUDAN, OIL RED polysaccharides PAS, A-PAS

Glycogen water soluble

easily lost in long lasting water based fixative solutions

CalcificationDef.:

depositions of Ca (mostly phosphate

salts) in tissues or organs Classification:

dystrophic

metastatic

Matrix vesicles - osteoblasts- nidus calcification

Non collagen proteins - osteopontin,

osteonektin, osteokalcin, Gla protein, sialoprotein

Alkalic phosphatase Phospholipids Collagen I Hydroxyapatite

Calcification - physiology

Calcification dystrophic metastatic

Calcinosis localized generalized

Chondrocalcinosis - pseudogout

Pathology Conditions with Calcium Deposits

Basophilic

Von Kossa - Ag impregnation

Alizarine red +

Tetracyclin fluorescence

Polarized light birefringence

Calcification - Microscopy

Calcification

Dystrophic Serum Ca level: normal

Tissues/Organs status

dystrophic changes

(necrosis, scar…, low

metab. turnover)

MetastaticSerum Ca level:


normal, local alcalisation

(acid secretion - urine,

stomach juice, sweat…)

Ca in mitochondria and GER

in cytoplasm bound to proteins

Released after cell damage

Activaton of protein kinases

Activaton of phospholipid

degradation and loss

Activaton of proteases

Cytoskeletal disassembly

Membrane damage

Phosphorylation of protein

andchromatin

phragmentation

Necrosis or degeneration

of tissue

Release of enzymes

Breakdown of organic

phophatesAlteration of pH

Increased deposition of calcium

Dystrophic Calcification

Calcification

Dystrophic Serum Ca level: normal


dystrophic changes

(necrosis, scar…, low

metab. turnover)

MetastaticSerum Ca level:


normal, local alcalisation

(acid secretion - urine,

stomach juice, sweat…)

Ca phophate Ca3(PO4)2

Ca diphosphate (Ca2P2O7)

Hydroxyapatite (Ca5 (PO4)3.OH

Ca Salts in the Calcified Foci



Chondrocalcinosis - pseudogout


Frequent necrotic tissue connective tissue vessels kalkospherites intracellular calcifiction of lysosoms

Less frequent tendon, cartilage, elastics, bas. membranes

Dystrophic Calcification

Forms - localised generalised

Localisation – connective tissue,

muscles

Calcinosis

pyrophophate and hydroxyapatite deposits

localisation – synovial membrane, cortilage, bone

Chondrocalcinosiscrystal deposit disease (pseudogout)

Calcium pyrophosphate deposition disease(Chondrocalcinosis, pseudogout)

Clinic: may simulate different diseasesArthroscopy - chalky white depositsTophaceus deposits with crystalline aggregatesCrystals stain with von Kossa techniqueForeign body type multinucleated giant cell reactionDeposits are in synovium, cartilage, bone

Vitamin D3 (1,25(OH)2D3) is a Hormone Vitamin D3 is not politically correct.

– It discriminates depending where you live, the further you live from the equator the less sun exposure consequently the lower your Vitamin D3 level.

– It discriminates against the elderly, as you age your skin loses up to 75% of its ability to make Vitamin D3.

– It discriminates against the obese. They have lower levels of Vitamin D3, due to the fact it is oil soluble, that it builds up in the fat tissue.

– It discriminates against skin color a dark complected person needs more sun exposure to produce their Vitamin D3 than a fair skinned person.

– It also discriminates against a person who does as they are told. It has been reported the incident of breast cancers have increased 40% in Australia due to Vitamin D3 deficiency caused by sunscreen use.

Metastatic calcification - causes

PTH secretion adenoma, carcinoma destruction of bone – leukemia, myeloma,

metastases, Paget (polyostotic) vitamin D intoxication

renal failure – phophate retention -

secondary hyperparathyreosis - PTH



Chondrocalcinosis – pseudogout

Calciphylaxix – extensive microvascular calcification and occlusion / thrombosis


Almafragi A, Vandorpe J, Dujardin K.

Calciphylaxis in a cardiac patient without renal disease. Acta Cardiol. 2009 Feb;64(1):91-3.

Calciphylaxis is a rare complication that occurs in 1% of patients with end-stage renal disease (ESRD) each year.

Extensive microvascular calcification and occlusion/thrombosis lead to violaceous skin lesions, which progress to nonhealing ulcers with secondary infection, often leading to sepsis and death.

The lower extremities are predominantly involved (roughly 90% of patients). Although most calciphylaxis patients have abnormalities of the calcium-phosphate axis or elevated levels of parathyroid hormone, these abnormalities do not appear to be fundamental to the pathophysiology of the disorder. We report on a case of histologically proven calciphylaxis in a 54-year-old woman with normal renal function and normal calcium-parathyroid homeostasis. She had a history of alcoholic cardiomyopathy, and was treated with warfarin anticoagulation. She has been successfully treated with antibiotics, i.v. biophosphonates and intensive local wound care. We recorded a complete wound healing in contrast to what is reported in other series.

Calciphylaxis reported in: hypoalbuminemia malignant neoplasm systemic corticosteroid use anticoagulation with warfarin chemotherapy systemic inflammation hepatic cirrhosis obesity rapid weight loss, and infection….

general pathology

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