Reversiblecellular injury

Part 2Intracellular accumulation of glycogen, proteins and pigments. Storage diseases.

Reversible cellular injury 2 Abnormal accumulation of proteins in the cell.

Abnormal accumulation of glycogen in the

cell. Glycogenosis. Classification of pigment depositions in the

cell. Hemoglobinogenic pigments. Hemosiderosis. Deposition of bilirubin. Types of jaundice. Deposition of non- hemoglobinogenic

/autochthonic/ pigments.

INTRAcellular ACCUMULATIONS

Lipids Neutral Fat Cholesterol

Proteins “Hyaline” = any “proteinaceous” pink “glassy”

substance Glycogen Pigments

Endogenous exogenous

Intracellular lipid accumulations

Sites of localization within the parenchymal cells -lipid

degeneration Liver, myocardium, kidney

within the fat cells Obesitas-subcutaneous fat tissue Lipomatosis-heart, pancreas

within the macrophages -lipid phagocytosis Atherosclerosis-aorta, arteries

Degeneratio Adiposa Hepatis(HE, Sudan III)

Atheromatosis Aortae (HE, SUDAN III)

Холестерол – в гладкомускулните клетки и макрофаги на интимата на големите артерии

Abnormal accumulation of proteins

Due to excesses proteins presented to the cells or because the cells synthesize excessive amounts

“Hyaline” = any “proteinaceous” pink “glassy” substance

Examples In the kidney

In nephrotic syndrome (disorders with heavy protein leakage across the glomerular filter and increased reabsorption of the protein

Pinocytic vesicles containing this protein fuse with lysosomes, resulting in the histologic appearance of pink, hyaline cytoplasmic droplets

The process is reversible -if the proteinuria abates, the protein droplets are metabolized and disappear.

Abnormal accumulation of proteins

Examples Russell bodies – rounded, eosinophilic bodies

in some plasma cells with accumulation of newly synthesized

immunoglobulins in the RER Mallory bodies or "alcoholic hyalin" -

eosinophilic cytoplasmic inclusion in liver cells in alcoholic liver disease, due to accumulations of intracellular proteins

composed of aggregated intermediate filaments that resist degradation.

The neurofibrillary tangles - in the brain in Alzheimer disease

aggregated protein inclusion that contains microtubule-associated proteins and neurofilaments,

Abnormal accumulation of glycogen

Excessive intracellular deposits of glycogen due to abnormalities in the metabolism of either glucose or glycogen

Water-clear vacuoles PAS positive

Examples In poorly controlled diabetes mellitus,

(abnormal glucose metabolism) Renal proximal tubules – Armani-

Ebstein cells Liver - cytoplasm, nuclei Cardiac myocytes

Glycogen storage diseases or glycogenoses

Glycogenosis

A group of autosomal recessive diseases with an inherited deficiency of any one of the enzymes involved in glycogen synthesis or degradation

can result in excessive accumulation of glycogen or some abnormal form of glycogen in various tissues

predominantly in liver or muscles A dozen forms of glycogenoses have been described on the

basis of specific enzyme deficiencies. The type of glycogen stored, its intracellular location, and

the tissue distribution of the affected cells vary depending on the specific enzyme deficiency

Regardless of the tissue or cells affected, the glycogen is most often stored within the cytoplasm, or sometimes within nuclei

One variant (Pompe disease) is a form of lysosomal storage disease, because the missing enzyme is localized to lysosomes

Glycogenosis On the basis of pathophysiology- 3 categories

Hepatic type a deficiency of the hepatic enzymes involved in glycogen

metabolism ⇒ enlargement of the liver due to storage of glycogen and hypoglycemia due to a failure of glucose production

Von Gierke disease (type I glycogenosis), resulting from a lack of glucose-6-phosphatase

Miopatic type When enzymes that are involved in glycolysis are deficient,

glycogen storage occurs in muscles and there is an associated muscle weakness due to impaired energy production

McArdle disease (type V glycogenosis), resulting from a deficiency of muscle phosphorylase

Generalized glycogenosis Pompe disease (type II)

deficiency of lysosomal acid maltase associated with deposition of glycogen in virtually every

organ - cardiomegaly is most prominent

Classification of pigment depositions in the cell

Pigments – specifically colored substances found in the cells and tissues Diagnostic significance

Classifications of pigments Exogenous - coming from outside the body

Carbon, tattoo Endogenous - synthesized within the body itself

Hemoglobinogenic pigments Hemosiderin, bilirubin

Non- hemoglobinogenic (autochthonic) pigments melanin, lipofucsin

Exogenous pigments Inorganic chemical substances

Macrophages and parencymal cells – lysosomes

Examples Carbon (an example is coal dust), a

ubiquitous air pollutant of urban life. When inhaled, it is phagocytosed by

alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes.

Aggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis).

Heavy accumulations may induce emphysema or a fibroblastic reaction that can result in a serious lung disease called coal workers' pneumoconiosis

Tatoo Lead poisoning (saturnism)

gums – blue-black strip, “lead edge”

TATTOO, MICROSCOPICThis tiny amount of microscopic tattoo pigment can make white

skin look quite black!

Endogenous pigmentsHemoglobinogenic pigments

Hemoglobin Complex protein

Heme –Fe protoporhhyrin Globin – 2 α chains and 2β chains

In breakdown of senescent erythrocytes -2 hemoglobinogenic pigments Hemosiderin

Fe-containing component of heme Bili lubin

From protoporhhyrin component of heme

Hemosiderin A hemoglobin-derived granular pigment

accumulates in tissues when there is a local or systemic excess of iron

Iron is normally stored within cells in association with the protein apoferritin, forming ferritin micelles.

Hemosiderin pigment represents large aggregates of these ferritin micelles is readily visualized by light microscopy

golden yellow to brown coloor the iron can be unambiguously identified by the

Prussian blue histochemical reaction Hemosiderin accumulation is usually pathologic

small amounts of this pigment are normal in the mononuclear phagocytes of the bone marrow, spleen, and liver, where there is extensive red cell breakdown.

Local excesses of iron, and consequently of hemosiderin, result from hemorrhage.

A bruise After lysis of the erythrocytes at the site of

hemorrhage, the red cell debris is phagocytosed by macrophages; the hemoglobin content is then catabolized by lysosomes with accumulation of the heme iron in hemosiderin.

Haemosiderosis pulmonis – alveolar macrophages

Hemosiderosis A condition whenever there is systemic overload

of iron and hemosiderin is deposited in many organs and tissues It is found at first in the mononuclear phagocytes of

the liver, bone marrow, spleen, and lymph nodes and in scattered macrophages throughout other organs.

With progressive accumulation, parenchymal cells throughout the body (but principally the liver, pancreas, heart, and endocrine organs) become "bronzed" with accumulating pigment.

Hemosiderosis occurs in the setting of :1. increased absorption of dietary iron2. impaired utilization of iron3. hemolytic anemias4. transfusions (the transfused red cells constitute an

exogenous load of iron). In most instances of systemic hemosiderosis, the

iron pigment does not damage the parenchymal cells or impair organ function despite an impressive accumulation Exception - hereditary hemochromatosis

With more extensive accumulations of iron and tissue injury including liver fibrosis, heart failure, and diabetes mellitus.

Hereditary hemochromatosis A genetic disorders characterized by the excessive

accumulation of body iron, most of which is deposited in the parenchymal organs such as the liver and pancreas.

There are at least four genetic variants of hereditary hemochromatosis The most common form is an autosomal recessive disease of adult onset

caused by mutations in the HFE gene, located on chromosome 6 regulate the levels of hepcidin, the iron hormone produced by the liver. hepicidin normally down-regulates the efflux of iron from the intestines and

macrophages into the plasma and inhibits iron absorption. When hepcidin levels are reduced there is

hepicidin levels are reduced in all currently known genetic forms of hemochromatosis ⇒ ⇑ iron absorption

Morphology deposition of hemosiderin - liver, pancreas, myocardium, pituitary, adrenal,

thyroid and parathyroid glands, joints, and skin; cirrhosis; HCC cardiomyopathy - arrithmias pancreatic fibrosis - skin pigmentation - increased epidermal melanin production, slate-gray.

Bilirubin metabolism and elimination. Bilirubin is the end product of heme degradation

1, Normal bilirubin production (0.2-0.3 gm/day) is derived primarily from the breakdown of senescent circulating erythrocytes, with a minor contribution from degradation of tissue heme-containing proteins.

2, Extrahepatic bilirubin is bound to serum albumin and delivered to the liver.

3, Hepatocellular uptake, and 4, glucuronidation by glucuronosyltransferase in the

hepatocytes generates bilirubin monoglucuronides and diglucuronides, which are water soluble and readily excreted into bile.

5, Gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. The urobilinogens and the residue of intact pigments are excreted in the feces, with some reabsorption and re-excretion into bileApproximately 20% of the urobilinogens are reabsorbed in the ileum and colon, returned to the liver, and promptly re-excreted into bile.

Approximately 20% of the urobilinogens are reabsorbed in the ileum and colon, returned to the liver, and promptly re-excreted into bile.

Conjugated and unconjugated bile acids are also reabsorbed in the ileum and returned to the liver by enterohepatic circulation.

Jaundice and Cholestasis Jaundice - occurs when systemic retention of bilirubin leads to

elevated serum levels above 2.0 mg/dL (the normal in the adult is <1.2 mg/dL)

may reach 30-40 mg/dL in severe liver disease a yellow discoloration of skin and sclerae (icterus) Liver ren

Cholestasis - systemic retention of not only bilirubin but also other solutes eliminated in bile (particularly bile salts and cholesterol)

↑ Alkaline phosphatase ↓ absorption of the fat-soluble vitamins A, D, and K. Pruritus Skin xantomas

Icterus renis

Jaundice Jaundice occurs when the

equilibrium between bilirubin production and clearance is disturbed by one or more of the following mechanisms:

1. excessive production of bilirubin,

2. reduced hepatic uptake, 3. impaired conjugation, 4. decreased hepatocellular

excretion, 5. impaired bile flow (both

intrahepatic and extrahepatic).

The 1-st, 2-nd and 3-th mechanisms

unconjugated hyperbilirubinemia

The 4-th and 5-th mechanisms

predominantly conjugated hyperbilirubinemia.

More than one mechanism may operate to produce jaundice

one mechanism predominates

Main Causes of Jaundice Predominantly Unconjugated

Hyperbil irubinemia Excess production of bilirubin Hemolytic anemias Resorption of blood from internal

hemorrhage (e.g., alimentary tract bleeding, hematomas)

Ineffective erythropoiesis syndromes (e.g., pernicious anemia, thalassemia)

Reduced hepatic uptake Drug interference with membrane

carrier systems Diffuse hepatocellular disease (e.g.,

viral or drug-induced hepatitis, cirrhosis)

Impaired bilirubin conjugation Physiologic jaundice of the newborn

Predominantly Conjugated Hyperbil irubinemia

Decreased hepatocellular excretion Deficiency in canalicular membrane

transporters Drug-induced canalicular

membrane dysfunction (e.g., oral contraceptives, cycloporine)

Hepatocellular damage or toxicity (e.g., viral or drug-induced hepatitis, total parenteral nutrition, systemic infection)

Impaired intra- or extra-hepatic bile flow

Inflammatory destruction of intrahepatic bile ducts (e.g., primary biliary cirrhosis, primary sclerosing cholangitis, graft-versus-host disease, liver transplantation)

Jaundice3 main types: Hemolytic (pre-hepatic)- ↑ destruction of

erythrocytes ↑unconjugated bilirubin ↑ feces stercobilin (pigmented) ↑ urine urobilinogen (-) urine bilirubin

Obstructive (post-hepatic)- cholestasis, intra- and extrahepatic obstruction of bile ducts

↑ AP, ↑ GGT ↑ conjugated bilirubin ↓ feces stercobilin (aholic stool) (-) urine urobilinogen (+) of urine bilirubin

Hepatocellular –hepatocellular damage (viral hepatitis, alcohol and drug-induced)

↑unconjugated bilirubin ↑ conjugated bilirubin

Jaundice May also result from inborn errors of metabolisms

Gilbert syndrome - a relatively common, benign, heterogeneous inherited condition

due to decreased hepatic levels of glucuronosyltransferase presenting as mild, fluctuating unconjugated hyperbilirubinemia may go undiscovered for years and does not have associated

morbidity. Dubin-Johnson syndrome - autosomal recessive defect

in the transport protein responsible for hepatocellular excretion of bilirubin glucuronides across the canalicular membrane

asymptomatic conjugated hyperbilirubinemia having a darkly pigmented liver and hepatomegaly, otherwise without

functional problems. Rotor syndrome – multiple defects in uptake and excretion of

bilirubin asymptomatic conjugated hyperbilirubinemia

Liver – not pigmented

Non- hemoglobinogenic pigmentsMelanin

Melanin is an endogenous, brown-black pigment produced in melanocytes

following the tyrosinase-catalyzed oxidation of tyrosine to dihydroxyphenylalanine.

It is synthesized exclusively by melanocytes located in the epidermis and acts as a screen against harmful ultraviolet radiation.

Although melanocytes are the only source of melanin, adjacent basal keratinocytes in the skin can accumulate the pigment (e.g., in freckles), as can dermal macrophages.

Increased melanin deposition-examples Pigmented naevus Addison’s disease Melanoma

Decreased melanin albinism –a leck of enzyme tirosinase vitiligo –a local defficiency of melanin in the

dermis

Naevus pigmentosus

Non- hemoglobinogenic pigments Lipofuscin

Lipofuscin represents complexes of lipid and protein that derive from the free radical-catalyzed peroxidation of polyunsaturated lipids of subcellular membranes

"wear-and-tear pigment" Lipofuscin is an insoluble brownish-

yellow granular intracellular material accumulates in a variety of tissues

-particularly the heart, liver, and brain as a function of age or atrophy.

The brown pigment when present in large amounts, imparts an appearance to the tissue that is called brown atrophy.

By EM - the pigment appears as perinuclear electron-dense granules

It is not injurious to the cell but is important as a marker of past free-radical injury.

Atrophia fusca hepatis