Documente Academic
Documente Profesional
Documente Cultură
Diseases of
Liver
Biliry system
Pancreas
Dr. Adel Montaser
♦ This note is not prepared for an exam rather than a summary for the diseases of
liver and pancreas for future use.
♦ This note contains extra information (box information) from Robbins basic
pathology book not mentioned by the doctor.
♦ We tried our best to avoid mistakes that are out of our responsibility if found.
DISEASES OF THE LIVER
Normal liver Anatomy
• Site: it occupies the right upper quadrant of the abdomen. It could be on the left side in case of situs
invertus. It is fixed in its site by several ligaments such as ligamentum falcifarum and ligamentum
teres.
1) Surface anatomy: from 5th intercostal space till lower border of costal margin. In case of
hepatomegaly, it exceeds the 5th space and can be palpated under the costal margin.
2) Normal weight: about 1500g. If it weighs more, this may indicates hepatomegaly.
3) Circulation: Liver has dual blood supply:
4) Portal vein, which is the main source, accounting for 2/3 of blood supply. This vein branches
in tree manner to become central hepatic vein.
5) Hepatic artery, from systemic circulation which terminates, together with portal vein, as central
hepatic vein. Hepatic vein, then, drains into inferior vena cava.
6) Portal vein + hepatic artery → hepatic vein → inferior vena cava.
N.B.: due to its dual blood supply, liver infarction is rare.
Histology (fig. 1)
• Lobule concept: hepatic lobule is the smallest functional unit.
• acinus concept: physiologic concept based on the blood supply.
o Lobular Concept
§ Hexagonal shape.
§ Terminal central hepatic vein.
§ Peripheral portal triads, which consist of hepatic artery, portal vein and bile duct.
§ Hepatic cords radially set.
§ Three zones:
i. Central zone: around the central hepatic vein.
ii. Mid zone: in between.
iii. Peripheral zone: away from central hepatic vein.
o Acinus Concept:
§ Metabolic concept, i.e. based on blood supply.
§ Triangle in shape, the apex is at terminal hepatic vein, and the base is at portal tracts.
§ Least oxygenated area (zone 3) is the apical, around terminal hepatic vein. This zone
is most vulnerable area to lesions and toxins.
2
Hepatic a.
Bile duct
Portal v.
Peripheral
Canaliculus Hepatocyte
Basement
memb.
3
Histology of the hepatic lobules (fig. 2)
• Cords of one-hepatocyte thickness. These cells are diploid containing large nucleus with prominent
nucleolus. Sometimes it may contain double chromatin.
• Separated by sinusoids.
• Entangle bile canaliculi.
• Other cells:
o Endothelial cells: which form fenestrated lining allowing blood to reach hepatocytes (other sites
wih fenestration are kidney, lymph node, bone marrow and spleen).
o Kupfer cells: monocytes of liver in the sinusoids that have phagocytic function.
o Ito cells: found in space of Disse. These cells act as store for vitamin A and undergo metaplasia,
after insults, to give myofibroblastic cells which secrete collagen. So they have a great
contribution in cirrhosis.
Liver Function
• Metabolism of amino acids.
• Synthesis of serum proteins (albumen).
• Synthesis of coagulation factors.
• Metabolism of CHO (glucose balance).
• Metabolism of lipids.
• Processing and storage of vitamins.
• Detoxication of endogenous waste product and xenobiotics.
• Bile execretion.
• Breaking down of hormones such as aldestrone and estrogen.
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ii. Macrovesicular is seen in conditions such as: alcoholism, diabetes mellitus
and Kwashiorkor disease (malnutrition). (Nucleus is displaced by one large fat
globule).
§ Substances accumulation: such as bile, iron pigment (hemosedrin), copper and
enzymes (e.g.α-1 antitrypsin).
o Necrosis:
§ Single cells
i. Apoptosis: after exposure to toxins or in immune-mediated necrosis.
Hepatocyte becomes shrunken and the nucleus is deeply stained (pyknotic
and eosinophilic).
ii. Councilman bodies: nucleus disappears (karyolysis) and the cell is deeply
stained. They are seen in acute viral infection.
iii. Lytic necrosis: nucleus becomes fragmented (kayorrhexis) as seen in bile
stasis.
§ Groups of cells:
i. Focal: presence of irregular area of necrosis.
ii. Zonal: necrosis affecting certain zone in the liver, e.g.centrilobular necrosis in
alcoholism and due to certain drugs and toxins and rarely mid lobular or
perilobular in acute fatty liver in pregnancy.
iii. Piecemeal: at the periphery near portal tract. The best example is chronic
hepatitis which is sometimes called interface hepatitis because it occurs
between portal tract and hepatic parenchyma (or two hepatic lobules).
iv. Extensive:
- Bridging: affect large area of liver to bridge between portal tract
and central hepatic vein.
- Submassive: when necrosis affect large area of liver leading to
destruction of entire lobule.
- Massive: destruction of most or the entire liver parenchyma
accompanied by liver failure.
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§ Type of infiltrate may point to the cause:
i. Neutrophils: alcohol, bile stasis, and pyogenic infection.
ii. Lymphocyte: viral infection
iii. Plasma cells: immune-mediated injury such as autoimmune hepatitis.
iv. Eosinophils: parasitic infection.
§ May be granulomatous reaction:
i. Granulomatous inflammatory diseases: TB, leprosy, syphilis, and sarcoidosis.
ii. Other liver diseases associated with granuloma: chronic hepatitis C, primary
biliary cirrhosis, foreign bodies and certain drugs.
o Regeneration:
§ Liver capacity to regenerate is great.
§ Signs:
i. Binucleation: cells are binucleated (normally they are seen in elderly and
rarely in children).
ii. Mitosis: This is seen rarely in normal tissue. It could be tumor if exessive.
iii. Basophilia: due to excessive protein production.
§ Pattern: it depends on the reticulum network whether it is intact or destroyed:
i. If intact: regenerate completely to normal.
ii. If destroyed: regenerating nodules are formed.
o Fibrosis:
§ Portal: as in schistosomaiasis and mild reactive hepatitis.
§ Septal: extention of portal fibrosis to the lobule.
§ Perivenular: around central vein.
§ Cirrhosis.
• Clinical notes:
o In bridging fibrosis, there is a firbrous band which could be central-central, portal-portal, or
cental-portal.
o Staging fibrosis:
§ Stage 0: no fibrosis
§ Stage 1: only portal
§ Stage 2: septal
§ Stage 3: large area
§ Stage 4: established cirrhosis
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• Gamma glutamyltransferase gamma-GT (GGT) these 3 enzymes are elevated due to hepatocellular
necrosis.
• Elevated alkaline phosphatase: due to injury to bile ducts. It has other isoenzyme which is elevated
in other diseases such as bone and prostate diseases. It confirms liver injury if it is added to elevated
GGT.
• Bilirubin: hyperbilirubinemia → jaundice.
N.B.: these tests are called Live Function Tests (LFT).
JAUNDICE
Definitions
• Yellow discoloration of the skin and sclera due to retention of bilirubin (hyperbilirubinemia, > 1. 2
mg/dl) which is better seen in sun light or UV.
• Cholestasis means retention of bilirubin and other soluble bile conistuents as bile acids and
cholesterol
Pathogenesis
Impaired liver function in relation to bilirubin metabolism.
Bilirubin metabolism
• Senescent RBCs → Heme in RES (mononuclear phagocytes system including spleen).
• Heme → Biliverdin (green in color).
• Biliverdin → unconjugated bilirubin (yellow) which is water insoluble.
• Bilirubin associated with serum albumin to give delta bilirubin. It is tightly bound to albumin and
cannot be excreted in urine (insoluble), also called (indirect bilirubin).
• Uncongugated bilirubin → uptaken by hepatocytes.
• Conjugation occurs in hepatocyte by UGT (uridine-glucoronide transferase) → bilirubin
glucouronides or conjugated bilirubin (direct bilirubin).
• Conjugated bilirubin → excecreted in the intestine as urobilinogen (deconjugated bilirubin) →
reabsorbed to be excecreted in bile mostly and some in urine.
Pathophysiology of jaundice
• Normal serum level of bilirubin is 0. 3-1. 2 mg/dl and the normal bilirubin production is 0. 2-0. 3 g/day.
In jaundice, it is above 2. 0 mg/dl.
• There are 2 forms of bilirubin:
o Unconjugated, insoluble, not excecreted in urine (tightly bound to albumin).
o Conjugated, soluble, excecreted in urine.
N.B.: long standing hyperbilirubinemia leads to covalent bonding between bilirubin and albumin
(delta albumin) which remains long time even after correction of the insult.
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• Processing of bilirubin:
o Uptake of unconjugated bilirubin at the sinusoidal side of hepatocyte, which is carrier-mediated.
o Transport to endoplasmic reticulum.
o Conjugation in ER.
o Excretion of conjugated bilirubin with other content of bile in bile canaliculus.
• Jaundice may be produced due to failure of one or more of these processes.
• Hyperbilirubinemia may be:
o Predominantly uncongugated:
§ Excess bilirubin production as in hemolytic anemia (e.g.erythroblastosis fetalis, a
hemolytic disease of newborns), large hematoma, abnormal hemopoiesis, (↑RBC
destruction).
§ Reduced uptake,
Ø Due to drugs.
Ø Gilbert syndrome (hereditary disease with membrane defect).
§ Impaired conjugation:
Ø Physiologic in neonates: due to ↑ bilirubin production and slow
conjugation machinery “cells still are not ready” which result in mild jaundice
during first 2 weeks. Breast-fed infants tend to exhibit jaundice with greater
frequency, possibly because of β-glucuronidases present in maternal milk.
Ø Hereditary
Ø Diffuse hepatic disease e.g.hepatitis.
o Predominantly conjugated: in which conjugated bilirubin ↑ in the cell and return to circulation
§ Decreased excecrtion.
§ Deficiency in transport whether Acquired or hereditary.
§ Impaired bile flow.
Hereditary Hyperbilirubinemia
• Unconjugated
o Criggler Najjar syndrome, 2 types:
i. Type I, absent UGT, fatal secondary to kernictrus and baby is incompatible
with life.
ii. Type II, decreased UGT, mild attacks of jaundice (extraordinal yellow skin),
liver look normal.
o Gilbert’s syndrome: This is benign, with no liver change and mild attacks of jaundice. It is
caused by decreased glucorosyl transferase.
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• Conjugated
o Dubin Johnson: membrane defect on the canalicular side (no excretion because of defect in
transport protein), benign, liver is deeply brown (due to polymerized epinephrine metabolite and
not bilirubin) and enlarged (hepatomegaly).
N.B.: most common causes of jaundice: haemolytic anaemia, hepatitis, and obstruction of the
flow of bile.
CHOLESTASIS
Definition
A state of hyperbilirubinemia due to intra or extra hepatic obstruction associated with retention
of other bile components as bile acids and cholesterol.
Clinically
• Pruritus: itching due to ↑ deposition of bile salts which are irritant to skin.
• Xanthomas: yellow small nodules under the skin composed of foamy macrophages loaded with
cholesterol (focal accumulation of cholesterol).
• Malabsorbtion: of fat and fat-soluble vitamins because of no bile leading to steatorrhea with
subsequent malabsorption of other nutrients..
• Increased serum alkaline phosphatase: this enzyme present in duct epithelium and canalicular
membrane of hepatocyte. Its elevation indicates biliary obstruction.
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CIRRHOSIS
Definition
Diffuse (affect most of liver), chronic, progressive liver disease characterized by:
• Fibrosis.
• Regenerating nodules.
• Loss of lobular pattern.
Additional features:
• May be associated with necrosis.
• Inflammation of variable degree.
• Proliferating bile ducts.
N.B. severe necrosis and inflammation occur in progressive (decompensated) cirrhosis, while
compensated cirrhosis contains no necrosis with less inflammation.
Classification
• Morphological
o Micronodular: nodular size between 3-5 mm with fine fibrous tissue bands separating nodules.
Cut-surface of liver is finely nodular.
o Macrondular: nodular size more than 5 mm with thick fibrous bands (scar) separating nodules.
Cut-surface is coarsely nodular.
o Mixed: starts as micronodular and some become macronodular → mixed
• Etiological classification
o Viral: most common cause in our region.
o Alcoholic: most common cause in western countries.
o Biliary: either primary or secondary.
o Hemochromatosis (iron overload).
o Wilson’s disease (copper accumulation).
o Alpha 1 antitrypsin deficiency: enzyme is retained in hepatocyte and becomes deficient in serum.
o Cryptogenic cirrhosis
o Others: all are not true cirrhosis
1) Schistosomiasis: portal fibrosis only.
2) Cardiac cirrhosis: long-standing chronic venous congestion (stasis) giving nut-meg
appearance and fibrosis by the way.
3) Syphilis:
i. Congenital: pericellular fibrosis (cirrhosis) which is not diffused while the
architecture is intact.
ii. Tertiary: sever gama → hepar lobulatum
4) Laennec’s cirrhosis: nutritional (alcoholic) cirrhosis.
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Pathogenesis of cirrhosis
• Steps:
1) Injury (insult) of liver → liberating cytokines (TNF, IL-1, lymphokines).
2) Disruption of extracellular matrix by cytokines stimulating Ito cells metaplasia.
3) Ito cells change to myofibroblastic cells which produce collagen.
4) Collagen deposition (fibrosis) in the wall of sinusoid → closure of fenestrations.
5) Capillarization of sinusoids with no fenestration and walls become thick.
6) Reduced hepatocytes perfusion.
7) More injury (death of cells) with some viable cells that compensate by regeneration.
8) Regenerating nodules.
9) Loss of lobular morphology.
• So, the main characteristic features of cirrhosis are:
o Fibrosis (point 4).
o Regenerating nodules (point 8).
o Loss of lobular architecture (point 9).
Complication of cirrhosis:
• Liver failure.
• Portal hypertension: due to:
o Capillarization of sinusoid.
o Regenerating nodules which compress blood vessels.
o Fibrosis.
o Formation of porto-systemic shunts inside the liver itself.
• Hepatocellular carcinoma:
Necrosis stimulates viable cells regeneration (compensation) that may cause hyperplasia and
finally neoplasia.
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HEPATIC FAILURE
Difinetion
Failure of liver to perform its function when 80-90% of liver capacity are lost as a result of
acute or chronic liver damage, with 70-95% mortality rate.
Predisposing factors
• GIT hemorrhage, due to portal hypertension leading to:
o Absorption of toxic substance to liver from intestine.
o Post-hemorrhagic anemia.
• Systemic infection.
• CHF
• Electrolyte imbalance.
• Stress (e.g. major surgery, heart failure).
Pathology
• Massive, and sometimes sub-massive, hepatic necrosis due to drugs or viral hepatitis (hepatotropic
and non-hepatotropic viruses which lead to fulminent hepatitis).
• Chronic liver diseases as cirrhosis, and chronic hepatitis. However, chronic liver diseases are
considered as the most common route to hepatic failure.
• No apparent liver necrosis as Reye syndrome, acute fatty liver of pregnancy, and tetracycline toxicity
in which, there is microvesicular fatty change with no necrosis leading to biochemical hepatic
dysfunction.
Clinical Features
• Jaundice: failure of bilirubin metabolism.
• Hypoalbuminemia → edema and ascitis (accumulation of fluid in peritoneal cavity).
1
• Fetor hepaticus: musty or sweet & sour odor result from failure of liver detoxification of certain
metabolites that reabsorbed into blood giving this bad odor.
• Hyperestrogenemia (due to failure in liver metabolism of this hormone) leading to:
o Gynecomastia (hyperplasia of breast ducts).
o Testicular atrophy and disturbance in hair distribution (resembling women pattern).
o Spider nevi (central, pulsating, dilated arteriole with radiating small vessels) and palmer
erythema (local vasodilatation) reflecting vascular changes.
• Coagulopathy with risk of bleeding and more failure caused by bleeding (GI & petichial bleeding →
↑hepatic load → ↑severity).
• Hyperammonemia: defective liver urea cycle.
1
It is related to formation of mercaptans by the action of GI bacteria on the sulfur-containing amino acid
methionine and shunting of splanchnic blood from the portal into systemic circulation.
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• Hepatorenal syndrome: Acute renal failure following hepatic failure with oligurea, high BUN (blood
urea nitrogen) and creatinine, and without renal lesion. It is not primary kidney disease and may be
due to splanchnic and systemic vasodilatation which results in impaired perfusion of kidney.
1
• Hepatic encephalopathy: Rigidity, hyper-reflexia, coarse flapy tremors (asterixies) and downgrading
mental status (loss of concentration, stooper, confusion, semicoma, and finally ends with hepatic
coma). The underlying pathology is brain edema.
• Abnormal liver function tests, e.g.↑bilirubin, ↑transaminases, and ↓albumin.
PORTAL HYPERTENSION
Definition
Increased resistance to portal flow.
Causes
• Prehepatic (before liver) usually related to vessels:
o Thrombosis of portal vein (idiopathic or following abdominal surgery).
o Massive splenomegaly.
• Intrahepatic (within liver):
o Cirrhosis (see complication of cirrhosis).
o Porta hepatis tumor (nodular regenerative hyperplasia, multiple metastasis or lymphoid tissue
tumor).
o Schistosomiasis (leading to portal hypertension).
o Granulomatous reactions: e.g.miliary TB and sarcoidosis.
o Sever fatty change.
• Posthepatic (after liver):
o Thrombosis of hepatic vein or inferior vena cava (may be obstructed by renal metastasis).
o Right-sided heart failure (CHF).
o Constrictive pericarditis.
1
Asterixis is a pattern of non-rhythmic, rapid extension-flexion movement of head and extremities best
seen when arms are held in extension and wrists are dorsi-flexed.
13
Fluid is transudate (serous) (↓protein, ↓specific gravity, ↓ no. of cells).
• Portosystemic shunts formation: seen in the following sites:
o Lower end of esophagus (esophageal varices) which is prone to bleeding. This is the
commonest site for these shunts and may cause fatal hemorrhage.
o Rectum (hemorrhoid or piles) which may cause iron deficiency as a result of chronic loss of
blood.
o Abdominal wall, especially around the umbilicus (a condition known as Capitus nedosi).
• Congestive splenomegaly: marked enlargement of spleen due to long standing congestion. This
enlargement increases function of the spleen (hypersplenism) leading to:
o ↑break down of RBC → anemia.
o ↑break down of WBC → leucopenia → infection tendency.
o ↑break down of platelets → thrombocytopenia → bleeding tendency.
• Hepatic encephalopathy.
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VIRAL HEPATITIS
Definition
Infection of the liver by a group of viruses having a particular affinity for the liver (hepatotropic).
Other viruse:
• Herpes simplex virus (HSV).
• Cytomegalovirus (CMV).
• Infective mononucleosis (IM): Epstein-Barr virus EBV.
• Yellow fever.
• Rubella, adenovirus, or enterovirus.
HEPATITIS A
• A benign self-limited disease.
• Short incubation.
• Fecal-oral transmission.
• Sporadic, occasionally in outbreaks especially in military camps.
• Solid immunity.
• Injury could be due to cytopathic effect or immune-mediated.
• Diagnosis: Antivirus antibodies high in acute infection, virus is found in the stools in icterus (jaundice)
phase.
• No chronicity or carrier state.
• Fate: Fulminent hepatitis occurs in 0. 1% in patients with pre-existing liver disease. Other cases
recover (99. 9%)
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HEPATITIS B
A serious form of hepatitis which may proceed to chronic state and possible cirrhosis and HCC.
It has a long incubation period. Transmission is parentral
Pathogenesis
• Immune mediated necrosis of the hepatocytes by sensitized cytotoxic T cells during proliferative
phase of the virus. It could be also cytopathic although there are several reasons to believe that HBV
does not cause direct hepatocyte injury1.
• The virus has 2 phases:
o Proliferative, in which the virus replicates with presence of antigens.
o Integrative, in which antibodies are found.
N.B. HBV is found in all body fluids (semen, saliva, milk... etc) but not in feces.
Serologic diagnosis
• The antigens are:
o HBsAg, HBV-DNA, DNA polymerase, HBcAg and HBeAg.
• Serologic diagnosis depends on the presence of these antigens and their antibodies in the serum of
the patient (hepatitis profile) which tell as about the patient status, whether acute, chronic, carrier…
etc, for example:
o Absence of HBeAg and its antibody is associated with fulminent hepatitis.
o Acute hepatitis shows all antigens together with IgM against the core antigen. IgM indicate
acute state.
o While in chronic hepatitis, IgM is absent.
o In carrier state, surface antigen is only found.
o See (table 2.) which summarizes serologic diagnosis of hepatitis B.
1
Robbins p. 603
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Fate of hepatitis B infection (fig. 3) 1
• Sub-clinical disease (65%)
o Recovery, 100%
• Acute hepatitis (25%)
o Recovery, 99%
o Fulminant hepatitis, 1%
• Healthy carriers (10%)
• Persistent infection (5%)
o Recovery, 80%, chronic hepatitis, 20%
o Cirrhosis, 35% (out of those with chronic hepatitis)
o HCC, 10 % (out of those with cirrhosis)
Hepatitis B
infection
Cirrhosis
35%
HCC
10 %
Fig. 3 Fate of HBV infection
HEPATITIS C VIRUS
• Important cause of chronic hepatitis.
• 50% of cases progress to chronic hepatitis, 25% of whom develop cirrhosis.
• Long incubation period as well as HBV, may be due to DNA integration. Parentral transmition (blood
and other body fluids).
• Pathogenesis: probably immune-mediated.
• Serologic diagnosis of antivirus antibodies or may be the RNA virus (PCR).
• HCV has multiple types and subtypes which make development of effective vaccine difficult.
1
Also see (fig 16-5) in Robbins Basic Pathology.
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HEPATITIS D VIRUS
(Delta agent - incomplete virus)
• It does not replicate except in the presence of HBsAg causing either co- or super-infection:
o Acute co-infection: infects patient together with HBV.
o Super-infection: HBV infection of chronic HBV carrier.
§ In case of carrier state: HDV leads to ACUTE hepatitis.
§ In case of acute hepatitis: HDV leads to FULMINANT hepatitis.
• Parentral transmition, relatively short incubation period.
• Serologic diagnosis: presence of the virus in early infection and IgM antiHDV.
• Endemic in Africa and Middle East.
• Effect: Accelerates the effect of HBV infection (fulminent hepatitis) (see above).
HEPATITIS E VIRUS
• Similar to hepatitis A in many respects.
• Usually occurs in epidemic form with high mortality in pregnants.
HEPATITIS G VIRUS
• Not hepatotropic virus, no increase in liver enzymes.
• Has protective effect in patient co-infected with HIV (inhibit HIV replication).
CLINICOPATHOLOGICAL SYNDROMES
• Asymptomatic (sub-clinical) infection: no pathological or clinical findings, only serological evidence.
• Carrier state:
o Completely healthy carrier: positive surface antigen serology with no change in liver histology.
o Mild hepatitis: Mild inflammation of liver and mild clinical symptoms. Liver biopsy is positive if
stained by special stain technique.
o Pathology of carrier:
§ Positivity of hepatitis viruses.
§ Mild inflammation.
§ Slight elevation of liver enzymes.
o There is no carrier state in HAV and HEV infection.
• Acute hepatitis
• Chronic hepatitis
• Fulminant hepatitis.
N.B.: serology is very important in viral hepatitis as other causes present with similar clinical
picture.
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Acute hepatitis
• Similar picture in all types.
• Clinically:
o Incubation period varies according to the virus: short in hepatitis A and E and long in hepatitis B
and C.
o Symptomatic preicterus phase:
§ Non-specific constitutional symptoms (fatigability, malaise, nausea, loss of appetite,
weight loss, low-grade fever, headache, muscle and joint pain, vomiting and diarrhea).
§ Serum sickness like symptoms in B infection, which is thought to be immune-mediated
(formation of immune complex).
§ Enlarged tender liver
§ Proteinurea, splenomegaly, enlarged lymph node, vasculitis.
o Symptomatic icteric phase which also shows 1 and 2.
o Convalescence.
• Laboratory findings:
o High transminases.
o High bilirubin (jaundice): initially of conjugated type and urine becomes dark. With
hepatocellular damage, jaundice become of unconjugated type.
o Slight elevation alkaline phosphatase (due to pressure of hepatocyte on bile canaliculi) but not
as much as in biliary cirrhosis.
o Prolonged prothrombin.
o Hyperglobulinemia (immune-mediated).
• Morphology of acute hepatitis:
o Gross: slight liver enlargement, greenish tinge secondry to bile retention.
o Microscopic: “lobular disarray”, that is, disorganized but not completely lost.
o Degeneration and necrosis of all patterns.
o Inflammation rich in lymphcytes.
o Other features as:
§ Kupfer cell hyperplasia.
§ Regeneration.
§ Cholestasis.
§ Slight fatty change (seen in Hepatitis C and not seen in hepatitis A and B).
Chronic Hepatitis
• Definition: Symptomatic, biochemical or serologic evidence of continuing or relapsing hepatitis for
more than 6 months with histologically documented inflammation and necrosis.
• Causes:
o Viral: most common cause.
o Drugs: e.g.isoniasid, α-methyldopa, methotrexate.
o Alcohol.
o Wilson’s disease (metabolic disease charectarized by copper accumulation).
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o Autoimmunity.
o Alpha 1 antitrypsin deficiency.
• Classification:
o Etiological: according to the type of virus either B, C or D (i.e. according to serology).
o Histological according to the degree of inflammation to mild, moderate or severe; with or without
fibrosis.
N.B.:
1. Etiology is single most important factor determining possibility of developing progressive chronic hepatitis.
2. Necrosis in chronic hepatitis is of piece-meal type.
• Clinical features: (highly variable):
o Like acute hepatitis but milder.
o Signs of hepatic failure may be present.
o Signs of immune complex disease like vasculitis, glomerulonephritis may be present in HBV.
o Spider angioma, palmer erythma, mild hepatomegaly, hepatic tenderness, and mild
splenomegaly.
• Laboratory findings:
o Persistance elevated of enzymes level.
o Prolonged prothrompine time.
o Hypergammaglubinemia.
o Hyperbilirubinemia.
o Mild elevation of alkaline phosphatase.
• Morphology:
o Mild: chronic inflammation limited to the portal tracts; minimal necrosis; no fibrosis. It was known
as (chronic persistent hepatitis).
o Moderate: piece-meal necrosis (interface hepatitis); peripheral lobular necrosis.
o Severe: similar to acute hepatitis picture with presence of Councilman Bodies and
disarrangement of lobules; may be bridging necrosis.
o Fibrosis starts in portal tracts then extends to lobules (septal) then bridging and finally cirrhosis.
Fibrosis is not found in most cases and is reported individually.
o Degree of chronic hepatitis is related to degree of inflammation and necrosis.
o Stage is determined according to degree of fibrosis (mild, moderate… established or actual
cirrhosis).
• Causes of death in chronic hepatitis:
o Cirrhosis, liver failure, hepatic encephalopathy, massive hemorrhage from esophagal varices,
and HCC in HCV infection.
Fulminant hepatitis:
• Disease with high mortality rate due to acute hepatic failure. Histologically, there is massive hepatic
necrosis.
• Etiology: Viral in about 60% (0. 1% of HAV and 1% in HBV). Non-viral mainly due to drug toxicity or
idiosyncrasy (treatment-induced).
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• Morphology:
o Gross: liver is shrunken; capsule is wrinkled, cut-surface is dirty reddish mottled yellow in color.
o Microscopic: Extensive necrosis, absent inflammation (because there is no time for it).
• Clinical features include jaundice, encephalopathy, and fetor hepaticus.
• Extra-hepatic complication: coagulopathy, bleeding, adult respiratory distress syndrome (ARDS) and
renal failure.
• Prognosis: fatal in most cases.
Route of infection
• Hematogenous: most commonly via arteries and portal vein coming from GIT.
• Ascending cholangitis: it is the most common rout. Bacteria ascend through bile duct (from gall
bladder) and infect the liver.
• Direct: e.g.penetrating injuries and trauma.
Predisposing factors
• Depressed immunity and old age.
Morphology
• Gross:
o Single or multiple abscesses (pyemic abscess).
o Small or large up to several centimeters.
o Commonly located in the right lobe (in the posterior part) but could be peripheral in pyemic
abscesses.
• Microscopic: Acute inflammation (abscess).
• Complications:
o Rupture causing septic peritonitis.
o Spread of infection.
• Liver abscess is associated with fever, right upper quadrant pain, tender hepatomegaly and jaundice
(secondary to extra-hepatic biliary obstruction).
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PARASITIC INFECTION
Amebic infection
• Gross:
o Amebic abscess is usually single and commonly located in upper posterior right lobe.
o It is not a true abscess because consists of necrotic tissue (remanents of cells) and blood
(chocolate necrotic contents) with necrotic wall. If this abscess gets infected by another
organism, then become true abscess.
• Microscopic:
o Necrotic liver tissue, mononuclear cells and the organism itself.
• Complications:
o Rupture.
o Spread to lung and brain.
o Infection and true abscess change.
Hydatid
• Gross:
o Multiple cysts with whitish semitransluscent gelatinous thin walls containing clear fluid with tiny
particles (Hydatid sand).
• Microscopic:
o Laminated homogenous chitinous layer; scolices (head of worm); hooks and fibrous tissue
reaction from the host.
• Complications:
o Rupture with anaphylactic shock
o Secondary infection leading to formation of true abscess.
• Unknown etiology
• More Common in females as other autoimmune diseases.
• Increased frequency is associated with HLA B8 or HLA DRw3
• Associated with other autoimmune diseases as Hashimoto thyroiditis, SLE and atrophic gastritis.
• Laboratory findings:
o Negative for viral profiles.
o High IgG levels and auto-antibodies as anti-nuclear antibodies (ANA), smooth muscle antibodies
(SMA), anti-mitochondral antibodies (AMA) and L. K. M. antibodies.
• Morphology:
o Chronic hepatitis with more plasma cells in the portal tracts and occasional granulomata.
• Prognosis: may proceed to cirrhosis. It responds well to immunosuppressive therapy.
22
DRUG INDUCED AND TOXIN INDUCED LIVER DISEASE
• It should be considered in any form of liver disease as a differential diagnosis. So, good history of
drugs should be taken.
• Pathogenesis:
o Direct effect of the drug on the hepatocytes.
o Indirect through metabolites or immune-mediated.
• Effect: Immediate or delayed effect in the form of necrosis, cholestasis, impaired liver function,
chronic hepatitis, and negative viral hepatitis profile.
• Examples:
o Microvesicular fatty change: tetracyclines, salycelates, and alcohol.
o Macrovesicular fatty change: alcohol, methotrixate.
o Centrilobular necrosis: halothane, rifampicin, acetaminophen.
o Massive necrosis: halothane, mushroom poison, acetaminophen.
o Hepatitis: methyl dopa, isoniasid.
o Fibrosis and cirrhosis: Alcohol, methotrixate.
o Granulomatous reaction: allopurinol.
o Cholestasis: contraceptive pills, anabolic steroids, and chlorpromazine.
REYE SYNDROME
(SALYCELATES TOXICITY)
23
o Alcoholic Hepatic Steatosis:
§ Microvesicular or macrovesicular according to the amount and duration of alcohol
consumption.
§ Grosslly the liver is enlarged, soft and yellow (greasy liver).
§ With continuing alcohol consumption, fibrous tissue appears around central vein
extending to adjacent sinusoids.
§ Alcoholic hepatic steatosis is reversible, unless fibrosis has been started.
§ Clinical features: hepatomegaly, ↑ bilirubin, ↑alkaline phosphatase, and may be no
evidence of liver disease.
§ Pathogenesis: (see mechanism of fatty change in alcoholism).
i. Shunting of fat metabolism toward lipid biosynthesis.
ii. Impaired lipoprotein synthesis and secretion.
iii. ↑peripheral catabolism of fat.
o Alcoholic Hepatitis:
The main microscopic features are:
§ Centrilobular necrosis.
§ Neutrophilic reaction to degenerating hepatocytes.
1
§ Mallory’s bodies : eosinophilic clumped cytoplasmic filaments. Although characteristic, it
is not specific for ALD.
§ Fibrosis, sinusoidal, perivenular (mainly), and periportal. Liver (grosslly) appears
mottled red with bile stained areas.
§ May be cholestasis.
o Alcoholic Cirrhosis:
Alcoholic cirrhosis is the final irreversible form of ALD. Women are more susceptible to develop
alcoholic cirrhosis.
§ Pathogenesis: It may follow fatty liver or alcoholic hepatitis. Hepatocytes injury may
result from:
i. Steatosis (pressure of fat → liver damage).
ii. Induction of cytochrome P-450 by the alcohol (enzyme inducer) →
transformation of other drugs to toxic metabolites.
iii. Free radicles generated during alcohol metabolism.
iv. Direct effect on microtubules and mitochondria and membrane fluidity.
v. Immune mediated due to formation of hepatic neoantigens.
vi. Injury may be related to host factors and so alcohol amounts producing
previous effects is not known.
1
Due to accumulation of tangled skeins of cytokeratin intermediate filament and other proteins.
24
§ Morphology:
i. Early; the liver is enlarged (may weight more than 2 kg), pale (yellow-tan: fatty)
with micronodular cirrhosis.
ii. Late; it is shrunken (secondary to fibrosis), brown (accumulation of iron), with
micro- and macronodular cirrhosis.
25
METABOLIC DISEASES
(IN.B.ORN ERRORS OF METABOLISM)
26
NEONATAL HEMOCHROMATOSIS
• Rare disaese.
• There is iron accumulation in parenchymatous organs, sparing mononuclear phagocyte system.
• An important cause of neonatal liver failure.
• May recur in sequential pregnancies even when paternity has been different, there may be a
mitochondrial basis of inheritance or an in utero environmental exposure.
o Morphology:
§ Liver: Pigmentary cirrhosis (micronodular).
§ Pancreas: atrophic and fibrotic.
§ Heart: cardiomyopathy.
§ Skin: slate blue color (bronze).
§ Testis: atrophy.
§ Joints: arthritis.
Iron accumulates as ferretin and hemosedrin and it is demonstrated by iron stains (Prussian blue
reaction).
o Hemosidrin deposits in the following organs (in decreasing order of severity):
o Liver, pancreas, myocardium, pituitary gland, adrenals, thyroid, parathyroid, joint, skin.
METABOLISM OF CUPPER
• Absorption of ingested cupper (2-5 mg/day).
• Plasma transport with albumin.
• hepatocellular uptake and binding to α-2-globulin to for.
• Secretion of ceruloplasmin, constitutes 40-95% of plasma copper.
• Reuptake and degredation of senescent ceruloplasmin.
• Free copper is secreted into bile.
• Pathogenesis: decreased ceruloplasmin formation that carries copper; so copper is free and
accumulates in tissues with increased urinary execration.
• Morphology:
o Liver: fatty change, acute or chronic hepatitis, cirrhosis.
o Brain: degenerative changes in the basal ganglia.
o Eye: green to brown ring in the cornea (Kysar-Fleischer ring).
• Clinically: liver cirrhosis, Parkinsonism (as copper damages basal ganglia).
27
• Diagnosis: biochemical by: ↓ serum ceruloplasmin, ↑ hepatic copper content and ↑ copper
excretion in urine.
• Copper causes injury to liver by:
o Promoting free radicals formation.
o Binding to cellular protein through sulfhydral group.
o Displacing other metals in hepatic metaloenzyme.
NEONATAL HEPATITIS
• Non specific term for a variety of hepatic disorders in the neonate with prolonged cholestasis,
hepatomegaly and hepatic dysfunction.
• Etiology:
o Idiopathic, 50-60%.
o Viral.
o Bacterial, syphilis and urinary tract infection.
o Extrahepatic biliary atresia.
o Alpha 1 antitrypsin deficiency.
• Morphology:
o Hepatitis with prominent cholestasis.
o Pan lobular giant cell transformation (intercellular walls are broken down to become giant cells).
o Extramedullary hematopoiesis (hemopoietic tissue of liver remains after birth beyond the time at
which it suppose to disappear).
• Causes of neonate jaundice:
o Physiologic (see above).
1
Mainly neutrophil elastase released at the site of inflammation.
2
Periodic Acid Schiff: give glycogen pink color.
28
o Biliary atresia.
o Neonatal hepatitis.
o Alpha 1 antitrypsin deficiency.
o Toxic
o Galactosemia.
1
For further information, see table 16-9 in Robbins.
29
• Commoner in females (by ratio of 40:1), middle age, insidious (gradual) onset, full blown picture of
cholestasis (that is, jaundice and pruritis).
• Patient may develop hepatic decompansation including portal hypertention, variceal bleeding and
hepatic encephalopathy.
• 20 -80 years old onset and peak between 40- 50 year old
• Pathogenesis:
o Autoimmune: lymphocyte-mediated destruction of bile duct epithelium and antimitochondrial
antibodies in 90% of patients (antibodies against mitochondrial pyrovate dehydrogenase).
o May be associated with other autoimmune diseases.
• Morphology
o Grosslly: enlarged yellowish green liver, finely nodular
o Microscopically: portal chronic inflammation, destroyed small bile ducts and granulomas. There
are NO neutrophils.
o By time there is extension to the lobules with fibrosis followed by cirrhosis.
• Lab. Findings:
o Markedly elevated alkaline phosphatase, high cholesterol and antimitochondrial antibodies
(AMA).
o Hyperbilirubinemia is developed later signifying incipient hepatic decompancation.
• Clinical features:
o Extrahepatic conditions include: dry eye and mouth (Sjogren syndrome), scleroderma, thyroiditis,
rheumatoid arthritis, Raynaud phenomenon, membranous glumerulonephritis and celiac disease.
30
RULE: any disease (either acquired or congenital) causing dilatation of bile ducts may end with
cholangiocarcinoma.
CIRCULATORY DIAORDERS1
31
• Passive congestion:
o Caused by HF, constrictive pericarditis.
o Effect:
§ Nutmeg liver: necrotic center, dilated sinusoids, atrophic cords and viable periphery.
§ Cardiac sclerosis.
• Peliosis Hepatis: (sinusoid dilation)
o Irregular reddish patches of irregular blood filled spaces with or without lining.
o Caused by anabolic steroids and rarely by contraceptive pills and danazol.
o Pathogenesis: not known.
o Lesions disappear after cessation of drug intake.
1
Originally described in Jamaican drinkers of pyrrolizidine alkaloid-containing bush tea.
32
HEPATIC DISEASES ASSOCIATED WITH PREGNANCY
Intrahepatic Cholestasis
• Jaundice and pruritus in 3rd trimester.
• Generally benign condition.
• Picture of cholestasis.
TRANSPLANTATION
33
TUMORS AND TUMOR LIKE CONDITIONS
Classification
• Tumor like lesions (form masses but not neoplastic):
o Hemangiomas.
o Biliary cysts.
o Nodular hyperplasia.
• Tumors:
o Benign
§ Adenoma either from:
i. Hepatocyte, or
ii. Bile duct epithelium.
o Malignant
§ Primary:
i. Hepatocellular carcinoma.
ii. Cholangiocarcinoma (arising from bile duct epithelium).
iii. Hepatoblastoma (tumor arising during childhood).
iv. Angiosarcoma (arising from blood vessels wall).
§ Secondary: Metastasis.
TUMOR-LIKE LESIONS
Hemangiomas
• It is (hamartoma) and not true tumor.
• Discrete red-blue soft nodules, less than 2 cm in size, usually subcapsular.
• Mostly cavernous type Hemangiomas.
• It is considered as an important source for clinically significant internal bleeding.
Nodular Hyperplasia
• Solitary or multiple hyperplastic nodules with or without cirrhosis.
• It may induce portal hypertension.
• Pathogenesis:
o Focal obliteration of the hepatic vasculature with secondary hyperplasia of well vascularised
lobules.
• It is of two forms:
o Focal: Noncapsulated mass with central stellate scar. It is more common in middle aged women.
Prognosis is excellent.
o Diffuse: with no central fibrosis. It occurs with any systemic inflammation and transplantations. If
the nodules are multiple, it may induce portal hypertension.
34
BENIGN TUMORS
Adenomas (hepatic adenoma)
• Commonest in women taking contraceptive pills. Regresses on stopping hormones intake.
• May attain large size, up to 30 cm, often beneath capsule (sub-capsular).
• No portal tracts.
• Complications: may rupture with fatal hemorrhage.
• Microscopically: large trabeculae of normal hepatocytes with no portal tracts.
• Liver adenomas are significant for two reasons:
o When they present as an intrahepatic mass, they may be mistaken for HCC.
o Subcapsular ademonas are at risk of rupture leading to hemorrhage especially in pregnancy.
MALIGNANT TUMORS
Hepatocellular Carcinoma
1
• Most common primary liver tumor (90%).
• Incidence: Middle to late decades. More common in males (by 4:1). Common in Far East (related to
types of food) and Egypt (due to HBV and HCV endemic).
• Etiology:
o Has a close link to HBV and HCV, proved by epidemiologic studies.
o Integration (insertion) of the virus in hepatocytes genomes → instability → transformation to
neoplastic cells.
o Related to cirrhosis due to other causes (regenerating nodules → neoplastic masses).
o Risk of carcinogenic substances as aflatoxin B1 (fungal toxin) and thorotrast (formerly used in
radiography of biliary tract).
• Morphology:
o Grosslly: Single or multiple masses of diffuse infiltration with marked hepatic enlargement.
Intrahepatic metastasis and gross vessel invasion may be present.
o Microscopically: Ranges from well differentiated to highly anaplastic tumors. The former shows
trabecular, tubular or pseudo-glandular pattern. The latter shows marked pleomorphism with
high mitotic rate. These cells form more than one-layer trabeculae. Bile may be seen. Staining
for alpha fetoprotein is usually positive. Background of cirrhosis is mostly found.
• Spread of tumor:
o Along the vessels (either blood or lymph vessels) to inside or outside liver such as to the lymph
nodes.
o Direct spread.
o Spread: HCC tends to remain confined to the liver until late in the course. Then, it may spread
to regional lymph nodes, lungs, bones, and adrenal glands.
1
The most common tumor (either primary or secondary) is metastasis.
35
• Clinical features:
o Enlarged liver mass.
o Right quadrant pain.
o Weight loss and worsening ascitis.
o Fever of unknown cause (PUC). This fever, together with unexpected weight loss, suggests
deep tumor.
o High serum and tissue levels of alpha fetoproteins. Alpha fetoproteins is an indicator of HCC but
not specific (not diagnostic). It could be seen in conditions like cirrhosis, massive liver necrosis,
and hepatitis. However, very high level (> 100 ng/mL) is rarely encountered except in HCC.
• Prognosis: bad. Death occurs within 6 months as a result of:
o Profound cachexia, GI bleeding or esophageal varices, hepatic failure and coma, and rupture of
tumor which leads to fatal hemorrhage.
• Treatment: resection of small sized HCC but recurrence rate is high.
• Variants:
Fibrolamellar Hepatocellular Carcinoma
o Children and young adults.
o No risk factors, no underlying liver disease.
o Single multinodular mass, encapsulated.
o Fibrous bands separating large eosinophilic hepatocytes with hyaline PAS positive
intracytoplasmic globules.
o Resectable. Good prognosis (well differentiated and can be removed surgically).
Cholangiocarcinoma
• Arises from the intrahepatic biliary tree.
• Risk factors include thorotrast, Clonorchis sinenses (liver flat worm which is endemic in East) and
Carole’s disease.
• No association with cirrhosis.
• Grosslly: as HCC. Microscopically: malignant gland (adenocarcinoma).
• Prognosis: bad because it is a deep seated malignancy.
• Spread: has greater propensity to spread than HCC to the same sites of HCC mentioned above.
• Bile pigment and hyaline inclusions are not found within the cells.
Hepatoblastoma
• Tumor of childhood.
• It could be either:
o Purely epithelial as fetal liver or,
o Mixed (the commonest): neoplasm, epithelial and mesenchymal (bone, muscles,
cartilage…est.).
36
Angiosarcoma
• Malignant tumor of blood vessels.
• Seen in adults.
• Risk factor: thorotrast.
Metastatic tumors
• The liver is a common site for metastasis. Other sites include lung (high O2), bone, brain, and kidney
(highly vascularized).
• Most commonly from the breast, lung and GIT.
• Usually multiple masses with umbilication (necrosis near the surface of the mass).
Congenital anomalies
• Gall bladder:
o May be absent, duplicated or in aberrant location.
1
• Choledochal cyst:
o Congenital dilation of the C. B. D., Children.
o Recurrent abd, pain and jaundice.
o Complications: Gall stones, pancreatitis and common bile duct carcenomai n adults.
1
i.e. common bile duct.
2
Always remember the 5 F’s: female, forty, fatty, fair and fertile.
37
§ Morphology:
Ø Pale yellow, hard, single or multiple, and faceted
+2
Ø Usually radiolucent (not seen in X-ray), Ca salts render it opaque.
Ø Exclusively in the gall bladder (do not move from gall bladder).
o Pigment:
§ More in developing countries.
§ Risk factors: hemolytic anemia’s and Biliary tract infections.
§ Pathogenesis:
Ø Increased excretion of insoluble unconjugated bilirubin (pigment) as occurs
in hemolytic anemias.
+2
Ø Infection resulting in precipitation of Ca .
Ø Change in mucosa and stasis.
§ Morphology:
Ø Color: (1) black (pure pigment) in sterile gall bladder which are small and
great in number; (2) brown in infected gall bladder which are single or few,
soft with grease or soap-like in consistency owing to presence of retained
fatty acids released by bacterial phosphlipases.
Ø Radio-opaque black stone and radiolucent brown stone.
Ø Site: gall bladder or bile ducts.
§ Clinical features:
Ø Gall stone is usually silent for decades before becoming symptomatic.
Ø Biliary pain: excruciating, constant or colicky (spasmodic) pain due to
obstruction or movement of stone. Inflammation may also lead to pain.
§ Complications:
Ø Cholecystitis (inflammation of gall baldder).
Ø Cholangitis (inflammation of common bile duct).
Ø Empyema (dilated gall bladder filled with pus).
Ø Perforation (leading to peritonitis) and fistula formation between gall bladder
and a loop of intestine (adhesion to intestine → necrosis → fistula).
Ø Obstructive cholestasis (a common cause).
Ø Pancreatitis: there will be reflux of pancreatic secretion due to obstruction of
hepatopancreatic duct (may cause hepatitis).
1
Ø Gall stone ileus : functional intestinal obstruction (sever colic pain →
temporary paralysis).
1
Cessation of intestinal movement.
38
Ø Organic intestinal obstruction. Rarely, a large stone may pass through a
fistula and obstruct intestinal lumen.
Ø Mucocele of the gall bladder (dilated, stone-obstructed gall bladder filled
with mucus after infection).
Cholecystitis
• Acute Calculous Cholecystitis1:
o Acute inflammation of the GALL BLADDER in presence of gall stones.
o Pathogenesis: Obstruction of the neck or cystic duct followed by secondary release of chemical
mediators, chemical irritation by bile acids and ischemia followed by bacterial contamination and
inflammation
o Morphology:
§ Gall bladder enlarged, bright red (due to inflammation), tense, may be patchy green to
black, serosal fibrin (flakes of fibrin) on the serousal surface and purulent content.
§ Microscopically: picture of acute inflammation (hyperemia and inflammatory reaction
rich in neutrophils)
o Clininically: Right upper quadrant or epigastric pain (may be referred to the right shoulder. Mild
fever, anorexia, nausea, vomiting and may be jaundice (obstruction → bile accumulation).
o Complications:
§ Spread of infection.
§ Cholangitis: inflammation of common bile duct (abscess may ascends to the liver)
§ Perforation or rupture with peritonitis.
§ Biliary enteric fistula (cholecystenteric fistula) formation: it provides a way to obstruct
the intestine by the stone if large enough.
§ Aggrevation of pre-existing illness with cardiac, pulmonary, renal, or liver
decompensation.
• Acute Acalculous Cholecystitis:
o About 10%
o May follow major surgery, postpartum, sepsis and multisystem failure (due to depressed
immunity).
o Morphology: similar to calculi Cholecystitis but no stones.
1
Acute calculous cholecystitis is the most frequent type of acute cholecystitis (90%). It is also considered
as the commonest major complication of gall stone and the most common reason for emergency
cholecystectomy.
39
o Causes:
§ Postoperative state after major non biliary surgery.
§ Svere trauma or burns.
§ Sepsis
§ Multiple events may contribute to acute acalculous cholecystitis including dehydration,
gall bladder stasis and sludging, vascular compromise, and ultimately bacterial
contamination.
• Chronic Cholecystitis:
o Follows repeated attacks of acute Cholecystitis or it may be chronic from the start.
o Usually associated with gall stones.
o Morphology:
o Gall bladder contracted (small in size), normal or large, frequently associated with stones.
o Wall thick and grey white (due o fibrosis), may be calcified (porcelain gall bladder).
o Mucosa may be atrophic.
40
• Cholangitis:
o Inflammation of the wall of the bile ducts. Always by duct infection of sterile lumen.
o Bacterial infection mostly secondary to E. coli.
o Causes: The most common is gallstones, others include catheters, pancreatitis, tumors and
benignstrictures
41
DISEASES OF PANCREAS
• Pancreas is two parts: exocrine & endocrine
EXOCRINE PANCREAS
Congenital anomalies
• Hypoplasia
• Annular pancreas
• Pancreas divisum
• Ectopic pancreas
Acute Pancreatitis
• Definition: Inflammation of pancreas with acute abdominal pain and elevated serum pancreatic
enzymes (e.g.lipase and amylase).
N.B.: if amylase is elevated alone, think of salivary gland disease
• Two degrees:
o Mild or interstitial.
o Severe or hemorrhagic.
1
• Etiology :
o Cholelithiasis
o Alcohol
o Idiopathic
o Other causes as major abdominal surgery, viral infection (e.g.mumps) and vasculitis.
2
• Pathogenesis :
o Pancreatic duct obstruction →
o Interstitial edema (edema of the wall due to retention of fluid and pressure) →
o Impaired blood flow →
o Ischemia →
o Acinar injury →
o Release of pancreatic enzymes →
o Harmful effect on the tissues.
• Morphology:
o Necrosis due to proteases.
o Hemorrhage due to elatases which destroys vascular wall.
o Fat necrosis (most characteristic histologic feature of acute pancreatitis) due to lipases which
affect pancreatic and peritoneal fat. Free fatty acids produced combine with calcium forming
radio-opaque calcium salt.
1
for more see Robbins table 17-1 p. 637
2
for summary see Robbins figure 17-3 p. 638
42
o Inflammation that lead to mild peritoneal fluid.
o Mild peritoneal fluid.
• Common squale of acute pancreatitis is the formation of pseudocysts (liquefied area of necrosis
walled by fibrous tissue).
• Clinical findings:
o Severe abdominal (epigastric) pain radiating to the back.
o One of the causes of acute abdomen.
o Elevated sreum amylases and lipases.
• Cause of death in acute pancreatitis
o Shock: circulatory collapse as a result of vascular dilatation due to enzymes.
o Adult respiratory distress syndrome: due to pulmonary edema rich in fibrin lining alveoli.
o acute renal failure due to renal tubular necrosis
o Secondary abdominal sepsis.
43
EXOCRINE TUMORS OF PANCREAS
Benign:
• Cystadenoma: Large, benign, cystic tumor of pancreas, either of mucinous or serous types.
Malignant:
• Mucinous cystadenocarcinoma: A large multiloculated tumor lined by columnar mucin-producing
epithelium, commonly seen in 40-60 year old women. It has a better prognosis of 40-90% survival
rate if resected.
• Serous cystadenocarcinoma.
• Pancreatic carcinoma: arise from ductal epithelium of pancreas.
o Very deadly cancer, due to its anatomic location.
o Pathogenesis.
o Risk factors: Smoking (indirect carcinogen i.e. from its metabolite which also affects breast and
urinary bladder), chemical carcinogens, high-fat diet, diabetes.
o Pathology: it is similar in morphology of adenocarcinoma. Desmoplastic reaction causes severe
abdominal pain due to nerve affection (perineural infiltration)
o Anatomic Distribution:
§ Head: 60% of cancers and is more quickly diagnosed, because it causes biliary
obstruction and distention of biliary tree (as a result of ampullary invasion). Ulceration
into duodenal mucosa may occur.
§ Tail / body: 35%, insidious onset, late detection, and dissemination.
§ Desmoplastic reaction: formation of collagen around the tumor, due to reaction to
secretory tumor cells.
§ Metastases go to liver, peritoneum, lungs, adrenals and bones.
§ Perineural or intraneural invasions almost always present in tumors extending to
adjacent tissues.
o Clinical features:
st
§ Symptoms: Pain (1 symptom), weight loss, loss of appetite, gnawing epigastric pain,
and obstructive jaundice.
§ Courvoisier Sign: Obstruction of the common bile duct → acute painless dilatation of
gallbladder, and jaundice.
§ Trousseau Sign: Increased risk for thromboembolism with pancreatic carcinoma. One
fourth of patients will develop thromboembolism (migratory thrombophlepitis).
§ Prognosis: Very grim prognosis, due to its anatomical location. Probably the worst
prognosis of all cancers.
44
ENDOCRINE TUMORS OF PANCREAS
Islet-Cell Tumors
• Insulinoma: 75% of islet cell tumors. It arises from Beta-Cells.
o Pathology: Usually benign.
§ Hyperinsulinemia.
§ Serum proinsulin levels are also elevated.
o Clinically: Whipple triad:
§ Hypoglycemic attack with serum glucose at 50 mg/dl.
§ Symptoms of hypoglycemia → CNS symptoms.
§ Hypoglycemic attacks relieved by glucose intake.
• Gastrinoma (Zollinger-Ellison Syndrome):
o 15-20% of islet cell tumors, arising from G-Cell.
o Pathology: Gastric hypersecretion leading to severe peptic ulcer disease (similar to that of
general population but differ in response to ulcer therapy). When ulcer is seen in jejunum, it is
Zollinger-Ellison Syndrome not another cause.
o 2/3 of tumors are malignant. They may occur in duodenum or pancreas, but not in stomach.
• Glucagonoma:
o 1-2% of islet cell tumors, arising from alpha-Cell.
o Symptoms: Triad of symptoms.
§ Necrotizing migratory erythema
§ Diabetes
§ Anemia
• Somatostatinoma: 1% of islet cell tumors. Delta-Cell Tumor.
• Vipoma:
o 1-2% of islet cell tumors. VIP-secreting tumor.
o Symptom Cluster:
§ Non-insulinoma tumor
§ Profuse watery diarrhea
§ Hypokalemia and achlorhydria (WDHA syndrome)
• PPOMA: 1% of islet cell tumors. Pancreatic Polypeptide-secreting tumor. Elevated pancreatic
polypeptide in blood, with no specific symptoms.
45
o MEN type II (Sipple syndrome): Cluster of findings
§ Bilateral Pheochromocytoma
§ No gastrinoma
§ Bilateral medullary carcinoma of the thyroid.
DIABETES MILLETUS
• Defenetion: group of disorders characterized by hyperglysemia OR a chronic disorder of
carbohydrate, fat, and protein metabolism.
1
• Classification :
o Primary
§ Type I
Ø Autoimmune
Ø Idiopathic
Type II
§
o Secondary
§ Chronic pancreatitis (loss of pancreatic substances)
§ Hemochromatosis
§ Pancreatectomy
§ Drugs as corticosteroids (induction of gloconeogenesis→ hyperglysemia)
§ Hormonal tumors (e.g.pituitary adenoma, pheochromocytoma)
1
for more, Robbins table 17-2 p. 642
46
o Insulitis: Auto-immune attack against beta-cell is one of the mechanisms by which beta-cells are
destroyed and insulin is deficient. Cause of auto-immune attack is unknown. Viral infection may
be the triggering factor.
o Viruses that could cause DM type 1A: mumps, coxachi, and infectious mononucleosis viruses.
Diagnosis1:
Two step process to establish diagnosis.
2
• Fasting plasma glucose (FPG) > 140 mg/dl on two occasions.
• Glucose Tolerance Test: Give oral glucose 75gm. Wait 2 hours and measure plasma glucose:
o Failed Test: 2 hours plasma glucose > 200 mg/dl at least twice (1/2 hours intervals) during the
two hour period.
o Impaired Test: 2 hours plasma glucose > 140 mg/dl, with one intervening value >200 mg/dl after
oral glucose tolerance test. About 25% of patients of this condition eventually become diabetic.
47
§ Binding of these products to receptors on endothelium, macrophages, monocytes,
lymphocyte and mesangeal cells leads to vasodilation, cytokines production and
increase permeability resulting in complications.
§ Hemoglobin A1C (Hb-A1C): Glycosylated hemoglobin that is often measured to
monitor the blood-sugar levels of diabetics.
o Polyol Pathway: The way to get rid of excess glucose in non-insulin-dependent tissues, such as
the brain, eye lens, nerve sheath, and renal glumeruli.
+ +
§ Glucose + NADH + N → Sorbitol (and to fructose) + NAD (Aldolase Reductase).
§ Accumulation of Sorbitol (and fructose) is believed to play a role in Diabetic retinopathy,
nephropathy, neuropathy, and microangiopathy.
§ Inhibition of aldolase reductase ameliorates development of cataract and neuropathy.
Accelerated Atherosclerosis
• Affects aorta, large and medium size arteries.
o Myocardial infarction by atherosclerosis of the coronary arteries is the most common cause of
death in diabetics.
Hyaline arteriosclerosis
• Seen in benign hypertension, and old age.
• Clinical: Major cause of death in older Type-II Diabetics.
o Silent MI is common (50%) in this group because of accompanying diabetic neuropathy.
o Coronary bypass is less effective in this group.
o There is thickening of the the intima with hyaline depositions and narrow lumen. It affects
afferent and efferent arterioles of renal glumeruli.
Neuropathy
• Loss of touch, pain perception, and proprioception, particularly in extremities. Pathogenesis is
complex.
• DM affects peripheral nervous system symmetrically and both the motor and sensory nerves
particularly the sensory.
• DM is a common cause of socks and gloves syndrome.
• DM also affects autonomic nerves leading to bowel movement disturbances and impotency.
Foot Problems
• They result from Neuropathy (they can not feel the sore), poor circulation (microvascular disease),
and tendency to infection.
• Greater than 50% of non-traumatic foot amputations occur in Diabetics.
48
Retinopathy
• Microvascular disease of the eye. Neovascularization, and Retinopathy with macular sparing.
• Cataract and glaucoma are common in diabetics.
Nephropathy
• Incidence: It is more prevalent in Type-I Diabetes (50% of cases) than Type-II (10% of cases).
• Clinically: Look for proteinuria (protein permeability is high although the basement membrane is thick),
nephrotic syndrome and hypertension.
• Pathology: A gradual increase in basement membrane (BM). After 10-20 years, material starts to
accumulate in mesangial zone → compromise vascular and urinary spaces.
Kimmelstiel-Wilson
• Nodular glomerulosclerosis. Still the hallmark of diabetic nephropathy.
Papillary Necrosis
• Can occur, as the renal pelvis can get infarcted due to microvascular disease (it is the least to
receive blood supply in the kidney). Necrotic pelvis can be sluffed into the ureters and cause kidney
stones.
• Renal failure is the second common cause of death in diabetics.
• Renal lesions in diabetics:
o Microangiopathy (diabetic glomerulosclerosis): thich membrane with edema.
o Pylonephritis (due to depressed immunity) leading to papillary necrosis.
o Papillary necrosis (necrotizing papillitis)
o Atrophic kidney changes due to atherosclerosis.
Infections
• Diabetics have depressed immunity and are prone to infection
o Mucormycosis.
o UTI's.
o Multiple boil, carbuncle and furuncle in skin.
Ketoacidosis
• Lack of insulin (i.e. high Glucagon: Insulin ratio) promotes lipolysis, breakdown of proteins, and
glycogenolysis.
o ↓ insulin → ↑glucagon → fat break down → ↑free fatty acid oxidation → keton bodies
→ ketonemia and ketonuria → dehydration and ↑ [ H+] → systemic ketacidosis → ketoic
coma
o infection in DM precipitate systemic ketacidosis
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Coma
• In hyperglycemia, high sorbitol in plasma → dehydration → coma.
• Coma is more often seen with hypoglycemia than with hyperglycemia.
• Biochemical cause:
o Glucagon promotes Lipolysis → lots of Acetyl-CoA in the blood.
o Acetyl-CoA builds up in liver.
o Glucagon promotes Gluconeogenesis → Oxaloacetate is diverted to work on making glucose
and is therefore unavailable for the TCA cycle.
o Excess Acetyl-CoA cannot be used in TCA cycle and is hence diverted to Ketone Body
production.
Hypoglycemia
• Symptoms: Palpitations, sweating, tachycardia, fainting, coma.
• Treatment: IV-Glucose.
• Coma: Hypoglycemic coma is more common in Diabetic than ketoacidosis coma, due to over
treatment with insulin.
• Give a comatose diabetic IV glucose, until their blood sugar is known for sure. If you give insulin to a
hypoglycemic patient, you will probably kill them!
• Alcohol inhibits gluconeogenesis and thus can lead to hypoglycemia in Diabetics. Alcohol combined
with insulin can lead to hypoglycemia.
Summary of complications1:
• Atherosclerosis: change in vascular wall and sticking of cholesterol.
• MI
• Gangrene (wet because of depressed immunity and high glucose level that enhances bacterial
growth)
• Hypertension due to renal disease.
• Blindness: retinal microangiopathy → retinal detachment
• Cataract: lens injury
• Renal failure: diabetic glumerulosclerosis
• Pyelonephritis
• Renal papillary necrosis
• Peripheral neuropathy
• Infections
• Ketosis
• Coma: ketotic, hyperglycemic, hypoglycemic
1
see Robbins figure 17-11 p. 648
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Additional notes:
Two main aspects of DM type II pathogenesis:
1- deranged secretion of insulin:
- early in disease course, insulin is higher than normal to compensate for resistance
(Rarely, severe insulin resistance may result from mutation of insulin receptor, but
these patients can maintain normal glucose level as β-cell can produce higher amount
of insulin)
- Then, insuline secretion (not synthesis) is impaired as phase 1 is lost.
- Then pancreas can not produce enough insulin (not clearly known mechanism)
may be due to loss of glucose signal as a result of accumulation of uncoupling
protein 2 inside β-cell.
(Lowering [UCP2] may be the treatment of DM type II)
- Another mechanism is amyloid deposition that makes β-cell refractory to receive
glucose signal. It is also toxic to β-cell.
*
for more, see Robbins Fgure 17-10 p. 647
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IMPORTANT SUBJECTS FOR ESSAYS
• Liver diseases:
o Cirrhosis
o Portal hypertension
o Viral hepatitis
o Chronic hepatitis
o Alcoholic liver disease
o Biliary cirrhosis
o Hepatocellular carcinoma
• Gall bladder:
o Cholelithiasis
o Cholecystitis (acute and chronic)
• pancreas:
o pancreatitis (acute and chronic)
o DM
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