Diseases of the liver and pancreas



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Rashmi’s tips
the breast pretty much know: acute mastitis, fat necrosis, fibrocystic change, blue doomed cyst, fibroadenoma, carcinoma of the breast, lobular carcinoma insitu, comedocarcionoma, pagets disease of the nipple, intraductal carcinoma, invasicve lobar carcionoma, No special type invasive ductal carcionoma page 10 slide 1, scirrhous carcionoma

\okay the topics she listed were from the male genital tract....they were leydig cell tumor, bowen's disease, yok sac tumor, seminoma

for female genital

1(page number) female genital tract infections, PID

2. bartholian cyst

3.squamous hyperplasia ,linchen sclerosis

4 nothing

5 carcinoma and vulvar interepithelial neoplasia(VIN)

6. extramammary pagets disease(everything!!!)

7 adenocarcinoma

8nothing

9 chronic cervicitis(whole page)

10. PAP smear how it helped cervical cancer

11. Cervical intraepithelial neoplasia (CIN 1, 2, 3

12 squamous cell carcinoma--epithelial pearls

13cervical carcinoma

14 stage zero=CIN III = carcinoma insitu, clinical course precancer precursors

15. tratment: cryotherapy, cone biopsy, and hysterectomy, dysfunctional uterine bleeding...irregular bleeding and no organic lesions, anovulatory cycle at adolesence and perimenopause....

16 ENDOMETRIOSIS!!!!!!! HUGE!!! pain  with defecation while on period

17 endometrial hyperplasia...HUGE

18morphology of endometrial hyperplasia, all slides on endometrial pgs 17-20

20 endomerial carcinoma,

21 leiomyoma

25 polycystic ovarian syndrome, polycystic ovarian disease

27 serous cystadenoma_beginin, serous cystadenocarcinoma,

28 mucinous cystadenocarcionma,

31 yoolk sac tumor dysgerminoma of the ovary

32granulosa cell thecal cell tumor

33 sertoli leydig cell tumors

37 pregnancy induced hypertension

38 hydatidiform mole, choriocarcinoma

Rashmi’s tips end
How to use this review:

Yellow = EXAM  what Dr. Ash has stated to be high yield

Green = info  info that is good to know

Purple = super exam test question  what Dr. Ash has stated to be highyield
Note. That the highlights, may not represent all HIGHYIELD POINTS for the exam.
The notes below are COMPLETE NOTES OF PATH II.

No deletions have been made.

These notes were prepared by Doug. THANK YOU DOUG.
I have only highlighted highyield points that Denham had marked during class as high yield.

Good luck: make sure to do webpath!!!
DISEASES OF THE LIVER AND PANCREAS

Normal Hepatic Architecture

Portal Triad (Red Arrow), Central Vein (Black Arrow), Zones 1,2,3, Cords of hepatic cells Sinusoids containing blood


Bilirubin and Hepatic Bile Formation

  • Hepatic bile formation serves two major functions:

  • Bile constitutes the primary pathway for elimination of bilirubin, excess cholesterol, and xenobiotics which are insufficiently water-soluble to be excreted into urine.

  • Disruption of bile formation becomes clinically evident :

  • Jaundice / Icterus : Yellow discoloration of the skin and sclerae owing to retention of pigmented bilirubin

  • Cholestasis : Retention of not only bilirubin but also other solutes eliminated in bile

  • Bilirubin is the end product of heme degradation

  • The majority is derived from breakdown of senescent erythrocytes by the mononuclear phagocytic system, especially in the spleen, liver, and bone marrow.

  • Bilirubin formed outside the liver is bound principally to serum albumin and transported to the liver.

  • Albumin binding is necessary because bilirubin is virtually insoluble in aqueous solutions at physiologic pH.

  • Hepatic processing of bilirubin involves

  • Carrier-mediated uptake at the sinusoidal membrane

  • Intracellular binding, especially to ligandin

  • Delivery to the endoplasmic reticulum, possibly by rapid membrane-membrane transfer;

  • Conjugation with one or two molecules of glucuronic acid by bilirubin UDP-glucuronosyltransferase (UGT)

  • Excretion of the water-soluble, nontoxic bilirubin glucuronides into bile

  • Most bilirubin glucuronides are deconjugated by bacterial beta-glucuronidases and degraded to colorless urobilinogens

  • Urobilinogens and the residue of intact pigment are largely excreted in feces.

  • Approximately 20% of the urobilinogens formed are reabsorbed in the ileum and colon, returned to the liver, and promptly re-excreted into bile – Enterohepatic Circulation

  • The small amount that escapes this enterohepatic circulation is excreted in urine.


Bile Acids and Bile Formation

  • Bile contains bilirubin and bile acids

  • Bile acids mostly are taurine and glycine conjugates of cholic and

chenodeoxycholic acid.

  • ~ 10 to 20% of excreted bile acids are deconjugated in the

intestines by bacterial action

  • Virtually all conjugated and deconjugated bile acids are reabsorbed

(especially in the ileum) and returned to the liver for uptake, reconjugation,

and resecretion.



for maintaining a large endogenous pool of bile acids for digestive and

excretory purposes.


Jaundice

  • Jaundice appears when bilirubin is elevated in blood and is deposited in tissues

  • Normal blood levels < 1.2 mg/dl.

  • Jaundice becomes evident when > 2.0 to 2.5 mg/dl

  • Unconjugated bilirubin is not soluble in aqueous solution and is tightly complexed to albumin

  • As such, it cannot be excreted in urine even when the blood levels are high

  • The small amount of unbound pigment, when present in excess, may cause toxic damage to the neonatal brain (kernicterus) owing to immaturity of the blood-brain barrier.

  • In contrast, conjugated bilirubin is water-soluble, nontoxic, and weakly associated with albumin.

  • When present in excess, it is readily excreted in urine (bilirubinuria).

  • With both unconjugated and conjugated hyperbilirubinemia, pigmentation of the skin and sclerae is readily visible.

  • Jaundice occurs when bilirubin production exceeds hepatic clearance capacity, via the following mechanisms:

  • Unconjugated hyperbilirubinemia:

  • Excessive production of bilirubin

  • Reduced hepatic uptake

  • Impaired hepatic conjugation.

  • Conjugated hyperbilirubinemia:

  • Decreased hepatic excretion of bilirubin conjugates

  • Impaired extrahepatic bile flow

  • In general one mechanism predominates in a given disease state.

  • Therefore, when a patient presents with jaundice, a knowledge of the predominant form of plasma bilirubin is of value in arriving at the possible cause of hyperbilirubinemia.




TEST: FROM TABLE:



Gilberts syndrome

Decreased intrahepatic excretion of bilirubin:

Crigler-Najjar syndromes types I and II)

Impaired canalicular transport of bilirubin glucuronides (Dubin-Johnson Rotors syndromes)

Extrahepatic biliary obstruction:

Gallsonte obstruction of biliary tree

Extrahepatic biliary atresia

Fluke infestation
Cholestasis

  • Refers to bile secretory failure per se, which is accompanied by the accumulation in blood of substances normally excreted in bile (bilirubin, bile salts, and cholesterol)

  • Cholestatic conditions, which may result from hepatocellular dysfunction or intrahepatic or extrahepatic biliary obstruction, may also present with jaundice. Alternatively, pruritus is a common presenting symptom, presumably related to the elevation in plasma levels of bile acids. Skin xanthomas sometimes appear, the result of hyperlipidemia and impaired excretion of cholesterol. A characteristic laboratory finding is elevated serum alkaline phosphatase, an enzyme present in bile duct epithelium and the canalicular membrane of hepatocytes. An isozyme is normally present in many other tissues such as bone, and so the increased levels must be verified as being hepatic in origin. Other manifestations of reduced bile flow relate to intestinal malabsorption, including deficiencies of the fat-soluble vitamins A, D, or K.

  • Three major conditions cause unconjugated hyperbilirubinemia (80% or more of the serum bilirubin is unconjugated):

  • Bilirubin overproduction:

  • Hemolytic disease is the most common cause.

  • Resorption of major hemorrhages into the lungs, alimentary tract or other tissues

  • Reduced hepatic uptake of bilirubin:

  • Gilbert’s syndrome #1 cause: dx?

  • After administration of certain drugs such as rifampin

  • Impaired conjugation of bilirubin:

  • The activity of hepatocellular bilirubin UGT is low at birth and does not reach normal levels until about two weeks of age.

  • Thus, almost every newborn develops transient and mild unconjugated hyperbilirubinemia, called neonatal jaundice or physiologic jaundice of the newborn.

  • Breast-fed infants tend to exhibit jaundice with greater frequency, possibly the result of beta-glucuronidases present in maternal milk.

Hereditary Hyperbilirubinemias Dubin-Johnson Syndrome

Coarse pigmented granules within the



cytoplasm of hepatocytes

Table exam questions:

Unconjugated hyperbilrubinemia:

Auto. Recessive (Crigler-Najjar syndrome type I)

Auto. Domin (Crigler-Najjar syndrome type II)

Gilberts syndrome:

Conjugated hyperbilrubinemia:

-dubin Johnson ndrome: aut recessive: impaired bilary excretion, pigmented cytoplasmic globules
Hepatic Failure

  • Hepatic failure reflects the destruction of overall hepatic function

  • Loss of hepatic functional capacity must exceed 80 to 90% before hepatic failure ensues

  • This may come about through

  • Insidious action of a chronic progressive disorder

  • Repetitive discrete bouts of parenchymal damage

  • Sudden and massive obliteration

  • In most cases of severe hepatic dysfunction, liver transplantation is the only hope for survival

  • Mortality from hepatic failure is 70 to 95%.

  • Major disorders causing hepatic failure can be divided into three categories:

  • Ultrastructural lesions that do not produce overt liver cell necrosis: Reye’s syndrome, acute fatty liver of pregnancy, tetracycline toxicity.

  • Chronic liver disease: Relentless chronic hepatitis, cirrhosis, inherited metabolic disorders.

  • Massive hepatic necrosis: Fulminant viral hepatitis; massive toxic damage as from acetaminophen, halothane, monoamine oxidase inhibitors used as antidepressants; industrial chemical agents such as carbon tetrachloride and phosphorus; and mushroom poisoning (e.g., Amanita species).





Table exam:

Jaundice

Fetor hepaticus

increased serums levels of hepatic enzymes

Gynecomastia

Low yield:

Hypoalbuminemia

Coagulopathy

Hepatorenal syndrome
Hepatic Failure - Hepatic Encephalopathy

  • A metabolic disorder of the central nervous system and neuromuscular system

  • Patients exhibit a spectrum of disturbances in consciousness

  • Subtle behavioral abnormalities - marked confusion and stupor- deep coma and death.

  • Fluctuating neurologic signs such as nonspecific electroencephalographic changes, limb rigidity and hyperreflexia, and rarely seizures.

  • Particularly characteristic is asterixis: nonrhythmic, rapid extension-flexion movements of the head and extremities, best seen when the arms are held in extension with dorsiflexed wrists.

  • Two physiologic factors appear to be important in the genesis of this disorder:

  • Shunting of blood around the liver

  • Spontaneous portosystemic connections - advanced cirrhosis

  • Surgical portocaval anastomosis

  • Severe loss of hepatocellular function

  • The net result is exposure of the brain to an altered metabolic milieu, the specifics of which are not yet clear


Hepatic Failure - Hepatorenal Syndrome

  • Refers to the appearance of renal failure in patients with severe liver disease, in whom there are no intrinsic morphologic or functional causes for the renal failure.

  • Kidney function improves if hepatic failure is reversed

  • Pathophysiology of renal failure unclear

  • The favored theory is reduction of renal blood flow, particularly to the cortex, the result of vasoconstriction

  • This is accompanied by a decreased glomerular filtration rate and avid renal retention of sodium.


Cirrhosis

  • End-stage form of liver disease

  • Defined by 3 characteristics:

  • Fibrosis in the form of

  • Delicate bands (portal-central, portal-portal, central-central)

  • Broad scars replacing multiple adjacent lobules

  • Parenchymal nodules created by regeneration of hepatocytes.

  • Parenchymal architecture of the entire liver is disrupted

Etiology

  • Alcoholic liver disease (60 - 70%)

  • Viral hepatitis (10%)

  • Biliary diseases (5 -10%)

  • Primary hemochromatosis (5%)

  • Wilson’s disease (rare)

  • Alpha1-antitrypsin (AAT) deficiency (rare)

  • Cryptogenic cirrhosis (10 - 15%)

Clinical Features

  • May be asymptomatic

  • When symptomatic, lead to nonspecific clinical manifestations:

  • Anorexia

  • Weight loss

  • Weakness

  • Frank debilitation

  • Ultimate mechanism of most cirrhotic deaths is

  • Progressive liver failure

  • Complication related to portal hypertension

  • Development of hepatocellular carcinoma.


Cirrhosis - Portal Hypertension

Increased resistance to portal blood flow



Causes:

  • Prehepatic

  • Obstructive thrombosis and narrowing of the portal vein before it ramifies within the liver.

  • Massive splenomegaly shunts excessive blood into splenic vein, which drains into the portal vein

  • Intrahepatic

  • Cirrhosis, accounting for most cases of portal hypertension.

  • Schistosomiasis

  • Veno-occlusive disease

  • Massive fatty change

  • Diffuse fibrosing granulomatous disease - sarcoidosis and miliary tuberculosis

  • Diseases affecting the portal microcirculation - nodular regenerative hyperplasia

  • Posthepatic

  • Severe right-sided heart failure

  • Constrictive pericarditis

  • Hepatic vein outflow obstruction

  • Four major clinical consequences are

  • Ascites

  • Formation of porto-systemic venous shunts

  • Congestive splenomegaly

  • Hepatic encephalopathy

Portal Hypertension

Portal Hypertension - Ascites

  • Refers to the collection of excess fluid in the peritoneal cavity.

  • Usually becomes clinically detectable when at least 500 ml has accumulated,

  • Many liters may collect and cause massive abdominal distention.

  • The pathogenesis of ascites is complex, involving one or more of the following mechanisms:

  • Sinusoidal hypertension

  • Percolation of hepatic lymph from the liver capsule into the peritoneal cavity

  • Renal retention of sodium and water, despite a total body sodium that is greater than normal.


Portosystemic Shunts

  • With the rise in portal system pressure, bypasses develop wherever the systemic and portal circulation share common capillary beds.

  • Principal sites are

  • Veins around and within the rectum (manifested as hemorrhoids),

  • Cardioesophageal junction (esophagogastric varices)

  • Retroperitoneum

  • Falciform ligament of the liver (periumbilical and abdominal wall collaterals)

  • Esophagogastric varices appear in about 65% of patients with advanced cirrhosis of the liver and cause massive hematemesis and death in about half of them

  • Abdominal wall collaterals appear as dilated subcutaneous veins extending from the umbilicus toward the rib margins (caput medusae)

  • Are an important clinical hallmark of portal hypertension.


Splenomegaly

  • Long-standing congestion may cause congestive splenomegaly.

  • The degree of enlargement varies widely up to 1000 gm and is not necessarily correlated with other features of portal hypertension.

  • Massive splenomegaly may secondarily induce a variety of hematologic abnormalities attributable to hypersplenism

Hepatitis Serology



Hepatitis B serology





KNOW EVERYTHING ON THE TABLES:

High yield:

Hep B Hep A and Hep E
Know: HBeAb: antibody to e antigen; indicates low transmissibility!!!
Window period: HbcAb IgM is +

Immunization is + at HbsAb IgG
Viral Hepatitis
Clinicopathologic Syndromes


  • A number of clinical syndromes may develop after exposure to hepatitis viruses:

  • Carrier state:

  • without clinically apparent disease

  • with chronic hepatitis.

  • Asymptomatic infection:

  • serologic evidence only.

  • Acute hepatitis:

  • Anicteric

  • Icteric.

  • Chronic hepatitis:

  • Without progression to cirrhosis.

  • With progression to cirrhosis.

  • Fulminant hepatitis:

  • Submassive to massive hepatic necrosis.

Viral Hepatitis - Carrier State

  • An individual who harbors one of the Hepatitis viruses without manifesting symptoms

  • Therefore can transmit an organism

  • A carrier can be

  • a “healthy” carrier - suffering from little or no adverse effects

  • having chronic disease but free of symptoms / disability

  • Both constitute reservoirs of infection

  • Carrier state is best characterized for Hepatitis B Virus

  • Infection early in life, particularly via vertical transmission during childbirth, produces a carrier state 90 to 95% of the time.

  • In contrast, only 1 to 10% of adult infections yield a carrier state.

  • “Healthy” HBV carrier state - liver biopsy normal

  • Viable isolated hepatocytes or clusters of cells have “ground-glass,” finely granular, eosinophilic cytoplasm laden with HBsAg

  • Other cells have “sanded” nuclei imparted by abundant HBcAg, indicating active viral replication.

Hepatitis B infection – Carrier State

  • Ground glass hepatocytes


Acute Viral Hepatitis

  • Any one of the hepatotropic viruses can cause acute viral hepatitis.

  • Whatever the agent, the disease is more or less the same and can be divided into four phases:

  • An incubation period

  • Peak infectivity occurs during the last asymptomatic days of the incubation period and the early days of acute symptoms.

  • A symptomatic preicteric phase :

  • Nonspecific, constitutional symptoms

  • Illness may be dismissed as flu-like, unless its true nature is revealed by elevated serum aminotransferase levels

  • Caused mainly by conjugated hyperbilirubinemia

  • Urine turns darker (conjugated bilirubinuria), and the stools may become lighter owing to cholestasis

  • Retention of bile acids can cause distressing pruritus

  • The liver may be mildly enlarged and moderately tender to percussion.

  • Laboratory findings include prolonged prothrombin time

  • Convalescence

  • The morphologic changes in acute viral hepatitis are virtually the same regardless of the causative agent and can be mimicked by drug reactions.

  • Grossly, the liver is slightly enlarged and more or less green depending on the phase of the acute disease and the degree of jaundice.

  • Histologically the major findings are

  • Necrosis of random, isolated liver cells or small cell clusters

  • Evident as fragmented, eosinophilic Councilman bodies

  • Bridging necrosis connecting portal-to-portal, central-tocentral, or portal-to-central regions of adjacent lobules

  • Diffuse liver cell injury – lobular disarray

  • Reactive changes in Kupffer cells and sinusoidal lining cells and an inflammatory infiltrate in portal tracts

  • Evidence of hepatocytic regeneration during the recovery phase.

Acute hepatitis

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