28. FIBROSIS
• FIBROSIS is the end stage of
MOST chronic liver diseases,
and is ONE (of TWO) absolute
criteria needed for the
diagnosis of cirrhosis.
• What is the other?
31. ALL CIRRHOSIS IS:
• IRREVERSIBLE
• The end stage of ALL chronic liver
disease, often many years, often several
months
• Associated with a HUGE degree of nodular
regeneration, and therefore represents a
significant “risk” for primary liver
neoplasm, i.e., “Hepatoma”, aka,
Hepatocellular Carcinoma
41. DEFINITIONS:
• CIRRHOSIS is the name of
the disease as demonstrated by
the anatomic changes
• LIVER FAILURE is the
series and sequence of
abnormal pathophysiologic
events
46. Hepatic Enzymology
• Transaminases (AST/ALT), aka (SGOT/SGPT),
and LDH are “hepatic INTRACELLULAR”
enzymes, and are primarilly indicative of
hepatocyte damage.
• Alkaline Phosphatase (AlkPhos), Gamma-GTP
(Gamma-glutamyl transpeptidase), and 5’Nucleotidase (5’N) are MEMBRANE
enzymes and are primarilly indicative of bile
stasis/obstruction
53. CHOLESTASIS
• Def: Suppression of bile flow
• Associated with membrane
enzyme elevations, “primarily”,
ie, AP/GGTP/5’N
• Familial, drugs (steroids and many common
antibiotics), but bottom line is
OBSTRUCTION
57. VIRAL HEPATITIS
• A, B, C, D, E
• They all look similar, ranging from a few
extra portal triad lymphocytes, to
“FULMINANT” hepatitis with total collapse
of lobules
• Associated with full recovery (usual),
chronic progression over years
leading to cirrhosis (not rare), risk of
hepatoma (uncommon), or death
(uncommon)
58. VIRAL HEPATITIS
•
•
•
•
Jaundice, urine dark, stool chalky
Usual viral “prodrome”
Upper respiratory infection
All have multiple antigen (virus) and
antibody (serology) serum tests
• “Councilman” bodies on biopsy are
very very nice to find. Why?
65. C
LESS common than B (one fourth)
LESS dangerous than B in the acute phase
MORE likely to go chronic than B
MORE closely linked with hepatoma than B
72. Points of Interest
-hepatic vs. EXTRA-hepatic
• PRIMARY biliary cirrhosis is a bona-fide
AUTOIMMUNE disease of the INTRA-hepatic
bile ducts
• SECONDARY biliary cirrhosis is caused by
chronic obstruction/inflammation/both of
the intrahepatic bile ducts
• CHOLANGITIS, or inflammation of the
INTRA-hepatic bile ducts, is associated with
chronic bacterial (often gram negative rods)
infections, or Crohns/Ulcerative colitis (IBD)
•
INTRA
74. Points of Interest
• Infarcts are rare. WHY? (hint: “lung”)
• Passive congestion with “centrolobular”
necrosis, is EXTREMELY COMMON in CHF,
and a VERY COMMON cause of cirrhosis,
i.e., “cardiac” cirrhosis
• Various semi reliable clinical and anatomic
findings are seen with disorders of:
– Portal Veins
– Hepatic veins/IVC
– Hepatic arteries
75.
76. MISC.
• Hepatic Diseases are seen often with
–Pregnancy
• PRE-Eclampsia/Eclampsia (HTN, proteinuria,
edema, coagulopathies, DIC)
• Fatty Liver
• Cholestasis
–Transplant—Bone Marrow or other
Organs
• Drug Toxicities
• GVH
77. BENIGN LIVER TUMORS*
• …..are, in most cases, really regenerative
nodules
• Have been historically linked to BCPs
• Can really be neoplasms of blood vessels
also, if they appear like angiomas
78. MALIGNANT LIVER TUMORS
• 99% are metastatic, i.e., SECONDARY, esp. from
portal drained organs
• Just about every malignancy will wind up
eventually in the liver, like the lungs
• PRIMARY liver malignancies, i.e., hepatomas,
aka hepatocellular carcinomas, arise in the
background of already very serious liver disease
chronic hepatitis/cirrhosis, are slow growing, and
do NOT metastasize readily
• CHOLANGIOCARCINOMAS are malignancies if
the INTRA-hepatic bile ducts and look MUCH more
like adenocarcinomas than do hepatomas
94. Cholecystitis
•
•
•
•
Acute: fever, leukocytosis, RUQ pain
Chronic: Subclinical or pain
Ultrasound can detect stones well
HIDA (biliary) nuclear study can help
• Go hand in hand with stones in
gallbladder or ducts, age, sex, weight
• If surgery is required, most is
laparoscopic
Like the pancreas, the liver, together with the gallbladder, is considered, also to be derived embryologically, as an outpocketing of the foregut.
ForegutCeliac, MidgutSuperior Mesenteric, HindgutInferior Mesenteric
Classical anatomic landmarks in the average 1400-1800 gram adult liver.
Relationship of the liver with neighboring organs
Wirsung = Main
Santorini = Accessory
The liver is nothing more than an array of cells between the portal and caval venous systems. This shows the direction of flow. The liver gets about 80% of its blood supply from the portal veins and 20% from the hepatic arterial system.
The IDEAL three-dimensional diagram: Hexagonal Hepatic “LOBULE”
From the point of view of anatomy, physiology, and pathology, you must clearly understand the DIRECTION is:
Portal vein
Sinusoids
Central vein
Hepatic Veins
IVC
The classical view of liver tissue from a liver biopsy.
Visualizing the “hexagonal” nature of the lobule is CRUCIALLY important in understand liver disease!
The hexagonal “normal” pattern is a concept, but rarely seen in real liver sections!
Recognizing those little holes grossly, is the same as recognizing them microscopically.
If they seem to have connective tissue or bile (green oozing) around them, they are PORTAL veins.
If they seem to have NO connective tissue or bile around them, they are central or hepatic veins.
What is the direction of venous blood flow, portal to central, or vice versa? Ans: From the point of view of anatomy, physiology, and pathology, you must clearly understand the DIRECTION is:
Portal vein
Sinusoids
Central vein
Hepatic Veins
IVC
The FIRST part of the lobule, i.e., portal triad is the FIRST to get blood flow, so it is also the FIRST to get the brunt of general toxic effects, and the LAST to get the brunt of ischemic effects. This is one of the MAIN KEY concepts in understanding liver disease!!!!! (but has more than a rare exception)
The LAST (central) part of the lobule, central vein, which is also the APEX of the acinus!
The classical classification of diseases!
Heatocyte cytoplasm is “balooned”
This is nothing more than the cloudy “swelling” we learned of in chapter 1, representing some compromise of the Na-K pump.
Hepatocytes have “feathery” cytoplasm
This is nothing more than the “swelling” we learned of in chapter 1, but possibly more severe than mere ballooning, and more likely, therefore to lead to irreversible changes.
You must always know the THREE common causes of fatty liver, also called fatty metamorphosis, also called fatty change, also called steatosis:
Obesity
Alcoholism
Diabetes
Fat vacoules are small enough to lie completely WITHIN the hepatocte cytoplasm are termed MICRO-vesicular
Fat vacuoles which are LARGER than hepatocytes is termed MACRO-vesicular.
Why is the differential diagnosis of MACRO vesicular steatosis the same as MICRO vesicular steatosis?
Answer: It is just a matter of severity.
Of the three types of common golden pigment found in the body, 1) hemosiderin, 2) melanin, and 3) bile, only hemosiderin stains BLUE with the prussian blue stain. There are special stains to identify melanin and bile however.
Can you confuse bile with hemosiderin all the time in the liver, unless you do a special stain? Yes
Crucially important concept worth repeating. KNOW the difference between an acinus and a lobule.
The best tip to understanding liver disease is to understand the direction of blood flow. TOXIC injuries generally do more damage in the part of the liver closest to the PORTAL vein, and HYPOXIC injuries generally do more damage in the parts of the liver around the CENTRAL vein, i.e., centrolobular necrosis.
The “hyalinized” appearing round structures are cells dying from a NORMAL replacement process called apoptosis. Where should we put the 2 arrows to demonstrate two apoptotic cells? If this was hepatitis, we might call them “Councilman” bodies.
The “hyalinized” appearing round structures are cells dying from a NORMAL replacement process called apoptosis. Where should we put the 2 arrows to demonstrate two apoptotic cells? If this was hepatitis, we might call them “Councilman” bodies.
Triads are involved with hepatitis earlier than general sinusoids. Why? Ans: There are NORMALLY more “inflammatory” cells in the portal tract
Is this type of hepatitis likely to be SUB-clinical? Answer: YES
Is most hepatitis SUB-clinical? Answer: YES
The disruption of the “limiting plate” is a classical concept in liver disease, especially chronic hepatitis. The “limiting plate” is the fence of connective tissue which delineates a portal triad area from the surrounding hepatocytes. When this is breached, the disease process is regarded as more severe, and many say is the earliest step to cirrhosis.
(Personal radiology anecdotes)
Answer: Irregular NODULES which are delineated and defined by the fibrosis.
There are only 2 times a year I force students to stand up and take an oath! And the other one is the hippocratic oath.
Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!!
Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!!
Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!!
Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!!
Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!!
Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!!
Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!!
Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!!
The hepatoma/cirrhosis cycle: Hepatomas often, perhaps usually, arise in a cirrhosis background, and can be thought of as regenerating nodules that have lost growth control, usually NOT metastasizing, the hepatoma itself causing FURTHER functional liver disease.
Even a blind man would know this liver surface feels “smooth” which generally rules out cirrhosis or tumors even before slicing it for examination.
Can you probably rule out cirrhosis on autopsy even if you were blind? Answer: YES
Why do the words “the surface is smooth and glistening” appear about 100 times in an autopsy report? Ans: To rule out oodles of diseases
How can a blind man differentiate cirrhosis from metastatic disease?
Answer: In cirrhosis there are no “SMOOTH” areas between nodules.
How would the blind man know this is metastatic cancer, rather than macronodular cirrhosis, even if he doesn’t slice it?
Take a look at the tiniest red “dot” in the normal liver. What is it?
In a normal liver, there is connective tissue ONLY in the small portal triad area.
Is this MACRO-nodfular or MICRO-nodular cirrhosis?
How can you tell who the hepato-pathologist is? Answer: He carries a magnifying glass in his lab coat pocket (no joke).
Why are TRICHROME stains recommended for every liver biopsy?
Where are the central veins? Answer: There are none, the the process of nodule formation, the central veins are lost.
Greek: kirrh(ós) orange-tawny
You will do the “fluid wave” test at bedside.
“Spider” nngiomas in cirrhosis are related to
Ther are twokinds of hepatic enzymes: INTRACELLULAR and MEMBRANE ASSOCIATED. This fact forms the basis for hepatic diagnostic enzymology.
But REMEMBER: Cholestasis can give rise to hepatocyte damage, and hepatocyte damage (swelling) can give rise to stasis!
Almost all primarilly INTRACELLULAR liver pathologies result in MEMBRANE elevations too, and VICE VERSA!
Sclera and conjunctiva are the best places to see early jaundice, palms too!
Which one is more polar? Which one is more fat soluble (i.e., NON-polar)?
23 Drugs known to cause cholestasis include the following:
aminosalicylic acid, androgens, azathioprine, benzodiazepines, carbamazepine, carbarsone, chlorpropamide, propoxyphene, estrogens, penicillin, gold, Na thiomalate, imipramine, meprobamate, methimazole, nicotinic acid, progestins, penicillin, phenothiazines, oral contraceptives, sulfonamides, sulfones, erythromycin estolate
A normal liver should NOT have this much bile pigment, in fact bile pigment in a normal liver biopsy should be scarce!
Bile accumulations, which can develop into “lakes”. Why does it look like a lot is BETWEEN hepatocytes in early stages? Ans: Canaliculi
Which two types are of most clinical significance? Answer: B + C
“swollen” liver? What are some of those individual tiny red dots? Ans: Central veins.
The inflammation of hepatitis starts in the portal triad areas, with increasing severity it extends to the sinusoids.
“Fulminant” hepatitis is associated with massive hepatic necrosis and often (usually) results in death. If you think this liver is abnormally SMALL, you are correct. Why? The lobules “collapsed” from necrosis. Can this be called hepato-MICROLY? Ans: Sure, why not?
Note complete COLLAPSE of lobules, and only remnants of biliary epithelium.
Could this be mistaken for metastatic adenocarcinoma on first glance? Ans: You betcha
It would be VERY nice to see Councilman bodies on a liver biopsy to enable the diagnosis of Hepatitis B. Unfortunately, you may not be lucky enough to find them. Does this remind you of the “apoptosis” image? Each “Councilman body” represents apoptotic death of a single liver cell.
Does this remind you that apoptosis and pathologic apoptosis (i.e., necrosis) look identical? YES
Consequences of hepatitis B, surprisingly, most cases of Hepatitis B are SUB-clinical. Why is the only arrow going TO the hepatoma box from cirrhosis?
Consequences of hepatitis C
Laboratory findings in hepatitis B, classical. Logical too!
The MAIN differential of NON viral “hepatitis”: 1) TOXIC (alcohol the most common), 2) autoimmune, and 3) non-viral infectious!
Many of the classical liver toxins can produce a fairly predictable pattern of liver changes. BUT, they can also be quite UN-predictable and varied as well! If your package insert recommends baseline transaminases BEFORE therapy, you can guess it has a good chance of being hepatotoxic.
The overwhelming majority of primary hereditary hemochromatosis cases depend on mutations of the HFE gene discovered in 1996.
Wilson’s disease is due to mutations in the Wilson Disease Protein (ATP7B) gene.
The alpha-1-antitrypsin encoding gene is located on the long arm of the fourteenth chromosome (14q32.1).
Neonatal cholestasis is persistent conjugated hyperbilirubinemia in the newborn with conjugated bilirubin levels exceeding 5.0 mg/dL of total bilirubin level. The disease is either due to defects in bile excretion from hepatocytes or impaired bile flow.
Alpha-1-antitrypsin PROTECTS tissues, especially lung, liver, from HARMFUL NATURAL PROTEASE. Lack of this enzyme, due to a genetic defect, would then be expected to cause destructive changes in these areas.
Why would IBD be associated with cholangitis? Answer: Biliary ductal cells are same embryologic derivation as colonic mucosal cells, and therefore subject to same pathologic patterns of injury and causes.
Would INTRA-hepatic ductal disease be associated with EXTRA-hepatic ductal diseases,? Ans: Absolutely!
The most common liver “vascular” disease “CENTRO-lobular” necrosis, secondary to CHF. Why is the CENTER of the lobule more likely to become necrotic than the portal areas?
Memorize this classical slide, visually!
* aka, focal nodular “hyperplasia”, or hepatic adenomas
The liver can be thought of as being a “lymph” node for early metastases of any organ which has a portal circulation!
The gross and microscopic features of this tumor ice the diagnosis, right? Encapsulation grossly, endothelial cells microscopically
How would the blind man know this is metastatic cancer, rather than macronodular cirrhosis? How would he also know this is probably NOT a hepatoma?
Individually, hepatoma “cells” usually very closely resemble normal hepatocytes! The toxin AFLATOXIN from certain ASPERGILLIS species of fungus is a carcinogen and aids carcinogenesis of hepatocellular cancer by building up in the liver. The combined high prevalence of rates of aflatoxin and hepatitis B in settings like China and West Africa has led to relatively high rates of heptatocellular carcinoma in these regions.
Cholangiocarcinoma is ALWAYS confused with liver metastases. Why? What feature of this gross specimen picture would NOT suggest metastases?
World’s most normal gallbladder. The beautiful orderly epithelium of the mucosa is always uses as a classic example of SIMPLE COLUMNAR.
Common gallbladder “anomalies” are usually developmental. Why are none of these surprising?
The Phrygians were ancient Turks, around 1000 AD. They wore caps like this.
Cholelithiasis is joined at the hip with (chronic) cholecystitis. Each is a result of, and causes, the other!
What is the 90% rule for gallstones as compared to kidney stones?
Is a gallbladder coated with cholesterol, like this one, associated with arteries coated with cholesterol? Ans: YES
Do the foamy cells look like cholesterol laden macrophages which we see in atheromas? Does it give the gallbladder mucosa a “papillary” appearance? What is a cholesterol papilloma?
What 2 chemicals are here? Ans: Cholesterol and bilirubin
What ONE chemical is here? Ans: Bilirubin
Cholecystitis predisposes to cholelithiasis, and VICE VERSA!
The same general rules, diets, and life styles which put cholesterol into your arteries, put it into your gall bladder also! (tongue in cheek)
Most pathologists will admit they have never seen long term survival with carcinoma of the gallbladder, even old pathologists like me.