Cyberfriends: The help you're looking for is probably here.
Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected.
DoctorGeorge.com is a larger, full-time service.
There is also a fee site at
www.afraidtoask.com.
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With one of four large boxes of "Pathguy" replies. |
I'm still doing my best to answer
everybody.
Sometimes I get backlogged,
sometimes my E-mail crashes, and sometimes my
literature search software crashes. If you've not heard
from me in a week, post me again. I send my most
challenging questions to the medical student pathology
interest group, minus the name, but with your E-mail
where you can receive a reply.
Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource. Someday you may be able to access these pictures directly from this page.
Also:
KCUMB Pathology Club
Freely have you received, freely give. -- Matthew 10:8. My
site receives an enormous amount of traffic, and I'm
handling about 200 requests for information weekly, all
as a public service.
Pathology's modern founder,
Rudolf
Virchow M.D., left a legacy
of realism and social conscience for the discipline. I am
a mainstream Christian, a man of science, and a proponent of
common sense and common kindness. I am an outspoken enemy
of all the make-believe and bunk that interfere with
peoples' health, reasonable freedom, and happiness. I
talk and write straight, and without apology.
Throughout these notes, I am speaking only
for myself, and not for any employer, organization,
or associate.
Special thanks to my friend and colleague,
Charles Wheeler M.D.,
pathologist and former Kansas City mayor. Thanks also
to the real Patch
Adams M.D., who wrote me encouragement when we were both
beginning our unusual medical careers.
If you're a private individual who's
enjoyed this site, and want to say, "Thank you, Ed!", then
what I'd like best is a contribution to the Episcopalian home for
abandoned, neglected, and abused kids in Nevada:
My home page
Especially if you're looking for
information on a disease with a name
that you know, here are a couple of
great places for you to go right now
and use Medline, which will
allow you to find every relevant
current scientific publication.
You owe it to yourself to learn to
use this invaluable internet resource.
Not only will you find some information
immediately, but you'll have references
to journal articles that you can obtain
by interlibrary loan, plus the names of
the world's foremost experts and their
institutions.
Alternative (complementary) medicine has made real progress since my
generally-unfavorable 1983 review linked below. If you are
interested in complementary medicine, then I would urge you
to visit my new
Alternative Medicine page.
If you are looking for something on complementary
medicine, please go first to
the American
Association of Naturopathic Physicians.
And for your enjoyment... here are some of my old pathology
exams
for medical school undergraduates.
I cannot examine every claim that my correspondents
share with me. Sometimes the independent thinkers
prove to be correct, and paradigms shift as a result.
You also know that extraordinary claims require
extraordinary evidence. When a discovery proves to
square with the observable world, scientists make
reputations by confirming it, and corporations
are soon making profits from it. When a
decades-old claim by a "persecuted genius"
finds no acceptance from mainstream science,
it probably failed some basic experimental tests designed
to eliminate self-deception. If you ask me about
something like this, I will simply invite you to
do some tests yourself, perhaps as a high-school
science project. Who knows? Perhaps
it'll be you who makes the next great discovery!
Our world is full of people who have found peace, fulfillment, and friendship
by suspending their own reasoning and
simply accepting a single authority that seems wise and good.
I've learned that they leave the movements when, and only when, they
discover they have been maliciously deceived.
In the meantime, nothing that I can say or do will
convince such people that I am a decent human being. I no longer
answer my crank mail.
This site is my hobby, and I do not accept donations, though I appreciate those who have offered to help.
This page was last updated February 9, 2008.
During the thirteen years my site has been online, it's proved to be
one of the most popular of all internet sites for undergraduate
physician and allied-health education. It is so well-known
that I'm not worried about borrowers.
I never refuse requests from colleagues for permission to
adapt or duplicate it for their own courses... and many do.
So, fellow-teachers,
help yourselves. Don't sell it for a profit, don't use it for a bad purpose,
and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about
your successes. And special
thanks to everyone who's helped and encouraged me, and especially the
people at KCUMB
for making it possible, and my teaching assistants over the years.
Whatever you're looking for on the web, I hope you find it,
here or elsewhere. Health and friendship!
Once again, consider this all "worth knowing".
Review the liver's architecture and function. Describe its capacity to regenerate, and the limits on this
capacity.
Describe the lesions that can produce jaundice. Cite physiology to place them into the appropriate
categories.
Use, and furnish (given the definition), each word in the glossary and elsewhere in the handout.
Tell how alcohol affects the liver.
Give a full account of what is known, and what remains unknown, about
non-alcoholic steatohepatitis. Tell how to use clinicial data to distinguish this from secret alcohol abuse.
Give a complete account of the generalized syndrome of liver failure, and the causes of massive hepatic
necrosis.
Describe various conditions that result in ischemia of the liver. Describe the causes and effects of thrombosis
of the hepatic and portal veins.
Describe the pathophysiology and clinical problems seen in portal hypertension.
Describe the viral hepatitis family in substantial detail. Describe the significance of various lab tests and
biopsy findings in various stages of these illnesses. Describe the "lupoid hepatitis" family of illnesses, and
primary biliary cirrhosis.
Define cirrhosis, and describe its pathophysiology in detail. Describe distinguishing features of each of the
many causes of cirrhosis.
Describe cholangitis, and liver abscesses.
Describe the common hepatotoxic agents, and their effects.
Tell how liver failure occurs in children, and what the clinician and pathologist will see.
Describe gallstones and their adverse effects. Describe all the common cancers of the hepatobiliary tree.
Recognize the following gross lesions:
acute yellow atrophy
Recognize and distinguish the following microscopic lesions:
acute cholecystitis
QUIZBANK: Liver and biliary (all)
ALPHA-1 ANTITRYPSIN (alpha-1 protease inhibitor): A useful protein produced by the liver for the bloodstream.
It keeps the body's tissues, notably its elastin, from being totally digested early in life by neutrophil
breakdown products. If its release from cells is damaged, it appears as d-PAS-positive granules of varying
sizes within hepatocytes. (* This can happen in advanced chronic liver disease
from any cause, but is far more likely an unrecognized antitrypsin
abnormality: Am. J. Clin. Path. 107: 692, 1997).
BALLOONING DEGENERATION: Hydropic swelling of a hepatocyte (i.e., mild, probably-reversible cell injury). If the cell
dies, it is BALLOONING NECROSIS.
BILE ACIDS (BILE SALTS): Sterols that help solubilize bile. From your biochemistry course.
BILE DUCTULE: The little bile ducts at the edges of the portal triads. They feed into the interlobular bile duct.
Also called "canals of Hering".
BILE LAKE: An accumulation of bile that has ruptured a canaliculus
BILE PLUG: Bile visible in a distended canaliculus
{12220} jaundice
BILOMA: A pool of bile in a traumatic (laceration, stab, surgery)
lesion of the liver.
BRIDGING NECROSIS: Necrosis linking two portal areas or a portal area and a central area.
CHOLESTATIC JAUNDICE: Jaundice caused primarily by failure of conjugated bilirubin to be sent successfully to
the gut
CHRONIC HEPATITIS Morphologic evidence of inflammation AND necrosis
plus labs and/or clinical
evidence of liver disease for six months or more.
* You'll find pathologists who prefer to call it "chronic necroinflammatory injury". CHRONIC ACTIVE HEPATITIS: This is an out-of-use term
that meant Inflammation + interface hepatitis
+ fibrosis involving the liver for six months or
more. This histologic pattern supposedly meant that the disease
would progress to cirrhosis.
CHRONIC PERSISTENT HEPATITIS: This is an out-of-use
term for lymphocytes and/or plasma cells in the portal areas, without ongoing necrosis;
symptoms and/or abnormal labs for >6 months. This histologic
pattern supposedly meant that the disease would not progress to cirrhosis.
The tendency nowadays is to group chronic persistent hepatitis and chronic
active hepatitis together as "chronic hepatitis", and not to try hard to distinguish them on
morphologic grounds.
* Future pathologists: Here's a scoring system for chronic hepatitis of
otherwise-obscure etiology!
Inflamed patches in the sinusoids, away from the interface:
To describe the hepatitis, choose whichever is worse.
CIRRHOSIS: Scarring of the whole liver sufficient to seriously interfere with proper perfusion of hepatocytes.
Instead of the familiar lobules, you'll see fibrous bands dividing the liver into
more-or-less round REGENERATIVE NODULES.
CONJUGATED BILIRUBIN: Bilirubin that has been conjugated to glucuronic acid, making it water-soluble
CONFLUENT-LYTIC NECROSIS: Death of clusters of hepatocytes (* attributed in the current literature to humoral
immunity)
COUNCILMAN (ACIDOPHIL) BODY: Single-cell necrosis (apoptosis) of a hepatocyte, typically in hepatitis As a result
of attack by a T-killer cell.
* CYTOPLASMIC DISSOCIATION means edema at the edges of a hepatocyte,
granular cytoplasm around its nucleus. The cell is injured.
FOCAL NECROSIS: Death of individual cells, evidenced either by Councilman bodies or lytic necrosis (i.e.,
collapse seen on reticulin stain). Inside the lobule, it's "focal lobular necrosis", as in
smoldering hepatitis from any cause.
* FEATHERY DEGENERATION: A pattern seen when a liver cell retains both bile salts and water. Ask a physical
chemist how it works. When the bile actually digests a group of liver cells, it's called a
BILE INFARCT.
GIANT MITOCHONDRIA: Monsters seen in hepatocytes in alcoholism. They are d-PAS negative (lets you
distinguish
them from alpha-1 antitrypsin). See J. Clin. Path. 45: 412, 1992.
* These mitochondria may have suffered a characteristic loss of DNA due to alcohol-induced free-oxygen-radical
damage or something; the deletion makes it harder for the liver cell to burn fat, and so forth (Gastroent. 108:
193, 1995.)
GROUND GLASS HEPATOCYTES: Distinctive hepatocytes seen in chronic (not acute) hepatitis B infection.
The "ground glass" cytoplasm is an unusual accumulation of a cytokeratin
(Hepatology 28: 347, 1998).
HEPATOCELLULAR JAUNDICE: Jaundice due primarily to failure of hepatocytes to properly take up / conjugate
bilirubin.
HEMOLYTIC JAUNDICE: Jaundice due to excessive destruction of red cells or their precursors at any site
* HELLP SYNDROME: Hemolysis, elevated liver enzymes, low platelets.
A poorly-understood and very serious
complication of pregnancy. Seizure and hypertension management, glucocorticoids,
and/or exchange transfusions may be required. More about this later.
INTERLOBULAR BILE DUCT: The big bile duct in the portal tract. It runs with the branch of the hepatic artery.
JAUNDICE: Too much bilirubin (conjugated or not) in the bloodstream, for any reason
{12220} jaundice
LIMITING PLATE: The row of hepatocytes immediately adjacent to the portal tract. It should be smooth and
uniform.
* LIVER CELL UNREST: Increased prominence of Kupffer cells and increased ploidy of many hepatocytes. This is a
totally non-specific finding, common to many (if not most) serious illnesses affecting the entire body.
LOBULAR DISARRAY: Loss of the normal radial arrangement of liver plates within the lobule, typically with
severe distortion of the sinusoids. The hallmark of acute hepatitis.
LUPOID HEPATITIS: An unfortunate term for the several kinds of non-viral (?), autoimmune hepatitis in which
the histology is that of chronic hepatitis, usually with a lot more
plasma cells than in the viral forms (worth remembering).
LYTIC NECROSIS: The hepatocytes in a region (large or small) are gone, leaving behind collapsed stroma.
Older references call this "dropout necrosis".
MALLORY'S HYALINE: Masses ("rope-like", "cottage cheese") of altered cytokeratin and cell stress proteins
(ubiquitin, others: Arch. Path. Lab. Med. 114: 589, 1990). Usually (but not always) a marker for alcoholism.
MASSIVE NECROSIS: Most of the hepatocytes on the slide are dead. Due to poisoning, viruses, medication reactions, or ischemia.
SUBMASSIVE NECROSIS
means that at least some entire lobules are destroyed, but in other lobules, enough cells are alive.
MACROVESICULAR FAT: One large lipid drop in a hepatocyte
MICROVESICULAR FAT: Several lipid drops in a hepatocyte
OBSTRUCTIVE JAUNDICE: Cholestatic jaundice caused by mechanical obstruction of the common bile duct or
hepatic ducts. Also called SURGICAL / SURGEON'S JAUNDICE; all other forms of jaundice are
MEDICAL / INTERNIST'S JAUNDICE.
* ONCOCYTIC HEPATOCYTES (oxyphilic hepatocytes,
i.e., mitochondrion-packed) are common
in many livers, especially
where there's been a lot of regeneration, i.e., cirrhosis, which has
let mutant mitochondria overgrow (Virch. Arch. 432:
349, 1998). Fibrolamellar hepatocellular
carcinomas are also mitochondrion-packed.
PIECEMEAL NECROSIS: Necrosis of groups of hepatocytes within the limiting plate.
Today the term INTERFACE HEPATITIS is preferred, to prevent confusion with
focal necrosis deeper within the lobule. Often the only evidence of "necrosis" that you see
is a little area with collapsed architecture; if you're lucky, you may spot a Councilman body.
INTRODUCTION
Is life worth living? It depends on the liver! The liver is usually our heaviest internal organ, and the most durable. Unlike lungs, kidneys, heart, and
brain, the livers of most 100-year-olds are morphologically and functionally normal.
Liver pathology includes only a few common diseases. The terminology and morphology of these lesions
are notoriously confusing for beginners. Further, you'll have to know them, because you'll frequently look at
livers.
It would be best for you to start by learning the definitions in the "Glossary", and making note of the material
under "For Future Liver Pathologists".
You already know that the liver is the great chemical plant of the body. You remember its location, its
anatomic relationships, its blood supply, and its essential architecture.
Worth mentioning: The "Ito" (perisinusoidal) cells sit in the space of Disse, store vitamin A, and turn on to
carry out fibrosis of the hepatic lobule in developing cirrhosis. All about it: J. Path. 170: 105, 1993.
Normal adult livers weigh 1400-1600 gm. Liver weight is widely variable at autopsy. I've autopsied an end-stage cirrhotic
with a 700 gm liver, and an alcoholic with a 7000 gm liver. The liver HURTS when, and only
when, its capsule is stretched.
Despite the discussion in "Big Robbins", the normal liver may or may not be palpable, depending on its
shape. Maybe 1% of livers have a "Riedel's lobe" easily felt on the right side; this is simply
an anatomic variant of no importance to one's health. Others have a small right lobe and
a large left lobe, while still others have random grooves across the organ ("hepar lobatum", or one variant).
The hyperinflated lungs of the emphysema patient usually push the liver downward and make the edge
palpable, but again, this is not reliable; "rib marks" (really from muscle pressure) in emphysema produce the
familiar COSTAL GROOVES. Remember that a newborn's liver edge is usually easily palpable 1-2 cm below the
costal arch.
The histology of the liver is worth reviewing. Remember that the
METABOLIC LOBULE ("ACINUS") is centered on
the portal areas, and the CLASSICAL LOBULE is centered on the central vein. Whichever system you use,
ZONE 1 is
the hepatocytes near the portal areas, ZONE 2 is the hepatocytes midway between the portal areas and central
veins, and ZONE 3 is the hepatocytes around the central veins.
The familiar polyhedral, pink-staining hepatocytes are often (maybe 10%) binucleate or tetraploid /
octoploid. This is normal. You remember the architecture of the liver plates and sinusoids, the passage of
bile from canaliculi to canals of Hering to bile ducts, and the appearance and function of the hepatic
endothelium and Kupffer cells.
* Prominent Kupffer cells and increased hepatocyte polyploidy is
LIVER CELL UNREST, common in people who
are sick for a variety of reasons. Its diagnostic significance is nil.
* Future pathologists: You can stain the canaliculi using your CEA stain.
You will learn about biopsying the liver (both the classic through-the-skin
technique and the probably-equally-good transjugular approach) on rotations (Gut 55: 1789, 2006).
Lately, a liver biopsy has come to be considered "adequate" if it is 20 mm long
and/or contains 11 or more complete portal tracts (Am. J. Clin. Path. 125:
710, 2006).
If individual hepatocytes are destroyed but the architecture of the lobule is
NOT destroyed, the remaining
hepatocytes will totally regenerate the liver parenchyma.
If whole lobules are destroyed, the remaining lobules will expand. They will function normally, though bile
may not be drained quite so well. Of course, if scar tissue alters the flow of blood through the liver (i.e., cirrhosis has occurred), regeneration
will only produce less-than-fully-perfused nodules of liver cells. (This will disappoint well-read problem
drinkers who understood that their hepatocytes had unlimited capacity to regenerate....)
* Liver biopsies are not always easy to read, especially if the community
hospital pathologist isn't focused on liver. The value of a second
opinion: Arch. Path. Lab. Med. 125: 736, 2001.
* Incredible as it may seem, your lecturer got his first exposure to pathology in 1970 with the dean of
experimental liver pathology, Brown's Nelson Fausto, whose focus was and is liver regeneration.
After years of bragging about this, I was delighted to see him as third author of the new "Big Robbins".
Increased bilirubin in the bloodstream is JAUNDICE.
There's no reason to review bilirubin production and metabolism here. You can check "Big Robbins" if you
need refreshing.
Here's a simple review, similar to the one in "Big Robbins", of the various causes of jaundice:
TOO MUCH BILIRUBIN BEING PRODUCED ("hemolytic jaundice")
"Ineffective hematopoiesis", i.e., normoblasts dying in the bone marrow
Thalassemias (even mild ones like beta-thal minor)
Megaloblastic anemias
Intravascular hemolysis (many, many kinds)
Extravascular hemolysis
Big hematomas
GI bleeding
Red infarcts
LIVER FAILS TO TAKE UP AND/OR CONJUGATE BILIRUBIN ("hepatocellular jaundice")
Newborns
Hypoperfusion
Bad alcoholism
Hepatitis (many causes)
Cirrhosis (many causes)
Gilbert's non-disease and the Crigler-Najjar syndromes
NOTE: From "Biochemistry". Gilbert's (officially pronounced as French Zheeel-BEAR's) is a forme fruste of Crigler-Najjar (Lancet 346: 314, 1995; Lancet
345: 958, 1995). Both result from mutations of the glucuronyl transferase
that solubilizes bilirubin. Crigler-Najjar (two subtypes) is always recessive, Gilbert's usually so.
Gilbert's is extremely common (several % of the population)
and usually a non-problem. One tipoff is that the bilirubin levels increase during fasting.
Gilbert's may be exacerbated by other illnesses or medications,
in particular the protease inhibitors used in anti-retroviral therapy (J. Inf. Dis. 192: 1381, 2005).
LIVER DOESN'T SEND BILIRUBIN TO THE RIGHT PLACE ("cholestatic jaundice")
Problems with the liver cells
Drugs (estrogen, anabolic steroids)
Dubin-Johnson (pigmented) non-disease
* A specialist can diagnose Dubin-Johnson without biopsy by its effect
on different urinary coproporphyrin levels. Don't worry about it.
Rotor (non-pigmented) non-disease.
* Byler's disease ("FIC"; familial intrahepatic cholestasis) -- deadly, with mental retardation
and retinitis pigmentosa; thankfully rare, autosomal recessive, the Byler family from which all the
index patients came is Amish and highly inbred;
See Hepatology 26: 155, 1997; gene is ATP8B1.
There is a Byler-like illness
at BSEP, the bile salt export pump, and another at the multidrug-resistance protein 3 site)
"Benign familial recurrent intrahepatic cholestasis", the forme-fruste of Byler.
Patients have intermittent cholestasis and elevated alkaline phosphatase.
Second locus Gastroent. 127: 379, 2004.
Really bad cases of other liver diseases (hepatitis, cirrhosis, alcoholism; i.e., when the liver fails, the picture is
likely to be mixed)
Problems with the bile ducts in the liver
Biliary cirrhosis
Biliary atresia
* Alagille's (dysmorphic child, bile ducts vanish over time; autosomal dominant, gene Jagged1 (Circulation 109: 1354, 2004, the variable liver disease itself Gut 49: 431, 2001;
molecular biology Am. J. Path. 171: 641, 2007)
Problems with the bile ducts beyond the liver (call a surgeon)
Gallstone in the common duct
Cancer (i.e., biliary, pancreatic, ampullary)
Iatrogenic (i.e., the surgeon nicked the common bile duct)
Note that in all but hemolytic jaundice, bile production will be diminished. Stools may become light-colored
(gray if the bile is completely obstructed), and there
will be diminished
intestinal absorption of fat (pee-yew!) and fat-soluble vitamins.
Lab tests are of considerable help in distinguishing these entities.
Obviously, in the first two categories, the serum unconjugated bilirubin will be elevated.
In the third category, only the conjugated bilirubin will be elevated until the liver cells themselves are damaged.
Serum BILE ACIDS ("bile salts") will also be increased from the onset, producing the troublesome
itching seen in these
syndromes. Conjugated (but not unconjugated) bilirubin in the bloodstream spills into the urine. You'll study
other markers for cholestasis in the unit on lab testing.
On biopsy, obstructive jaundice presents the familiar BILE PLUGS, which begin as dilatations of the canaliculi
and end up forming BILE LAKES when the canaliculi rupture.
* As the liver cells become damaged, they fill with soap bubbles (i.e., bile salts and water), producing
FEATHERY DEGENERATION. You won't need to recognize this. Later, you'll see necrotic cells surrounding bile lakes.
WHEN THE LIVER FAILS
Regardless of cause, when the liver can no longer function as chemical plant, several unwholesome things
happen.
JAUNDICE is usual. When the liver is really scrambled, hyperbilirubinemia is mostly the conjugated sort, i.e.,
the cells remember how to conjugate, but not what to do with, the bile. There is usually some unconjugated
hyperbilirubinemia, too.
HYPOALBUMINEMIA is usual, since the liver isn't making albumin. Without albumin in the bloodstream, ascites
and edema develop. By the way, HYPOCHOLESTEROLEMIA is usual in liver disease too (unless the primary
problem is obstruction of bile flow -- why?), since the liver isn't producing LDL's. (This is part of the reason
for the silly myth that "too low cholesterol is bad for you".)
COAGULOPATHY of liver disease results from diminished hepatic synthesis of factors II, V, VII (first to go), IX, and X.
(Note that absent vitamin K from malabsorption also prevents synthesis of II, VII, IX, and X.) Monitor all
this by following the prothrombin times.
Further, as the liver fails to clear factors that have become activated in the course of living, low-grade DIC
is likely to develop.
As liver cells fail, detoxification of nasty compounds fails and
HYPERAMMONEMIA and FETOR HEPATICUS (a
distinctive odor to the breath). Other side-effects are reddening of the thenar and hypothenar eminences
("palmar erythema"), spider "angiomas" (you'll learn about these in physical diagnosis), and (in men)
gynecomastia and testicular atrophy. In longstanding liver failure, the parotid glands often enlarge for some
reason (still completely unknown as of 2007).
THROMBOCYTOPENIA is due to lack of thrombopoietin: Am. J. Gast. 94:
1918, 1999.
HEPATORENAL SYNDROME is a syndrome of kidney failure.
We used to precipitate this by "lasixing" cirrhotics with ascites.
The pathophysiology, once obscure, is now clear.
First, liver failure interferes with the breakdown of the vasodilator nitric oxide.
Second, portal hypertension itself forces the splanchnic arteries
to open wider at the expense of circulation to the rest of the body.
We now manage all but the worst cases by giving plasma expanders and vasopressin analogues
(Gastroent. 122: 923, 2002)
(to constrict the systemic circulation) plus dopamine (to
open the renal microcirculation)
helps (Hepatology 27: 35, 1998; Am. J. Gastroent.
92: 2113, 1997; Clin. Sci. 92: 433, 1997;
Mayo. Clin. Proc. 71: 874, 1996; Lancet 362: 1819, 2003).
Unless the liver disease is reversible (i.e., alcoholic hepatitis
or a drug allergy), this is just buying time while waiting for a liver transplant.
HEPATOPULMONARY SYNDROME is a poorly-understood
phenomenon in which the arteries dilate in the lungs
as the liver fails, causing V/Q mismatching. There is no current remedy.
See Gastroent 113: 606, 1997;
Surg. Clin. N.A. 79: 23, 1999;
Mayo Clin. Proc. 79: 42, 2004;
Lancet 363: 1461, 2004 ("notoriously underdiagnosed").
HEPATIC ENCEPHALOPATHY is not a pretty sight, and probably results from a combination of factors, including
nitrogen-containing false neurotransmitters (supposedly including octopamine -- remember that from "Biochemistry"? --
and some others)
produced by the gut flora.
* Fatigue in liver failure may respond to ondansetron: Lancet 354:
397, 1999.
Early in the process, there's a curious distortion of spatial perception. (The stereotype
of accelerated confusion in the problem drinker
is all too familiar -- he pours the whiskey onto his lap,
rather than into the glass in his other hand;
he cannot find his way home even when he sobers up. Whatever the
cause, hepatic encephalopathy makes life far more difficult.) The first
change on physical exam is ASTERIXIS, a curious flappy falling-asleep-and-waking-back-up of the fingers-hands-arms-whole body.
Clinicians monitor hepatic encephalopathy by measuring blood ammonia.
{01383} Alzheimer II glia in hepatic encephalopathy (best one is in the center of the field;
it appears as a swollen, pale nucleus)
In acute massive liver failure, cerebral edema is the pathway out of life in about 50% of cases (Lancet
351: 719, 1998).
We're still making educated guesses about the mechanism.
When the liver finally gives up completely, REFRACTORY HYPOTENSION supervenes from total-body
vascular
relaxation (which we can suppose is due to the failure
of the liver to metabolize some vasodilator, most likely one that's not yet
been discovered.)
Nothing you can do will save the patient.
Reminder: Serum liver enzyme (transaminases, lactate dehydrogenase) concentrations become elevated when
liver cells are acutely injured. Note that in burned-out cirrhosis when drinking is stopped, liver enzymes will
be normal.
CIRRHOSIS
Cirrhosis ("roaches of the liver", etc.) is scarring
of
the whole liver sufficient to permanently interfere with circulation of blood to the hepatocytes, no matter what
the cause. You will see
NOTE: Nobody really understands all about how fibrosis supervenes following liver cell death in any disease,
or what we might do to stop it (J. Path. 170: 105, 1993 will leave you confused, but with an appreciation of
the "Ito" cell). Sometimes, you can see layer upon layer of reticulin fibers being laid down as liver cells die in
waves; this is the sign of irreversible (?) damage in chronic
hepatitis, and probably is how scars build up, at least in part.
{00005} cirrhosis
MICRONODULAR CIRRHOSIS: Most of the nodules are smaller than 0.3 cm, and the fibrous-scar bands are relatively
thin.
Think of alcoholism, hemochromatosis (since alcohol and iron will involve all lobules equally), primary-autoimmune biliary
cirrhosis (since portal areas tend to link to adjacent portal areas), or biliary
infection/obstruction (same reason, "secondary biliary cirrhosis"; remember cystic fibrosis).
{08285} micronodular cirrhosis (this happens to have been a case of primary biliary cirrhosis);
liver on left is normal
MACRONODULAR CIRRHOSIS: Most of the nodules are larger than 0.3 cm, and the fibrous-scar bands are relatively
thin.
Think of chronic hepatitis, with its uneven pattern of inflammation,
progressed to cirrhosis (since viral disease is generally patchy and will not
involve all lobules equally).
Wilson's disease, galactosemia, and alpha-1 antitrypsin deficiency may produce either pattern. As a
matter of fact, a rehabilitated alcoholic's micronodular liver will, after a few years of sobriety, exhibit enough
large regenerative nodules to qualify as macronodular.
* Pathologists only: "Incomplete septal cirrhosis" is stabilized (regressing?)
macronodular cirrhosis with only thin fibrous
bands and really no nodules. Liver function tests are better, but portal hypertension may be is more severe --
hence the tendency to say "cirrhosis" despite no nodules.
See
Gastroent. 106: 459, 1994.
{08441} macronodular cirrhosis
POST-NECROTIC CIRRHOSIS ("end-stage liver"): Macronodular cirrhosis with really big, thick fibrous-scar bands.
Usually results either from submassive necrosis (i.e., whole lobules were destroyed), or (much more often) progression of another type of
cirrhosis to the end stage.
{25659} macronodular cirrhosis (some big scars show
progression to postnecrotic cirrhosis)
Especially in kids cured of thalassemia by marrow transplantation,
extensive reversal of cirrhosis is now known to take place (Ann. Int. Med. 136:
667, 2002); there is also often some regression when fibrosis due to
hepatitis C (Dig. Dis. Sci. 43:
2573, 1998) and autoimmune hepatitis (Ann. Int. Med. 127: 981, 1997)
are successfully treated. * Death rates from cirrhosis (age-corrected)
have run a curious pattern over the past 100 years.
Between 1900 and 1934, deaths dropped by about 2/3; this coincided with
the temperance movement and the massive decline in alcohol consumption.
The end of Prohibition and the Great Depression resulted in a tremendous resurgence of alcohol
overindulgence, and the rate of death from cirrhosis skyrocketed, peaking
in 1970. Since then, they've dropped dropped dramatically; I suspect
the explanation is better nutrition and the recovery movement
(Postgrad. Med. 115: 13, Jan 2004.)
CIRCULATORY PROBLEMS
CONGESTION of the liver receives excessive attention. There's no mystery; if the right side of the heart isn't
pumping well enough, blood pools in the liver.
Except in the most sudden violent death, the central areas of the liver will be more or less congested. (If
you're at an autopsy and someone asks, "Is that a nutmeg liver?", you can safely guess "Yes!")
Clinicians enjoy showing the hepatojugular reflux of those with
congested livers, especially behind failing right ventricles.
Pathologists enjoy exhibiting their cut nutmegs, which have light-and-dark areas that resemble congested
liver.
{03949} nutmeg liver
If death has been preceded by a few hours of inadequate circulation (heart failure, shock), count on seeing
some hepatocyte necrosis in the centers of lobules. (This is
CENTRAL HEMORRHAGIC NECROSIS. Why the liver?
Why in the centers? Think about it!)
This isn't "due to the congestion", but merely results from inadequate perfusion with oxygenated blood.
Clinicians may have noted "elevated liver transaminases" ("ISCHEMIC HEPATITIS"), and even mild jaundice.
You can experience the transaminase elevations yourself by running a marathon. Don't worry, the liver will
completely regenerate (since its connective tissue framework is still intact.
If hepatic congestion and underperfusion have been extreme and longstanding, the rare
CARDIAC SCLEROSIS
may supervene. This is substantial fibrosis in the central areas of the
lobule. (Grossly, the liver surface looks like a football, since scar contracts in the centers of the lobules.)
In extreme cases (i.e., tricuspid insufficiency, certain
congenital heart surgeries), the fibrous tissue may bridge adjoining lobules (true
CARIAC CIRRHOSIS.
* That cardiac cirrhosis is real has recently been demonstrated
by a study of people who have undergone the Fontan procedure for
single-ventricle, a consequence of which is longstanding increased
right-sided venous pressure. See J. Thorac. Card. Surg. 129: 1348, 2005.
Otherwise, cardiac sclerosis is usually just an anatomic pathologist's curiosity.
LIVER INFARCTS
The liver has a dual blood supply and, while hepatocytes are vulnerable to hypoxia, the stroma is very
resistant and hepatocytes regenerate easily. This makes it difficult to truly
arterially infarct the liver.
When a branch of the portal vein is compromised, the worst that usually happens is atrophy of hepatocytes in
a region ("Zahn's infarct"; fresh lesions have much stasis of blood in the sinusoids and thus look blue).
HEPATIC VEIN THROMBOSIS("Budd-Chiari")
{49262} Budd-Chiari; liver is engorged with blood
and you can see the clots;
Sounds serious, and is. The most common cause is polycythemia vera. Most any other cause of
hypercoagulable blood can produce "Budd-Chiari". Another important cause is invasion of the hepatic veins
by hepatocellular carcinoma.
As you'd expect, in the acute case, the liver swells (ouch!), ascites develops rapidly, and the patient usually
dies of venous infarction of the liver unless surgery or thrombolysis are performed.
In some foreign countries, "chronic Budd-Chiari" is a common problem. Nobody
knows why. At autopsy, look for fibrous "webs"
in the hepatic veins.
* Diabetic micro-angiopathy occasionally produces non-cirrhotic fibrosis (like hyaline arteriolar sclerosis)
of the sinusoids. The entity is newly-named "diabetic hepatosclerosis"
(Arch. Path. Lab. Med. 130: 27, 2006). Probably it is common but under-recognized.
HEPATIC VENO-OCCLUSIVE DISEASE, clinically a Budd-Chiari mimic
but with no thrombus,
results from intimal thickening of the veins
(onion-skinning, etc.). Think of Jamaican bush-tea (as
in the lung: terrible health problem West. Ind. Med. J. 64: 60, 1997), comfrey,
graft-vs.-host, radiation effect. Review, emphasizing the "herbal tea"
connection: Arch. Surg. 125: 525, 1990).
* Sickle-cell patients often have chronic venous outflow obstruction (why?).
Be careful about biopsying these people. Blood 101: 101, 2003.
PORTAL VEIN THROMBOSIS
Again, this is serious. It results from hypercoagulable blood, invasion by hepatocellular carcinoma,
pancreatitis, or cirrhosis.
The major problems are ascites and venous infarction of the bowel.
NECROSIS OF THE LIVER
Infections tend to produce random areas of necrosis ("focal", "spotty"), ranging from tiny (viral hepatitis) to
massive (* typhoid).
Poisons and other noxious things, on the other hand, tend to damage distinctive portions of the lobule (why?)
More about this later.
CENTRAL NECROSIS: Ischemia, carbon tetrachloride, chloroform, acetaminophen
{07020} carbon tetrachloride, gross; note the necrosis (yellow, of course)
MID-ZONAL NECROSIS: Yellow fever. (Think about why. It is in the virus's interest to have
regenerating hepatocytes on both sides.)
PERIPHERAL NECROSIS: Acute iron poisoning (J. Tox. 39: 721, 2001),
phosphorus, eclampsia (in the latter, fibrin microthrombi should be visible in the
sinusoids near the portal areas).
{07023} liver showing phosphorus poisoning; note periportal necrosis
PELIOSIS HEPATIS ("blood cysts", a misnomer)
Lakes of blood among the hepatocytes. On section, the liver features many easily visible
holes filled with blood.
The pathology has recently been reviewed in depth (For. Sci. Int. 149:
25, 2005.)
Other cases are lined only by hepatocytes ("parenchymal peliosis"); in this case, the lesions
are irregularly-shaped.
Anabolic steroid use is the best-known cause, but many others
are known (oral contraceptives, cachexia) or suspected (hemangiomas,
congestion in people with mild weakness of the veins).
A blow to (or biopsy of) the involved organ may cause these to rupture, with serious hemorrhage.
INFECTIONS
VIRAL HEPATITIS: GENERAL CONSIDERATIONS
The hepatitis family is an alphabet-soup of viruses, several newly-discovered. However, the anatomic
pathology is generally similar. Some viruses are better at producing different patterns than are others.
You can get each of these infections only once.
But B can linger, and C usually does linger, as a minor or major problem.
As with most viral diseases, infectivity peaks just before symptoms appear. Acute hepatitis is heralded by the
blahs. As the immune system gears up, joint pains and rash can occur. Appetite vanishes, and the patient
typically becomes utterly revolted by tobacco. (Smoking cessation is a redeeming feature of the acute
hepatitis family.)
In the acute disease, the liver swells and becomes tender, jaundice often appears (mild cases are "anicteric"),
and (with influx of bile into the bloodstream) the patient starts to itch and to pass brown urine (why?) Serum
transaminases go sky-high, and other lab evidence of liver disease may become apparent.
The best treatment your lecturer knows for the acute phase is masterful inactivity for all but C, intensive therapy for C. Educate the patient, find
out who else needs to be checked for hepatitis or get prophylactic gamma globulin, and give clotting factors if
you must.
ACUTE VIRAL HEPATITIS: You will see
Note that in hepatitis,
the cells may die either by lysis or apoptosis, or both. Probably the lysis is due to
the viruses or to antibodies, while the apoptosis is caused by instructions
to self-destruct delivered by the T-cells.
{05961} acute viral hepatitis with Councilman body
MASSIVE NECROSIS ("FULMINANT HEPATITIS"; "ACUTE YELLOW ATROPHY") may supervene on any kind of acute
hepatitis, and often kills the patient in short order.
Grossly, as you would expect, the liver is shrunken, red, soft, and flabby, with a wrinkled capsule.
Histologically, the hepatocytes are almost all gone (lytic necrosis and/or apoptosis), leaving a collapsed
fibrous tissue framework. Don't expect to see much inflammation.
SUB-MASSIVE NECROSIS is a little less striking histologically and lasts a little longer, killing the patient in a few
months. (Or the patient may recover after being super-sick for a few months.)
If a patient survives either process, the parenchyma is usually intact, and recovery should be complete,
without cirrhosis. Rarely, the collapsed reticulin meshwork of the liver turns into broad scars (instant
"post-necrotic cirrhosis").
{13320} massive necrosis after hepatitis, gross (nothing left but the reticulin and endothelial framework!)
CHRONIC HEPATITIS: Inflammation of the liver for more
than six months.
You will see a dense, mostly-lymphocytic inflammatory infiltrate in the portal areas,
with or without spill-over into
the parenchyma.
There may be some smoldering changes resembling acute
hepatitis in the parenchyma.
In mild cases, the limiting plate is intact (i.e., there is no interface hepatitis).
We used to call this "chronic persistent hepatitis".
{12779} mild chronic hepatitis, story
These findings are more ominous when the patient has chronic hepatitis clinically:
Drug-induced liver disease (most notably methotrexate),
Wilson's, alpha-1 antitrypsin deficiency, and the autoimmune "lupoid"
hepatitis family also typically pass through a "chronic active hepatitis" histopathology stage on their way to
cirrhosis.
{12800} severe chronic hepatitis, piecemeal necrosis
Future pathologists please note: Any and all of these patterns (from acute hepatitis to post-necrotic cirrhosis)
can be mimicked by idiosyncratic reactions to various drugs.
Chronic hepatitis and its sequelae are
often caused by autoimmunity.
HEPATITIS A ("infectious hepatitis")
This is an unpleasant but almost always self-limited disease caused by a tiny RNA enterovirus (* picornavirus;
"pico-" means "tiny", and "rna" you can figure out).
{0444} hepatitis A virus
Hepatitis A is transmitted by the fecal-oral route, i.e., poor sanitation, small kids (i.e., day-care or institutions),
hands (J. Clin. Micro. 30: 757,
1992,
note that there are countries where toilet paper isn't used),
raw oysters (be sure to ask),
some gay male sexual practices (JAMA 267: 1587, 1992), others.
Hepatitis A is more common overseas but is no rarity in the U.S.
* Hepatitis A, until recently
an endemic scourge on many Indian reservations (MMWR 46: 600, 1997)
has become much less common thanks to the recommendation to immunize all these
children (Am. J. Pub. Health 94: 996, 2004).
* The 1998 strawberry outbreak: NEJM 340: 595, 1999.
The incubation period is about two weeks, and this is the time when virus is shed in the feces. The infection in
kids is usually asymptomatic. Adults who get symptoms at all
suffer jaundice and discomfort for a few weeks. Once in a while, the
disease is fatal.
You'll hear different versions of whether the virus itself damages hepatocytes (the other enteroviruses are
cytotoxic), or whether the liver damage is actually wrought by the body's immune response.
Immune response is exactly what you'd expect:
IgM ANTI-HAV appears in the blood when the symptoms begin, clears the infection, and disappears within 12
months.
IgG ANTI-HAV appears in the blood during the symptomatic period, and usually stays around for life,
rendering the patient immune.
Occasionally the disease causes acute yellow atrophy and death/transplantation
(Am. J. Gastro. 98: 448, 2003).
Hepatitis A very seldom becomes chronic or leads directly to cirrhosis. There is probably no carrier state. At
worst, the disease might be a trigger for autoimmune chronic hepatitis, but the virus won't stay around.
* How the vaccine came about: Lancet 343: 321 & 322, 1994; J. Inf. Dis. 169: 996, 1994; JAMA 271: 1328,
1994;
JAMA 273: 906, 1995 (now classic).
Hepatitis A vaccine for post-exposure prophylaxis seems to work
about as well as immune globulin: NEJM 357: 1685, 2007.
HEPATITIS B ("serum hepatitis")
The world's most serious DNA-virus-related health problem. The reservoir for the virus ("HBV", "Dane
particle") is the world's 300 million (Proc. Nat. Acad. Sci. 93: 6542, 1996) carriers, most of whom are
asymptomatic and have histologically normal or near-normal livers.
{0445} hepatitis B virus
Even an infinitesimal amount of infected blood, when introduced into another person's tissues, is highly
effective in transmitting the infection.
Routes include
People born uninfected in the poor nations also frequently turn positive during their childhood. This has been
blamed on bedbugs; probably this isn't the main problem (Lancet 343: 761, 1994).
In the U.S. underclass, infection is also rampant, with around 25% of forensic-service deaths being core-antibody positive
(J. For. Sci. 38: 1075, 1993).
* Hepatitis B immunization has resulted in a triumphant reduction in the prevalence of carriage in Taiwan
and the rate of hepatocellular carcinomas
(JAMA 276: 906, 1996). In 1997, I predicted the 1998-9 media hype
that
the vaccine causes multiple sclerosis. The activists don't have the numbers,
but even after the claim was already totally discredited, many
lawsuits still got filed
(Science 281: 630, 1998).
* Catching hepatitis B from the surgeon, even when e-antigen-negative ("low-risk"): NEJM 336: 178, 1997.
Virus antigens:
HBsAg ("Australia antigen"): Surface antigen. Envelope protein. During the productive infection, the liver
cells make considerable excess non-infectious HBsAg, facilitating diagnosis.
HBcAg: Core antigen. Nucleocapsid.
HBeAg: Another nucleocapsid antigen, which means the virus is being replicated.
* Interestingly, entry of the virus into the hepatocyte is by means of binding to polymerized serum albumin.
After a person first meets the virus, the incubation period is usually 1-4 months.
Antigens and antibodies:
HBsAg first appears in the blood shortly before symptoms begin (if they are to begin). It remains in the blood
for the duration of the infection, whether it is acutely symptomatic, slowly-progressive / subclinical, or merely
the carrier state.
HBeAg appears in the blood just after HBsAg, and before symptoms start. It remains as long as there is acute
viral replication (you're VERY contagious....), and disappears if (and only if) viral replication stops. The
patient is still sick when HBeAg disappears, but can take comfort in the good news.
Anti-HBeAg appears soon after viral replication and HBeAg production stop (if they stop). The patient can
still be sick, but this is another piece of good news.
Don't ask for an assay of
HBcAg, the core antigen in the blood. It's an intranuclear
protein and there's almost none in the blood. However, Anti-HBcAg, in its IgM form, appears in the blood
typically before symptoms begin, and generally remains present for years (IgG anti-HBcAg will eventually
take over, maybe). If a person with clinical hepatitis has cleared his blood of HBsAg, but has not yet
developed detectable anti-HBsAg, the presence of IgM anti-HBcAg confirms that the infection is, indeed,
hepatitis B and is in the CORE WINDOW.
Anti-HBsAg generally appears when the infection is pretty much over, and is a sure sign of recovery.
BEWARE! During the time between disappearance of HBsAg and appearance of anti-HBsAg, the patient
may experience a potentially-lethal type III systemic vasculitis. (Why?)
If your patient is anti-HBsAg positive and anti-HBcAg negative, probably this person has had the hepatitis B
vaccine (why?)
* Well, maybe it's not a SURE sign of recovery; the Scripps crew has found viral DNA up to five years after
appearance of the antibody, but the patients don't seem sick or catching (J. Clin. Inv. 93: 230, 1994).
Symptoms begin in hepatitis B infection only when T-cells become angry with HBsAg and HBcAg and start
killing the hepatocytes that produce them. Histopathologists find T-cytotoxic cells where the hepatocytes are
dying. Eventually, the only surviving liver cells are the ones that won't continue making viruses, and these
replenish the liver.
The acute disease may be subclinical, or can cause weeks of jaundice and misery, or can cause fulminant
hepatitis and death, or sub-massive hepatic necrosis with resolution or cirrhosis.
Survivors (and 99% of people survive the acute episode) usually clear themselves of the virus, but maybe
10% fail to do so. These can become healthy carriers, develop chronic hepatitis
that may remit or progress to cirrhosis if untreated.
Rule of thumb: The more severe the initial illness, the less chance of remaining
chronically infected (why?) Terminology: Chronic hepatitis B means HBsAg has been present in the
bloodstream for 6 months or more.
NOTE: Carrying hepatitis B, with or without ongoing liver disease, is an important cause of
cryoglobulinemia and/or "polyarteritis nodosa of hepatitis B" (both immune complex, type III immune injury
problems).
NOTE: People who become carriers are those who mount a poor immune response. Men (weaker immune
response) are more at risk than women; different HLA types differ in susceptibility (Lancet 344: 1194, 1994).
Further, anyone who carries around the virus for a long time is at substantial risk for hepatocellular
carcinoma. (Hepatitis B and/or hepatitis C contribute to
most cases of this cancer, which worldwide is one
of the most common fatal diseases. In the case of hepatitis B, the virus may be acting as a mitogen that
allows
Nowell's law
to act, and/or mutating genes at or near its insertion sites: J. Virol. 65: 6761, 1991; there
is no doubt that insertion of the virus can and does scramble chromosomes: Proc. Nat. Acad. Sci. 88: 9248,
1991.)
People who continue to harbor the
virus are probably those that are not especially good at making interferon (the chronically sick, the
immunocompromised, little kids, the unlucky, men much more often than women). Alpha-interferon was the
original the mainstay of therapy
for
chronic hepatitis B infections, and the results are encouraging, with maybe half of people clearing the
infection. Of course, interferon therapy was
expensive and produces 'flu-like symptoms, but it was
better than dying or infecting your spouse.
And thankfully
the risk for hepatocellular carcinoma also dropped greatly
(Cancer 66: 2395, 1990 was the first big one).
Future histopathologists: You can stain for HBsAg in the cytoplasm, or core antigen in the nucleus.
"GROUND GLASS HEPATOCYTES", with altered cytokeratin suggest chronic hepatitis B infection.
We may hope that the hepatitis B vaccine will eventually make this infection, and its dread sequelae, a thing
of the past. Gambia institutes HBV vaccination of its population (Lancet 341: 1129, 1993). Kids in the U.S.
should get immunized, too (Pediatrics 93: 747, 1994). Please be sure you, too, are immune, Doc.
HEPATITIS D
"Delta hepatitis virus" (HDV) is an incomplete RNA virus that can replicate only while synthesis of
HBsAg is also taking place. Unlike HBV, delta is directly cytopathic to hepatocytes.
Delta may CO-INFECT (i.e., arrive under a person's skin at the same time as the HBV particle) or
SUPERINFECT
(i.e., arrive under the skin of a person already infected with HBV). Fortunately, delta is relatively hard to
transmit (somewhere between HBV and HIV in infectivity), and hepatitis D is most common
in gay men and IV-drug-abusers.
The results are grim. In co-infections, fulminant disease is common (maybe 5%). In a superinfection,
the victim experiences a second round of acute hepatitis, which tends (maybe 50% of the time) to turn chronic
and progressive. Treating chronic hepatitis D with alpha-IF: NEJM 330: 88, 1994 (it helps around half of
them while being treated; half of these relapse.)
Fortunately, carriers of delta are probably uncommon. Delta kills maybe 1000 people a year.
HEPATITIS C (the vast majority of the old non-A, non-B hepatitis Cases)
updates Ann. Int. Med. 132:
296, 2000; Mayo Clin. Proc. 73: 355, 1998; Lancet 362: 2095, 2003.
This flavivirus (HCV) and its related disease spectrum are now well-characterized. In the U.S., 1% of
asymptomatic people are positive for HCV (more than this among swingers and MUCH more among IV drug users; maybe 0.3% in those
not in these risk groups; health care workers aren't at increased risk: Lancet 343: 1618, 1994; ear-piercing is
a risk factor: NEJM 334: 1691, 1996; 19% positive for inner-city forensic-pathology service deaths J. For.
Sci. 38: 1075, 1993); in the 2000's, intravenous drug use was the most
common cause in the USA, with 98% of junkies positive in some communities;
in the poor nations, it's around 5%; worldwide 3%;
the highest known prevalence is around 20% in
Egypt (see below). At least 170 million people are infected worldwide (Science 288:
339, 2000), at least 3 million in the USA, with about 10000 deaths yearly
(that mortality figure is conservative and is going to increase: JAMA 297:
784, 2007).
Hepatitis C virus is transmitted by the same routes as hepatitis B, but is probably not nearly so catching. The
best route seems to be blood transfusion or needle-sharing (J. Inf. Dis. 162: 823, 1990; hemophiliacs Blood
84: 1020, 1994).
Needlesticks from infected blood carry about a 6% chance of infection (Br. Med. J.
315: 333, 1997) and
prophylactic treatment with anti-hepatitis C medicines is now
administered routinely after such events.
Strangely, nobody yet knows the prevalence of perinatally-transmitted hepatitis C,
but it can declare itself later in life as a fulminant illness: Arch. Dis. Child. 88: 160, 2003.
Thankfully, with changing lifestyles (maybe) and surveillance
in the hospital (certainly), the transmission rate of hepatitis C is
only about 1/5 what it was in the 1980's (Sci. Am. 280(3):
17, March 1999.)
The risk from a transfusion is now about 1 in 2 million (Lancet 361: 161, 2003).
* Among several hundred Irish women infected in the '70's
by bad
RhoGam, half still had demonstrable virus,
most of these had some inflammation, many had some fibrosis,
but only two had cirrhosis (NEJM 340: 1228, 1999).
* Hepatitis C transmission by acupuncture is now so well-known that you'd do
well to warn your patients to be sure they know who's doing it
(Can. Fam. Phys. 49: 985, 2003).
Sexual transmission seems much less efficient but probably occurs (JAMA 269: 361 and
392, 1993; Gut 45: 7, 1999; the risk to MSM's seems very low Am. J. Pub.
Health 95: 502, 2005);
around a quarter of spouses do eventually catch it (Ann. Int. Med. 120: 748, 1994). Vertical
transmission from Mom is common, especially if Mom has lots of virus on board: NEJM 330: 744, 1994. In
striking contrast to HIV, hepatitis B, and so forth, around 40% of people who carry the virus haven't got a
clue how they got it. In the US, if you're living clean enough to donate blood, your chance of
coming down with hepatitis C is very low (BMJ 316: 1413, 1998;
NEJM 341: 556, 1999).
A majority of people with the antibody
do have detectable virus by PCR in the blood.
The presence of the virus's RNA in the blood
(or liver tissue, which is harder to obtain) is today's standard for proving
infection. The exact specificity of a positive antibody depends on the test
(the cheap first-generation assays are less specific than the costly second-generation
RIBA) and of course the population screened (clean-living people's positive screens are more
likely to be false than needle-drug-user's positive screens). For an update
on the difficult subject of who to screen and how, see Am. J. Gastro. 100: 607, 2005.
We used to teach that only a few folks do clear the virus quickly after being infected
(Science 288: 333, 2000); with newer methods of detecting acute
infection, some folks say that around 67% clear themselves without
treatment within 8 weeks (Hepatology 37: 60, 2003), though it's also
known that many people's viral levels simply become undetectable
and the infection does recut. There's still
a question of whether to treat immediately or wait-and-see.
And some people who are chronically
infected have viremia only intermittently, and in some studies,
rates of spontaneous clearance over the years are relatively
high (Irish J. Med. Sci. 174: 37, 2005 gives a surprising 31%,
perhaps just the luck o' the Irish.)
Egypt, with around 20% of its people infected, has the highest rate.
Probably because of needles (used to administer antimony
in the treatment of schistosomiasis Incubation period is a week to six months; texts give the
average as 8 weeks. The acute infection is more likely to be subclinical (or cause
minor "belly trouble"), and massive necrosis does not occur.
However, infection usually becomes progressive (Only 15-30% or
so of people shake the bug. Fortunately, progression is slow, and
severe liver failure results in only about 10-30% of people and usually only
after decades.
You can get sick several times if you get
a big dose of the bug several times (Lancet 343: 388, 1994). After acquiring the virus via blood transfusion,
chronic infection with abnormal liver histology happens more often than not (Ann. Int. Med. 137:
961, 2002).
The impact on overall length of life is usually small (NEJM 327: 1906, 1992; Gut 47:
845, 2000) but the
infection is still a serious business.
Around a third of hepatitis C virus carriers have aggressive-looking chronic
hepatitis or cirrhosis (Br. Med. J. 308: 695,
1994). Unlike the other viral diseases, there is often quite a bit of
fatty change (correlates with severity: J. Inf. Dis. 192:
1943, 2005) and/or regenerative change in the bile ducts,
rather few inflammatory cells (maybe just lymphoid aggregates)
in the parenchyma
and a portal infiltrate that's all lymphocytes (no plasma cells or eosinophils)
suggests hepatitis C. The progression to fibrosis usually takes decades; if you're male,
a drinker, and/or older, it may take only a decade or so (Lancet 349:
825, 1997.)
NOTE: As with hepatitis B, carrying hepatitis C, with or without ongoing liver disease, is an important cause
of cryoglobulinemia (Am. J. Med. 96: 124, 1994; NEJM 330: 751, 1994 for the success of alpha-IF therapy).
The cryoglobulins are immune complexes made of the virus and the antibodies.
* How does hepatitis C virus produce fibrosis? There is often remarkably
little inflammation. In one model, the virally-infected hepatocytes produce
huge amounts of transforming growth factor beta, causing stellate cells
to produce collagen. Stay tuned; this may become the basis for a novel
anti-fibrogenic therapy (Gastroenterology 129: 246, 2005).
* NOTE: hepatitis C virus tends to drive out hepatitis B virus over the long-term in patients infected with both
(Gastroent. 106: 1048, 1994, others).
The NIH study -- you're probably recovered if your transaminases are normal and you have no circulating
viral DNA: Ann. Int. Med. 123: 330, 1995. That's about 15% of the asymptomatic-but-antibody-positive
folks.
* Nowadays we monitor disease and therapy using assays for hepatitis C messenger RNA (Am. J. Clin. Path.
107: 362, 1997).
* Strangely, quite a few of these people never have elevated transaminases,
even as they progress to cirrhosis. We have to wonder how these people's infections
were detected (Am. J. Gastro. 98: 1588, 2003).
We now eliminate about half of chronic infections using a combination of pegylated interferon
and ribavirin. This is one of the most important triumphs of medicine in the last few years.
Like hepatitis B, longstanding infection with hepatitis C places a person at grave risk for hepatocellular
carcinoma (Lancet 345: 413, 1995).
Immunology:
In contrast to hepatitis B, the presence of ANTI-HCV usually indicates the persistent presence of hepatitis C
virus in the body. The original work
found that around 60% of people found to be positive with the
first-generation antibody assay did indeed have virus detectable by PCR. Whether or not the others were
false-positives, occult-infections, or cleared infections (it was never
sorted out), the people with the virus in the blod
were much more likely to be infectious and to be seriously ill (NEJM 330: 744, 1994).
This is now a robust finding.
* There's hope that we'll have a hepatitis C vaccine, but it's a long way off.
Like HIV, the virus is notorious for mutating rapidly, even in the same patient, and
this isn't good for vaccine-makers. And like HIV, antibodies aren't very protective.
Updates J. Imm. 176: 6065, 2006; Gastroenterology 130: 453, 2006.
HEPATITIS G and the HEPATITIS GC family are hepatitis-C-like flaviviruses.
Hepatitis G virus is a relatively common infectious agent
that produces a chronic viremia. It's known to be
transmitted by blood products, sex, needles, and mother-to-child
(Arch. Dis. CHild. 80: F72, 1999). There's an antibody test (Lancet 349: 318, 1997).
Whether these critters make you sick is still under study.
There doesn't seem to be an acute illness (NEJM 336: 741 & 747, 1997).
More studies failing to show any evidence
that they make you sick: Gut 103: 103, 1998; Arch. Dis. Child.
80: F72, 1999; Ann. Int. Med. 126: 874, 1997.
A person may clear the virus, or have persistent virus infection.
Around 85% of hepatitis C patients have evidence of past or present
infection (J. Inf. Dis. 194: 410, 2006).
The virus also multiplies in B- and T-lymphocytes (J. Inf. Dis. 193: 451, 2006).
It inhibits HIV replication in vitro (J. Inf. Dis. 192: 2147, 2005; Lancet 363: 2040, 2004),
and it is claimed that persistent GB virus C coinfection
slows the rate of progression of HIV disease (J. Inf. Dis. 194: 410, 2006; NEJM 350: 981, 2004),
Stay tuned.
* People who study these things say that
C, G, and the GC's all evolved from yellow fever or dengue fairly recently.
* TTV ("transfusion transmitted virus") is a DNA virus that's very common
(10% of folks) in Japan, less common in the West. It elevates transaminases
after a transfusion, but nobody's found anyone sick from it yet (Lancet 352:
164, 1998).
HEPATITIS E: An important, water-borne, epidemic calicivirus infection in the poor nations.
You'll make the diagnosis on the presence of IgM antibodies.
Around 25% of people from the Middle East
have had it, but it is less prevalent in the rest of the world (J. Inf. Dis. 16: 801, 1994). Review from
the CDC in Inf. Dis. Clin. N.A. 14: 669, 2000. Vaccine NEJM 356:
895, 2007.
The first cases of chronic hepatitis E, progressing to cirrhosis,
were reported in transplant recipients in 2008 (NEJM 358: 811 & 859, 2008).
YELLOW FEVER: Councilman bodies, necrosis especially in the mid-zone of the lobule, and a surprising lack of
inflammatory response. Yellow fever today in Bolivia: Lancet 353: 1558, 1999.
Death from yellow fever is probably not so much due to liver failure as to
overactivation of cytokines, much as in sepsis: J. Inf. Dis. 190: 1821, 2004.
CHRONIC HEPATITIS NOT CAUSED BY VIRUSES
AUTOIMMUNE ("lupoid"; "plasmacytic") HEPATITIS: Chronic hepatitis progressing to cirrhosis, without chronic virus
infection but with evidence of immune injury. Review NEJM 354: 54, 2006.
Poorly understood, but fairly common, and deadly. We'll distinguish the different types (which bear little
relationship to real lupus) when we discuss liver function testing. The most common
type features autoantibodies against smooth muscle.
Review: Am. J. Med. 96(1A): 23-S, 1994.
Current thinking is that something first damages the liver (probably one of the viral hepatitis family, or some
drug or poison, or whatever), and patients then get sensitized to their livers and start destroying them over the
long haul. More about this later.
Drugs that trigger "lupoid hepatitis" include some of the older ones, and today minocycline (Br. Med. J. 312:
169, 1996).
Future pathologists: Autoimmune chronic hepatitis usually features a lot more plasma cells than does viral chronic hepatitis.
Unlike in viral infection, the response to immunosuppression (i.e., glucocorticoids) is generally good. The
common protocol, which often cures, is based on azathioprine (NEJM 333: 958 & 1004, 1995;
update on why some patients tolerate it poorly: Dig. Dis. Sci. 51: 968, 2006).
* Future pathologists! Here's your scoring system (J. Hep. 31: 929, 1999)
Transplantation may eventually be necessary.
After ten years, the transplant
has about a 50/50 chance of being involved
by recurrent disease
(Gut 52: 893, 2003).
PRIMARY BILIARY CIRRHOSIS: An autoimmune disease caused (we don't know exactly how) by antibodies against
pyruvate dehydrogenase ("anti-mitochondrial antibodies"). Lancet 362:
53, 2003. We'll talk more about this under "Liver Testing".
The bile ducts are selectively attacked by the immune system, eventually resulting in severe obstructive
jaundice.
For some reason, the biliary epithelial cells express pyruvate dehydrogenase, or something very much like it,
on their luminal surfaces (J. Clin. Invest. 91: 2653, 1993). This is evidently the target.
The histopathology begins with chronic inflammation (mostly
portal, sometimes some interface hepatitis), and progresses through
bile-duct obliteration and collateral formation to micronodular (why?) cirrhosis.
For the details see Mayo Clin. Proc. 73: 179, 1998.
Less easy to explain are the frequent appearance of granulomas and Mallory's hyaline.
* Patients typically complain of severe fatigue, even early in the disease.
One group attributes this to retained mangangese (Gut 53: 587, 2004).
{24568} primary biliary cirrhosis, early; cirrhosis has not really developed yet, but portal areas are
inflamed; you could not tell at this magnification that this is primary biliary cirrhosis
Primary biliary cirrhosis was found in the 1990's to be
considerably more common than we had once thought,
and to responds to therapy with bile salt analogues (nobody knows why; Br. Med. J. 312: 1181, 1996.)
* "Primary autoimmune cholangitis" looks something like primary biliary cirrhosis, but
has high ANA titers and no anti-mitochondrial antibodies. See Am. J. Surg. Path. 18: 91, 1994;
update on sorting out the autoimmune hepatitis family histologically Am. J. Clin. Path. 114: 705, 2000.
* IDIOPATHIC ADULTHOOD DUCTOPENIA is disappearance of the interlobular bile ducts; it may be asymptomatic
(elevated GGT prompts its discovery) or pr
I am presently adding clickable links to
images in these notes. Let me know about good online
sources in addition to these:
MedEdPORTAL -- American Association of Medical Colleges. Primarily for medical school faculty.
Pathology Education Instructional Resource -- U. of Alabama; includes a digital library
Pathopic -- Swiss site; great resource for the truly hard-core
Syracuse -- pathology cases
Alabama's Interactive Pathology Lab
"Companion to Big Robbins" -- very little here yet
Alberta
Pathology Images --hard-core!
Alberta Tumor Photos -- and lots more. Highly recommended.
Bristol Biomedical
Image Archive
EMBBS Clinical
Photo Library
Chilean Image Bank -- General Pathology -- en Español
Chilean Image Bank -- Systemic Pathology -- en Español
Connecticut
Virtual Pathology Museum
Australian
Interactive Pathology Museum
Semmelweis U.,
Budapest -- enormous pathology photo collection
Iowa Skin
Pathology
Loyola
Dermatology
History of Medicine -- National Library of Medicine
KU
Pathology Home
Page -- friends of mine
The Medical Algorithms Project -- not so much pathology, but worth a visit
National Museum of Health & Medicine -- Armed Forces Institute of Pathology
Telmeds -- brilliant site by the medical students of Panama (Spanish language)
U of
Iowa Dermatology Images
U Wash
Cytogenetics Image Gallery
Urbana
Atlas of Pathology -- great site
Visible
Human Project at NLM
Karolinska Institutet -- pathology links
Johns Hopkins CPC's
U. of Virginia Case Studies
Oklahoma Teaching Cases
Indiana U. Teaching Cases
SUNY Histopathology
West Virginia Case of the Month
Upstate NY Cases -- works only on some browsers
Society for Ultrastructural Pathologi -- electron microscope cases
WebPath:
Internet Pathology
Laboratory -- great siteEd Lulo's Pathology Gallery
Bryan Lee's Pathology Museum
Dino Laporte: Pathology Museum
Tom Demark: Pathology Museum
Dan Hammoudi's Site
Claude Roofian's Site![]()
Medmark Pathology -- massive listing of pathology sites
Pathology Handout -- Korean student-generated site; I am pleased to permit their use of my cartoons
Estimating the Time of Death -- computer program right on a webpage
Pathology Field Guide -- recognizing anatomic lesions, no pictures
St.
Jude's Ranch for Children
I've spent time there and they are good. Write "Thanks
Ed" on your check.
PO Box 60100
Boulder City, NV 89006--0100
More of my notes
My medical students
Clinical
Queries -- PubMed from the National Institutes of Health.
Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites that may work well for you
Yahoo! Medline lists other sites that may work well for you
We comply with the
HONcode standard for trustworthy health
information:
verify
here.
LEARNING OBJECTIVES
cavernous hemangioma
cirrhosis (various types)
congestion ("nutmeg liver")
costal grooves
focal nodular hyperplasia
hepatocellular carcinoma
hepar lobatum
metastases to the liver
Riedel's lobe
acute viral hepatitis
alcoholic hepatitis
alpha1-antitrypsin globules (PAS+)
ascending cholangitis
bridging necrosis
bile plugs and lakes
cavernous hemangioma
cholangiocarcinoma / adenocarcinoma of gallbladder
chronic hepatitis
chronic cholecystitis
cirrhosis (generic, and various etiologies)
congestion / central ischemic necrosis
Councilman body
fatty change (microvesicular, macrovesicular)
giant cell ("neonatal") hepatitis
giant mitochondria (PAS-)
ground glass hepatocytes
hepatocellular carcinoma
interface hepatitis ("piecemeal necrosis")
iron overload (1, 2)
liver cell unrest
lobular disarray
Mallory's hyaline
massive necrosis
primary biliary cirrhosis
Wilson's disease
Pathology of liver/pancreas infections
Great site
Yutaka Tsutsumi MD
Tulane Pathology Course
Great for this unit
Exact links are always changing
Gastrointestinal Pathology
Virginia Commonwealth U.
Great pictures
Hepatitis-Like Lesions
Histopathology and essay
For pathologists
Liver Exhibit
Virtual Pathology Museum
University of Connecticut
Liver Transplant Pictures
Great site
Transplant Pathology Internet Services
PARTIAL GLOSSARY
ASTERIXIS: "Liver flap". The tremor of early hepatic encephalopathy.
* Francophiles: Cartoon character
"Asterix the Gaul" is ancestor of a wine-loving nation with
an unusually large prevalence of
cirrhosis.
Intrahepatic lithiasis
Intrahepatic bile duct obstruction
WebPath
* This is obviously an ominous finding in chronic hepatitis, but the old
idea that is was a bad sign in acute hepatitis has been discredited.
Piecemeal necrosis / interface hepatitis:
Hard to see? Mild
Less than 50% of total interface involved? Moderate
50% or more of total interface involved? Severe
Fewer than 5 per 10 high power fields: Mild
5-20 patches per 10 high power fields: Moderate
More than 20 patches per 10 high power fields: Severe
Cirrhosis of the Liver
Australian Pathology Museum
High-tech gross photos
Liver Cirrhosis
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
Jaundice
WebPath Photo
-- Anonymous
The liver's ability to regenerate is legendary. (The Greek titan
Prometheus
had his liver devoured each day by a monster bird, but it always
grew right back.)

* These people lack a pump, which is coded by, of all things,
the hated MRP2 multidrug-resistance protein (Gastroent. 117: 653, 1999)
that pumps cancer chemotherapy agents out of cancer cells.
* Making the call is easy because the liver refuses to take up
the Tc99m-DIPA biliary scan radionuclide (Clin. Nuc. Med. 22: 635, 1997). The gene awaits discovery..
Future clinicians: Try grapefruit juice for pruritus of
liver disease (Ann. Int. Med, 126: 920, 1997).

* The pediatricians review why "20 mg/dL" is still (after many decades) considered
the magic number below which
a newborn's bilirubin must be kept to avoid brain damage: Pediatrics 115: 1747, 2005.
Gynecomastia in cirrhosis
Patient photo
Brazilian Medical Students
* Future clinicians: In contrast
to congestive heart failure, dyspnea in hepatopulmonary syndrome
improves when lying flat ("platypnea"), since the V/Q mismatching
is worst in the lung bases. Any idea why?
{08846} cirrhosis, trichrome stain (fibrous tissue is blue, of course);
micronodular
{39710} cirrhosis after hepatitis, gross photo showing uneven involvement of the liver lobules.
Just recognize cirrhosis.
The traditional wisdom has been that the fibrosis in cirrhosis does not regress.
Only recently have we begun to recognize that there may be regression, though not complete
reversal, if the underlying process goes quiet.
Look
for thin septa with holes in them, lone thick fibers (i.e.,
the surrounding thin stuff is gone), and other stuff that's harder to
see why it means regression. See Arch. Path. Lab. Med. 124:
1599, 2000; update Hum. Path. 37: 1519, 2006 (the underlying
problem must be corrected, and healing is incomplete and unpredictable, with
only a minority showing convincing healing).

{31889} nutmeg, real
Nutmeg and nutmeg liver
Someone really had fun
making this photo!
* Future pathologists: If you see dilated sinusoids in zone 3, the cause is usually
impairment of venous outflow, but a variety of other illnesses
can cause it as well -- and even obtaining a wedge biopsy during surgery
(Arch. Path. Lab. Med. 128: 901, 2004).
Vaso-occlusive disease
Joel K. Greenson MD
U. of Michigan
Comfrey is used both topically and as a "holistic" herbal tea;
amazingly, this stuff is still around and still killing people: Pub. Health Nutr. 3: 501, 2000;
the FDA merely sent a "warning to dietary supplement industry leaders" in 2001 and comfrey
tea is still readily
available and being promoted by a handful of distributors for internal use (2007).
{07022} carbon tetrachloride, microscopic
Sometimes it is due to dilated veins ("phlebectatic peliosis"); in this case, the lesions are round
and lined by endothelium and/or fibrosis, and the liver
looks like swiss cheese.
{08834} acute viral hepatitis; sinusoids are
not visible, lots of inflammatory cells
{11787} acute viral hepatitis, great bile plugging
{12764} acute viral hepatitis
{12758} acute viral hepatitis
{12767} acute viral hepatitis
{12770} acute viral hepatitis (do you see a Councilman body?)
{12773} acute viral hepatitis
{12776} acute viral hepatitis
Hepatitis
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery
{13321} massive necrosis after hepatitis, histology
{13322} massive necrosis after hepatitis, histology
{12785} mild chronic hepatitis, H&E (not a very good case, since lymphocytes are very few, and a
portal
area is not even shown; indistinguishable from mild acute hepatitis)
{12788} mild chronic hepatitis, reticulin stain (see the limiting plate intact);
you don't need to tell this isn't normal liver;
{12791} mild chronic hepatitis, trichrome (again, see the limiting plate intact);
again, you can't tell this isn't normal liver;
{12803} severe chronic hepatitis; subtle
{20328} severe chronic hepatitis; almost to cirrhosis (the
nodules are not yet completely separate)
{40279} severe chronic hepatitis, note the necrotic cells
{20183} severe chronic hepatitis with good bridging necrosis;
the hepatocytes are stained orange and the bridge is an area of lytic necrosis
Chronic viral hepatitis
Photo and mini-review
Brown U.
Hepatitis C
Joel K. Greenson MD
U. of Michigan
{08173} hepatitis A virus
{08175} hepatitis B virus
{10532} hepatitis B, * orcein stain (stains the virus)
{11708} hepatitis B, core antigen stained in nuclei
Other anti-viral agents include lamivudine, adefovir, and dipivoxil
(NEJM 348: 800 & 808, 2003). They are unlikely to eradicate the virus,
but they keep it under control and it is now clear that even the cirrhosis tends to
reverse under this treatment (Lancet 362: 2089, 2003).
Entecavir (a guanine analogue: NEJM 354: 1001, 2006) and telbivudine
(the L-isomer of thymidine: NEJM 357: 2576, 2007; Ann. Int. Med. 147: 745, 2007)
are new entries.
A few mutant viruses that can affect the immunized are now
appearing (Epid. & Inf. 124: 295, 2000).
* Maybe from the barber (?! the macho man's horror; see Lancet 345: 658, 1995).
* Children exposed from blood transfusion do much better,
often clearing themselves (NEJM 341: 912, 1999).
)
not being sterilized between patients (Lancet 355: 887, 2000).
The big news in hepatitis C is reports that almost all patients
with the acute illness are apparently cured if given by interferon alfa-2b (NEJM 345: 1452 & 1495, 2001)
if you get it to them. This is complicated by the discovery that many people
who actually get sick when they meet the virus clear themselves of infection anyway
(Gastroent. 125: 80, 2003 -- currently the acute-stage cure rate is estimated
at 15% Am. J. Gastro. 100: 607, 2005); people with anicteric hepatitis C or who
keep the virus on board for twelve weeks are unlikely to self-cure.
What's best to do? Stay tuned.
* Transgenic mice carrying only the core protein develop steatosis,
adenomas, and then hepatocellular carcinomas (Nat. Med. 4:
1065, 1998).
* Echazabal vs. Chevron. Mario Echazabal had hepatitis C, and Chevron
refused to allow him to work around chemicals that might be hepatotoxic.
He claimed that this violated his rights under the Americans with Disabilities
Act. His supporters accused Chevron of "paternalism", which as you know
is currently anathema in many circles but is (like it or not) the foundation
of occupational health and safety policy.
The Supreme Court decided unanimously for
Chevron in 2002. I agree.
See Am. J. Pub. Health. 93: 540, 2003.
For some reason, pregnant women are likely to be severely affected, and may die.
It does not become
chronic. There is no specific treatment.
Doing it:
Interpreting it:
* Pitfall: Sarcoidosis can look exactly like PBC-with-granulomas, but the
AMA is negative.
{24569} primary biliary cirrhosis, histology (i.e., the bile duct is gone)
Primary biliary cirrhosis
Joel K. Greenson MD
U. of Michigan
Primary biliary cirrhosis
Chronic inflammatory infiltrate
WebPath