LIVER AND BILIARY DISEASE
Ed Friedlander, M.D., Pathologist
scalpel_blade@yahoo.com

No texting or chat messages, please.

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. No texting or chat messages, please.

DoctorGeorge.com is a larger, full-time service. There is also a fee site at www.afraidtoask.com.


If you have a Second Life account, please visit my teammates and me at the Medical Examiner's office.

Freely have you received, give freely 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.

I am presently adding clickable links to images in these notes. Let me know about good online sources in addition to these:

Freely have you received, freely give. -- Matthew 10:8. My site receives an enormous amount of traffic, and I'm still handling dozens of 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:

I've spent time there and they are good. Write "Thanks Ed" on your check.

Help me help others

My home page
More of my notes
My medical students

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. 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 June 30, 2009.

During the fourteen 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!

We comply with the HONcode standard for trustworthy health
information:
verify here.

PicoSearch
 Help

More of Ed's Notes: Ed's Medical Terminology Page

Perspectives on Disease
Cell Injury and Death
Accumulations and Deposits
Inflammation
Fluids
Genes
What is Cancer?
Cancer: Causes and Effects
Immune Injury
Autoimmunity
Other Immune
HIV infections
The Anti-Immunization Activists
Infancy and Childhood
Aging
Infections
Nutrition
Environmental Lung Disease
Violence, Accidents, Poisoning
Heart
Vessels
Respiratory
Red Cells
White Cells
Coagulation
Oral Cavity
GI Tract
Liver
Pancreas (including Diabetes)
Kidney
Bladder
Men
Women
Breast
Pituitary
Thyroid
Adrenal and Thymus
Bones
Joints
Muscles
Skin
Nervous System
Eye
Ear
Autopsy
Lab Profiling
Blood Component Therapy
Serum Proteins
Renal Function Tests
Adrenal Testing
Arthritis Labs
Glucose Testing
Liver Testing
Porphyria
Urinalysis
Spinal Fluid
Lab Problem
Quackery
Alternative Medicine (current)
Preventing "F"'s: For Teachers!
Medical Dictionary

Courtesy of CancerWEB

LEARNING OBJECTIVES

    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
      cavernous hemangioma
      cirrhosis (various types)
      congestion ("nutmeg liver")
      costal grooves
      focal nodular hyperplasia
      hepatocellular carcinoma
      hepar lobatum
      metastases to the liver
      Riedel's lobe

    Recognize and distinguish the following microscopic lesions:

      acute cholecystitis
      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

QUIZBANK: Liver and biliary (all)

Liver Pathology
Photomicrograph collection
In Portuguese

Hepatobiliary
Iowa Virtual Microscopy
Have fun

Hepatobiliary Diseases

Chaing Mi, Thailand

Pathology of liver/pancreas infections
Great site
Yutaka Tsutsumi MD

Hepatobiliary
Brown Digital Pathology
Some nice cases

Tulane Pathology Course
Great for this unit
Exact links are always changing

Hepatobiliary
Great pathology images
Indiana Med School

Gastrointestinal Pathology
Virginia Commonwealth U.
Great pictures

Liver
Photos, explanations, and quiz
Indiana U.

Gross Liver Photos
U. of Pittsburgh
Great pictures

Gross Liver
Tulane
Big selection

Liver
Webpath
University of Utah

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

Lacerated liver
Car wreck
WebPath Photo

Liver in place
Autopsy photo
WebPath

Liver Path
Great tutorial!
Loyola
PARTIAL GLOSSARY

    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).

    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.

    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

Cholestasis of liver
Bile accumulation
WebPath

Intrahepatic lithiasis
Intrahepatic bile duct obstruction
WebPath

Bile plugs
Cholestasis
WebPath Photo

    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.

      * 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.

    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 any etiology!

        Piecemeal necrosis / interface hepatitis (0-3):

          Hard to see? Mild (1)
          Less than 50% of total interface involved? Moderate (2)
          50% or more of total interface involved? Severe (3)

        Inflamed patches in the sinusoids, away from the interface:

          Fewer than 5 per 10 high power fields: Mild (1)
          5-20 patches per 10 high power fields: Moderate (2)
          More than 20 patches per 10 high power fields: Severe (3)

        To describe the hepatitis, choose whichever is worse. To use the METVAR algorithm for "histological activity", add the two numbers (0-3 for each), and report the sum, or three if it is more than three.

      It also makes sense to talk about both grade (i.e., how nasty it looks) and stage (i.e., how far has it gotten) for chronic hepatitis. Here is a popular system:

        Grade:

          Report some version of the histological activity as above.

        Stage:

          0 No fibrosis
          1 Fibrosis confined to portal tracts
          2 Periportal or portal-portal septa but intact vascular relationships
          3 Fibrosis with distorted structure but no obvious cirrhosis
          4 Probable or definite cirrhosis

    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.

Cirrhosis
WebPath

Cirrhosis of the Liver
Australian Pathology Museum
High-tech gross photos

Hepatic cirrhosis
Trichrome stain
KU Collection

Liver Cirrhosis
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery

    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

Jaundice

WebPath Photo

    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.

Liver
Gross photo
WebPath

Liver
normal histology
WebPath

INTRODUCTION

Is life worth living? It depends on the liver!

        -- Anonymous

    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).

    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.)

      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.


    Prometheus

      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. Some folks do find it troublesome. 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

            * 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.

            * 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.

            * 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..

          * 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.

          Future clinicians: Try grapefruit juice for pruritus of liver disease (Ann. Int. Med, 126: 920, 1997).

      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.

      * 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.

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 2009).

    Gynecomastia in cirrhosis
    Patient photo
    Brazilian Medical Students

    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 seen when the liver fails. The small arterioles and capillaries of the lungs dilate preposterously causing V/Q mismatching (i.e., the oxygen cannot reach the centers of the vessels, and there are some shunts opening that bypass the alveoli altogether). There is no current remedy apart from curing the liver disease. See Gastroent 113: 606, 1997; Surg. Clin. N.A. 79: 23, 1999; Mayo Clin. Proc. 79: 42, 2004; Lancet 363: 1461, 2004 ("notoriously underdiagnosed"); NEJM 358: 2378, 2008.

      * 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?

    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

    • DISRUPTION OF THE NORMAL LIVER ARCHITECTURE BY FIBROUS SCARS that have resulted from loss of liver cells; i.e., you can no longer distinguish the nice, individual lobules. At a minimum, the scars connect portal regions either to other portal regions (kind of bad) or to the central veins (really bad).
      • 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.

    • NODULES OF "REGENERATIVE" LIVER CELLS, which represent successful regeneration of the ill-perfused remaining hepatocytes. In cirrhosis, the liver may actually contain MORE hepatocytes than in health, though it may instead contain fewer.
    • if you really look, the vascular architecture is scrambled, and at least some branches of hepatic arteries directly enter hepatic and/or portal venules. This is probably the most unwholesome thing about cirrhosis, and the reason the liver fails despite having plenty of good hepatocytes.

{00005}    cirrhosis
{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.

    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

Micronodular cirrhosis
Urbana Atlas of Pathology

Micronodular cirrhosis
Chronic alcoholism
WebPath

MRI photo, cirrhosis
small nodular liver
WebPath

Micronodular cirrhosis and fatty change
Alcoholism
WebPath

CT scan with contrast
Small liver with cirrhosis
WebPath

Micronodular cirrhosis
Fatty change
WebPath

Micronodular cirrhosis
Fatty change
WebPath

Micronodular cirrhosis
Urbana Atlas of Pathology

Cirrhosis I
From Chile
In Spanish

Cirrhosis II
From Chile
In Spanish

    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

Macronodular cirrhosis
Necrosis and fibrosis
WebPath

Macronodular cirrhosis
WebPath

    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)

    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).

      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 often some regression when hepatitis&C virus is eradicated from a long-time patient (Dig. Dis. Sci. 43: 2573, 1998; Ann. Int. Med. : 399, 2008) and autoimmune hepatitis (Ann. Int. Med. 127: 981, 1997) are successfully treated.

      There are now animal models for stem cell work in partially-repairing the damged liver (as is already in use for the damaged heart). Stay tuned: Gastroent. 135: 438, 2008.

    * 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
{31889}    nutmeg, real

Congested liver, live cells in zone 1
Slide from Andrea McCollum MD
Cuyahoga County Coroner's Office

Congested liver, dead cells in zone 3
Slide from Andrea McCollum MD
Cuyahoga County Coroner's Office

Chronic passive congestion
Nutmeg liver
WebPath

Chronic passive congestion
WebPath

Nutmeg and nutmeg liver
Someone really had fun
making this photo!

      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.)

Chronic passive congestion
"Cardiac cirrhosis"
WebPath

          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.

        * 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).

    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).

Infarcted liver
WebPath

    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).

      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).

      * 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 (* think of a very bad case of 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

        * Test-takers: Notice that all three of these famous poisons do their work by generating free radicals; perhaps this is rougher on the central areas because of the lower concentrations of oxygen found their. And please remember too that we usually see the livers of poisoning victims after they've been in shock -- which damages the central areas, anyway.

{07020}    carbon tetrachloride, gross; note the necrosis (yellow, of course)
{07022}    carbon tetrachloride, microscopic

Necrosis with acetaminophen overdose
"Limp liver"
WebPath

      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.)

        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.

        In the more familiar sort of peliosis the lakes are lined only by hepatocytes ("parenchymal peliosis"); in this case, the lesions are irregularly-shaped.

      Anabolic steroid use is the best-known cause (generally parenchymal), 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

      • widespread liver cell injury, with cell swelling ("hydropic change"; "cloudy swelling"; "ballooning degeneration"). This scrambles the normal radial appearance of the liver plates and squeezes the sinusoids closed ("LOBULAR DISARRAY");
      • lysis of liver cells, individually or in small groups (lytic necrosis);
      • apoptosis of individual liver cells as eosinophilic COUNCILMAN BODIES, which are likely then to be phagocytized;
        • Note that in hepatitis, the cells may die either by lysis or apoptosis, or both. Probably the lysis is due to the viruses and/or to antibodies, while the apoptosis is caused by instructions to self-destruct delivered by the T-cells.

      • hypertrophy / hyperplasia of Kupffer cells (look for gobbled lipofuscin; why?) and the other cells that line the sinusoids;
      • inflammatory cells (mostly lymphocytes) in the portal areas, and some among the hepatocytes, too;
      • hepatocyte regeneration (i.e., purple cells with big nuclei) during the recovery phase.

{05961}    acute viral hepatitis with Councilman body
{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 I
From Chile
In Spanish

Hepatitis II
From Chile
In Spanish

Hepatitis III
From Chile
In Spanish

Hepatitis
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery

Viral hepatitis
WebPath

Viral hepatitis
Necrosis and lobular collapse
WebPath

Viral hepatitis B
Low power
WebPath

Viral hepatitis B
High power
WebPath

Viral hepatitis C
Low power
WebPath

Viral hepatitis C
High power
WebPath

Viral hepatitis with collapse
Trichrome stain
WebPath

      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-to-yellow, 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!)
{13321}    massive necrosis after hepatitis, histology
{13322}    massive necrosis after hepatitis, histology

Fulminant hepatitis
Bridging
Pittsburgh Pathology Cases

Massive hepatic necrosis
Review article
Great photos

      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
{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;

      These findings are more ominous when the patient has chronic hepatitis clinically:

      • a heavy inflammatory infiltrate of lymphocytes (and often other cells), spilling from the portal areas into the parenchyma;
      • INTERFACE HEPATITIS (formerly "piecemeal necrosis") apoptosis of cells at the edge of the inflammatory infiltrate, causing disruption of the limiting plate of liver cells;
      • BRIDGING NECROSIS, confluent-lytic areas in which all hepatocytes have died (lytic necrosis), leaving behind only collapsed reticulin stroma;
      • FIBROSIS, radiating outward from the portal areas, eventually linking the portal areas to the central areas
      • Cirrhosis

      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
{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

Hepatitis C
Joel K. Greenson MD
U. of Michigan


      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).

{00444}    hepatitis A virus
{08173}    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"; update NEJM 359: 1486, 2008; Lancet 373: 582, 2009)

    Hepatitis B
    Great photos
    Loyola

      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) or 350 million (WHO 2009) carriers, most of whom are asymptomatic and probably have histologically normal or near-normal livers.

        Perhaps one person in three worldwide has met the hepatitis B virus; most people cure themselves.

{00445}    hepatitis B virus
{08175}    hepatitis B virus
{10532}    hepatitis B, * orcein stain (stains the virus)
{11708}    hepatitis B, core antigen stained in nuclei

      Even an infinitesimal amount of infected blood, when introduced into another person's tissues, is highly effective in transmitting the infection.

        Routes include

        • transfusions (of course, we check donor units)
        • shared needles
        • hospital mishaps (cuts, needle sticks; hepatitis B only became a common infection in the U.S. around the beginning of the 20th century, when needles became popular with both physicians and addicts)
        • Improper re-use of medical equipment remains a terrible cause of epidemic hepatitis B in the poor nations, including "today's India", where an underground trade in used medical equipment led to at least 60 deaths and the discovery of warehouses filled with medical waste for resale, mostly to quacks (their word, Lancet 373: 1067, 2009).

        • sex (the virus abounds in most body fluids, so pretty much anything more than holding hands will do; hepatitis B was rampant among "swingers" in recent decades), and...
        • probably most important worldwide, especially in the poor nations... vertical transmission mother-to-child (which typically produces a lifelong carrier with variable liver pathology: Arch. Dis. Child. 89: F-456, 2004). In the poor countries of Africa and Asia, up to 25% of people are lifelong carriers. Before the vaccine, hepatitis B was a scourge in Eskimo communities; the vaccine has been a tremendous help (J. Inf. Dis. 175: 674, 1997).

        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 good sign of recovery.

          NOTE: Now that we use viral DNA to discover hepatitis B infection, we're discovering quite a few folks who never mount an antibody response. These folks seem to fail to expand their clone of HBV-specific T-cells (Gastroent 134: 1470, 2008).

          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).

          NOTE: Quite a few patients with hepatitis B in the blood but persistently normal transaminases do indeed go on to fibrosis and cirrhosis (Gastroent. 134: 1376, 2008).

        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).

        Nucleotide analogues (inhibit the virus's polymerase) including e lamivudine and adefovir dipivoxil (NEJM 348: 800 & 808, 2003) inhibit polymerase. 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), telbivudine (the L-isomer of thymidine: NEJM 357: 2576, 2007; Ann. Int. Med. 147: 745, 2007) and tenofovir (NEJM 359: 2442, 2008) are new entries.

      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.

        A few mutant viruses that can affect the immunized are now appearing (Epid. & Inf. 124: 295, 2000).

    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 in the USA.

      * Disturbingly, there's a fair amount of hepatitis D in school children in Mongolia, and it seems to be acquired through dirty needles in the health care setting (Am. J. Trop. Med. Hyg. 75: 365, 2006).

      LABREA HEPATITIS, noted in the western parts of the Amazon region, is a fulminant, deadly hepatitis of children and young adults caused by hepatitis B and D. There is inflammation of the portal and central veins, and "morula cells", macrophages loaded with virus (Trans. Royal Soc. Trop. Med. 101: 831, 2007).

    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 (maybe 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.

        * Maybe from the barber (?! the macho man's horror; see Lancet 345: 658, 1995).

        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.)

          * Children exposed from blood transfusion do much better, often clearing themselves (NEJM 341: 912, 1999).

        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) not being sterilized between patients (Lancet 355: 887, 2000).

      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.

        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.

      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.

          * As with hepatiis B, 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).

      * Transgenic mice carrying only the core protein develop steatosis, adenomas, and then hepatocellular carcinomas (Nat. Med. 4: 1065, 1998).

      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.

      * 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.

Cirrhosis from hepatitis C
Pittsburgh Illustrated Case

    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.

      For some reason, pregnant women are likely to be severely affected, and may die. It does not become chronic. There is no specific treatment.

      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 (still the pattern: Trans. Royal. Soc. Trop. Med. 101: 831, 2007). 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.

    Yellow fever

    Yutaka Tsutsumi MD

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. Other types are distinguished by other antibodies (anti-LKM-1, auto-SLA/soluble liver antigen: Gastroent. 135: 2107, 2008), but the havoc is wrought by the T-cells.

      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 (maybe not so good if it's anti-LMK-1 disease). 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)

        Doing it:

        • +2 if you're a female patient
        • -2 if your alkaline phosphatase is more than three times your ALT or AST, +2 if it is less than 1.5 times as much
        • +1 if IgG and/or serum globulin is above normal, or +2 if above 1.5 times normal, or +3 if above 2 times normal
        • +1 for ANA, SMA (smooth muscle antibody), and/or LKM1 titer 1:40, +2 for 1:80, +3 for more than 1:80
        • -1 if anti-mitochondrial antibodies are positive
        • -3 if there is any marker for current viral hepatitis infection
        • -4 if you've been taking some notable hepatotoxic drug
        • -2 if you drink alcohol >60 gm/day, +2 if <25 gm/day
        • +3 if there is interface hepatitis, +1 if there is a lymphocytic-plasmacytic infiltrate, +1 if there are rosettes of liver cells, -1 if it's granulomas around the bile ducts, -1 if there is concentric periductal fibrosis, -1 if the bile ducts are mostly gone, -1 if the bile ductules at the edges of the portal areas are proliferated, -5 if there is neither interface hepatitis, nor lymphocytes-and-plasma-cells, nor rosettes.
        • +2 if you have another autoimmune disease
        • +2 if you don't have ANA, SMA, or LKM-1, but do have p-ANCA, anti-LC1, anti-ASGPR, anti-LP, or anti-sulfatide. Gut 44: 886, 1999.
        • +1 if you are seronegative but have DR3 or DR4.
        • +2 if the treatment worked, or +3 if you relapsed when it was discontinued.
        Interpreting it:

        • >15: Definitely got autoimmune hepatitis. If you were treated before the full workup, you need >17.
        • 10-15: Probably got it. If you were treated before the full workup, you need 12-17.

      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 anti-nuclear antibodies often seen in primary biliary cirrhosis are usually directed at glycoprotein 210 and/or nucleoporin 62, on the nuclear surface pores.

        * There are several known associations with HLA and Interleukin 12 genes: NEJM 360: 2544, 2009).

      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).

        * Pitfall: Sarcoidosis can look exactly like PBC-with-granulomas, but the AMA is negative.

{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
{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

Anti-mitochondrial antibody
Immunofluorescence
WebPath

      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 progress to cirrhosis (NEJM 336: 835, 1997).

      "Secondary biliary cirrhosis" is more likely to be just fibrosis, due to obstruction of the common bile duct, usually in chronic pancreatitis. If the stenosis is relieved, the fibrosis often regresses some (NEJM 344: 452, 2001).

    DRUGS AND POISONS (a problem easily overlooked; reviews Gut 44: 731, 1999, NEJM 354: 731, 2006; including how to establish the relationship and warnings about what will happen if you leave the patient on the medication that's causing the liver disease)

      As before, "all poisons are drugs, all drugs are poisons".

        Drug-induced liver disease is a medicolegal nightmare. Since it is caused by hypersensitivity to medication, and since only a very few people are vulnerable to a particular drug, it's often missed in clinical trials.

        To make the call, you want to see one of these:

        • SGPT/ALT three times the upper limit of normal
        • Alk phos twice the upper limit of normal
        • Bilirubin twice the upper limit of normal with any elevation of alk phos or SGPT

      Especially rough on the liver:

      • acetaminophen (paracetamol, "Tylenol") overdose
      • acetaminophen plus alcohol (bad combination, all you hangover sufferers....)
      • AMANITA PHALLOIDES toadstools ("the death angel" / "death cap")
      • Amanita phallodes

      • Ecstasy (this particular amphetamine is infamous for this)
      • carbon tetrachloride and chloroform
      • isoniazid (especially in older folks; the risks are less than you've been told, but do monitor them JAMA 281: 1014, 1999)
      • methyldopa (acute hepatitis)
      • * old-fashioned monoamine-oxidase inhibitors
      • phosphorus
      • * arsenic (as for syphilis therapy)
      • "Kampo medicines", combinations of various herbs used in "Chinese medicine" (this has become infamous: Am. J. Chinese Med. 31: 643, 2003).

      Any of these can produce massive hepatic necrosis. The toadstool and the acetaminophen overdose will produce massive hepatic necrosis; "Ecstasy" in recreational amounts is famous for the same (Transplant. Proc. 33: 2743, 2001). The others are more likely to produce a hepatitis-like picture.

      ACETAMINOPHEN OVERDOSE is very common.

        The drug is metabolized by two different pathways, one "safe", the other productive of noxious free radicals. Ordinarily, we use only the "safe" pathway, but when that is overloaded, the drug gets shunted into the bad pathway.

          * We've already seen the "two-pathway" concept in our discussions of atherosclerosis and Alzheimer's disease. Stay tuned for the discovery of more "two-pathway diseases".

        Three or four days after the overdose, the patient gets sick and lapses into hepatic failure. By this time, the drug itself may be mostly gone.

        Future emergency room specialists: You can block the "bad" pathway using good old N-acetyl-cysteine, or "Mucomist", from the respiratory care department.

      * The most widely-used industrial agent that causes an idiosyncratic hepatitis in certain exposed workers is the solvent 1,1,1-trichloroethylene.

CHOLANGITIS

    BACTERIAL CHOLANGITIS ("ascending cholangitis", etc.) is suppuration involving bile ducts.

    Ascending cholangitis / biliary obstruction
    Joel K. Greenson MD
    U. of Michigan


      The underlying cause is almost always obstruction. Pretty much any gut bacterium can be the opportunist. E. coli is most common; clostridial gas gangrene of the liver is ultra-deadly.

      As you would expect, patients are super-sick with the acute infection. Call a surgeon, since the bile has to be drained.

        "Charcot's triad" is jaundice, right upper quadrant pain, and a bad fever.

      The give-away on histologic exam is neutrophils within the bile ducts. Since there's obstruction, look for bile plugs, too.

    LIVER ABSCESSES, in the U.S. are usually of bacterial origin, spreading either up the bile ducts ("cholangitis abscess" -- ascending cholangitis) or via the portal vein ("pyelophlebitic abscess" -- appendicitis, diverticulitis), or from septic emboli (bacterial endocarditis), or following a dirty wound.

      Naturally, patients are super-sick, as with ascending cholangitis.

      "Amebic abscesses", a misnomer, are areas of "anchovy paste" necrosis without much inflammation. Hydatid cysts can become infected, forming real abscesses.

Amebic Liver Abscess
CDC
Wikimedia Commons

Amebic liver abscess

Yutaka Tsutsumi MD

    PERICHOLANGITIS, broadly defined, is inflammation AROUND the bile ducts. This generally takes the form of extra lymphocytes, maybe with any other kind of inflammatory cells, in the portal areas.

      This is extremely common at autopsy, but its significance is obscure. One could conjecture that the liver clears the blood of foul products of fatal disease, and that these are excreted in the bile and attract inflammatory cells.

      Patients with ulcerative colitis and Crohn's generally have pericholangitis, which may eventually become fibrosis (SCLEROSING CHOLANGITIS) and biliary obstruction / biliary cirrhosis.

    Or one can have idiopathic PRIMARY SCLEROSING CHOLANGITIS, a curious, probably-immune-mediated entity. The extra-hepatic bile ducts in these diseases come to look like uneven strings of beads. Under the microscope, there is onionskin fibrosis around the intrahepatic bile ducts.

      * The majority of these patients have positive p-ANCA, often with curious specificities (Am. J. Med. 105: 393, 1998; Gut 44: 886, 1999.)

      More recently, there are claims that there are distinctive autoantibodies against biliary epithelium (Gastroent. 132: 1504, 2007), and this seems to be holding up.

Chronic ductopenic rejection
No inflammation, just no ducts
Joel K. Greenson MD, U. of Michigan


Primary sclerosing cholangitis
Onion-skinning around bile duct
KU Collection

Sclerosing cholangitis
Trichrome stain
WebPath

Sclerosing cholangitis
WebPath

    OTHER INFECTIONS:

      Malaria can load the Kupffer cells with pigment, but seldom causes hepatic dysfunction.

      KALA-AZAR (a vicious form of leishmaniasis) packs Kupffer cells with organisms but does not interfere with liver function.

      INFECTIOUS MONO from any of the usual causes can produce elevated transaminases and/or mild hepatocyte failure.

      SECONDARY SYPHILIS can give an acute hepatitis, while TERTIARY and especially CONGENITAL syphilis are noted causes of hepar lobatum, due to scar contraction.

      Don't forget LEPTOSPIRA in unexplained jaundice.

      PENICILIUM MARNEFFEI is an opportunist in AIDS, especially in Southeast Asia (Arch. Path. Lab. Med. 128: 191, 2004).

    Hepar lobatum
    Syphilis

    PORTAL HYPERTENSION

      Increased pressure in the portal venous system, for whatever reason (usually increased resistance to flow and/or increased anastomoses with the arterial circulation).

      PRE-HEPATIC CAUSES

        Portal vein obstruction / compression

          Thrombus (typically from tumor invasion, hypercoagulability, or polycythemia vera)

          Tumors (hepatic, biliary, pancreatic)

          Really bad pancreatitis

      INTRA-HEPATIC CAUSES

        Cirrhosis (both fibrosis of the vasculature, especially hepatic veins, and AV-shunting contribute)

        * Central hyaline sclerosis without cirrhosis

        Really bad fatty change

          Alcoholism / "alcoholic hepatitis", etc.

          NASH

          Reye's

        Schistosomiasis (eggs plug portal vein radicles)

        * Sarcoid / TB

        * Congenital hepatic fibrosis (a thankfully-rare birth defect, with very few veins in the expanded portal areas; one known locus is a variant autosomal recessive polycystic kidney disease gene, and hepatic fibrosis is common in the fully-expressed condition as well: Medicine 85: 1, 2006)

        Osler-Weber-Rendu telangiectasisa (abnormal vascular communications: NEJM 343: 931, 2000).

        "Idiopathic" (dubious)

      POST-HEPATIC CAUSES

        Budd-Chiari

        Constrictive pericarditis

        Tricuspid insufficiency

        Really bad right-sided heart failure

    Regardless of cause, portal hypertension is troublesome.

      Patients get ASCITES, or large accumulations of fluid in the abdomen. This is troublesome. Mechanisms of formation include

      (1) the obvious increase in hydrostatic pressure in the venules;

      (2) the increase (most mechanisms) in hydrostatic pressure within the hepatic sinusoids themselves (the "increased hepatic lymph formation" of "Big Robbins"; this stuff is likely to be rich in protein, since the hepatic sinusoidal "endothelium" is discontinuous)

      (3) diminished circulatory volume due to low serum albumin, with a tendency of the kidneys to retain sodium and water. (BEWARE! If you give these patients a diuretic, you can send them into shock, kidney failure, "hepatorenal syndrome", etc., etc.)

{19381}    ascites
{05952}    ascites in a known cirrhotic
{05953}    ascites in a known cirrhotic

Caput medusae
Caused by cirrhosis
WebPath

Esophageal varices
Dilated submucosal veins
WebPath

Splenomegaly with portal hypertension
(Ignore the "hyaline perisplenitis")
WebPath

Massive ascites
Patient photo
Brazilian Medical Students

      PORTO-SYSTEMIC SHUNTING results when blood from the guts finds other routes back to the right side of the heart.

        This results in ESOPHAGEAL VARICES (which can bleed profusely), HEMORRHOIDS (which can bleed profusely), and the distinctive CAPUT MEDUSAE around the belly-button. Since this blood isn't detoxified in the liver, HEPATIC ENCEPHALOPATHY is likely to be exacerbated.

        * This also probably is the cause of the usually-mild IMMUNOGLOBULIN A NEPHROPATHY typical of cirrhotics (i.e., asymptomatic hematuria). IgA from the gut ends up in the kidneys, rather than being cleared by the liver.

      FIBROCONGESTIVE SPLENOMEGALY produces big, firm spleens that often produce clinically significant hypersplenism (i.e., they make the person anemic, neutropenic, and/or thrombocytopenic). This is bad.

    You can treat portal hypertension effectively by doing a porto-caval shunt operation. If the underlying problem is cirrhosis, this will result in blood flowing directly from the bowel to the systemic circulation, making hepatic encephalopathy much, much worse. But this beats dying of bleeding varices.

      Sclerosing agents save the lives of patients during acute bleeds. Today, banding ("band ligation") is doing the same (Br. J. Surg. 86: 437, 1999.)

      For lasting control, the patient is likely to have the shunt placed inside the liver itself, by the radiologist who passes a catheter down the jugular vein ("transjugular intrahepatic portosystemic shunt").

      * Old-fashioned "prophylactic sclerotherapy" of esophageal varices actually increased the risk of dying. Perhaps it just made whatever vein didn't get sclerosed into a bigger varix. NEJM 324: 1779, 1991.

    Of course, portal hypertension isn't the only problem that the cirrhotic has. See "When the liver fails", above.

ALCOHOLIC LIVER DISEASE (Lancet 345: 227, 1995; Mayo Clin. Proc. 76: 1021, 2001)    

Fatty metamorphosis
H & E stain
WebPath

Fatty metamorphosis
Cross section
WebPath

Fatty liver
Double normal weight
KU Collection

Fatty liver

KU Collection

Fatty metamorphosis
Lipid vacuoles
WebPath

Fatty liver

WebPath Photo

Mallory's hyaline
"Alcoholic" hyaline
WebPath

Acute alcoholic hepatitis
"Binge" drinkers
WebPath

Mallory's alcoholic hyaline

WebPath Photo

Cirrhosis

WebPath Photo

Alcoholic liver disease
Joel K. Greenson MD
U. of Michigan


Alcoholic Liver Disease
Text and pictures
From "Big Robbins"

Fatty liver
Alcohol vs. NASH
Wikimedia Commons

Microvesicular steatosis
Substance abuser
KCUMB Team

Woe to those who demand strong drink as soon as they rise in the morning, and linger into the night while wine inflames them!

        -- Isaiah 5:11

Sir, I have known more old drunkards than old doctors.

        -- Dr. Rabelais

Wine god's procession
"The Wine God's Procession"

    Everybody knows alcohol is bad for the liver, but there is considerable confusion about the various patterns of liver injury and their outcome.

    ALCOHOLIC STEATOSIS ("alcoholic fatty liver")

      We've already reviewed why fat accumulates in liver cells damaged by alcohol.

        To review: The drunken hepatocytes make too much fatty acid, make it into excess triglyceride instead of burning it, then can't complex the triglyceride to apolipoproteins, and can't export the lipoproteins they do make.

        Current thinking supports popular wisdom that alcohol itself does the damage (in fatty change and the more severe forms of "alcoholic liver disease"). Poor nutrition doesn't help, either (i.e., few people make daily trips to the salad bar while on benders.)

      If you've ever drunk a case of beer over a great football weekend, I bet you've had fatty liver. Did you notice? Probably not. The "disease" is usually just a pathology finding, unless:

      • you find you need to let your belt out a notch to accommodate the enlarged liver (and perhaps mild ascites);
      • you die of something else and the big, yellow, greasy liver gives you away ("Look! This chunk of liver floats!");
      • the doctor finds your serum transaminases are a bit high, and your either tell all or submit to a biopsy;
      • the damaged liver cells can't keep your blood glucose levels up, and you die of sudden hypoglycemia when stressed (unlikely....);
      • somebody gives you a swift karate kick to the liver and you get a fat embolus (rare, rare);
      • there's more the matter, i.e., you've been drinking for enough years to have some fibrosis (pre-cirrhosis) and/or heavy enough for enough weeks to have necrosis + alcoholic hyaline + inflammation (alcoholic hepatitis). See below.

      Fatty liver is, by itself, completely reversible once the drinker sobers up. The same applies to fatty liver from other causes i.e., after bariatric surgery (Gastroenterology 130: 1617, 2006), in obesity, in ill-controlled adult-onset diabetes, in problem pregnancy, in galactosemia, in methotrexate toxicity, in Wilson's disease, and as a complication of a few rare disorders of lipid metabolism.

{49271}    fatty cirrhotic liver vs. normal

      NOTE: "Microvesicular steatosis" (smaller vacuoles, usually several per cell) is typical of Reye's syndrome, problem pregnancies, mitochondrial problems (Gastroent. 108: 193, 1995), and toxicity from outdated-tetracycline poisoning. It's also reversible; really, "microvesicular" steatosis can occur in any fatty liver.

        * In my opinion, the "microvesicular vs. macrovesicular" distinction is of no value. I have seen only one Reye's autopsy, and it was pure macrovesicular fat. I've autopsied many, many problem drinkers, and the pattern is often mixed, and sometimes microvesicular-only. I addressed this question to the pathology on-line group in 1996, and there was no disagreement from a few hundred experienced pathologists.

      NOTE: "Fatty change" confined to the "Ito cells" (stellate cells) is vitamin A overdose. "Stellate cell lipidosis" is often due to vitamin A overdose or Retin-A: Am. J. Clin. Path. 119: 254, 2003.

      * Of course, if you continue drinking, you're at serious risk to get cirrhosis, even if "you only had fatty change" on a biopsy. Bad prognostic indicators include giant mitochondria and mixed microvesicular and macrovesicular fat. See Lancet 346: 987, 1995..

    ALCOHOLIC HEPATITIS

      Much more serious. Here, we have liver cells dying. The process is worst in the centrilobular regions.

      Surviving liver cells often bear MALLORY'S ALCOHOLIC HYALINE (not pathognomonic, but suggestive). This is masses of altered prekeratin fibers plus stress proteins. Free Mallory's hyaline is chemotactic for neutrophils.

      Also look for GIANT MITOCHONDRIA, (* Yokoo bodies, after one of the professors who trained your lecturer), PAS-negative blobs in the cytoplasm.

        * Mitochondria (giant or no) in alcoholics' livers often have genetic damage, presumably because alcohol generates toxic free radicals inside them (Gastroent. 108: 193, 1995). This is one more mechanism of fatty liver (how)?

      Cholestasis is usual because of compromise of bile canaliculi, with bile lakes and bile plugs. At the same time, the bile ducts may proliferate within the portal areas.

      As the liver cells die off, look for FIBROSIS, notably around the central veins ("central hyaline sclerosis"; see Virch. Archiv. 614: 11, 1989; Postgrad. Med. J. 76: 280, 2000). This won't go away, and seems to be a rapid route to cirrhosis. (* In some experimental models and some communities, cirrhosis need not be preceded by alcoholic hepatitis. According to others, it is inflammation, rather than fibrosis, that predicts progression. This'll confuse you.)

{39929}    alcoholic hepatitis, good Mallory's hyaline
{26702}    alcoholic hepatitis, good Mallory's hyaline
{08832}    alcoholic hepatitis with fibrosis; there is no good hyaline; cells are becoming entrapped in the fibrous tissue
{21056}    "alcoholic hepatitis", looks like early cirrhosis to me
{26693}    "alcoholic hepatitis", looks like early cirrhosis to me

Alcoholic hepatitis
Alabama
Wikimedia Commons

      Again, the histology is not pathognomonic for alcoholism. The heart-drug amiodarone in particular is infamous for producing the same histopathology, and post-ileal bypass hepatitis, Wilson's disease (shouldn't miss this one!), NASH, and * East Indian childhood cirrhosis (copper toxicity in the genetically-predisposed; J. Path. 195: 264, 2001) can be dead-ringers.

      If you have alcoholic hepatitis, you're in trouble. You may have jaundice, hepatic encephalopathy, and all the signs and symptoms of portal hypertension (not the least being fatal GI bleeding). Further, if you need a general anesthetic, you're likely to die from it.

        Some Hippocrates who thinks you're too sick for a biopsy ("His pro-time is prolonged and I don't want to transfuse him") will give you a diagnosis of "cirrhosis", which will stay with you as your chart thickens.

        If you've really overdone the alcohol, you can get yellow atrophy and die. This is very unusual.

      If you are actually in the hospital and your primary diagnosis is alcoholic hepatitis, you probably have it very, very bad... explaining why the mortality figures in some studies are so high (for example, J. Clin. Gastro. 40: 833, 2006).

      Fortunately, if you sober up, all that will remain is whatever minor scarring has occurred. The liver cells will regenerate nicely, and your liver will probably be fine.

    ALCOHOLIC CIRRHOSIS ("Laennec's cirrhosis", other names)

      Exactly what causes the progression (if it is a progression) from reversible changes (fatty change, Mallory bodies, inflammation) to irreversible (?) disease (i.e., fibrosis-cirrhosis) is obscure.

        In order to get cirrhosis, one needs at least 15 pint-years (i.e, a pint of the hard stuff per day for fifteen years, three pints a day for five years, or similar). Many cirrhotics have much more. Yet 2/3 of heavy drinkers die without cirrhosis. Nobody knows why.

      At first, the liver is big because of widespread hepatocyte overgrowth and fatty change from ongoing drinking. Later, with advanced scarring and enforced sobriety, the liver becomes rather small.

      Microscopically, you'll see fibrosis and nodules instead of the normal architecture and proliferated bile ducts in the scar tissue (a good sign of alcoholism).

        Early Laennec's cirrhosis has fine bands and a micronodular pattern. Late, the pattern becomes post-necrotic. When the scar tissue starts seriously obstructing bile flow, clinicians see jaundice and the pathologist sees bile plugs.

{10538}    alcoholic cirrhosis, gross
{10844}    alcoholic cirrhosis, gross
{18795}    alcoholic cirrhosis, gross
{20163}    alcoholic cirrhosis, histology; trichrome stain
{08835}    alcoholic cirrhosis
{40412}    alcoholic cirrhosis
{10535}    "alcoholic cirrhosis" closeup of a lobule; note the Mallory's hyaline and the neutrophils attacking it. There may be fibrosis elsewhere, but this merely looks like alcoholic hepatitis.
{39593}    alcoholic cirrhosis; lots of bile duct proliferation (as is usual in alcoholic cirrhosis); edge of a nodule on each side of the screen

      The cirrhotic must decide what he or she wants out of life. Continuing drinking is overall as lethal as untreated AIDS. Sobriety gives maybe a 90% chance of not dying of the cirrhosis within the next five years.

    * During the early 1990's, liver transplants for alcoholic liver disease got discussed as showcasing problems with our "no-guilt" / "you have a right" ideas. "Unconstitutional discrimination and a violation of the Americans with Disabilities Act" or not (the story of Mr. Bush's 1992 policy change is now history), good used livers and other resources are (as always) in limited supply. See Gastroent. 102: 1806, 1992 (the now-famous Pittsburgh study), JAMA 265: 1295, 1991; JAMA 266: 213, 1991; Br. Med. J. 299: 693, 1989. Half of alcoholics who receive liver transplants return to problem drinking within one year (Gut 43: 140, 1998), but the good news is that they seldom wreck their new livers in doing so (Gut 45: 421, 1999). In the late 20th century, a few philosophers continued to maintain that alcoholics "may justifiably be given lower priority than others in receiving these [limited] resources" (J. Med. Philos. 23: 31, 1998). However, the most recent article I could find was in Transplant International 14: 170, 2001 (essentially, lifelong alcoholics are no more responsible for their ruined livers than are babies with biliary atresia). Uh, sure. The "ethical debate" seems to be over and alcoholics are competing on an equal basis for liver transplants with the dying babies. Especially if we continue to make it difficult to obtain organs for transplantation, this will eventually start getting media attention -- the truth is that I'm surprised it hasn't already.

NON-ALCOHOLIC FATTY LIVER DISEASE (non-alcoholic steatohepatitis, NASH, non-alcoholic fatty liver diseae, NAFLD, Am. Fam. Phys. 73: 1961, 2006; pathologists see Am. J. Clin. Path. 128: 837, 2007; J. Clin. Path. 60: 1384, 2007; Gastroent. 134: 1682, 2008)

    NASH -- non-alcoholic steatohepatitis, fatty change into which acute inflammation, necrosis and fibrosis can creep -- is a poorly-understood but very real, very common condition that is only now getting the attention it deserves.

    In countries where little alcohol is consumed and there is not much hepatitis or schistosomiasis, this is the most prevalent liver disease.

    The anatomic pathology is much like alcoholic liver disease, with fatty change, often Mallory hyaline, and sometimes even cirrhosis.

      * One tip-off that this is NASH is "chicken-wire" perisinusoidal fibrosis around hepatocytes in the central region. It is not pathognomonic.

    There is always insulin resistance as well. Presently, discussions of pathophysiology emphasize the "adipokines" TNF-α and leptin, produced by bodyfat and causing insulin resistance. TNF-α is considered responsible for the cell injury, and leptin for fibrosis. The whole business is still very puzzling (Am. J. Path. 169: 846, 2006; Dig. Dis. Sci. 53: 1099, 2008); new players Gastroent. 134: 556, 2008; Am. J. Clin. Nutr. 89: 558, 2009.

    The disease now easily the most common chronic liver disease in children and teens in the industrialized world, and many of these kids have fibrosis (Gastroent. 135: 1961, e2, 2008; Gastroent. 136: 160, 2009).

    The mainstay of therapy has historically been weight loss and exercise in the overweight, masterful inactivity and perhaps metformin in the non-overweight (Med. Clin. N.A. 80: 1147, 1996; rationale for metformin Am. J. Gastro. 98: 2093, 2003). Betaine as a remedy: Am. J. Gastro. 96: 2534, 2001; Am. J. Gastro. : 2711, 2001 (I'd try this). Rosiglitazone study (no miracles: Gastroent. 135: 100, 2008). Pioglitazone: Gastroent. 135: 1176, 2008. Link to "metabolic syndrome X": Am. J. Gastro. 96: 2957, 2001; J. Clin. Endo. Metab. 84: 1513, 1999; and of course to polycystic ovary disease (also runs with insulin resistance: J. Clin. Endo. Metab. 91: 1741, 2006). A promising medication is pioglitazone (NEJM 355: 2297, 2006 -- lots of biopsy work to support it). Probucol seems perhaps even better (Dig. Dis. Sci. 53: 2246, 2008).

      * See also Gastroenterologist 5: 316, 1997; Gastroenterology 120: 1183 & 1281, 2001; the latter shows crystalloids in mitochondria from these people that are not present in most controls, and suggests that this is a mitochondrial disease that expresses itself in the setting of obesity. (More on adult-onset diabetes itself as a likely mitochondriopathy later.) We await confirmation.

      The animal model (Am. J. Clin. Nutr. 79: 502, 2004) is straightforward -- give rats a very high-lipid diet, let them eat as much as they want, and they get NASH, with steatosis, necrosis, inflammation, abnormal mitochondria (lost cristae, rarified matrix), and greatly elevated TNF-alpha production in the liver.

    Big review emphasizing how little is really known: Gastroenterology 122: 1649, 2002. NASH as a cause of cryptogenic cirrhosis: JAMA 289: 3000, 2003; 1/3 of patients will get fibrosis, and 1/9 will get rapid progression to cirrhosis Am. J. Gastro. 98: 2042, 2003. NASH is rampant among America's fat children (Am. J. Clin. Path. 127: 954, 2007), and we are now recognizing it as a fairly common cause of death among young adults (Am. J. Clin. Path. 127: 20, 2007).

    As you know well, not everybody tells the truth about their alcohol intake. Mayo's has a formula using other labs that distinguishes boozers from NASH patients (Gastroent. 131: 1057, 2006). High MCV (mean corpuscular volume), high AST/ALT ratio, and high carbohydrate-poor transferrin ("the new drunk screener"), mean alcoholism; staining of the biopsy specimen for PTP1b (protein tyrosine phosphatase 1b) means NASH (see also Am. J. Clin. Path. 123: 503, 2005).

IRON OVERLOAD (update NEJM 350: 2383, 2004)

{49253}    hemochromatosis causing cirrhosis (Prussian Blue stain, of course)

Pathology of Iron Metabolism
WebPath Tutorial

Hemochromatosis
Liver, H&E stain
KU Collection

Hemosiderosis of liver
WebPath

Hemochromatosis of liver
WebPath

Hereditary hemochromatosis
Cirrhosis
WebPath

Hemosiderosis of liver
Prussian blue stain
WebPath

Hemochromatosis
Joel K. Greenson MD
U. of Michigan


Hemochromatosis
Pittsburgh Pathology Cases

Pathology of Iron Metabolism
WebPath Tutorial

Hemochromatosis
Pittsburgh Illustrated Case

    The human body cannot make iron atoms (see Science 226: 922, 1984 for how the Good Lord does it). We must get what we need from outside. The healthy adult has total body iron content of around 4 gm. The red cells contain close to 3 gm total. The cytochromes and other redox enzymes together contain much less than a gram, and most people have some stored iron. An iron storage problem is definitely present when the amount of iron in the body exceeds 10 gm.

    A reasonably normal diet contains at least 10 mg of iron daily. This is more than adequate to replace a healthy man's daily losses, and is enough for a non-pregnant woman who does not have heavy menstrual flow. Heme iron is absorbed much more readily than non-heme iron, especially non-heme iron that is complexed with certain small organic molecules. (This explains why what worked for Popeye doesn't work for us.) Dietary iron deficiency anemia can be expected when a girl has been menstruating for about a year while consuming mostly twinkies, french fries, and diet Pepsi. Pregnant women, zealous blood donors, people with diseases in which blood loss (GI, urinary, uterine) cannot be easily controlled, and some growing children are the only people who might need to take iron supplements. (In normal adults, "prophylactic" iron supplementation can only mask serious disease. Taking iron supplements when they are not indicated kills people by delaying the diagnosis of GI and gynecologic cancers. One iron supplement in particular was famous for decades for its TV ads warning of "iron-poor tired blood". Fortunately for the public, the heavily-advertised nostrum used ferric iron, which makes the stool black so people would know the medicine was working, didn't upset the tummy very much, and wasn't absorbed very much. That's nice.) Healthy people absorb and lose around 1.0 mg of iron daily (1.5 mg for menstruating women).

    Ferrous (Fe+2), and not ferric (Fe+3) iron, is absorbed across the "mucosal barrier", mostly in the duodenum. It is complexed to a protein called NRAMP-2 that transports much more efficiently when body iron stores are low. So the amount of iron absorbed varies inversely with the amount of ferritin already present in the duodenal epithelial cells, which in turn reflects total body iron stores. Iron absorption by the gut also increases when there is increased normoblastic activity. (The mechanism remains unknown; the latest stuff Blood 96: 4020, 2000.) Absorption is mildly increased in hemolytic anemias or after hemorrhage. Absorption is more markedly increased in "ineffective erythropoiesis", notably in severe sideroblastic anemia and thalassemias. Huge doses of dietary iron can override the regulatory mechanism.

    Iron atoms are slowly released into the plasma, where they are bound to the globulin transferrin. The amount of transferrin present is also regulated, so that more will be present when more iron is required. The iron is then carried where it is needed. (* Transferrin will only carry ferric iron, while most of the other forms of iron are ferrous.) Likewise, when a red cell (or any other cell) is destroyed, its iron is carried away by transferrin. Extra iron is stored, mostly in the liver and bone marrow. In health, it is available for incorporation into RBC's or for transport by transferrin should a shortage develop.

    Storage iron (somewhere in the range of 1 gm in most people) exists in two principal forms. (1) Ferritin is a bit of iron at the center of a protein micelle. The protein shell explains the negative Prussian blue stain. This is the short-term storage form. It is the form found, for example, in bone marrow when it is soon to be incorporated into new RBC's. (2) HEMOSIDERIN is aggregates of ferritin with much of the protein gone. This is "Prussian blue positive" iron. It is a less labile storage form that accumulates when there is excess ferritin. (* "Hemosiderin" is an archaic name chosen by von Recklinghausen. "Exogenous hemosiderin" is an iron-protein complex that forms around sites of iron injection and foreign bodies composed of iron). Hemosiderin is the yellow pigment in the halo surrounding a bruise. Tip: If an injured area is pigmented yellow three months after bruising, the patient probably has iron overload.

    Humans have no special mechanism for excreting excess absorbed iron. There is ordinarily a loss of 1 mg/day or so through GI and skin cell turnover and microhemorrhages into the gut and GU tracts. A typical menstrual period results in a loss of 10-20 mg of iron. During the course of a pregnancy, the fetus absorbs 500-1000 mg of iron from the mother's bloodstream. The fetus "gets priority" and often the mother becomes iron-deficient. Donating a 500 mL unit of blood removes approximately 250 mg of iron from the body.

    Iron does harm to cells by generating free radicals. Primary iron storage problems are very common, under-diagnosed, easily and inexpensively detected, potentially fatal, and very treatable. And these patients are often considered hypochondriacs for many years before the diagnosis is finally made (Ann. Int. Med. 101: 707, 1984). During the early 1990's, it was finally appreciated that around 1 man in 200 is affected (NEJM 318: 1355, 1988). HEMOSIDEROSIS ("systemic siderosis", etc.): increased total body iron (as ferritin and hemosiderin), from any cause. Most of the excess iron is in the reticuloendothelial cells. Spill-over into parenchymal cells is what can cause trouble. It is now known that 13% of people carry an autosomal gene (HFE, within the HLA complex; update Arch. Int. Med. 166: 294, 2006) for excessive iron absorption via the gut. Homozygotes have worse problems; thankfully, we have finally come to recognize this as "the most common genetic disorder in populations of European ancestry": Am. J. Med. 119: 391, 2006; the vast majority of patients of Northern European stock have a C282Y mutation, and around 0.7 of people of Northern European ancestry are homozygous for the allele (update NEJM 358: 221, 2008; of these, one man in 4, and one woman in 10 is sick from it). H63D is common worldwide. Depending on diet and iron losses, these people may or may not express their PRIMARY HEMOSIDEROSIS.

    SECONDARY HEMOSIDEROSIS ("acquired hemosiderosis", etc.) occurs in a variety of illnesses. The best-known of these are diseases that require frequent blood transfusions in the absence of bleeding. Except as noted below, these do not usually progress to symptomatic iron overload.

    HEMOCHROMATOSIS is hemosiderosis that has damaged parenchymal cells. Total body iron stores in excess of ten gm are very dangerous. In classic cases, total body iron stores often exceed 100 gm. PRIMARY HEMOCHROMATOSIS (formerly "idiopathic", now "familial", "genetic", "hereditary", or "HLA-linked"): in which the problem is greatly increased absorption of iron from the gut. These are "primary hemosiderosis" people in which the iron overload causes illness. Perhaps 1 man in 200 will be symptomatic with this during life, and thankfully we are diagnosing it more often. Review Am. Fam. Phys. 65: 853, 2002; Lancet 370: 1855, 2007. Update on screening (from the USPSTF): Ann. Int. Med. 145: 204, 2006. So do you screen using transferrin saturation (which is awfully sensitive and not very specific), the HFE gene (which is too expensive), or a serum ferritin (which picks up the people at risk for cirrhosis, albeit late, and is also up in acute or ongoing liver abuse/disease)? The case for ferritin: Blood 111: 3373, 2008. Expect continued disagreement.

      * Other loci encode rare, severe forms. See below for an update.

    SECONDARY HEMOCHROMATOSIS most often occurs in thalassemia major and in severe sideroblastic anemias. In these conditions, there is greatly increased iron absorption through the gut, and the patient requires many blood transfusions with no way of disposing of the iron load. Obviously you cannot treat these patients by bleeding (why not?) Deferoxamine is life-saving in thalassemia major: NEJM 331: 567, 1994.

    So, in primary hemosiderosis and hemochromatosis, the problem is that iron is absorbed too easily through the gut. A patient homozygous for primary hemochromatosis who donates blood every eight weeks will remain iron-depleted.... The tendency is encoded at HFE (Proc. Nat. Acad. Sci. 94: 2534, 1997 review, was HLA-H), discovered in 1996 in the HLA complex on chromosome 6, very closely linked to HLA-A and much like it; mouse hemochromatosis is caused by a bad beta2-microglobulin gene (Proc. Nat. Acad. Sci. 93: 1529, 1996) while the abnormal HLA-H doesn't bind properly to its microglobulin component. (* HLA-A3, B7, and B14 are often present, but the defect is linked with the chromosomes. Almost all B14 owners have the hemochromatosis gene, which is one reason (our of three) that your lecturer is confident that he carries it.) The frequency of the allele is about 14 out of every 100 chromosome 6's. Iron losses due to menstruation and pregnancies prevent expression primary hemochromatosis from ever developing in most women with the gene(s). Primary hemochromatosis is diagnosed nine times more frequently in men.

    The classic hemochromatosis triad is liver trouble, diabetes mellitus, and skin discoloration. Today's list of major problems also includes cardiac arrhythmias, cardiac pump failure, and loss of sexuality. The liver may be enlarged on physical exam, or transaminases may be a bit high (South Med. J. 83: 1277, 1990). Around half of identified hemochromatosis patients develop overt diabetes mellitus. For over a decade, it has been considered good practice to screen everybody for iron overload (Gastroenterology 107: 453, 1994.) Most get the peculiar skin discoloration to some degree. The classic form of the disease is usually fully expressed around age 40-60 years. Patients, however, say their ill-health began during their 20's (Am. Fam. Physician 29: 55, March 1984).

    LIVER DISEASE is the most serious problem in the majority of diagnosed hemochromatosis patients. The hepatocyte lysosomes and mitochondria are packed, and total liver iron stores are often more than one hundred times normal. There is often extensive fibrosis prior to the onset of symptoms (Arch. Int. Med. 166: 294, 2006), helping explain the classic observation that the liver enlarges even before cirrhosis develops. (The fibrosis reverses on iron removal unless cirrhosis is fully-developed.) The radiologist may notice it is unusually radio-dense. Micronodular cirrhosis (scarring that ruins the architecture of each lobule) is usually present by the time the diagnosis is made. When caused by hemochromatosis, this is called "pigment cirrhosis"). For the degree of fibrosis, the liver works surprisingly well, and clinical manifestations of cirrhosis are less severe than in alcoholic cirrhosis. However, cirrhosis is general considered irreversible and will finally kill the patient unless something else does first. (And something else usually does; only 25% of patients diagnosed to have primary hemochromatosis die of cirrhosis.) Once cirrhosis due to hemochromatosis has developed, the patient is at great risk for hepatocellular carcinoma (and to a lesser extent cholangiocarcinoma; histology Am. J. Clin. Path. 116: 738, 2001; hepatocellular carcinoma in iron over load without cirrhosis Am. J. Med. Sci. 334: 228, 2007). This is fatal and kills another 30% of patients diagnosed to have primary hemochromatosis.

    Although more iron is deposited in the acinar cells than in the ISLETS OF LANGERHANS, around 50% of patients have enough damage to their beta cells to develop symptomatic glucose intolerance.

    CARDIAC INJURY is also caused by iron overload. Many hemochromatosis patients have pump failure and/or rhythm disturbances, either of which can be disabling or fatal. This is the other leading cause of death in iron-overloaded people. (How many of these deaths are assumed to be due to some other disease process? No one knows.)

    ENDOCRINE INJURY is an additional problem. Patients are commonly troubled first by loss of libido, and eventually lose their secondary sex characteristics. Testicular atrophy secondary to pituitary failure with deposition in anterior lobe and Leydig cells too. It is quite reversible. Loss of testosterone in both men and women is now considered the explanation for the osteoporosis that develops in hemochromatosis patients (Ann. Int. Med. 110: 430, 1989). In addition, the adrenals, thyroid, and parathyroids are likely to be damaged, with various endocrine insufficiency syndromes. (* The role of "melanocyte stimulating hormone" in "bronze diabetes" is dubious.)

    JOINT INJURY caused by iron overload (Am. J. Med. 75: 957, 1983) is yet another major problem. Iron deposition in synovium results in synovial hyperplasia and erosion of bone and cartilage, eventually ruining the joint. In hemochromatosis, this usually affects the fingers, and is a problem for 50% of patients. In addition, the knees (and other weight-bearing joints) of hemochromatosis victims occasionally get accumulations of pyrophosphate crystals ("pseudogout", chondrocalcinosis).

    SKIN PIGMENTATION in hemochromatosis is primarily due to increased melanin. (* Iron inhibits the enzyme that normally breaks down melanin.) Melanin imparts the "bronze" color; if there is enough hemosiderin in the skin, the combination looks "slate-gray".

    Sepsis: For some unknown reason, Vibrio vulnificans (a raw seafood bug), Pasteurella pseudotuberculosis and Yersinia enterocolitica are much more pathogenic in the presence of iron overload. Even E. coli may get a boost in hemochromatosis (Am. J. Med. 87(3N): 40N, 1989).

    You'll learn to make the diagnosis soon. In primary iron storage disease, it is important to make the diagnosis early. By the time the patient is obviously sick with hemochromatosis, he is 40 years old, has at least 20 grams of iron stored, has cirrhosis, and will probably be dead within ten years (though you can still help). If you find the tendency to accumulate iron, do this:

    • Educate the patient.
    • Evaluate family members for the same tendency. (Order the easy tests, and remember the gene assorts with HLA-A haplotype.)
    • Take the patient off iron-containing medications.
    • Remove the iron from the body by draining out blood. You or the lab can withdraw two pints a week, and the patient will soon report a subjective improvement. In 2002, blood banks finally abandoned the old, stupid (lawyer-shy) practice of discarding this blood, which is perfectly good for transfusions as long as the person is otherwise healthy.
      • * "Why don't you give an iron chelator instead?" Retinal damage from deferoxamine is supposedly reversible.... Some new iron chelator drugs are available now, but I'd still stick with the no-drug approach.

    • Continue doing this as needed for years, monitoring body iron stores as you go.
    • Sex steroids and gonadotropins help while iron stores are being removed.
    • If cirrhosis has developed, do all the above, and support complications. Sudden deterioration probably means hepatocellular carcinoma has developed. This is bad.

    Secondary hemosiderosis and hemochromatosis: Except for the secondary hemochromatosis developing as a result of thalassemia major and severe sideroblastic anemia, these tend not to be severe or result in cirrhosis (though the liver may be enlarged). The abnormal anatomy is similar to primary iron storage disorders, but most of the iron is usually in the Kupffer cells, not the hepatocytes. Hemosiderosis due to red cell transfusions ("transfusional" or "iatrogenic siderosis") is unavoidable in patients with severe anemias of decreased production. These include a variety of bone marrow disorders and some cases of renal failure. Remember, 100 red cell transfusions delivers 25 gm of iron! This is more than enough to produce hemochromatosis. These patients are now being treated with the new iron chelator drugs.

    Hemosiderosis due to chronic alcohol abuse results from increased absorption of iron through the gut. The mechanisms are obscure, and this fact makes it hard to distinguish pigment cirrhosis from alcoholic cirrhosis. A few old-timers blame iron-rich wine for hemosiderosis in alcoholics. (A few wines are adulterated with iron, with up to 50 mg/mL. Most have much less). See Arch. Int. Med. 112: 184, 1963. Of course, if a hemochromatosis patient drinks heavily, the liver is doomed (Gastroent. 122: 281, 2002).

    Vitamin-and-mineral faddists can occasionally make themselves chronically sick by iron-overloading themselves. (This is difficult to do and probably requires the genetic predisposition. See J. Roy. Soc. Med. 77: 690, 1984.) The Bantu people ingest 100 mg or more of iron daily from beer brewed in "iron pots" (really, steel drums). They tend to get hemosiderosis ("Bantu siderosis"), and a few get pigment cirrhosis. (Again, genes must be important; we now know that a Bantu beer-drinker with one dose of the hemochromatosis gene will probably get hemochromatosis; NEJM 326: 95, 1992.)

    You'll screen for common hemochromatosis by checking the transferrin saturation levels, and confirm by serum ferritin levels. The current cutoffs ("transferrin saturation over 45% for women or 50% for men") probably miss too many people (Am. J. Med. 120: 999, e1-7, 2007). The actual iron assays on liver biopsy tissue will probably be replaced soon by MRI (Lancet 363: 341 & 357, 2004).

    Hemosiderosis due to increased or ineffective erythropoiesis ("hematopoietic siderosis", typically when there is longstanding hemolysis), mild hemosiderosis is usual because of increased absorption of iron through the gut. In the severe thalassemias and sideroblastic anemias, red cell transfusions are required, erythropoiesis is ineffective, and absorption of iron through the gut is greatly increased. The iron overload progresses to fatal hemochromatosis. These are the patients who are most often treated experimentally with iron chelator drugs.

    PORPHYRIA CUTANEA TARDA is a hereditary partial defect of uroporphyrin decarboxylase that is expressed only in the presence of iron overload. You'll encounter this if you keep your eyes open! Update Blood 95: 1565, 2000.

    You'll diagnose hemochromatosis by labs, and confirm with genetic testing. Liver biopsy is still handy for judging the severity (Am. J. Clin. Path. 118: 73, 2002).

    Here's a summary of the genes that are understood so far (Blood 106: 3710, 2005)

      HFE: In the HLA class 1 locus. The protein is expressed throughout the body. To this day, we do not know exactly what it does; however, it's found complexed to transferrin receptor 1 in the duodenal crypts and it's reasonable to think it has to do with preventing overabsorption of iron through the duodenum. The healthy protein also apparently required in order to increase hepcidin levels when apropriate.

      TFR2: Transferrin receptor 2. The protein is expressed by hepatocytes and interacts with transferrin. It's believed to sense the body's overall transferrin saturation. Mutation causes an uncommon illness identical to common HFE hemochromatosis but on the average more severe and earlier. It's also believed that a healthy TFR2 is required in order to increase hepcidin levels when required. Gastroent. 122: 1295, 2002.

      HAMP: The gene for HEPCIDIN, expressed by liver and striated muscle. The hormone hepcidin controls absorption of iron through the duodenum and its release from macrophages. Deficiency is rare but causes a severe juvenile hemochromatosis. Hepcidin: Nat. Genet. 33: 21, 2003.

      HJV / HFE2): The gene for HEMOJUVELIN. This hormone binds to the protein NEOGENIN. This seems to be the another hormone that inhibits absorption of iron through the duodenum. When normal, it's lowered by anemia, hypoxia, and iron deficiency, permitting a higher rate of iron absorption. Nat. Genet. 36: 77, 2004; mouse J. Clin. Inv. 115: 2187, 2005; hemojuvelin senses the amount of iron in the diet overall J. Clin Inv. 115 2180, 2005.

      SLC40A1 (was SLC11A3): The gene for FERROPORTIN, which is the hepcidin receptor. Another protein expressed throughout the body. It seems to permit the exit of iron from cells. Mutions here produce a dominant hemochromatosis with iron-overloading of body macrophages but not parenchymal cells, and normal or low transferrin saturation, and usually not the classic findings of hemochromatosis unless there is another gene. They do not give up their iron on phlebotomy, but develop iron deficiency anemia. Autosomal dominant hemochromatosis is in fact most often due to deficiency in ferroportin (J. Clin. Inf. 108: 512 & 619, 2001; Blood 100: 692, 2002; Blood 106: 1092, 2005).

      CERULOPLASMIN: Aceruloplasminemia Gut 47: 858, 2000 (hepatocytes and Kupffer cells involved uniformly, no fibrosis, neurologic disease rather than liver failure; this is NOT Wilson's).

WILSON'S DISEASE ("hepatolenticular degeneration"; Mayo Clin. Proc. 78: 1126, 2003; Lancet 369: 379, 2007)

    Rare but very, very important. Don't miss this diagnosis. Untreated, it is lethal. Treated, it's harmless. You'll never diagnose it unless you think of it. And it always masquerades as something else.

    Wilson's disease is an autosomal-recessive problem in which the liver is unable to dispose of excess dietary copper via the bile.

      The gene was cloned in 1997, and named ATP7B; it is (no surprise) a copper-transporting ATP-ase (Am. J. Hum. Genet. 61: 317, 1997).

      Nobody really understands why serum levels of ceruloplasmin, the copper transport protein, are often (but not always) low in Wilson's. What we do know is that serum copper, not properly carried, spills copiously into the urine in Wilson's disease. This represents the only route of copper excretion, and it is inadequate.

      Eventually, the copper accumulates, damaging liver, joints, brain (especially basal ganglia), proximal renal tubule (causing wasting of solutes) and red cells (mild ongoing hemolysis is the rule), and making the distinctive Keyser-Fleischer corneal ring (you probably won't see them without a slit lamp).

      The copper itself probably damages the cells in which it accumulates, maybe by free radicals or inhibiting enzymes. * Future pathologists: Stain for copper using rhodaNine or rubeanic acid!

    The histology in the liver passes through fatty change to a histopathology basically identical to alcoholic hepatitis to chronic hepatitis to micronodular cirrhosis to post-necrotic cirrhosis. At autopsy, you see an unforgettable bluish-coppery colored liver, and the same discoloration in the basal ganglia.

    The treatment, of course, is to remove the copper with a metal chelator. Penicillamine works wonders, but it won't cure cirrhosis or restore dead neurons.

    Lab diagnosis is treacherous. Serum ceruloplasmin is low more often than not, but this is a notoriously poor screening test. Staining the liver itself for copper is treacherous. Even assaying liver tissue for copper ("normal is less than 55 micrograms/gm of liver; Wilson's has more than 250") is unreliable because you may have sampled a regenerative nodule that's copper-poor. I recommend a urinary copper assay.

    Missing the diagnosis of Wilson's disease clinically is still a notoriously common blunder, especially when it presents as "mental illness" (update Gut 56: 115, 2007). The physician's mistake WILL cost the patient his/her long-term health or even life.

{00018}    Wilson's

Wilson's disease
Joel K. Greenson MD
U. of Michigan


HEPATIC AMYLOIDOSIS: You already know about this. Amyloid accumulates in the vessels and space of Disse, and can eventually give a large, very firm liver that usually still functions acceptably. Past concerns about biopsying the liver in suspected amyloidosis seem to be groundless (Medicine 82: 291, 2003).

{53548}    amyloid in the liver

Amyloidosis of the liver
Joel K. Greenson MD
U. of Michigan


LIVER POISONS

    A host of drugs-poisons produce typical reactions in the liver. These range from predictable ("Take enough 'Tylenol' at once and your liver cells all die") to highly idiosyncratic ("Take 'Halothane' anesthesia a second time and there's a tiny chance that sensitivity will kill you.") "Inflammation" may mimic acute or chronic hepatitis.

    Acetaminophen ("Tylenol")... Massive hepatic necrosis

    Allopurinol... Granulomas

    Alpha-methyldopa... Inflammation, granulomas, massive necrosis (idiosyncratic)

    Amiodarone... Inflammation, "alcoholic hepatitis" mimic, cirrhosis (idiosyncratic); kupffer cells loaded with phospholipid ("phospholipidosis")

    Anabolic steroids... Cholestasis (at least)

    Carbamazepine... Granulomas

    Chlorpromazine... Cholestasis (idiosyncratic)

    Diltiazem... Granulomas

    Estrogens... Cholestasis (idiosyncratic), thrombosis (idiosyncratic)

    Ethanol... Fatty change, alcoholic hepatitis, cirrhosis

    Fenfluramine... Massive necrosis (idiosyncratic; a dozen Japanese find out what was really in their Red Chinese holistic-wholesome weight-loss pills beside lotus leaves and chrysanthemum petals: Ann. Int. Med. 139: 488, 2003)

    Halothane... Massive hepatic necrosis (idiosyncratic)

{24392}    "Halothane hepatitis" case; simply massive necrosis

    * Hydralazine... Granulomas

    * Hydrazine (a quack cancer remedy)... liver necrosis (Ann. Int. Med. 133: 877, 2000).

    Isoniazid... Inflammation (idiosyncratic) (especially >age 35)

    Methotrexate... Inflammation, cirrhosis (sometimes even at "safe" doses)

    Oxyphenisatin (laxative)... Inflammation ("lupoid hepatitis") (who'd abuse THAT?)

    Pennyroyal ("holistic herbal tonic" / amateur abortifacient) ... simulates viral hepatitis (update on poisoning from Mayo's: Acad. Emerg. Med. 10: 1024, 2003)

    * Phenylbutazone... Granulomas (who still uses THAT?)

    * Quinidine... Granulomas

    * Sulfa drugs... Granulomas

    Tetracycline (outdated)... Microvesicular fatty change (get rid of yours!)

    * Total parenteral nutrition... Fatty change (nobody knows why; this and malnutrition are the major illnesses in which it's likely to be periportal rather than central; Gastroent. 104: 286, 1993)

    Valproic acid: Mixed hepatitis-like and cholestatic

REYE'S SYNDROME (Am. Fam. Phys. 50(7): 1491, 1994; NEJM 340: 1423, 1999; NEJM 340: 1377, 1999)

    This poorly-understood, dread entity is an acute illness that follows another viral illness, usually 'flu or chicken pox, usually in a child or young teen.

    The biphasic clinical story is typical. The pathology is, too. You will see:

    • cytotoxic cerebral edema;
    • microvesicular fatty change of the liver (and sometimes other organs prone to fatty change, i.e., skeletal and cardiac muscle, proximal renal tubule);
    • subtle damage to the mitochondria throughout the body. (The damage is reproducible in vitro using Reye's serum or dicarboxyl-fatty acids. This is very interesting. See Lab. Invest. 60: 568, 1989; also Neurology 41: 1815, 1991).
    • extreme elevations of serum ammonia.

    The increased intracranial pressure produces vomiting. Later, in severe cases, liver enzymes rise in the serum, and then the liver itself fails. The patient may die, or be left mildly or moderately brain-damaged.

    The pathogenesis of classic Reye's was never really worked out.

      Several inborn errors of metabolism (notably in urea-genesis, ketogenesis, branched amino-acid metabolism, and uncoupling of oxidative phosphorylation) produce crises similar to Reye's. Studies of patients with Reye's have showed a plethora of abnormal compounds around their bodies. See JAMA 260: 3167, 1988; also Enzymes 45: 209, 1991.

      Reye's, and only true Reye's, gives spectacular edema of the mitochondria, visible by electron microscopy.

    In 1986, the public was strongly warned not to give aspirin to children. As a result, true Reye's has nearly vanished.

      "Reye's" cases nowadays are most likely to be children with decompensated metabolic defects.

      Skeptics or no, "the animal model" for Reye's is a rat, which must be given both aspirin and several low doses of endotoxin (Metabolism 38: 73, 1989).

Reye's Liver
CDC
Wikimedia Commons

PEDIATRIC LIVER DISEASE

    EXTRAHEPATIC BILIARY ATRESIA ("EHBA")

      A catastrophic birth defect in which the common bile duct and/or hepatic ducts ("extrahepatic") and/or many larger intra-hepatic ducts are without lumens along some or all of their length.

      Sometimes this occurs with syndromes. More often, there's only mild inflammation and replacement of the involved areas with granulation tissue, perhaps from an intrauterine viral infection. Over time, the lesion progresses, and eventually the large bile ducts (extrahepatic, then intrahepatic) become replaced by granulation tissue (Mayo Clin. Proc. 73: 90, 1998. (* Sounds like a slow virus?)

      These children (most often girls) suffer severe neonatal hyperbilirubinemia. Unless surgery can correct the problem early, the disease will progress to biliary cirrhosis, liver failure, and the need for a transplant.

      * A rare illness in which the intrahepatic ducts disappear in childhood is caused by defective villin, a cytoskeletal protein that maintains the microvilli in the canaliculi (Lancet 362: 1112, 2003).

Extrahepatic biliary atresia
WebPath

Extrahepatic biliary atresia
Hepatic fibrosis
WebPath

    NEONATAL HEPATITIS ("giant cell hepatitis")

      Ongoing liver cell destruction in a baby.

      This has a very long differential diagnosis. It includes:

      • alpha1-antitrypsin deficiency
      • CMV
      • cystic fibrosis (really bad cases; * clinicians now give some kids ursodeoxycholic acid J. Ped. 124: 393, 1994)
      • galactosemia (the bad kind)
      • hepatitis viruses (A,B)
      • herpes simplex (check the adrenals, too)
      • * herpes 6 (NEJM 359: 598, 2008)
      • Herpes hepatitis
        Joel K. Greenson MD
        U. of Michigan


      • iatrogenic (drugs, total parenteral nutrition)
      • syphilis
      • toxoplasmosis
      • * tyrosinemia (amino acid metabolism defect)

      Regardless of cause, the histology tends to be similar in babies.

        Look for the lobular disarray, focal cell necrosis, cholestasis, and kupffer cell hyperplasia you'd see in any kind of hepatitis.

        In addition, the infant's liver regenerates well, producing prominent GIANT HEPATOCYTES with many nuclei.

{38758}    neonatal hepatitis, gross
{38761}    neonatal hepatitis, microscopic; with giant cells and bile stasis

Neonatal giant cell hepatitis
Idiopathic or viral
WebPath

        Liver biopsy may show distinctive features (i.e., inclusions in herpes and CMV, basophilic smudge nuclei in adenovirus infection, organisms in toxoplasmosis, hyaline globs in alpha-1 antitrypsin deficiency.) Don't expect these always to be present.

{46222}    herpes simplex hepatitis, gross; trust me; all that you can appreciate is severe injury
{46223}    herpes simples hepatitis, microscopic (note the cell with two nuclei and herpes intranuclear inclusions)

        Worth mentioning again here: cirrhosis can result from galactosemia (kids) or alpha-1 antitrypsin (kids or adults).

{20137}    cirrhosis, galactosemia (* future pathologists: Note the "flowers" formed by hepatocytes in this condition)
{13301}    cirrhosis, alpha-1 antitrypsin deficiency (trust me)
{13302}    cirrhosis, alpha-1 antitrypsin deficiency (trust me)
{13304}    cirrhosis, alpha-1 antitrypsin deficiency; PAS stain shows alpha-1 antitrypsin granules well

Alpha-1-antitrypsin deficiency
PAS stain
WebPath

        As a rule, the prognosis is much more favorable than in biliary atresia. Nevertheless, a few of these children do die.

BENIGN LIVER MASSES

Liver Tumors I
From Chile
In Spanish

Liver Tumors II
From Chile
In Spanish

    HAMARTOMAS

      CAVERNOUS HEMANGIOMAS are little birthmarks, seen in maybe 1% of livers. If you see them at surgery, don't biopsy them. They used to give high-resolution scanners fits: Am. J. Roent. 162: 1113, 1994.

        * Occasionally a giant hemangioma may need to be resected.

Liver hemangioma
Pittsburgh Pathology Cases

      FOCAL NODULAR HYPERPLASIA (World J. Surg. 19: 13, 1995) is a curious lesion that looks like a chunk of a cirrhotic liver grafted onto a healthy one. There is usually a central star-shaped large scar.

        Small FNH's are very common and (unfortunately) often get found on modern imaging studies. Unless it's huge or the radiologist can't be confident it's FNH, or it hurts, leave it alone.

      * NODULAR REGENERATIVE HYPERPLASIA is a picturesque lesion in which the entire liver becomes nodular, but without fibrosis. The cause is damage to the small portal veins, as from bone marrow or kidney transplantation (nobody really knows why), thioguanine (famous; Arch. Path. Lab. Med. 128: 2004), or some other cause of portal hypertension without cirrhosis.

      * MESENCHYMAL HAMARTOMA is a mix of myxoid mesenchyme and bile ducts. It is a benign-but-potentially-troublesome pediatric lesion with a trademark chromosomal marker (Cancer 74: 1237, 1994; update Arch. Path. Lab. Med. 130: 1216 & 1567, 2006).

      BILE DUCT HAMARTOMAS are polka-dots, mere autopsy curiosities ("Von Meyenberg complexes"). I'm asking you to learn them because they're quite common. There's no central necrosis and because of this, surgeons seldom mistake them for cancer at surgery.

    CYSTS are bounded by biliary epithelium. In CAROLI'S DISEASE, some of the bile ducts are dilated (and thus, more prone to stasis and infection, and for some reason cholangiocarcinoma).

    POLYCYSTIC LIVER may occur with either mendelian polycystic kidney disease, or as a distinct autosomal dominant or sporadic disease (Hepatol. 23: 249, 1996).

      * Mouse model Am. J. Path. 150: 2231, 1997.

      * There is also an autosomal dominant form (gene PRKCSH Nat. Genet. 33: 345, 2003; Am. J. Hum. Genet. 72: 691, 2003; Another gene SEC63: Nat. Genet. 36: 575, 2004). Yet another is a variant of the autosomal recessive polycystic kidney disease gene: Medicine 85: 1, 2006.

      If patients are uncomfortable, the cysts can be aspirated and a sclerosing agent injected. One happy patient was relieved of an extra 4200 mL of fluie (Dig. Dis. Sci. 53: 2251, 2008).

Polycystic changes in the liver
Transverse CT scan
WebPath

Dominant polycystic kidney disease
with polycystic liver
WebPath

    LIVER CELL ADENOMAS may occur sporadically, but are most common in women on birth control pills and men on anabolic steroids, and these are considered somehow etiologic.

      Grossly, adenomas present as soft masses. The histology resembles normal liver, minus bile ducts and good lobular architecture. There may be cholestasis. Around a quarter are multiple (syndrome: Mayo Clin. Proc. 71: 478, 1996).

      Usually liver cell adenomas cause no problems. The lesions are likely to regress when the exogenous hormones are removed. They seldom turn malignant, though occasionally this happens (Arch. Surg. 129: 712, 1994).

      * Not surprisingly, patients with mutated hepatocte nuclear factor 1-alpha, the gene for maturity onset diabetes of the young type 3, get a lot of hepatic adenomas (Gastroenterology 125: 1470, 2003). This is the only familial syndrome I've heard of.

      * A paraneoplastic syndrome is pseudo-iron deficiency anemia from hepcidin production by hepatic adenomas (Blood 100: 3776, 2002). Hepcidin prevents iron from leaving macrophages and entering young erythrocytes.

      * Future pathologists: Telling hepatocellular adenoma from hepatocellular carcinoma on biopsy can be tricky. One group recommends glypican-3 stain (adenomas do not stain; hepatocellular carcinomas and some nasty cirrhotic nodules usually stain: Arch. Path. Lab. Med. 132: 1723, 2008).

Liver adenoma
Photo is too poor to r/h FHN
WebPath Photo

Hepatic adenoma
WebPath

Hepatic adenoma
Cut surface
WebPath

Hepatic adenoma
WebPath

PRIMARY CANCERS OF THE LIVER (i.e., the hepatocytes, the intrahepatic bile ducts, and the sinusoidal lining cells)

    HEPAOCELLULAR CARCINOMA ("hepatoma", "Mickey Mantle's disease"): A deadly disease clearly caused, in the large majority of cases, by longstanding infestation with hepatitis B and/or C viruses and/or iron overload. Reviews: Lancet 353: 1253, 1999; Lancet 362: 1907, 2003.
Mickey Mantle
Mickey Mantle

      In the poor nations where HBV is endemic and typically transmitted mother-to-child, hepatocellular carcinoma is easily the most common cancer in men (at extra risk both because of higher HBV carriage and more body iron), and second only to cervical cancer in women. (Watch lung cancer rise to first for both sexes in the next decades.)

        *  The hepatitis B virus X antigen (HBxAg) integrates into the host genome to permit chronic infection, and produces a product that inactivates p53 (Am. J. Path. 150: 1141, 1997). This is now well-established as causing progression of hepatocellular carcinoma (Cancer Res. 64: 7329, 2004).

        The level of virus in the blood correlates very strongly with cancer risk: JAMA 295: 65, 2006.

      We now know that hepatitis C virus is also a very important cause, though again we don't know how (Cancer 73: 2253, 1994, still valid). One thing we do know is that hepatitis B and C viruses are much more likely to produce hepatocellular carcinoma when they cause rapid, prolonged cell turnover, i.e., making Nowell's law operate more readily (Cancer 73: 1149, 1994).

      Other factors enter into the picture, as well. Iron overload strongly increases risk. Aflatoxin (from aspergillus in moldy food) is probably responsible for the trademark p53 mutation required for epidemic African hepatocellular carcinomas (update Gastroent. 117: 154, 1999); sporadic cancers elsewhere show different mutations in p53 (Cancer 74: 30, 1994).

      "Thorotrast" exposure places a person at risk for hepatocellular carcinoma, and anabolic steroids (from the gym) supposedly do, too.

      If alcohol is a real risk factor, it is minor and abuse must be heavy, and it's common for patients to have hepatitis B and/or C and/or iron overload as well (Gastroent. 127(5 S 1): S-2 and S-87, 2004; JNCI 96: 1851, 2004; Cancer 101: 1009, 2004). It is most reasonable to think that alcoholic hepatitis, with ongoing cell necrosis and regeneration, is acting as a promoter. Interestingly, NASH seems to be a risk because of the ongoing cell turnover (Gastroent., same reference).

        * You'll still find the claim that "alcohol is a major risk factor for hepatocellular carcinoma." It's been known for years that without coexisting viral infection, the danger is minimal unless one already has alcoholic cirrhosis (Eur. J. Cancer. Pev. 10: 107, 2001). The studies that "show" alcohol to be a risk factor are retrospective, and there's a likely recall bias -- "everybody knows" that alcohol is bad for your liver. And people with hepatitis B and C are more likely to be poly-substance abusers. A German group calls the claim that alcohol alone is a major risk factor a myth: Liver 20: 312, 2000.

        * The same claim is of course made for smoking on the basis of retrospective studies, where the link is even weaker. Again, people with hepatitis B / C are likely to be poly-substance abusers and perhaps hence smokers; recall bias is probably also a confounder ("Everybody knows smoking causes cancer.")

        * Strangely, the retrospective studies I've seen that have focused on alcohol and/or smoking do not take iron status into account. This would be easy to determine by drawing blood levels.

        Is NASH without cirrhosis a risk factor? We don't know, but data is suggestive (Arch. Path. Lab. Med. 132: 1761, 2008).

      In the U.S., many (but not all) patients have cirrhosis (from their hepatitis virus and/or iron overload), but this is less common where most victims are "healthy carriers" of hepatitis B.

        Wilson's cirrhosis, lupoid cirrhosis, and primary biliary cirrhosis do not place a person at risk, and alcoholic cirrhosis itself is a very minor risk factor.

        Hepatocellular carcinomas in cirrhotic and non-cirrhotic livers: Am. J. Clin. Path. 105: 3, 1996.

      Grossly, the tumor may be a single mass, or arise multicentrically. The better-differentiated the tumor, the greener it tends to be (since hepatocytes want to make bile). Hepatocellular carcinomas, unlike most carcinomas, have a great propensity to invade veins, and you will probably see this grossly and microscopically.

        A dominant mass in a cirrhotic liver is likely to be hepatocellular carcinoma.

          Future pathologists: If the histology is quite benign, it's probably just a large regenerative nodule instead ("macroregenerative nodule"); one has to think there's been at least one genetic hit. If there is slight atypia, you may be able to diagnose "borderline dysplasia". Don't worry about it now.

        * Worth learning sometime:

          The five carcinomas that invade veins in preference to lymphatics (pretty reliable):

          • Follicular carcinoma of the thyroid
          • Hepatocellular carcinoma
          • Renal cell carcinoma
          • Yolk sac carcinoma
          • Adrenal cortical carcinoma

          The two sarcomas that invade lymphatics in preference to veins (unreliable):

          • Rhabdomyosarcoma
          • Synovial sarcoma

      Histologically, the hepatocellular carcinoma may look like nearly-normal liver, or be wildly anaplastic, or something in between. Appearances vary tremendously. Pathologists look for:

      • bile production by the tumor cells (pathognomonic of hepatocellular carcinoma, of course)
      • absent/scanty reticulin (helps distinguish benign/premalignant liver from hepatocellular carcinoma)
      • Mallory's hyaline (helps recognize hepatocellular carcinoma, but not really pathognomonic)
      • stainable hepatitis B virus proteins (a cancer with these is probably hepatocellular carcinoma)
      • stainable alpha-fetoprotein (remember this is also the most familiar, though not entirely specific, serum marker for hepatocellular carcinoma; * another serum marker is des-gamma-carboxy prothrombin, the PIVKA; why?); markers update Gastroent. 127 (5S1): S-113, 2004).
      • * for the truly hard-core pathologist, a gene probe for albumin mRNA is sensitive and specific: Mayo Clin. Proc. 73: 533, 1998; Am. J. Surg. Path. 26: 989, 2002
      • nearby "liver cell dysplasia", from which the cancer arose. This is real (Nowell's law again).
        • The existence of liver dysplasia is now well-established (Gastroent. 108: 812, 1995). It's distinguished from hepatocellular carcinoma primarily because there is not (yet) any invasion of the stroma (today's pathologists use DR/CK7 keratin immunostaining to spot invasion: Cancer 109: 915, 2007) and it has ordinary hepatic sinusoids with good reticulin. It precedes hepatocellular carcinoma and is likely to turn into it. Today's imaging techniques are supposedly able to distinguish dysplastic nodules from simple regenerative nodules in cirrhosis (Br. J. Rad. 77: 911, 2004).

          * To tell not-yet-malignant from malignant, proliferating-cell nuclear antigen, a marker for a cell thinking about dividing, is an excellent immunostain: Cancer 73: 2259, 1994. Pathologists are also counting nucleolar organizer regions (Cancer 73: 289, 1994; neat pictures of Nowell's law in action.) If hepatitis C is the underlying disease, GPC3 immunostain positivity supposedly marks the transition to true hepatocellular carcinoma (Gastroenterology 131: 1758, 2006). Of course, dysplastic nodules should still have reticulin.

          * Hepatocellular carcinomas tend to stain positive for the markers "Hep Par-1" (carbamoyl phosphate), glypican-3, and MOC-31, unlike dysplasia (review Arch. Path. Lab. Med. 131: 1648, 2007).

      Not surprisingly for a tumor that arises in this way, hepatocellular carcinomas often appear to arise multifocally (but not entirely independently; see Hum. Path. 19: 403, 1988).

      * The presence of a "capsule" means exactly nothing (Cancer 70: 45, 1992).

      The grading system is of little value in predicting the behavior of a particular tumor.

        * Future pathologists:

        • Grade I: "Normal liver plates that metastasized"
        • Grade II: Scrambled architecture, big cells, nuclei not really malignant-looking
        • Grade III: No bile, obvious nuclear anaplasia, often lots of giant cells
        • Grade IV: Hard to tell it was once liver, bizarre nuclei
        • You can use aspiration cytology to tell whether a liver nodule is cancer (Gut 53: 1356, 2004). You can't use cytology to grade: Cancer 102: 247, 2004.

      * Fibrolamellar hepatocellular carcinomas are rather tame and are a different disease from common hepatocellular carcinoma. Grossly they look like focal nodular hyperplasia. Their "pale bodies" contain albumin and fibrinogen. See Arch. Path. Lab. Med. 128: 222, 2004; Cancer 106: 1331, 2006.

      * Spindle cell hepatocellular carcinomas exhibit mesenchymal markers and have an extremely bad prognosis (Cancer 77: 51, 1996).

      Third-world, hepatitis B-belt hepatocellular carcinoma is usually thoroughly anaplastic and very aggressive: Cancer 65: 130, 1990.

{18799}    hepatocellular carcinoma in macronodular cirrhosis; hepatocellular carcinomas are white
{24571}    hepatocellular carcinoma in cirrhosis
{39624}    hepatocellular carcinoma in cirrhosis
{39708}    hepatocellular carcinoma in cirrhosis
{40330}    hepatocellular carcinoma in cirrhosis
{40331}    hepatocellular carcinoma histology (one of many variants)

Hepatocellular carcinoma
in lymphatic vessels
KCUMB Team

Hepatocellular carcinoma
Anaplasia, no sinusoids; hep C
KCUMB Team

Hepatocellular carcinoma with
admixture of cholaniocarcinoma
KCUMB Team

Hepatocellular carcinoma
Arising in post-necrotic cirrhosis
KU Collection

Hepatocellular carcinoma
Bizarre hepatocytes
KU Collection

Hepatocellular carcinoma
Satellite nodules
WebPath

Hepatocellular carcinoma
WebPath

Hepatocellular carcinoma
WebPath

Hepatocellular carcinoma
WebPath

Hepatocellular carcinoma
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery

Hepatocellular carcinoma
Ed Uthman

Hepatocellular carcinoma
Joel K. Greenson MD
U. of Michigan


Hepatocellular carcinoma
Ed Uthman MD
Wikimedia Commons

Hepatocellular carcinoma
Ed Uthman MD
Wikimedia Commons

Hepatocellular carcinoma
H&E
Wikimedia Commons

Hepatocellular carcinoma
H&E, nice bile production
Wikimedia Commons

      You can deduce the symptoms from the behavior of the tumor, but by the time the patient knows he or she is sick, it's often too late. When a cirrhotic deteriorates rapidly, it's common to find a hepatocellular carcinoma at autopsy.

        Paraneoplastic syndromes include polycythemia (erythropoietin production) and hypoglycemia (insulin-related growth factor production).

        Death occurs through rupture, venous obstruction, liver failure, or (less often) lung metastases.

      Without treatment, the disease is of course lethal. Nowadays, many hepatocellular carcinomas are discovered incidentally, and especially if there is no cirrhosis, the disease is often curable (Gastroenterology 122: 1609, 2002).

        Surgery is often successful since since the tumor tends to metastasize (to the lungs) only late.

        More recently, resection of the whole liver with liver transplant is becoming a mainstay of therapy, with about half of well-chosen patients are alive three years later, and a 30% cure rate claimed (early studies Am. J. Surg. 167: 317, 1994; Mayo Clin. Proc. 69: 509, 1994; Br. J. Surg. 81: 427, 1994; surgery plus chemotherapy Cancer 73: 2721, 1994; Am. J. Surg. 169: 28, 1995).

        Since the early 1990's, good palliation hasoften achieved simply by embolizing the hepatic artery, since the cancer's blood supply is mostly arterial (Cancer 73: 2259, 1994). Chemotherapeutic agents on particles can be delivered in this way ("chemoembolization"). And nowadays, radiofrequency ablation or even injecting absolute alcohol under CT guidance (which gets the patient drunk) can supposedly produce cures.

        * Oncologists have a variety of interesting approaches. Small tumors have been treated with microwaves (Cancer 74: 817, 1994; "residual tumor" may be non-active -- future pathologists will enjoy reading about the picturesque after-effects in Am. J. Gasto. 98: 2052, 2003) or ethanol injection (Radiology 192: 407, 1994). Both are tributes to our ability to detect tiny tumors by serum screening and scanning.

        Today's standard will probably soon be a combination of chemoembolization (embolization of the hepatic arteries with particles bearing antineoplastic drugs) plus radiofrequency ablation (JAMA 299: 1669, 2008; from the new China; also Ann. Surg. 248: 617, 2008).

        Still, the long-term outlook is grim without major surgery plus a lot of good luck. As with lung cancer, after non-surgical "cure" of one hepatocellular carcinoma, it is not unusual for a new clone to arise from the same premalignant cellular milieu (Nowell's law triumphant; Cancer 63: 2207, 1989).

        My favorite pathology article from 2008 was a study that showed really good prognostication from gene expression studies on formalin-fixed tissues (NEJM 359: 1995, 2008). This is the future of surgical pathology -- enjoy it.

    CHOLANGIOCARCINOMA-type cancers (see below) can occur within the liver, or as a mix with hepatocellular carcinoma.

      They are desmoplastic adenocarcinomas, often mucin-positive. Of course, the cells will not secrete bile.

      The risk factors for this lesion are (1) "Thorotrast" exposure; (2) liver fluke infestation; (3) idiopathic sclerosing cholangitis; * (4) Caroli's.

      Surgons see Ann. Surg. 245: 755, 2007. Only the stage seems to matter for prognosis.

Biliary Tumors
From Chile
In Spanish

Cholangiocarcinoma
WebPath

    HEPATOBLASTOMA is a pediatric solid cancer. Surgical resection (followed by liver transplant, of course) is often curative.

      Ask a pediatric pathologist to show you a sample. As in Wilms' tumor, there's often a variety of different kinds of epithelial and/or mesenchymal-derived structures. Alpha-fetoprotein is high, and FSH/LH often high too. (What would the latter do?)

      The important prognostic factor is stage; histologic type Is less important (Ped. Path. 12: 167, 1992).

      Histopathologists are now talking about the "cell of origin" (obviously a stem-cell) even predating the differentiation into endoderm and mesoderm (Am. J. Path. 148: 321, 1996). Update Cancer 98: 668, 2003.

    HEPATIC ANGIOSARCOMA, a rapidly lethal cancer, is infamous for having been caused by exposure to industrial poisons (vinyl chloride, arsenic) and the radioactive contrast medium "Thorotrast".

      Nowadays they have become very rare, but still occur once in a great while (South. Med. J. 94: 336, 2001).

    METASTASES TO THE LIVER need to be mentioned, too.

      Liver and lung are the two organs most often involved in fatal cancer. Around 35% of patients dying of cancer have "liver mets", and about the same percent have "lung mets". The biggest livers are those bearing metastatic carcinoma.

      Primary cancers of the liver (hepatocellular carcinoma, angiosarcoma, cholangiocarcinoma) often appear multiple. But you can distinguish metastatic cancer from primary liver cancer fairly easily:

        Metastatic tumor in the liver tends to umbilicate (i.e., undergo central necrosis because of the watershed effect). Hepatocellular carcinomas (which are very vascular) and cholangiocarcinomas seldom do this.

        If it's a cirrhotic liver, chances are it's hepatocellular carcinoma.

      Here's a rule that usually works: Untreatable liver metastases portend death within twelve months.

        * Some folks are living longer now thanks to cryoablation: Am. J. Surg. 171: 27, 1996.

        Remember, families of patients dying with liver metastases often believe the patient died of "liver cancer", unrelated to any known primary.

      Lymphomas and leukemias in the liver cluster on the portal areas. Erythroid cells in the liver cluster in the sinusoids.

Liver Metastases
Tom Demark's Site

Metastatic adenocarcinoma
WebPath

Metastatic adenocarcinoma
CT scan without contrast
WebPath

Metastatic adenocarcinoma
WebPath

Metastatic adenocarcinoma
CT scan with contrast
WebPath

Metastatic adenocarcinoma
Infiltrating ductal carcinoma
WebPath

Primary lymphoma of the liver
Pittsburgh Pathology Cases

Liver metastases
Oat cell
X-ray from NEJM

Metastases to Liver
Text and photomicrographs. Nice.
Human Pathology Digital Image Gallery

Liver metastases, renal cell carcinoma
AFIP
Wikimedia Commons

Liver metastases
Primary was pancreas
Wikimedia Commons

FOR FUTURE LIVER PATHOLOGISTS AND EXAM-TAKERS:

    Necrosis in zones of the liver:

      ZONE 1 (periportal) is hit hardest in phosphorus poisoning and eclampsia

      ZONE 2 (mid-zonal) is hit hardest in yellow fever

      ZONE 3 (centrilobular) is hit hardest in hypoxia and shock (i.e., it gets the least oxygen), in acetaminophen toxicity, and in CCl4 toxicity. NOTE: This is the best place to look for bile plugs. Why?

    Other keys to the diagnosis:

      LOTS OF HEMOSIDERIN Is it located predominantly...

      • in most hepatocytes?
        • PRIMARY HEMOCHROMATOSIS (zone 1 is most heavily involved, then zone 2, then zone 3). If there's cirrhosis, you'll see iron in the fibrous tissue and biliary epithelium.

      • in the Kupffer cells?
        • HEMOLYSIS (and some cases of transfusional hemochromatosis)

      • in central hepatocytes?
        • LONGSTANDING CONGESTION / REPETITIVE ISCHEMIA (why?)

        Hint: If there is cirrhosis from most any cause, secondary iron overload is common. If the bile ducts and fibrous stroma of a cirrhotic are iron-poor, the problem is NOT primary hemochromatosis.

      Chronic hepatitis with a large predominance of plasma cells: AUTOIMMUNE (LUPOID) HEPATITIS (chronic active hepatitis from any cause can look the same)

      Chronic hepatitis with lots of fatty change in a non-drinker (and nothing that says NASH): HEPATITIS C

      Mallory's hyaline in zone 3, plus fat and polys: ALCOHOLIC HEPATITIS / NASH (also consider ileal bypass or amiodarone toxicity)

      Random confluent-lytic necrosis: UNUSUAL VIRAL INFECTIONS, IN A BABY OR IMMUNOSUPPRESSED PERSON (* CMV, herpes simplex or zoster, adenovirus, echovirus; also consider whether the biopsy was obtained during surgery)

      Polys in the lumens of bile ducts: ASCENDING CHOLANGITIS

      * Mallory's hyaline in zone 1: Wilson's disease, primary biliary cirrhosis

      * Lipofuscin in Kupffer cells: A sign of recent (last few months) hepatocellular necrosis

      * d-PAS positive stuff in Kupffer cells: A marker that the patient is on hyperalimentation

      Polys in the portal areas, bile duct proliferation: Chronic or intermittent bile duct obstruction

      Bile lakes, bile duct proliferation, edema of the portal areas: Acute bile duct obstruction.

      Onion-skinning around the interlobular bile ducts (and eventual replacement by fibrous onions): Primary sclerosing cholangitis

      Lots of eosinophils in the portal areas: Drugs, parasites (remember schistosomes), * primary biliary cirrhosis, * primary sclerosing cholangitis

      Granulomas in the liver: TB, histoplasmosis (Am. J. Clin. Path. 113: 64, 2000 -- huge array of different lesions, with good granulomas being the exception), primary biliary cirrhosis, sarcoid, drugs as above, Crohn's disease, Hodgkin's, remote effect of Hodgkin's, Q-fever, listeria, brucella.

      TB of the liver
      Great granulomas
      Pittsburgh Pathology Cases

      * Fibrosis around individual cells: Congenital syphilis

      Star-shaped portal-tract scar containing proliferating bile ducts filled with eosinophilic globs: Cystic fibrosis.

      Star-shaped scar around central vein: Central hyaline sclerosis (EtOHism)

      * Fibrosis with bridging and regeneration, but no nodules: Hepatoportal sclerosis

      * Fibrosis with bridging, but no nodules or regeneration: Non-cirrhotic bridging fibrosis

      Cholestasis without other abnormalities: Think of drug-effect, post-surgery, sepsis, pregnancy.

      Ground-glass hepatocytes: Those caused by hepatitis B virus infection stain positive with * orcein, * Victoria blue, and the appropriate immunostain.

      * Scarring around, or loss of, portal veins in the portal areas, but everything else is okay? Idiopathic hepatoportal sclerosis! Thankfully, very uncommon.

    Update on how to percuss and feel the liver (and whether it's worthwhile; it is): South. Med. J. 87: 182, 1994.

Centrilobular necrosis
Lipofuscin
WebPath

Lipofuscin pigment in liver
WebPath

Hepatocellular carcinoma
Chronic alcoholism and viral hepatitis
WebPath

Yolk sac carcinoma
Liver
Pittsburgh Pathology Cases

BILE DRAINAGE SYSTEM

Gall Bladder Images
University of Washington
Pictures and comments

{15774}    normal gallbladder, from the outside
{15775}    normal gallbladder, opened up to show mucosa
{08820}    "normal gallbladder" with Rokitansky-Aschoff sinuses; lumen and mucosa on right
{15287}    normal gallbladder

    Worth remembering from previous course work:

    • The liver produces around a quart of bile daily.
    • The bile salts and lecithin keep cholesterol and unconjugated bilirubin-biliverdin solubilized in the bile.
    • In 70% of humankind, the bile ducts and main pancreatic duct have a common entry into the duodenum.
    • Like the appendix, the gallbladder seems to be more of a liability than an asset.

    BIRTH DEFECTS

      We've already looked at the dread EXTRAHEPATIC BILIARY ATRESIA.

      PHRYGIAN CAP is an anomaly of the gallbladder in which the fundus is folded over on itself. It's a radiologist's curiosity in which gallstones are more likely to form.

        * Western civilization fans: A real "phrygian cap" is the flop-over headgear worn by the French Revolution Lady allegorical figure, and on the swordpoint on the US Army seal. Smurfs wear phrygian caps.

    GALLSTONES (all about them: NEJM 328: 412, 1993; laparoscopic surgeons JAMA 269: 1018, 1993; lithotripsy Gut 35: 417, 1994)

      About 1 adult in 10 has gallstones. Usually these are asymptomatic for life. However, they can cause major problems. There are 600,000 gallstone surgeries in the U.S. yearly.

      CHOLSTEROL STONES may be pure or contaminated with calcium, oxalate, and/or bilirubin. They result from bile becoming super-saturated with cholesterol. They are yellow and range in size from infinitesimal (in aggregate, these are the potentially-lethal "sludge") to large barrel-shape casts of the gallbladder.

        You can read for yourself about "lithogenic bile", etc., etc. Bile that is merely cholesterol-supersaturated becomes liquid crystals; excess mucin production from the gall bladder that follows causes nidus formation and growing crystals (Nat. Med. 10: 1303, 2005). Harvard team on the physics of cholesterol gallstone formation: Front. Biosci. 13: 401, 2008.

        Decide for yourself whether gallstones are "a disease caused by the Western diet", or whether paleontologists are correct in exhibiting dinosaurs' gallstones, or whether there may be truth in both.

        Everybody knows "the typical cholesterol stone patient" and the "F's": fair-skinned, fat, female, fertile, flatulent, forty year old.

{00041}    faceted, mostly-cholesterol stones; despite the black bilirubinate coating, the large size and smooth faceted surfaces say "cholesterol" is their major component
{08425}    gallstone city!
{17591}    gallstone city!

Mixed stones
WebPath Case of the Week

Gallstones
From Chile
In Spanish

      BILIRUBIN STONES ("mulberry stones"; "pigment stones") are calcium bilirubinate. They result from bile becoming super-saturated with unconjugated bilirubin, i.e., when there is hemolysis (sickle cell, hemoglobin C, spherocytosis, autoimmune Coombs-positive anemia; also remember intramedullary hemolysis, especially in the thalassemias).

{18772}    bilirubin stones

      Regardless of composition, gallstones present problems when they:

      • obstruct the cystic duct, causing pain ("biliary colic") and inviting cholecystitis or mucocele formation;
      • obstruct the common bile duct, causing pain ("biliary colic") again, and inviting ascending cholangitis;
      • obstruct the pancreatic duct, perhaps at the ampulla, causing pancreatitis. The small stones (especially if there's one under 5 mm) are most troublesome (Arch. Int. Med. 157: 1674, 1997.

{10544}    common duct stone
{49247}    common duct stones; common bile duct has been opened. Liver at top

      • erode through the wall of the gallbladder and the duodenum, then passing along and getting hung up at the ileocecal valve ("gallstone ileus")

{49181}    gallstone ileus
{49182}    gallstone ileus

      • cause cancer of the gallbladder.

    ACUTE CHOLECYSTITIS (NEJM 358: 2804, 2008)

      Inflammation of the gallbladder, usually containing gallstones, usually with infection.

        The usual bugs are E. coli or enterococci. Less common are clostridia and salmonella (typhoid is carried in the gallbladder as a biofilm on gallstones).

          Enterocytozoan bienensi is an opportunist in AIDS (NEJM 328: 95, 1993).

        No one really understands the pathogenesis of acute cholecystitis, and "Big Robbins" maintains that the bacteria are secondary invaders. It is inviting to think that a stone may plug the outlet, and the gallbladder mucosa may then become infarcted due to compression by the muscularis propria's futile efforts to push the stone out. Read about "poisoning by lysolecithin", etc., etc., on your own time; it is speculative.

        In the absence of gallstones ("acalculous" cholecystitis, 10% of cases), there's generally some systemic disease, and/or perhaps edema of a Reister valve obstructs the outlet.

      The pathology is what you'd expect. The gallbladder is red, swollen, and tense. There may be pus on the inside (even an "empyema"), fibrin all over the outside, or even gangrene of the wall.

{49242}    cholecystitis, acute-on-chronic

Cholecystitis
From Chile
In Spanish

    CHRONIC CHOLECYSTITIS

{08822}    chronic cholecystitis, histology

Acute-On-Chronic Cholecystitis
Australian Pathology Museum
High-tech gross photos

      This just means fibrosis of the gallbladder, maybe from repeated bouts of mild or severe acute cholecystitis, maybe "just from the irritation of having gallstones". There are almost always gallstones. Look for:

      • Hypertrophy and hyperplasia of the smooth muscle (how might this happen?);
      • "Rokitansky-Aschoff sinuses", pseudo-diverticula where the mucosa has pooched into or through the muscularis propria. Maybe all the pressure in the gall bladder causes this. You can see these in normal gallbladders, too.

      The "porcelain gallbladder" has undergone dystrophic calcification.

    NON-PROBLEMS

      "Cholesterolosis", or "strawberry gallbladder", is a pathologist's delight seen in maybe 5% of autopsies. Little clusters of cholesterol-laden macrophages develop just under the epithelium, looking like strawberry seeds. Its significance to human health is zero.

{13362}    strawberry gallbladder ("cholesterolosis"), gross
{08108}    strawberry gallbladder, histology; foam cells (phagocytic macrophages) contain cholesterol

      "Inflammatory polyps" are benign nubbins on the gallbladder wall.

      "Mucocele" ("hydrops") is a gallbladder filled with mucus instead of bile, because its cystic duct has become obstructed. The gallbladder won't visualize on x-ray.

{38827}    hydrops ("mucocele") of the gallbladder

      Benign tumors of the gallbladder are uncommon, and usually incidental findings.

    CARCINOMA OF THE GALLBLADDER

      Adenocarcinomas of the gallbladder are uncommon (but more common than cholangiocarcinomas of the bile ducts). They are usually preceded by (and most people think caused by) gallstones. As you would expect, women are at increased risk.

        * It's been claimed that chronic carrying of typhoid or paratyphoid bacteria increases the risk by about fifty times (Lancet 343: 83, 1994; somebody please take a look at this study and tell me if it's flawed.)

      Usually, these have already invaded the liver by the time they become symptomatic (i.e., have obstructed the common bile duct).

{26327}    adenocarcinoma of the gallbladder, gross
{26330}    adenocarcinoma of the gallbladder
{26333}    adenocarcinoma of the gallbladder
{49249}    adenocarcinoma of the gallbladder
{38821}    adenocarcinoma of the gallbladder, with stones
{38824}    adenocarcinoma of the gallbladder, no stones

    CANCER OF THE BILE DUCTS

      Adenocarcinomas arising from these structures are uncommon. Of course, they produce obstructive jaundice.

        Risk factors include ulcerative colitis and infestation with liver flukes or ascaris worms. Unlike for cancer of the gallbladder, men are at greater risk.

      The most common site is at the ampulla of Vater, and this is often considered separately. The "Klatskin tumor" at the junction of the hepatic and common ducts is also common, but any point on the common bile duct or a hepatic duct can be the primary.

      Cancer of the ampulla tends to be mucin-producing. Cancers arising elsewhere from among the bile ducts tend to be desmoplastic.

      The symptomatology is what you'd expect. Itching makes these patients particularly miserable.

*  *  * 

Future surgeons: COURVOISIER'S LAW!

    In obstructive jaundice, if the gallbladder is palpable, the patient has cancer.

Explanation:

    In obstructive jaundice below the level of the cystic duct, and assuming the cystic duct is patent, the pressure in the gallbladder will be high.

    If the problem is a common duct stone, the gallbladder will be scarred up due to previous episodes of acute cholecystitis, or chronic cholecystitis. Therefore, it will not expand.

    If the problem is cancer of the pancreas, common duct, or ampulla, the gallbladder wall itself is normal, so it will be tremendously expanded and easily palpated.

    This works pretty well, but nobody's going to base a decision on it nowadays. Can you think of EXCEPTIONS? Sure you can!

To date, there is no established role for "alternative and complementary medicines" in the treatment of any liver disease, though it's possible some of the herbal remedies might have some effect. A famous and elaborate protocol by a naturopath for treatment of chronic hepatitis C, which centers around a very special recipe for breakfast museli, led to drops in transaminase levels but he made no effort to control for the fact that he also made his patients stop drinking alcohol. This invites an obvious conclusion. Plus, the risk of hepatotoxicity from herbal concoctions is well-known. See Liver Int. 23: 213, 2003; Lancet 361: 101, 2003; Med. J. Aust. 178: 442, 2003; Clin. Liver Dis. 7: 453, 2003; Clin. Tox. 46: 819, 2008 (from Hong Kong, where the proble is horrible.) In Korea, use of "alternative medicine" seems to be the most common cause of elevated liver enzymes in breast cancer patients (J. Kor. Med. Sci. 19: 397, 2004). In Oregon, "complementary herbal remedies" are now THE cause of massive hepatic necrosis requiring transplantation, exceeding even acetaminophen overdoses and all the viruses combined. (Arch. Surg. 138: 852, 2003). Even the much-touted "milk thistle" (silibindin; review Am. Fam. Phys. 72: 1285, 2005), though non-toxic, hasn't shown any robust evidence of working (Am. J. Med. 113: 506, 2002). There is a recent positive report for hepatitis C (Gastroent. 135: 1561, 2008) and another for NASH (Dig. Dis. Sci. 2387, 2007); both are small overseas studies.

* SLICE OF LIFE REVIEW

{08820}    gall bladder, normal
{08826}    liver, normal
{11798}    liver, normal
{11807}    liver, normal
{14874}    liver, porcine
{14875}    liver human, normal
{14875}    liver human, normal
{14876}    liver human, normal, central vein
{14876}    liver human, normal
{14877}    liver (sinusoids), normal
{14877}    liver (sinusoids), normal
{14878}    liver (sinusoids), normal, space of Disse
{14878}    liver (sinusoids), normal
{14879}    liver, portal triad
{14880}    liver, portal triad; a=vein, b=duct
{14883}    gallbladder, normal
{14885}    gallbladder (epithelium), normal
{15104}    liver
{15105}    liver
{15106}    liver
{15107}    liver, pig
{15281}    liver, normal
{15281}    liver, normal
{15282}    liver, normal
{15282}    liver, normal
{15283}    liver, normal
{15283}    liver, normal; a=vein, b=artery, c=duct
{15284}    liver, pig
{15285}    liver, pig
{15286}    gall bladder, normal
{15286}    gall bladder, normal
{15287}    gall bladder, normal
{15287}    gall bladder, normal
{15288}    gall bladder, normal
{15288}    gall bladder, normal
{15773}    gall bladder, normal
{15774}    gall bladder, normal
{15775}    gall bladder, normal
{15776}    liver, normal
{15778}    liver, normal
{16043}    liver, normal in fetus
{16074}    necrosis, liver junct.; normal
{17592}    gallbladder, normal
{19721}    gall bladder, normal
{20888}    liver, portal triad
{20889}    liver, portal vein
{20890}    liver, hepatic artery
{20891}    liver, bile duce
{20892}    liver, hepatocyte plate
{20893}    liver, central vein
{20894}    liver, central vein
{20895}    liver, portal triad
{20896}    liver, portal triad and central vein
{20897}    gall bladder
{26039}    liver, normal
{26042}    hepatocytes, normal aspirate
{26045}    hepatocytes, normal aspirate
{39498}    liver, normal
{39764}    liver, normal

I hate liver, liver makes me quiver,
liver makes me curl right up and die, makes me cry...
it gives you hives, gives you scurvy, turns my stomach topsy turvy,
liver just simply ain't my bag, makes me gag, makes me want to throw up...
Now liver is neither solid or liquid, but merely an amorphous, viscous colloid of putrid protein...
It is located between the 7th and the 10th dorsal vertebrae,
JUST south of the diaphragm, "lounging like a worm on a pillow of fat."
Now did you ever look at the word liver?
Is it any coincidence that there are 5 letters in the word liver?
The same number of letters as in the word death? the word drugs? the word hippy?...

Well, maybe you just haven't had it cooked right...

Naaah, I've had that stuff sauteed, I've had it breaded and broiled and broasted and braised,
I've had it diced and sliced and riced and sunnyside up over easy fried, and it still comes out, LIVER....
I hate liver, liver makes me quiver, liver makes me curl right up and die, (makes me cry)...
Why, first time I had it, I didn't like it at all...

Well, what happened?

Well, I was about 9 months..my mammy gave me a hunk of that Gerber's baby food.
Well, I rolled it around, looked at her eyeballs, spit it out and uttered my first words...

At nine months, what'd you say?

I said... I hate liver, liver makes me quiver,
liver makes me curl right up and die, makes me cry...
it gives you hives, gives you scurvy, turns my stomach topsy turvy,
liver just simply ain't my bag.

        -- "Second City", Chicago radio group, 1970's

BIBLIOGRAPHY / FURTHER READING

Visitors to www.pathguy.com
reset Jan. 30, 2005:

Ed at homeDrop by and meet Ed

Ed says, "This world would be a sorry place if people like me who call ourselves Christians didn't try to act as good as other good people ." Prayer Request

If you have a Second Life account, please visit my teammates and me at the Medical Examiner's office.

Teaching Pathology

Pathological Chess


Taser Video
83.4 MB
7:26 min