{0444} 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 is an endemic scourge on some Indian reservations (MMWR 46: 600, 1997; Am. J. Pub. Health. 80: 1091, 1990).

* 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.

hepatitis B ("serum hepatitis")

The world's most serious DNA-virus-related health problem. The reservoir for the virus ("HBV", "Dane particle") is the world's 300 million (Proc. Nat. Acad. Sci. 93: 6542, 1996) carriers, most of whom are asymptomatic and have histologically normal or near-normal livers.

{0445} hepatitis B virus
{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)
• 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 death 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, the claim is already totally discredited, and many lawsuits got filed (Science 281: 630, 1998).

* Catching hepatitis B from the surgeon, even when e-antigen-negative ("low-risk"): NEJM 336: 178, 1997.

Virus antigens:

HBsAg ("Australia antigen"): Surface antigen. Envelope protein. During the productive infection, the liver cells make considerable excess non-infectious HBsAg, facilitating diagnosis.

HBcAg: Core antigen. Nucleocapsid.

HBeAg: Another nucleocapsid antigen, which means the virus is being replicated.

* Interestingly, entry of the virus into the hepatocyte is by means of binding to polymerized serum albumin.

After a person first meets the virus, the incubation period is usually 1-4 months.

Antigens and antibodies:

HBsAg first appears in the blood shortly before symptoms begin (if they are to begin). It remains in the blood for the duration of the infection, whether it is acutely symptomatic, slowly-progressive / subclinical, or merely the carrier state.

HBeAg appears in the blood just after HBsAg, and before symptoms start. It remains as long as there is acute viral replication (you're very contagious....), and disappears if (and only if) viral replication stops. The patient is still sick when HBeAg disappears, but can take comfort in the good news.

Anti-HBeAg appears soon after viral replication and HBeAg production stop (if they stop). The patient can still be sick, but this is another piece of good news.

Don't ask for an assay of HBcAg, the core antigen in the blood. It's an intranuclear protein and there's almost none in the blood. However, Anti-HBcAg, in its IgM form, appears in the blood typically before symptoms begin, and generally remains present for years (IgG anti-HBcAg will eventually take over, maybe). If a person with clinical hepatitis has cleared his blood of HBsAg, but has not yet developed detectable anti-HBsAg, the presence of IgM anti-HBcAg confirms that the infection is, indeed, hepatitis B and is in the core window.

Anti-HBsAg generally appears when the infection is pretty much over, and is a sure sign of recovery.

BEWARE! During the time between disappearance of HBsAg and appearance of anti-HBsAg, the patient may experience a potentially-lethal type III systemic vasculitis. (Why?)

If your patient is anti-HBsAg positive and anti-HBcAg negative, probably this person has had the hepatitis B vaccine (why?)

* Well, maybe it's not a sure sign of recovery; the Scripps crew has found viral DNA up to five years after appearance of the antibody, but the patients don't seem sick or catching (J. Clin. Inv. 93: 230, 1994).

Symptoms begin in hepatitis B infection only when T-cells become angry with HBsAg and HBcAg and start killing the hepatocytes that produce them. Histopathologists find T-cytotoxic cells where the hepatocytes are dying. Eventually, the only surviving liver cells are the ones that won't continue making viruses, and these replenish the liver.

The acute disease may be subclinical, or can cause weeks of jaundice and misery, or can cause fulminant hepatitis And death, or sub-massive hepatic necrosis with resolution or cirrhosis.

Survivors (and 99% of people survive the acute episode) usually clear themselves of the virus, but maybe 10% fail to do so. These can become healthy carriers, develop chronic hepatitis that may remit or progress to cirrhosis if untreated. Rule of thumb: The more severe the initial illness, the less chance of remaining chronically infected (why?) Terminology: Chronic hepatitis B means HBsAg has been present in the bloodstream for 6 months or more.

NOTE: Carrying hepatitis B, with or without ongoing liver disease, is an important cause of cryoglobulinemia and/or "polyarteritis nodosa of hepatitis B" (both immune complex, type III immune injury problems).

NOTE: People who become carriers are those who mount a poor immune response. Men (weaker immune response) are more at risk than women; different HLA types differ in susceptibility (Lancet 344: 1194, 1994).

Further, anyone who carries around the virus for a long time is at substantial risk for hepatocellular carcinoma. (hepatitis B and/or hepatitis C contribute to most cases of this cancer, which worldwide is one of the most common fatal diseases. In the case of hepatitis B, the virus may be acting as a mitogen that allows Nowell's law to act, and/or mutating genes at or near its insertion sites: J. Virol. 65: 6761, 1991; there is no doubt that insertion of the virus can and does scramble chromosomes: Proc. Nat. Acad. Sci. 88: 9248, 1991.)

People who continue to harbor the virus are probably those that are not especially good at making interferon (the chronically sick, the immunocompromised, little kids, the unlucky, men much more often than women). Alpha-interferon is now 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 is expensive and produces 'flu-like symptoms, but it's better than dying or infecting your spouse. The new trend will probably be intermittent therapy (cheaper, more acceptable, just as effective: Gastroent. 107: 479, 1994). And thankfully the risk for hepatocellular carcinoma also drops greatly (Cancer 66: 2395, 1990 was the first big one).

Other anti-viral agents include lamivudine and adefovir dipivoxil (NEJM 348: 800 & 808, 2003). They are unlikely to eradicate the virus, but they keep it under control and it is now clear that even the cirrhosis tends to reverse under this treatment (Lancet 362: 2089, 2003).

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.

hepatitis C (the vast majority of the old non-A, non-B hepatitis Cases) updates Ann. Int. Med. 132: 296, 2000; Mayo Clin. Proc. 73: 355, 1998; Lancet 362: 2095, 2003.

This flavivirus (HCV) and its related disease spectrum are now well-characterized. In the U.S., 1% of asymptomatic people are positive for HCV (more than this among swingers and MUCH more among IV drug users; maybe 0.3% in those not in these risk groups; health care workers aren't at increased risk: Lancet 343: 1618, 1994; ear-piercing is a risk factor: NEJM 334: 1691, 1996; 19% positive for inner-city forensic-pathology service deaths J. For. Sci. 38: 1075, 1993); in the poor nations, it's around 5%; 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.

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 produce about a 6% rate 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); around a quarter of spouses 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).

If you have the antibody, you have about an 85% chance that you'll have detectable virus by PCR in your blood, and it's nearly certain you'll have it in your liver (Gut 42: 570, 1998) -- this is a virus adults are unlikely to get rid of naturally. A few folks do clear the virus quickly after being infected (Science 288: 333, 2000).

* 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. 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 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); 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.

* Nowadays we monitor disease and therapy using assays for hepatitis C messenger RNA (Am. J. Clin. Path. 107: 362, 1997).

* Strangely, quite a few of these people never have elevated transaminases, even as they progress to cirrhosis. We have to wonder how these people's infections were detected (Am. J. Gastro. 98: 1588, 2003).

We now eliminate about half of chronic infections using a combination of pegylated interferon and ribavirin. This is one of the most important triumphs of medicine in the last few years.

* Future pathologists: The less iron in the sinusoidal cells and portal tracts, the better the response. Nobody knows why. See Am. J. Clin. Path. 103: 419, 1995.

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. Around 60% of people with the antibody have virus detectable by PCR; they're probably more infectious and more likely to be seriously ill (see, for starters, NEJM 330: 744, 1994).

People with other liver diseases may show false-positives or have persistence of the antibody after elimination (?) of the virus. PCR has finally made it possible to sort the mess out.

* There's hope that we'll have a hepatitis C vaccine, but it's a long way off: Proc. Nat. Acad. Sci. 91: 1294, 1994 (poxvirus-based). 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.

* 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.

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). A link to hepatocellular carcinoma is statistically possible but unproven (Cancer 86: 936, 1999). 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.

* 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.

Yellow fever: Councilman bodies, necrosis especially in the mid-zone of the lobule, and a surprising lack of inflammatory response. Yellow fever today in Bolivia: Lancet 353: 1558, 1999. Death from yellow fever is probably not so much due to liver failure as to overactivation of cytokines, much as in sepsis: J. Inf. Dis. 190: 1821, 2004.

CHRONIC HEPATITIS NOT CAUSED BY VIRUSES

Autoimmune ("lupoid"; "plasmacytic") hepatitis: Chronic hepatitis progressing to cirrhosis, without chronic virus infection but with evidence of immune injury. Review NEJM 354: 54, 2006.

Poorly understood, but fairly common, and deadly. We'll distinguish the different types (which bear little relationship to real lupus) when we discuss liver function testing. The most common type features autoantibodies against smooth muscle. Review: Am. J. Med. 96(1A): 23-S, 1994.

Current thinking is that something first damages the liver (probably one of the viral hepatitis family, or some drug or poison, or whatever), and patients then get sensitized to their livers and start destroying them over the long haul. More about this later.

Drugs that trigger "lupoid hepatitis" include some of the older ones, and today minocycline (Br. Med. J. 312: 169, 1996).

Future pathologists: Autoimmune chronic hepatitis usually features a lot more plasma cells than does viral chronic hepatitis.

Unlike in viral infection, the response to immunosuppression (i.e., glucocorticoids) is generally good. The best protocol, which often cures, is based on azathioprine (NEJM 333: 958 & 1004, 1995).

* 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. This is new stuff. 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.

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).

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.

* 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 Chronic inflammatory infiltrate WebPath

Anti-mitochondrial antibody Immunofluorescence WebPath

Primary biliary cirrhosis is BIG news right now. It is considerably more common than we had once thought, and it responds to therapy with bile salt analogues (nobody knows why; Br. Med. J. 312: 1181, 1996.)

* The newly-recognized "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")
• 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

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

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.

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.

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

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 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. Penicillium 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 (guess the causes?)

Tumors (guess which ones?)

Really bad pancreatitis

Intra-hepatic causes

Cirrhosis (both fibrosis and AV-shunting contribute)

Central hyaline sclerosis without cirrhosis

Really bad fatty change

Alcoholism / "alcoholic hepatitis", etc.

Reye's

Schistosomiasis (eggs plug portal vein radicles)

* Sarcoid / TB (supposedly, I've never seen this)

* Congenital hepatic fibrosis (a thankfully-rare birth defect, with very few veins in the expanded portal areas)

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

Massive ascites
Patient photo
Brazilian Medical Students

Caput medusae Caused by cirrhosis WebPath

Esophageal varices Dilated submucosal veins WebPath

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

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 IgA 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)  

Alcoholic Liver Disease Frank Mitros MD Virtual Hospital

Fatty metamorphosis Cross section WebPath

Fatty metamorphosis H & E stain WebPath

Fatty liver Photo and mini-review Brown U.

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 hepatitis Photo and mini-review Brown U.

Alcoholic Liver Disease Text and pictures From "Big Robbins"

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

How many ship captains does it take to cause the Alaska oil spill?
One and a fifth!

-- Ed

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

-- Dr. Rabelais

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 other faces 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 ileal bypass, in obesity, in ill-controlled adult-onset diabetes, in problem pregnancy, in galactosemia, in methotrexate toxicity, in Wilson's disease, in a few rare disorders of lipid metabolism, and in a few unusual situations.

{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.

Non-Alcoholic Steatohepatitis
Frank Mitros MD
Virtual Hospital


* 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 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). This won't go away, and is undoubtedly a principal 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

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.

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 function normally.

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. 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). "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. The "debate" seems to be over and alcoholics are competing on an equal basis for liver transplants with babies dying of biliary atresia. Especially if we continue to make it difficult to obtain organs for transplantation, this will eventually start getting media attention.

NON-ALCOHOLIC STEATOHEPATITIS

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

The anatomic pathology is much like alcoholic liver disease, with fatty change, 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.

In countries where little alcohol is consumed and there is not much hepatitis or schistosomiasis, this is the most prevalent liver disease. The histology is exactly the same as alcoholic fatty liver, alcoholic hepatitis, or advanced alcoholic cirrhosis.

There is always insulin resistance as well. The mainstay of therapy is 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). Link to "metabolic syndrome X": Am. J. Gastro. 96: 2957, 2001; J. Clin. Endo. Metab. 84: 1513, 1999.

* 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.) 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.

IRON OVERLOAD

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. Health frauds like you-know-what kill by delaying the diagnosis of GI and gynecologic cancers. Fortunately for the public, you-know-what itself uses ferric iron, which makes the stool black, doesn't upset the tummy very much, and isn'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. And a relative abundance or lack of ascorbic acid (vitamin C) facilitates or inhibits absorption.

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 for excessive iron absorption via the gut. (Homozygotes have worse problems.) 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.

* Other loci encode rare, severe forms. Hepcidin: Nat. Genet. 33: 21, 2003. Aceruloplasminemia Gut 47: 858, 2000 (hepatocytes and Kupffer cells involved uniformly, no fibrosis, neurologic disease rather than liver failure; this is NOT Wilson's). Autosomal dominant hemochromatosis is due to deficiency in ferroportin (SLC11A3; J. Clin. Inf. 108: 512 & 619, 2001; Blood 100: 692, 2002; Blood 106: 1092, 2005), which prevents macrophages from giving up their iron. Juvenile hemochromatosis: HFE2/hemojuvelin: 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. Transferrin receptor 2 deficiency: Gastroent. 122: 1295, 2002.

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.

Obviously, the distinction between "hemosiderosis" and "hemochromatosis" is not clear-cut. Iron overload is a spectrum of disorders. Thus, it is an extremely common disease. (It is not usually so devastating as better-known genetic diseases).

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 HLA-H (Proc. Nat. Acad. Sci. 94: 2534, 1997 review, also called HFE), 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 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. (* It is worth screening all adult-onset diabetics for iron overload: Lancet 2: 233, 1989.) It is worth screening 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. The liver enlarges even before cirrhosis develops. 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 ("hepatoma"; histology Am. J. Clin. Path. 116: 738, 2001). This is fatal and kills another 30% of patients diagnosed to have primary hemochromatosis.

{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

Hemosiderosis of liver Prussian blue stain WebPath

Iron overload Liver Rockford Case of the Month

Hemochromatosis of liver WebPath

Hereditary hemochromatosis Cirrhosis WebPath

Hemochromatosis, liver Photo and mini-review Brown U.

Hemochromatosis Pittsburgh Pathology Cases

Pathology of Iron Metabolism WebPath Tutorial

Hemochromatosis Pittsburgh Illustrated Case

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 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. * Other unusual genetic diseases include congenital absence of transferrin, in which the liver becomes packed with iron while the marrow remains depleted; no one knows why (NEJM 326: 1705, 1992); and a new not-so-severe non-HLA-linked syndrome with normal transferrin saturation (treacherous: Lancet 349: 95, 1997). 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).

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

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 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.

{018} Wilson's

HEPATIC AMYLOIDOSIS: You already know about this. Past concerns about biopsying the liver in suspected amyloidosis seem to be groundless (Medicine 82: 291, 2003).

{53548} amyloid in the liver

LIVER POISONS

Drug-induced liver injury
Emilio Orfei
Loyola; great photos

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 (even at "safe" doses)

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

Pennyroyal ("holistic herbal tonic" / amateur abortifacient) ... simulates viral hepatitis

* 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 etiology of Reye's is obscure.

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).

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.

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

Herpes simplex hepatitis
Please don't let this happen
Loyola Med


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, 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

Antitrypsin deficiency, liver
Photo and mini-review
Brown U.

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

Liver Tumors
Frank Mitros MD
Virtual Hospital

Hamartomas

Cavernous hemangiomas are little birthmarks, seen in maybe 1% of livers. If you see them at surgery, don't biopsy them. They 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 pediatric lesion with a trademark chromosomal marker (Cancer 74: 1237, 1994).

* Bile duct hamartomas are polka-dots, mere autopsy curiosities ("Von Meyenberg complexes").

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).

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).

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 and their sinusoidal lining cells)

Hepatocellular 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.

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).

We now know that hepatitis C virus is also a very important cause, though again we don't know how (Cancer 73: 2253, 1994). 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; 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 risk factor, it is minor.

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 course)
• Mallory's hyaline (not really pathognomonic)
• stainable hepatitis B virus proteins
• stainable alpha-fetoprotein (remember this is also a really good 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 precedes hepatocellular carcinoma. 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 benign 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.)

* UCLA got their five favorite international liver pathologists to sit down and draw up some criteria for a standard nomenclature, which was nice. Am. J. Surg. Path. 17: 1113, 1993.

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
• Grade III: No bile, lots of giant cells
• Grade IV: Hard to tell it was once liver

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 almost certainly a different disease. Grossly they look like focal nodular hyperplasia. Their "pale bodies" contain albumin and fibrinogen. See Arch. Path. Lab. Med. 128: 222, 2004.

* 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 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 Ed Uthman

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 usually 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.

Clinical behavior of hepatocellular carcinomas: Cancer 66: 2174, 1990. Without treatment, you're dead. 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. The procedure seems to cure about 25% of patients (Arch. Surg. 129: 738, 1994.

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).

Or you can get good palliation by embolizing the hepatic artery, since the cancer's blood supply is mostly arterial (Cancer 73: 2259, 1994). 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. Recently, 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. Big tumors have been treated with protons (Gastroent. 106: 1032, 1994).

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 benign cellular milieu (Nowell's law triumphant; Cancer 63: 2207, 1989).

* The "fibrolamellar variant" of younger women (mostly) without cirrhosis carries a relatively good prognosis after surgery and transplantation. It's really a different disease. See Hum. Path. 22: 396, 1991; Hum. Path. 19: 784, 1988.

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.

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".

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 in 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). Hepatocellular carcinomas 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

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.

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, 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: hepatitis C

Mallory's hyaline in zone 3, plus fat and polys: Alcoholic hepatitis (* less often, nonalcoholic steatohepatitis, 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

* 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.

* No portal veins in the portal areas, but everything else is okay? Hepatoportal sclerosis! Not an undergraduate medical student's concern.

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

Biliary Tract Disease
Frank Mitros MD
Virtual Hospital

{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.

Cholesterol 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).

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.

* Slow intestinal transit time as a risk factor in those without the usual risk factors: Lancet 341: 8, 1993. Smoking as a risk for symptomatic stones: Gut 35: 107, 1994.

{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

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

Gallstones From Chile In Spanish

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

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); * 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.

* Recently 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 tend 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!

Malignant melanoma
Bile duct primary
Loyola Med

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. An 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. 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", though non-toxic, hasn't shown any robust evidence of working (Am. J. Med. 113: 506, 2002).

* 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... [repeat Chorus]

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

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