{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, until recently an endemic scourge on many Indian reservations (MMWR 46: 600, 1997) has become much less common thanks to the recommendation to immunize all these children (Am. J. Pub. Health 94: 996, 2004).

* The 1998 strawberry outbreak: NEJM 340: 595, 1999.

The incubation period is about two weeks, and this is the time when virus is shed in the feces. The infection in kids is usually asymptomatic. Adults who get symptoms at all suffer jaundice and discomfort for a few weeks. Once in a while, the disease is fatal.

You'll hear different versions of whether the virus itself damages hepatocytes (the other enteroviruses are cytotoxic), or whether the liver damage is actually wrought by the body's immune response.

Immune response is exactly what you'd expect:

IgM ANTI-HAV appears in the blood when the symptoms begin, clears the infection, and disappears within 12 months.

IgG ANTI-HAV appears in the blood during the symptomatic period, and usually stays around for life, rendering the patient immune.

Occasionally the disease causes acute yellow atrophy and death/transplantation (Am. J. Gastro. 98: 448, 2003).

Hepatitis A very seldom becomes chronic or leads directly to cirrhosis. There is probably no carrier state. At worst, the disease might be a trigger for autoimmune chronic hepatitis, but the virus won't stay around.

* How the vaccine came about: Lancet 343: 321 & 322, 1994; J. Inf. Dis. 169: 996, 1994; JAMA 271: 1328, 1994; JAMA 273: 906, 1995 (now classic). Hepatitis A vaccine for post-exposure prophylaxis seems to work about as well as immune globulin: NEJM 357: 1685, 2007.

HEPATITIS B ("serum hepatitis")

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

{0445}    hepatitis B virus
{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 deaths being core-antibody positive (J. For. Sci. 38: 1075, 1993).

* Hepatitis B immunization has resulted in a triumphant reduction in the prevalence of carriage in Taiwan and the rate of hepatocellular carcinomas (JAMA 276: 906, 1996).

In 1997, I predicted the 1998-9 media hype that the vaccine causes multiple sclerosis. The activists don't have the numbers, but even after the claim was already totally discredited, many lawsuits still got filed (Science 281: 630, 1998).

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

Virus antigens:

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

HBcAg: Core antigen. Nucleocapsid.

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

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

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

Antigens and antibodies:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

People who continue to harbor the virus are probably those that are not especially good at making interferon (the chronically sick, the immunocompromised, little kids, the unlucky, men much more often than women). Alpha-interferon was the original the mainstay of therapy for chronic hepatitis B infections, and the results are encouraging, with maybe half of people clearing the infection. Of course, interferon therapy was expensive and produces 'flu-like symptoms, but it was better than dying or infecting your spouse. And thankfully the risk for hepatocellular carcinoma also dropped greatly (Cancer 66: 2395, 1990 was the first big one).

Other anti-viral agents include lamivudine, adefovir, and dipivoxil (NEJM 348: 800 & 808, 2003). They are unlikely to eradicate the virus, but they keep it under control and it is now clear that even the cirrhosis tends to reverse under this treatment (Lancet 362: 2089, 2003). Entecavir (a guanine analogue: NEJM 354: 1001, 2006) and telbivudine (the L-isomer of thymidine: NEJM 357: 2576, 2007; Ann. Int. Med. 147: 745, 2007) are new entries.

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 2000's, intravenous drug use was the most common cause in the USA, with 98% of junkies positive in some communities; in the poor nations, it's around 5%; worldwide 3%; the highest known prevalence is around 20% in Egypt (see below). At least 170 million people are infected worldwide (Science 288: 339, 2000), at least 3 million in the USA, with about 10000 deaths yearly (that mortality figure is conservative and is going to increase: JAMA 297: 784, 2007).

Hepatitis C virus is transmitted by the same routes as hepatitis B, but is probably not nearly so catching. The best route seems to be blood transfusion or needle-sharing (J. Inf. Dis. 162: 823, 1990; hemophiliacs Blood 84: 1020, 1994).

Needlesticks from infected blood carry about a 6% chance of infection (Br. Med. J. 315: 333, 1997) and prophylactic treatment with anti-hepatitis C medicines is now administered routinely after such events.

Strangely, nobody yet knows the prevalence of perinatally-transmitted hepatitis C, but it can declare itself later in life as a fulminant illness: Arch. Dis. Child. 88: 160, 2003.

Thankfully, with changing lifestyles (maybe) and surveillance in the hospital (certainly), the transmission rate of hepatitis C is only about 1/5 what it was in the 1980's (Sci. Am. 280(3): 17, March 1999.)

The risk from a transfusion is now about 1 in 2 million (Lancet 361: 161, 2003).

* Among several hundred Irish women infected in the '70's by bad RhoGam, half still had demonstrable virus, most of these had some inflammation, many had some fibrosis, but only two had cirrhosis (NEJM 340: 1228, 1999).

* Hepatitis C transmission by acupuncture is now so well-known that you'd do well to warn your patients to be sure they know who's doing it (Can. Fam. Phys. 49: 985, 2003).

Sexual transmission seems much less efficient but probably occurs (JAMA 269: 361 and 392, 1993; Gut 45: 7, 1999; the risk to MSM's seems very low Am. J. Pub. Health 95: 502, 2005); around a quarter of spouses do eventually catch it (Ann. Int. Med. 120: 748, 1994). Vertical transmission from Mom is common, especially if Mom has lots of virus on board: NEJM 330: 744, 1994. In striking contrast to HIV, hepatitis B, and so forth, around 40% of people who carry the virus haven't got a clue how they got it.

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

In the US, if you're living clean enough to donate blood, your chance of coming down with hepatitis C is very low (BMJ 316: 1413, 1998; NEJM 341: 556, 1999).

A majority of people with the antibody do have detectable virus by PCR in the blood.

The presence of the virus's RNA in the blood (or liver tissue, which is harder to obtain) is today's standard for proving infection. The exact specificity of a positive antibody depends on the test (the cheap first-generation assays are less specific than the costly second-generation RIBA) and of course the population screened (clean-living people's positive screens are more likely to be false than needle-drug-user's positive screens). For an update on the difficult subject of who to screen and how, see Am. J. Gastro. 100: 607, 2005.

We used to teach that only a few folks do clear the virus quickly after being infected (Science 288: 333, 2000); with newer methods of detecting acute infection, some folks say that around 67% clear themselves without treatment within 8 weeks (Hepatology 37: 60, 2003), though it's also known that many people's viral levels simply become undetectable and the infection does recut. There's still a question of whether to treat immediately or wait-and-see. And some people who are chronically infected have viremia only intermittently, and in some studies, rates of spontaneous clearance over the years are relatively high (Irish J. Med. Sci. 174: 37, 2005 gives a surprising 31%, perhaps just the luck o' the Irish.)

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

Egypt, with around 20% of its people infected, has the highest rate. Probably because of needles (used to administer antimony in the treatment of schistosomiasis) not being sterilized between patients (Lancet 355: 887, 2000).

Incubation period is a week to six months; texts give the average as 8 weeks. The acute infection is more likely to be subclinical (or cause minor "belly trouble"), and massive necrosis does not occur. However, infection usually becomes progressive (Only 15-30% or so of people shake the bug. Fortunately, progression is slow, and severe liver failure results in only about 10-30% of people and usually only after decades.

The big news in hepatitis C is reports that almost all patients with the acute illness are apparently cured if given by interferon alfa-2b (NEJM 345: 1452 & 1495, 2001) if you get it to them. This is complicated by the discovery that many people who actually get sick when they meet the virus clear themselves of infection anyway (Gastroent. 125: 80, 2003 -- currently the acute-stage cure rate is estimated at 15% Am. J. Gastro. 100: 607, 2005); people with anicteric hepatitis C or who keep the virus on board for twelve weeks are unlikely to self-cure. What's best to do? Stay tuned.

You can get sick several times if you get a big dose of the bug several times (Lancet 343: 388, 1994). After acquiring the virus via blood transfusion, chronic infection with abnormal liver histology happens more often than not (Ann. Int. Med. 137: 961, 2002). The impact on overall length of life is usually small (NEJM 327: 1906, 1992; Gut 47: 845, 2000) but the infection is still a serious business.

Around a third of hepatitis C virus carriers have aggressive-looking chronic hepatitis or cirrhosis (Br. Med. J. 308: 695, 1994). Unlike the other viral diseases, there is often quite a bit of fatty change (correlates with severity: J. Inf. Dis. 192: 1943, 2005) and/or regenerative change in the bile ducts, rather few inflammatory cells (maybe just lymphoid aggregates) in the parenchyma and a portal infiltrate that's all lymphocytes (no plasma cells or eosinophils) suggests hepatitis C. The progression to fibrosis usually takes decades; if you're male, a drinker, and/or older, it may take only a decade or so (Lancet 349: 825, 1997.)

NOTE: As with hepatitis B, carrying hepatitis C, with or without ongoing liver disease, is an important cause of cryoglobulinemia (Am. J. Med. 96: 124, 1994; NEJM 330: 751, 1994 for the success of alpha-IF therapy). The cryoglobulins are immune complexes made of the virus and the antibodies.

* How does hepatitis C virus produce fibrosis? There is often remarkably little inflammation. In one model, the virally-infected hepatocytes produce huge amounts of transforming growth factor beta, causing stellate cells to produce collagen. Stay tuned; this may become the basis for a novel anti-fibrogenic therapy (Gastroenterology 129: 246, 2005).

* NOTE: hepatitis C virus tends to drive out hepatitis B virus over the long-term in patients infected with both (Gastroent. 106: 1048, 1994, others).

The NIH study -- you're probably recovered if your transaminases are normal and you have no circulating viral DNA: Ann. Int. Med. 123: 330, 1995. That's about 15% of the asymptomatic-but-antibody-positive folks.

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

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

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

Like hepatitis B, longstanding infection with hepatitis C places a person at grave risk for hepatocellular carcinoma (Lancet 345: 413, 1995).

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

Immunology:

In contrast to hepatitis B, the presence of ANTI-HCV usually indicates the persistent presence of hepatitis C virus in the body. The original work found that around 60% of people found to be positive with the first-generation antibody assay did indeed have virus detectable by PCR. Whether or not the others were false-positives, occult-infections, or cleared infections (it was never sorted out), the people with the virus in the blod were much more likely to be infectious and to be seriously ill (NEJM 330: 744, 1994). This is now a robust finding.

* There's hope that we'll have a hepatitis C vaccine, but it's a long way off. Like HIV, the virus is notorious for mutating rapidly, even in the same patient, and this isn't good for vaccine-makers. And like HIV, antibodies aren't very protective. Updates J. Imm. 176: 6065, 2006; Gastroenterology 130: 453, 2006.

* Echazabal vs. Chevron. Mario Echazabal had hepatitis C, and Chevron refused to allow him to work around chemicals that might be hepatotoxic. He claimed that this violated his rights under the Americans with Disabilities Act. His supporters accused Chevron of "paternalism", which as you know is currently anathema in many circles but is (like it or not) the foundation of occupational health and safety policy. The Supreme Court decided unanimously for Chevron in 2002. I agree. See Am. J. Pub. Health. 93: 540, 2003.

HEPATITIS G and the HEPATITIS GC family are hepatitis-C-like flaviviruses.

Hepatitis G virus is a relatively common infectious agent that produces a chronic viremia. It's known to be transmitted by blood products, sex, needles, and mother-to-child (Arch. Dis. CHild. 80: F72, 1999). There's an antibody test (Lancet 349: 318, 1997).

Whether these critters make you sick is still under study. There doesn't seem to be an acute illness (NEJM 336: 741 & 747, 1997). More studies failing to show any evidence that they make you sick: Gut 103: 103, 1998; Arch. Dis. Child. 80: F72, 1999; Ann. Int. Med. 126: 874, 1997.

A person may clear the virus, or have persistent virus infection. Around 85% of hepatitis C patients have evidence of past or present infection (J. Inf. Dis. 194: 410, 2006).

The virus also multiplies in B- and T-lymphocytes (J. Inf. Dis. 193: 451, 2006). It inhibits HIV replication in vitro (J. Inf. Dis. 192: 2147, 2005; Lancet 363: 2040, 2004), and it is claimed that persistent GB virus C coinfection slows the rate of progression of HIV disease (J. Inf. Dis. 194: 410, 2006; NEJM 350: 981, 2004), Stay tuned.

* People who study these things say that C, G, and the GC's all evolved from yellow fever or dengue fairly recently.

* TTV ("transfusion transmitted virus") is a DNA virus that's very common (10% of folks) in Japan, less common in the West. It elevates transaminases after a transfusion, but nobody's found anyone sick from it yet (Lancet 352: 164, 1998).

HEPATITIS E: An important, water-borne, epidemic calicivirus infection in the poor nations.

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

You'll make the diagnosis on the presence of IgM antibodies. Around 25% of people from the Middle East have had it, but it is less prevalent in the rest of the world (J. Inf. Dis. 16: 801, 1994). Review from the CDC in Inf. Dis. Clin. N.A. 14: 669, 2000. Vaccine NEJM 356: 895, 2007.

The first cases of chronic hepatitis E, progressing to cirrhosis, were reported in transplant recipients in 2008 (NEJM 358: 811 & 859, 2008).

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

CHRONIC HEPATITIS NOT CAUSED BY VIRUSES

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

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

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

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

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

Unlike in viral infection, the response to immunosuppression (i.e., glucocorticoids) is generally good. The common protocol, which often cures, is based on azathioprine (NEJM 333: 958 & 1004, 1995; update on why some patients tolerate it poorly: Dig. Dis. Sci. 51: 968, 2006).

* Future pathologists! Here's your scoring system (J. Hep. 31: 929, 1999)

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

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

Transplantation may eventually be necessary. After ten years, the transplant has about a 50/50 chance of being involved by recurrent disease (Gut 52: 893, 2003).

PRIMARY BILIARY CIRRHOSIS: An autoimmune disease caused (we don't know exactly how) by antibodies against pyruvate dehydrogenase ("anti-mitochondrial antibodies"). Lancet 362: 53, 2003. We'll talk more about this under "Liver Testing".

The bile ducts are selectively attacked by the immune system, eventually resulting in severe obstructive jaundice.

For some reason, the biliary epithelial cells express pyruvate dehydrogenase, or something very much like it, on their luminal surfaces (J. Clin. Invest. 91: 2653, 1993). This is evidently the target.

The histopathology begins with chronic inflammation (mostly portal, sometimes some interface hepatitis), and progresses through bile-duct obliteration and collateral formation to micronodular (why?) cirrhosis. For the details see Mayo Clin. Proc. 73: 179, 1998.

Less easy to explain are the frequent appearance of granulomas and Mallory's hyaline.

* Patients typically complain of severe fatigue, even early in the disease. One group attributes this to retained mangangese (Gut 53: 587, 2004).

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

{24568}    primary biliary cirrhosis, early; cirrhosis has not really developed yet, but portal areas are inflamed; you could not tell at this magnification that this is primary biliary cirrhosis
{24569}    primary biliary cirrhosis, histology (i.e., the bile duct is gone)

Primary biliary cirrhosis
Joel K. Greenson MD
U. of Michigan

Primary biliary cirrhosis Chronic inflammatory infiltrate WebPath

Anti-mitochondrial antibody Immunofluorescence WebPath

Primary biliary cirrhosis was found in the 1990's to be considerably more common than we had once thought, and to responds to therapy with bile salt analogues (nobody knows why; Br. Med. J. 312: 1181, 1996.)

* "Primary autoimmune cholangitis" looks something like primary biliary cirrhosis, but has high ANA titers and no anti-mitochondrial antibodies. See Am. J. Surg. Path. 18: 91, 1994; update on sorting out the autoimmune hepatitis family histologically Am. J. Clin. Path. 114: 705, 2000.

* IDIOPATHIC ADULTHOOD DUCTOPENIA is disappearance of the interlobular bile ducts; it may be asymptomatic (elevated GGT prompts its discovery) or pr