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Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected.

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Especially if you're looking for information on a disease with a name that you know, here are a couple of great places for you to go right now and use Medline, which will allow you to find every relevant current scientific publication. You owe it to yourself to learn to use this invaluable internet resource. Not only will you find some information immediately, but you'll have references to journal articles which you can obtain by interlibrary loan, plus the names of the world's foremost experts and their institutions.

Clinical Queries -- PubMed from the National Institutes of Health. Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites which may work well for you

Alternative (complementary) medicine has made real progress since my generally-unfavorable 1983 review linked below. If you are interested in complementary medicine, then I would urge you to visit my new Alternative Medicine page. If you are looking for something on complementary medicine, please go first to the American Association of Naturopathic Physicians. And for your enjoyment... here are some of my old pathology exams for medical school undergraduates.

I cannot examine every claim which my correspondents share with me. Sometimes the independent thinkers prove to be correct, and paradigms shift as a result. You also know that extraordinary claims require extraordinary evidence. When a discovery proves to square with the observable world, scientists make reputations by confirming it, and corporations are soon making profits from it. When a decades-old claim by a "persecuted genius" finds no acceptance from mainstream science, it probably failed some basic experimental tests designed to eliminate self-deception. If you ask me about something like this, I will simply invite you to do some tests yourself, perhaps as a high-school science project. Who knows? Perhaps it'll be you who makes the next great discovery!

Our world is full of people who have found peace, fulfillment, and friendship by suspending their own reasoning and simply accepting a single authority which seems wise and good. I've learned that they leave the movements when, and only when, they discover they have been maliciously deceived. In the meantime, nothing that I can say or do will convince such people that I am a decent human being. I no longer answer my crank mail.

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The business of liver testing is fraught with pitfalls. Learning objectives for this unit are limited to knowing this handout at the recognition level, and supplying the appropriate tests when you suspect a particular disease.

You will hear the following terms often used with respect to liver function testing:

Hepatocellular disease: The liver cells are hurt. Transaminases are up, more so than alkaline phosphatase. "Transaminasitis."
Your next step (you did your H&P already) will probably be...
• consider first simply discontinuing alcohol and such meds as you can, and repeating in 2 weeks;


• serum iron and iron binding capacity (and ? serum ferritin)


• alpha-1 antitrypsin


• anti-nuclear antibody


• serum ceruloplasmin (and ? urine copper)


• hepatitis B antigen and antibody


• hepatitis C antibody


• maybe a serum protein electrophoresis


• whatever test the future develops for non-alcoholic steatohepatitis (for now, perhaps ultrasound is best; I suspect this is the most common cause of "transaminasitis" except for boozing)


• while all the time you remember that many medications can also do this (today amiodarone, ketoconazole, the statins, glyburide, the NSAIDs, and isoniazid are infamous)



Cholestatic disease: The bile is not getting out of the liver. Bilirubin and alkaline phosphatase are up more than the transaminases.
Your next step (you did your H&P already) will probably be...
• sending the patient for ultrasonography to assess the bile ducts (to be followed by endoscopy if they are dilated)


• while you remember that many medications can also do this (anabolic steroids and some of the old phenothiazines are notorious)



Infiltrative disease: Something is growing in the liver and plugging some bile ducts, but bile still has other routes out of the liver. Alkaline phosphatase is up and it's clearly coming from the liver, but bilirubin is not up, and transaminases are probably normal also.
Your next step (you did your H&P already) will probably be...
• a biopsy; OR...


• a non-invasive workup to find whether this is sarcoidosis, TB, histoplasmosis, amyloidosis, or metastatic cancer (or something else more exotic, like brucellosis or an echinococcal cyst)


• and remember the medications which produce granulomatous hepatitis (allopurinol, carbamazepine, diltiazem, quinidine)



Immunologic disease: Any or none of the above, with something positive from the serology lab.

* Not to memorize just now:

Bilirubin, total... <1.5 mg/dL

Bilirubin, direct...<0.5 mg/dL

Albumin (serum)... 3.5-5.5 gm/dL

Globulin (serum)... 2.3-3.5 gm/dL

Alpha-1 protease inhibitor... >180 mg/dL

Aspartate aminotransferase (SGOT, AST)

adult men 8-46 U/L
adult women 7-34 U/L


Alanine aminotransferase (SGPT, ALT)

adult men 7-46 U/L;
adult women 4-35 U/L

Lactate dehydrogenase (adult) ... 100-190 U/L

Alkaline phosphatase (adult) ... 25-100 U/L

Anti-smooth muscle antibody ... <1:20

Anti-M2, anti-LKM1, anti-SLA ... none

Bilirubin

Terminology and assay:

"Direct bilirubin" ("conjugated bilirubin", fast van den Bergh reaction) consists of glucuronide, diglucuronide, and bilirubin bound covalently to albumin ("delta bilirubin").

The remaining bilirubin (i.e., the unconjugated component, "total" minus "direct")

The three mechanisms of jaundice:

(1) Hemolysis (all those causes of hemolytic anemia; also remember intramedullary hemolysis as in megaloblastic anemia and thalassemia, resorption of hematomas, red hepatization of lung, and lung infarcts): Increase only in unconjugated bilirubin, and seldom more than 6 mg/dL;

(2) Hepatocellular disease (injured hepatocytes cannot take up unconjugated bilirubin, and the small bile ducts between hepatocytes are disrupted): Increase in both unconjugated and conjugated bilirubin. Remember alcoholism, hepatitis A, B, C, D, autoimmune hepatitis, CMV, Epstein-Barr mononucleosis, drug effects (remember rifampin, isoniazid, methyldopa, and methotrexate; there are many others), ischemia (Ravel's "passive congestion"), ongoing necrosis (Ravel's "active cirrhosis"), and bacterial sepsis (don't miss this).

(3) Extrahepatic biliary obstruction (common duct stone, pancreatic head or common duct cancer): Increased conjugated bilirubin only. Remember that in renal failure, there is likely to be a mild increase in conjugated bilirubin (why?). (Note that occlusion of one of the two hepatic ducts will not produce jaundice, though it will raise alkaline phosphatase.) Any medication causing intrahepatic cholestasis will elevate conjugated bilirubin. If the kidney are normal, conjugated bilirubin will not exceed about 30 mg/dL (why not?).

NOTE: Having cited these three elegant mechanisms, I am almost sorry to have to add that the most common reason (by far) for an elevated bilirubin on screening is "Gilbert's non-disease", affecting 5% of humankind. Usually the non-problem is a mild allele at the Crigler-Najjar UDP-glucuronosyltransferase locus (Lancet 345: 958, 1995 -- like p53, the enzyme is a tetramer which needs 4 good subunits, which is probably why one bad gene out of two causes more than 50% reduction in activity). Only unconjugated bilirubin is elevated, and values seldom exceed 4 mg/dL. If this fits, and the reticulocyte count is normal, you're probably safe to assume Gilbert's non-disease is the non-problem. Of course, neonatal jaundice is a bit worse too (J. Ped. 132: 656, 1998; Pediatrics 103: 1224, 1999). If you must prove this patient has Gilbert's, a fairly specific test is that a 72 hour fast (<400 calories/day) causes the bilirubin to double. You already know that the thankfully-rare Crigler-Najjar syndromes feature partial or complete inability to conjugate bilirubin, with marked indirect hyperbilirubinemia.

NOTE: Two other non-diseases, Dubin-Johnson and Rotor syndrome, feature problems with the transfer of conjugated bilirubin into the bile, resulting in conjugated hyperbilirubinemia. In Dubin-Johnson, the liver is darkly pigmented too. Other liver function tests are normal in both non-diseases.

NOTE: Metastatic cancer in the liver produces jaundice only late, or with obstruction the common bile duct or both hepatic ducts.

Urine bilirubin and urobilinogen: Too insensitive for screening (Arch. Path. Lab. Med. 113: 73, 1989), and not particularly specific (but good enough to warrant an investigation if abnormal: South. Med. J. 81: 1229, 1988)

"Urine bilirubin" is of course conjugated bilirubin (glucuronide makes the molecule water-soluble). Why the urine of hepatitis patients is brown and foamy.

You are familiar with the metabolism of bilirubin into urobilinogen. (It's produced from bile in the gut, and the urobilinogen in the urine has been reabsorbed from the gut.)

If there's no urobilinogen in the urine, chances are it broke down on exposure to light or air, or the urine is dilute. If you suspect the patient has complete biliary obstruction (the other cause), ask about clay-colored stools instead!

Increased urobilinogen in the urine indicates excess bilirubin production (i.e., hemolysis) or failure of the liver to recycle urobilinogen (hepatocellular disease).

Alkaline phosphatase: a marker for poor bile flow

This enzyme, the real purpose of which (if any) is unknown, is induced in liver cells and appears in the bloodstream wherever there is backup of bile in any part of the biliary tree.

The enzyme takes several days to rise, i.e., if you have just impacted a gallstone in your ampulla, the "alk phos" (and the other obstructive enzymes) will be normal.

You are familiar with other sources of alkaline phosphatase. When liver (but not bone, placenta, or intestinal) alkaline phosphatase is elevated, leucine aminopeptidase, 5'-nucleotidase, and gamma-glutamyl transferase (transpeptidase; GGT; GGTP) will be generally elevated.

Ask the lab which assays are available. GGT has a reputation as a "drunk screen", since it tends to be up in people who take 3 or more alcoholic drinks per day; see below.

If these are normal and "alk-phos" is high on a screen, evaluate the patient for pregnancy or bone disease.

* Some labs are starting to pay attention to alkaline phosphatase isoenzymes, "slow" (AKA "fast", depends on the medium) fractions, etc., etc.

Elevated hepatic alkaline phosphatase suggests that at least some of the biliary tree are obstructed, i.e., that the patient has (1) extrinsic bile duct obstruction (tumor, common duct stone, sclerosing cholangitis) or damage (primary biliary cirrhosis, PBC), (2) hepatocellular damage sufficient to obstruct small bile ducts, or (3) a space-occupying lesion in the liver (usually metastatic tumor, but don't forget hepatocellular carcinoma, cholangiocarcinoma, abscesses, amyloidosis, fungal infection, echinococcus, sarcoid, or TB).

If you do primary care and order chemical profiles, you'll find plenty of people with isolated elevated GGT's. These people are likely to be "moderate" (3+/day) drinkers but the liver is unlikely to have serious histopathology (Br. Med. J. 302: 388, 1991).

NOTE: Don't confuse an alkaline phosphatase on a chemical profile with a leukocyte alkaline phosphatase. (* The latter, of course, is the histochemical stain for rapid differentiation of leukemoid reaction from chronic granulocytic leukemia).

Gamma-glytamyl transferase (GGT, GGTP, see above) deserves special mention here because of its abuse as "proof of alcohol abuse".

Several times each year, I have to write letters to correspondents who have isolated elevations of serum GGT's, which somebody considers to be proof that they are an alcoholic.

This is bunk. GGT does tend to rise early in problem drinkers, and is often the only 'zyme to be elevated. If the transaminases are high-normal, especially if the AST is around twice the ALT and the red cell MCV is a bit over 100 fL, I'd think we're most likely dealing with a drinker. But there are many other causes of high GGT, especially when there's no other reason to suspect alcohol abuse. People on barbs or phenytoin for seizure disorders often have elevated GGT's, and there's a familial trait (NEJM 330: 1832, 1994).

Transaminases: markers for hepatocyte integrity.

The bell-curves are highly skewed, with the vast majority of people below the middle of the "normal range".

Aspartate aminotransferase (AST, SGOT) leaks from injured liver, heart, or skeletal muscle cells or erythrocytes (less often kidney).

Alanine aminotransferase (ALT, SGPT) is more specific for liver. (* Warning: It's also less stable in blood samples: Br. Med. J. 301: 557, 1990. And there is ALT in muscle.)

• >10x normal

think of massive hepatic necrosis, hepatitis A, B, C, or D, unusually bad alcoholic hepatitis, really bad ischemia

• 2-10x normal

think of infectious mononucleosis (Epstein-Barr, CMV), chronic hepatitis (viruses B, C, or D; Wilson's (don't miss this one), autoimmune I, II, or III, many α1-protease inhibitor deficiency PiZZ), drug-related hepatitis, hypoxemia of the liver ("passive congestion"), recovering hepatitis, milder degrees of boozing, NASH, cocaine (? at least in mice, maybe people: Arch. Int. Med. 151: 1126, 1991), many cases of hemochromatosis (South. Med. J. 83: 1277, 1990; don't miss this one, either); people who JUST impacted a gallstone in the common bile duct

Remember that overweight people may have slightly elevated AST/ALT "on the basis of obesity".

• often normal

metastatic liver disease, amyloid, cirrhosis without any current cell necrosis (i.e., the currently-sober cirrhotic)

NOTE: A few of these diseases are ones you can actually treat effectively, i.e., Wilson's disease (remove the copper using penicillamine), drug injury (stop the drug), hemochromatosis (remove the iron by phlebotomy), & autoimmune chronic active hepatitis (* glucocorticoids and/or azathioprine). Treatment of chronic hepatitis B infection (interferon, etc.) and α1-protease inhibitor deficiency (recombinant protein) is less satisfactory but still worthwhile. And of course, "you are powerless over another person's drinking".

NOTE: While AST and ALT generally follow the same upward and downward courses in liver disease, ALT rises less in alcoholism.

The traditional wisdom is that this is because alcoholics have low levels of pyrixodine. However, both enzymes use pyrixodine, and most alcoholics are still eating. I think instead that the reason is that alcohol is especially rough on the mitochondria, which contain AST but not ALT. Stay tuned.

You will learn rules such as "ALT greater than 300 suggests that underlying problem is not alcoholism", "AST/ALT > 2 means alcoholism", etc.

NOTE: A common situation in clinical medicine is the isolated elevated AST (+ ALT) on screening. If your history and physical exam turn up no clue, one approach is to test the patient in 2-4 weeks off alcohol (the usual culprit) and medications, before proceeding to more expensive tests.

* Macro-AST (i.e., it does not clear because an autoantibody is attaced) has been reported.

NOTE: Lactate dehydrogenase fraction V comes from liver and skeletal muscle (the latter will often be accompanied by elevated creatine kinase MM). Its rise is as sensitive an indicator of liver disease as is the AST.

* Someday we may order glutathione S-transferase instead of transaminases in the acute-care setting, since it rises earlier (Arch. Surg. 135: 198, 2000).

Autoantibodies (Clin. Lab. Med. 12: 25, 1992)

Anti-mitochondrial antibodies cause primary biliary cirrhosis.

Among the dozen-or-so known anti-mitochondrial antibodies of human disease, anti-M2 (the main one; Hepatology 10: 247, 1989), anti-M4, and anti-M8 are almost completely sensitive and specific for primary biliary cirrhosis (Proc. Nat. Acad. Sci. 85: 8654, 1988; elegant review Gastroent. 100: 822, 1991).

M2 is the dihydrolipoamide acetyl-transferase component of pyruvate dehydrogenase, and other antibodies in PBC attack the homologous components of α-ketoacid dehydrogenase and other enzymes complexes (NEJM 320: 1377, 1989; Proc. Nat. Acad. Sci. 85: 7317, 1988); * they seem to attack the same auto-epitope (E2, where lipoic acid binds).

As you'd expect, biliary epithelium expresses the epitope on its surface (J. Clin. Inv. 91: 2653, 1993).

The old fluorescent assay on HEp-2 cells remain standard, but there are now ELISA assays. Update J. Clin. Path. 53: 813, 2000.

The antibodies actually inhibit function of the enzymes (J. Immunol. 141: 2321, 1988). Their titers correlate well with disease activity and prognosis (Gastroenterology 99: 1786, 1990). A monoclonal antibody that does the same thing (Scand. J. Immunol. 33: 749, 1991).

Clinical aspects of primary biliary cirrhosis: Med. Clin. N.A. 73: 911, 1989 (no discussion of basic biology). The disease is not rare, and is probably mild or asymptomatic in most cases (Scand. J. Gastroent. 24: 57, 1989).

* Perhaps it is triggered by rough strains of enterobacteriaceae: Lancet 2: 1166, 1988 ("molecular mimicry" again, since the bacteria have a similar epitope; of course, this can't be a whole explanation).

The presence of anti-smooth muscle antibodies OR anti-nuclear antibodies (either must be >1:40) are used to diagnose autoimmune ("lupoid" -- no real relationship to lupus) chronic active hepatitis type I.

So far, the antigen recognized by "anti-SMA" has not yielded up its mysteries like the others. Low titers are seen occasionally in other liver diseases.

* Many of these patients, and others which have similar clinical pictures but lack the defining antibodies, are positive for anti-ASPG-R (asialoglycoprotein receptor). This may define a disease soon.

* Splitters: ANA-negative anti-smooth-muscle antibody disease is now called "chronic active hepatitis type IV". Table:

Anti-liver kidney microsome 1 antibody (anti-LKM1) is the marker for autoimmune chronic active hepatitis type II (pediatric disease).

This turned out to be a group of antibodies against P450db1 antigen and its kin (J. Clin. Invest. 83: 1066, 1989; Immunol. Res. 10: 503, 1991), and the new test is apparently completely sensitive and specific.

* More LKM1 stuff: anti-HCV-negative patients have type IIa; anti-HCV-positive patients have type IIb. Hepatitis D patients have type III, which is antibodies against uridine diphosphate glycuronosyl transferase, another drug-metabolizer (Lancet 344: 578, 1994).

Anti-soluble liver antigen antibody is the marker for autoimmune chronic active hepatitis type III (Lancet 2: 292, 1987).

Autoimmune Chronic Active Hepatitis

Type I: Anti-smooth muscle antibodies (usually) & ANA


Type II: Anti-LKM1


Type III: Anti-soluble liver antigen


Type IV: Anti-smooth muscle antibodies, negative ANA

Other tests:

You will learn about prothrombin time (if long in the absence of a blood problem, reasonably specific for bad liver disease) and viruses (hepatitis A-D, CMV, EBV) in other units during the month. For hepatitis A, the IgM anti-hepatitis A antibody is always positive by the time there's jaundice. Hepatitis B surface antigen lasting more than 24 weeks after onset of illness means chronicity. Hepatitis D RNA and anti-HDV are needed to detect hepatitis D superinfection.

Hepatitis C:

You will screen needle-users and people with elevated transaminases. Remember that since cell loss in chronic hepatitis C is primarily by apoptosis, the transaminases are often normal. The screen is the enzyme-linked immunoassay, and confirm with RIBA and/or HCV RNA assay (the lab may do this automatically for you). If positive, you will follow up with HCV genotype.

The new HCV core antigen detects early infection before conversion, and can help monitor response to treatment (J. Clin. Micro. 39: 3110, 2001).

The PCR's are still troubled with false-positives and false-negatives (J. Clin. Vir. 27: 83, 2003); the enzyme-linked immunoassay for the antibody has long been infamous for false-positives (J. Clin. Micro. 41: 1788, 2003; Clin. Chem. 49: 479, 2003). If your antibody screen is positive but the PCR is negative, repeat in a month (Am. Fam. Phys. 69: 1429, 2004).

As you'd expect, some people who meet the virus rid their bodies of it, some never become sick, and some develop chronic liver disease (NEJM 327: 916, 1992). Seroconversion (i.e., antibody production) may take up to two years (NEJM 327: 910, 1992).

The confusion is compounded by the likelihood that at least some acute viral infections can trigger the chronic autoimmune hepatitis syndrome. Hepatitis A is implicated (Lancet 337: 1183, 1991); one group wants to exonerate hepatitis C (Arch. Int. Med. 151: 1548, 1991), another implicates it (Gastroenterology 106: 1672, 1994) etc. We can hope this gets unscrambled in the next few years.

Blood ammonia levels are usually, but not always, elevated in hepatic encephalopathy (depends on how much protein you have been catabolizing). This is best as a screen for people with altered mental status of unknown etiology.

Screening for hemochromatosis has been revolutionized by genetic testing.

The screen is still the transferrin saturation, i.e., total iron divided by iron binding capacity.

You remember that the most common gene gene is HFE, and the alleles to remember are C282Y (most severe) and H63D. You'll order a HFE genotype if the transferrin satuation is >45% or a close blood relative has known hemochromatosis.

For C282Y homozygotes or C282Y/H63D heterozygotes, get a serum ferritin and liver function tests. Current recommendations are to do phlebotomy-alone if serum ferritin is >300, and biopsy if serum ferritin is >1000 or transaminases are elevated. Practice guidelines JAMA 280: 172, 1998.

I predict these practice guidelines will change, with biopsy (which is expensive and a bit dangerous) giving way to labs and measures of empirical response to phlebotomy.

Of course, high transferrin saturation is also likely if the patient just popped a few iron pills (ask), or has been extensively transfused (you know), or has * TfR2-mutation hemochromatosis instead of the classic kind.

* In ferroportin-1 deficiency hemochromatosis, in which iron gets stuck in phagocytes, transferrin satuation is normal but serum ferritin is high and patients are sick.

* Liver biopsy in iron overload: Am. J. Clin. Path. 118: 73, 2002.

The old iron index depended on a liver biopsy. It was iron (micrograms per gram of dry weight)/(56 x age). Less than 1 supposedly meant alcoholism while more than 2 supposedly meant hemochromatosis. Think about this... isn't this largely just a measure of fatty change?

Ceruloplasmin is lower than 20 mg/dL in most cases of Wilson's disease. Also check urine copper (more than 100 micrograms in 24 hours). Remember that Wilson's is likely to present as a "psychiatric problem": Postgrad. Med. 95: 135, 1994, and it is notoriously impossible fully to rule it out using any single lab: Gastro. 113: 350, 1997.

Serum bile acids are a very sensitive indicator of hepatocellular disease.

Alpha-fetoprotein: Tumor marker for hepatocellular carcinoma; levels over 500 ng/mL are a reasonably specific indicator.

* Lower elevations are common in non-neoplastic liver disease with cell injury and regeneration.

* We can now distinguish the isoform for hepatocellular carcinoma from the kind seen at low concentrations in the serum of patients with benign liver diseases: Cancer 74: 25, 1994.

* Des-gamma-carboxy prothrombin (a PIVKA) is an much-used marker for hepatocelular carcinoma (why?). Mechanism: Cancer 74: 1533, 1994.

α-1 protease inhibitor (" α1-antitrypsin"): to detect patients in whom deficiency of this factor causes hepatitis and cirrhosis. WARNING: Patients who are deficient, but not totally lacking, can have normal levels during the acute phase reaction.

* Apolipoprotein A1 is advocated by a French group as a way of telling drinkers with cirrhosis from those without. The marker is reported to be high in non-fibrotic liver disease, low when cirrhosis supervenes (Gastroent. 100: 1397, 1991).

Other tests to see which drinker has cirrhosis may eventually include serum laminin, serum N-terminal procollagen III, and serum type VI collagen (Hepatology 15: 637, 1992). Among these, the N-terminal procollagen III has found a role as an alternative to liver biopsy in patients on methotrexate; so long as it remains normal, fibrosis is very unlikely (Br. J. Derm. 144: 100, 2001).