Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
 Home | Pathology Group MembersOur Hospital  Search This Website:
        Liver disease

Hepatobiliary Diseases

Case workups: "Transaminitis" and such as a serum ASMA level of 1:640 by IFA is not enough evidence to diagnose autoimmune hepatitis, being only serum chemistry and serologigical lines of evidence. Many lines of evidence must be considered in order to arrive at a working or presumptive diagnosis and later and with more evidence, a final diagnosis. Biopsies are one very strong line of evidence when properly interpreted, usually in light of the knowledge of status of several other lines of evidence.

Web Links:

Liver biopsy "heads up":

  • young patient & "bad" biopsy features: think Wilson's disease and AIH (document a normal serum copper level) [LMC-06-8934] & possibly cardiac sclerosis [L09-338] in a congenital heart patient.
  • abnormal liver or LFT history and biopsy looks "normal":
    1. think of (a) non-cirrhotic idiopathic extrahepatic "increased flow" portal hypertension (look for peripheralized portal triad venules & rule out splenomegally) and (b) look for evidence of congestion due to any etiology that will raise inferior vena caval pressure (tricuspid valve incompetence may give a pulsatile U/S flow pattern in the portal vein while constant congestion likely won't [L12-2959]).
    2. Look carefully for even rare acidophil bodies and/or some hepatocyte swelling [L09-1613].
    3. If is histologically normal (and an adequate study so that at least 5 portal tracts are seen), our report can assure against the presence of a number of causes of liver disease [L09-541].


  • Gastric emptying & GB function tests
  • Standard Hepatic Function (LFTs) info
  • Histology review
  • gallbladder disorders
  • medical liver issues
  • Hepatic tumors, masses, nodules:
    1. usually micronodular, miliary or microscopic:
      • benign:
        1. bile duct hamartoma
        2. cirrhotic nodularity
        3. infected Caroli's nodular fibro-polycystic liver [LMC-00-4308]
      • malignant:
        1. metastatic malignancy
    2. usually bean-sized or larger (macroscopic):
      • benign:
        1. hemangioma
        2. hepatic adenoma
        3. focal nodular hyperplasia (FNH)
        4. lymphoid hyperplasia (pseudotumor)
        5. cirrhotic nodularity
        6. focal fatty change (can also occurr in adenoma, FNH, and HCC)
      • malignant:
        1. metastatic malignancy
        2. hepatoma (hepatocellular carcinoma...HCC) [need to detail the size, grade, mitotic rate, and margins...LMC-01-6453].
          • hepatoma, NOS
          • fibrolamellar HCC
            1. clear cell variant
        3. cholangiocarcinoma
        4. intrahepatic biliary cystadenocarcinoma
        5. malignant lymphoma
        6. sarcoma
        7. primary malignant melanoma [LMC-02-5801].


  • Benign:
    • gallbladder (GB)16 disease & cholecystodynia causes: Murphy's sign by physical exam is when the examining hand is pressed gently beneath the right subcostal margin at the time of respiratory expiration & then causeing pain there upon inspiration, while sonographic Murphy's sign is pain elicited as the sonographic probe presses over the GB. Something similar is reproduction of the patient's pain complaint when CCK is injected during the HIDA scan. The cystic duct node is sometimes within the hepatobiliary triangle (cystohepatic triangle; Calot triangle) and then called "Calot or Calot's node (or Lund's node) [L11-4284].
        • cholecystitis without stones: see below.
        • incidental mucosal dysplasia or malignancy, see below.
        • cholelithiasis (presence of, or imaging history of, stones, grit, sludge...grit-cholelithiasis or micro-cholelithiasis [L13-7641]) and cholecystitis (acute, subacute, chronic inflammation). Any of these agents might be "seen" on ultrasound & not be appreciable in the grossing room exam. The muscular layer in routinely 10% NBF fixed GB is about 0.2 MM & clearly thick when over 0.4 MM [L09-3908].
          • standard chronic:
            1. usual:
            2. chronic: with stones; or without (acalculous...may see thickly inspissated bile) stones; may include extramuscular liposclerosis or scleredema thickening.
            3. subacute: eosinophiles ; extramuscular stromo-vascular thickening.
            4. acute: suppurative, necrotizing, or gangrenous.
            5. xanthogranulomatous cholecystitis: thick & with visible yellowish histiocytic zones, likely arising from a background of hyperplastic cholecystopathy with rupturing of an element.
            6. ***hyalinizing cholecystitis or cholecystopathy: non-thickened paucicellular fibrous GB walls (about a 1.6% of GBs). Remarkable percentage of occult cancer in these cases22!
            7. calcified gallbladder (a type of potentially clinically palpable "Courvoisier gallbladder")...porcelain
          • cholelithiasis limited to A/R sinuses: when the GB is involved by Rokitansky-Aschoff sinusosis (below), those diverticulae can become filled with calculi, with or without complicating inflammation [L11-14615].
        • cholecystopathy or cholecystosis (chronic acalculous gallbladder disease; pericholecystitis21): advances in radiology with ultrasound and nuclear medicine HIDA scans have advanced the knowledge of GB disease greatly since 1980. Therefore, a pathologist can focus the pathology gross & micro exam greatly by checking any readily available preoperative imaging studies & the operative note.
          • surgeon removed the stones: the GB comes to the lab with some sort of opening & the operative note will never state that the surgeon removed the stones to show to the family [L09-3832]; or,
          • stones were spontaneously passed: in the interval between imaging demonstration of small stones, the patient can pass them unbeknownst to anyone [L09-3832].
          • preop imaging showed a lesion: but, lesion (such as polyp) not found, yet (1) GB has inflamation [L12-1016] vs. (2) does not have inflamation.
          • sludge was demonstrated preoperatively by imaging [L11-14538]. I find this to be false positive info fairly frequently in that pathology can't appreciate the sludge.
          • abnormal kinetic function IS demonstrated: (decreased or increased ejection fraction by HIDA scan) & usually little or no histological chronic inflammation but may see A-R sinuses and some muscular thickening = "dyskinetic cholecystopathy" [L09-470] which may take years to form and less likely when young patient & lesser sum of dyskinetic years [L09-2497]. Hypokinesis is usually assumed to be due to "cystic duct syndrome" wherein the duct constricts rather than relaxing when the GB squeezes & emptying graph blunt and percentage expelled less than 35%. Hyperkinesis with pain reproduction may simply squeeze too fast (peaked emptying graph) for the duct to accomodate [L12-5421; L13-266; L14-3604] & reproduce the pain = hyperkinetic cholecystopathy (percentage emptied over 80%...usually over 85%). But couldn't adhesion plications or deposits such amyloidosis or other deposits or diabetic neuropathy effects cause dyskinesia?
          • abnormal function IS NOT demonstrated (HIDA scan normal but not really high ejection fraction) & no histological chronic inflammation [L08-13447] but may see A-R sinuses and some muscular thickening. This might mean that there is distal common bile duct spincter of Oddi spasm if the GB ejection was normal but contents don't follow into duodenum.
          • everything histologically & kinetically normal: with good & high HIDA ejection fraction...but (1) not too high & (2) no pain reproduction = doubtful cholecystopathy. Surgery may have found another etiology for pain and the GB incidentally removed because it did not appear to be perfectly normal [L09-596]. Really concentrated, thick bile might result in poor function in vivo even though CCK test was normal [L09-2253 "thick bile dyskinesia"]. Otherwise, being all normal, one might warn surgeon, et. al., in your report to think of hereditary angioneurotic edema if episodes of N&V are prominent (HAE) [L12-3454], cholecystodenia-like fatty-liver-associated abdominal pain, non-cutaneus "shingles" (VZV) neuropathy, or acute intermittent porphyria (AIP) [L09-266]. Or, surgeon might have even repaired (without alerting the pathologist) such an occult cause of pain as some occult abdominal wall or internal incarcerated hernia [L09-3762] or taken down pericholecystic adhesions between such as omentum, stomach, or colon [L12-1168] (adhesions = see below).
          • hyperplastic cholecystopathy (radiological term: hypertrophic or hyperplastic cholecystosis):
            1. cholesterolosis, polypoid.
            2. Rokitansky-Aschoff (or Aschoff-Rokitansky) sinusosis: the GB wall may seem grossly unremarkable or be distorted by grossly visible, multiple A/R sinuses (GB diverticulosis) to the point that at least some of the GB wall seems thickened, even prominently thickened (localized, segmental, diffuse), even with one or more intra-diverticular calculi.
              1. localized:
                1. adenosis: incidental focal mucosal adenosis [L08-11597; L09-470].
                2. adenomyoma: (usually in fundus & has increased smooth muscle) admixture of benign A-R-sinus epithelium & smooth muscle [LMC-05-6849] forming a plaque; can centrally ulcerate [L09-1778].
                3. sinusosis: hyperplasia of intramural A-R sinuses without (1) grossly easily discernible mural thickening or with (2) significant smooth muscle participation [L13-2300, with one intra-AR calculus]. It can be focal, multifocal, and from mild to extensive. Can be diverticulosis. Sinusosis & adenomyosis CAN look infiltrative & even be in perineural spaces23; can give a positive PET scan when there is much inflamation24; has very low Ki67 proliferation and negative p53 [L13-2300].
              2. adenomyomatosis (adenomyosis): from mural grossly "normal' to mural thickening and very prominent Aschoff-Rokitansky...Rokitansky-Aschoff...sinuses [A-R sinuses]) [L07-324; L07-1966]; A-R "sinus" formation with patterns from pseudoinfiltrative (chlocystitis glandularis proliferans) to mucosal herniations or diverticuli prominent enough to be seen by preoperative ultrasound as a "comet tail defect" when stones in sinuses & "pearl necklace gallbladder" by oral cholecystogram (...a reflection of chronic cholecystitis and GB dyskinetic function. The sinuses can contain calculi; ruptures may be the etiology of xanthogranulomatous cholecystitis. Sinusosis & adenomyosis CAN look infiltrative & even be in perineural spaces23; can give a positive PET scan when associated with much inflamation24; has very low Ki67 proliferation and negative p53 [L13-2300].
                1. segmental adenomyomatosis.
                2. diffuse adenomyomatosis.
            3. metaplasia: pyloric or mucinous; intestinal (to include Paneth).
            4. papillary hyperplasia: highly velvety mucosa due to mucosal elongations (can be focal, segmental, diffuse).
          • adhesive cholecystopathy: these cases can only be appreciated by the pathologist if he/she reads the surgeon's operative note. They may be hepatocholecystic or connected to many other different areas/organs. As the gallbladder contracts, it tugs the adhesions and causes pain (cholecystodynia or cholecystalgia); in the absence of another etiology, this is a clinically recurring abdominal pain problem due to cholecystodyniogenic (cholecystalgiogenic) adhesions [L13-9153]. On the other hand, if the CCK test did not reproduce the pain, but adhesions were found, there are likely coincidental [L13-9538] & may not be problematic.
          • pericholecystitis/pericholecystic metastatic disease: gallbladder removed from within or on the edge of other pathology, such as perforated ulcer[L12-2489].
        • shape abnormality: Phrygian cap (of distal body...area bulges or protrudes & folds slightly like a broad diverticulum due to a mural/mucosal fold).
        • adenomatous change: unifocal or multifocal, incidental truly adenomatous change of mucosa [LMC-02-3532; L12-15511].
        • mucosal papilloma.
        • polyps: cholesterolosis polyps (range from 1-5mm); inflamatory polyps; metaplastic polyps [L12-9976]; villous papilloma; adenoma; granular cell tumor; adenomyoma.
        • mucosal lymphoid hyperplasia: lymphoid follicular cholecystitis [L14-3503].
        • Mucocele: cystic duct obstruction so complete & chronic that GB distended with mucous.
        • calcification: murally calcified porcelain gallbladder ("Courvoisier gallbladder"); sometimes focal or zonal [L13-2924].
        • heterotopia (ectopic, ectopia, choristoma): normal tissue in abnormal location...gastric, pancreatic nodule [LMC-07-361], hepatic, thyroid, adrenal cortical.
        • duplication: this can be as an apparent diverticulum or as an additional GB that might get left behind and lead to what appears to be a bile pool or abscess...biloma [L14-2962].
        • ciliated foregut cyst.
        • cystic duct lymph node enlarged: this may be due to nonspecific hyperplasia, sarcoid, lymhoma, metastatic carcinoma or oleogranulomatous lympadenopathy [L09-3729].
  • uncertain biological behavior:
      • carcinoid,typical: a 3 mm incidental (surgery & pathologist) cystic duct carcinoid in 79 y/o female [LMC-02-2548]. Oddities, below.
  • malignancy (all biliary adenocarcinomas arise via a "field effect"12):
      1. gallbladder or cystic duct adenocarcinoma: 8 mm in distal cystic duct arising in accessory glandular "saccules of Beale" in 50 y/o male[LMC-98-956]; resect and radiate13,14. Found (several times a year in our practice) in routine cholecystectomy specimens [L12-11982].
      2. psuedocarcinoma "picture": sinusosis & adenomyosis CAN look infiltrative & even be in perineural spaces23; can give a positive PET scan when there is much inflamation24; has very low Ki67 proliferation and negative p53 [L13-2300].
      3. common bile duct adenocarcinoma:
        1. proximal = Klatskin tumor [T-06-182]
        2. distal
        3. ampulla of Vater
      4. malignant carcinoid: some can be pigmented (1.1 cm melanin-containing carcinoid of common duct in 48 y/o husband of our employee).
      5. adenoendocrine carcinoma (mixed exocrine endocrine; amphicrine; adenocarcinoid mixed endocrine/exocrine, adenocarcinoid, or amphicrine carcinoids) and have H&E & IHC features of both epithelilal and neuroendocrine cells in same cells): worse actor than pure neuroendocrine tumor. Tumors composed of a mixture of endocrine and exocrine cells have been recognized especially in the digestive tract15.


      • BENIGN:
      • MALIGNANT:
        • carcinoma:
          • hepatocellular:
          • biliary:
            • pure cholangiocarcinoma:
            • cholangio with intrahepatic nodules vs. met. adenoca. [CN09-12].
          • metastatic malignancies:
        • lymphoma:
        • sarcoma:


    • Histological patterns or markers:
      • biopsy processing & stains
      • lobule: [...especially in a younger person [L07-8934], liver disease without fairly easy diagnosis: think of Wilson's disease (diagnose with Kayser-Fleisher ring... a rusty brown ring around the cornea of the eye that can best be viewed using an ophthalmologist’s slit lamp; and by a heavy metal analysis of serum specimen for "serum free copper level" or quantitative tissue copper level from liver biopsy, and by finding low levels of serum ceruloplasmin (< 20 mg/dl)]. And, for a patient wanting to track therpeutic response, plug values for serum copper, ceruloplasmin, & non-ceruloplasmin [free] copper using the The Wilson's Disease Patient Lab Tracker.
        1. hepatocytes:
          • whole cell:
            1. acidophile body: necrotic dense shrunken hepatocyte with pyknotic nucleus or no nucleus; were called a Councilman body in days of yellow fever (and contained tiny fat droplets and ceroid pigment). Biopsy done for abnormal LFTs & not much change, look hard for these [L09-1613].
            2. atrophic hepatocytes: centrilobular sinusoidal dilation due to increased systemic venous pressure [L08-13713].
            3. apoptotic body: fragment of an acidophile body.
            4. microhepatocytes: on an FNA cell smear are strongly indicative of hepatoma.
          • nuclear:
            1. inclusions:
            2. atypical nuclei:
              • reactive anisonucleosis: notable nuclear and cell size variation.
              • cirrhotic dysplasia: more pronounced than reactive variability.
              • multinucleation:
          • cytoplasmic alteration:
            1. generally in the cell:
              • ballooning degeneration: swollen hepatocytes which are relatively pale and are edematous (viropathic ballooning of viral hepatitis), have ground-glass change (see below), feathery degeneration when due to cholestasis, or "hydropic" or "foamy cell" change (which can be very spotty & subtle & "callable" at that mild stage when ALT only a couple hundred & no other real findings [L09-1613]) when due to other injuring or damaging insults. Fatty foamy change may look very similar.
              • ground-glass change:
                1. acquired immunodeficiency syndrome (oncocytes)
                2. cirrhosis (alcoholic or hep. B or C...oncocytes)
                3. drug-induced cholestatic hepatitis or drug hepatopathy (induction cells): the endoplasmic reticulum is hyperplastic to amplify enzymes available to deal with the steroids/drugs...can look a little like Golgi enhancement [LMC-04-4500]
                4. fibrinogen storage disease
                5. glycogen storage disease, type IV
                6. hepatocellular ca. (fibrinogen or hep. B virus)
                7. progressive familial myoclonic epilepsy (Lafora bodies)
                8. viral hepatitis B cells 
              • storage diseases:
                1. hemochromatosis: it is clearly possible to have genetic hemochromatosis, yet liver biopsies be only slightly positive (low/mild iron burden) in the hemochromatosis pattern of hepatocyte cytoplasmic positivity (rather than predominately in macrophages.
                2. cholesterol ester storage disease
                3. phospholipids of drug-induced induction cells
                4. Fabry's disease (glycosphingolipid)
                5. fibrinogen storage disease (fibrinogen)
                6. fucosidosis (glycolipid, glycoproteins, other metabolites)
                7. incidental, focal hepatocellular glycogen deposition
                8. hepatocellular ca. (fibrinogen)
                9. I-cell disease (mucolipid)
                10. mannosidosis (alpha-D mannose)
                11. Mauriac's syndrome (diabetic steatohepatosis): childhood diabetic dwarfism with hepatosplenomegally.
              • Mallory bodies: see with drugs (amiodarone) and alcoholic, etc., and high-light with IHC for CK8 or ubiquitin.
              • megamitochondria:
              • pigment:
            2. serum markers: ALT (SGPT); ornithine carbamoyltransferase; sorbitol dehydrogenase; LDH (liver ischemic necrosis marker); albumin (produced solely in liver); prothrombin time is functional marker of severity6.
          • lobule (hepatocytes as groups):
            1. hepatocyte cell change:
              • feathery degeneration: cholestatic ballooning, see above.
              • foamy cell change: fatty ballooning, see above.
              • syncytial change (poor cell membrane definition) of hepatocytes: alcoholic hepatitis.
            2. hepatocytic cells necrotic:
              • bile infarct: alcoholic hepatitis; ascending cholangitis in a cirrhotic [LMC-05-6894].
        2. cannaliculi:
          • plugged with bile...cholestatic jaundice:[LMC-04-4500...steroids].
          • duct of Hering particularly dilated, to point of almost small bile lake (porto-lobular cholestasis) & some ductule proliferation chemotacting polys even barely into lobule...TPN-associated cholestasis [L07-3345].
        3. sinusoids: 
          • acute congestion & maybe even evidence of thrombosis: acute Budd-Chiari syndrome [LMC-02-23; FA08-157] (classical presentation is of abd. pain, ascites, fever, & splenomegally); chronic in a case of extramedullary hematopoiesis [LMC-04-11140].
          • dilation: increased (1) general systemic right-sided or (2) focal (space occupying lesional [e. g. mets, L13-14894]) intrahepatic venous pressure (may cause U/S pattern of coarsened echotexture), see VOI, below, gives dilation of central sinusoids (due to hepatic vein, IVC, incompetent cardiac valves, right heart failure [L08-13713], constrictive pericarditis...anything that increases venous pressure from central vein into hepatic lobule [L12-2959]). A review of the hepatic ultrasound can (1) confirm correct portal flow direction and (2) detect pulsatile flow of incompetent tricuspid valve as the cause. BUT, appearing dilated can also be due to general hepaticytic atrophy due to portal vein or hepatic artery insuffciency18! Some toxic or medication effect can cause a pre-pelosis like central dilation. AND, a cautery-biopsy thermal artifact can cause angioma-like dilations17 due to hot vapor bubbles irregularly dissecting the sinusoids and incompletely lined by reticulin and not lined by endothelium...and may even seem to contain some type of lumenal matter [L07-2170].
          • perivenular sinusoidal collagen or reticulin deposition in post jejunoileal bypass for obesity: this also has macrovesicular fatty & portal tracts & septae may have polys & lymphs. When extramedullary hematopiesis induces increased hepatic blood flow, may get sinusoidal fibrosis [LMC-04-11140; L11-12010] which can lead to portal hypertension. Reticulin stain needed to ascertain.
          • CBC peripheral blood smear:this may show atypical or even CLL-type lymphocytosis which may or may not [L07-1938] be appreciable in the liver biopsy & may reflect current or waning EBV or CMV (which had caused "elevated LFTs".
          • lymphocytosis: EBV, HCV, CMV [LMC-77-2430; LMC-79-2489; LMC-03-7591; LMC-03-8574; ?LMC-04-106], CLL
          • macrophage-rich inflammatory infiltrates: think of rickettsia-like infections
          • metastatic ca.: especially small cell lung ca. [LMC-84-3358/9; LMC-03-7065]
          • extramedullary hematopoiesis: [LMC-03-8574]
        4. sinusoidal lining cells:
          • d-PAS stain: if single or clusters of lining cells contain positive, fine granules, this is a sign of hepatocyte necrosis within the past 6 months
        5. Ito cells: these sinusoidal cells in space of Disse become prominent in hypervitaminosis A and PBC4; if you can see them (whether nuclei are pressed into stellate shapes or not), it is "prominence" of Ito cells.[LMC-97-4366; LMC-04-4500]
      • central:
        1. vein (lesions cause venous outflow impairment...VOI): 
          • thrombosis: Budd-Chiari [LMC-02-23, above] (check for some type of hypercoagulable syndrome) is appelation for more of an extrahepatic or large caliber thrombosis..."veno-occlusive disease" for smaller-vessel lesions. Many cases have quite elevated alk phos & GGT and some portal changes suggestive of chronic bile duct disease9.
          • fibrosis:
            1. perivenular sinusoidal collagen deposition in post jejunoileal bypass for obesity: this also has macroves. fatty & portal tracts & septae may have polys & lymphs.
        2. lobule:
      • portal:
        1. connective tissue profile: watch out for amyloid deposits causing relatively acellular portal profile expansion and/or portal arteriolar enlargment [A11-13].
        2. bile ducts:
        3. vein: is typically fairly small, in center of triad, and not dilated. Banti's syndrome, in a broadest sense, is any case of splenomegally not due to (1) large caliber thrombosis of the hepatic vein or (2) cirrhosis.
          • extrahepatic lesions:intraluminal vs. extraluminal lesions; usually no change in liver
          • intrahepatic lesions: idiopathic portal hypertension...non-cirrhotic portal hypertension (due to wide variety of causes, one specific but poorly understood cause being hepatoportal sclerosis [HPS]...increased reticulin sinusoidal fibrosis). HPS is hard to diagnose on needle biopsy, but you may note portal triad peripheralization of triad vein, thickening of portal venule, corrugation of vein profile, dilation of vein profile, or subdividing of vein profile as if a thrombus was recanalized. When dilated & maybe complex, the presence of terminal bile ductule lets you know that you are looking at a portal triad. As opposed to cirrhotic portal hypertension, that due to HPS tends to retain plenty of parenchymal functional reseerve; is apparently irreversible; check patient for thrombophilic hypercoagulation (some think this may be part of the etiology).[S04-4874]
        4. artery: being adjacent to bile duct and/or as "naked arterioles" may indicate ductopenia; look for amyloidal thickening [A11-13].
        5. cells:
          • macrophages:
            • if contain d-PAS positive granules, may reflect hepatocyte necrosis within past 6 months
            • granulomata: see sarcoid and fibrin-ring & other photos & granuloma info @ Dr. Yale Rosen's website.
          • lymphoid: heavy lymphoid, especially when forms lymphoid nodule (Poulsen lesion), brings up PBC5 & HCV.
          • plasma cells: when seen, these bring to mind AIH or a mixed etiology with an autoimmune component. When serologies are negative, autoimmune features are not ruled out; but sero-negative AIH [L10-11828] can can be addressed by an analysis of the factors HERE.
          • eosinophiles: these bring to mind a drug reaction component.
          • polys: in bariatric post-bypass cases, see above; any time there is bile ductule proliferation; medication induced; ascending cholangitis; ascending pericholangitis, infectious [L06-2862] or metastatic tumorigenic induction [L13-14894].
    • Inflammatory disease:
      • viral:
        1. hepatitis A (HAV):
        2. hepatitis B (HBV):
          • vaccination: even if serological test becomes "negative" over the years (as of 1/2002), one is considered to have lifetime immunity if a positive antibody response to vaccination was ever demonstrated.
        3. hepatitis C (HCV):
          • Poulsen lesion (portal lymphoid nodule...especially with biliary duct in center) [LMC-03-3712; LMC-03-6375 HCV neg.]
          • 70% of USA cases are HCV-1, only 30% of which respond to interferon (whereas 65-70% of HCV-other respond) 
          • hepatitis C blood tests work-up rationale
          • HCV can present with elevated ALT, cryoglobulinemia, membranoproliferative glomerulonephritis, and PCT.
        4. hepatitis D (has to have hepatitis B with it)(HDV):
        5. hepatitis E (HEV):
        6. CMV hepatitis
        7. HHV6 (can even be fulminant)
        8. parvovirus B19 (almost never jaundiced)
      • uncertain mechanism:
        1. primary sclerosing cholangitis (PSC):
          • clinical: chronic cholestatic situation, mostly in chronic ulcerative colitis patients
          • serological: usually distinctive marker
          • histology: there is the classical disease; and the small-duct variant may be impossible to distinguish histologically from PBC; may need to use ck7 and ck19 to hunt residual cholangiocytes
        2. secondary sclerosing cholangitis: usually due to lesions obstructing (or "low flow") vascular flow to biliary tree [LMC-03-5668]
      • autoimmune (spectrum)...(AJCP 114:705-711, 11/2000):
        1. vs. biliary cells: nonsuppurative destructive cholangitis (florid duct lesion)...
          • PBC (primary biliary "cirrhosis"):
            1. clinical: middle-aged females; cholestatic
            2. serological: AMA titers high in >90% [LMC-01-2794; LMC-02-4906; LMC-02-5844] There can be AMA negative PBC [LMC-03-4430]
            3. chemical: significant elevation of alk. phos., elevated IgM
            4. histology:  bile duct loss (50% or greater of portal tracts lack ducts); may see Poulsen lesion19[L07-2104]; 80% of cases with small granulomas; heavy portal cellularity and cells involve duct epithelial interface...duct injury ("florid duct lesion")...may need to use ck7 and ck19 to hunt residual cholangiocytes; periportal hepatocytes may be swollen and contain copper.
          • AIC (autoimmune cholangitis [immunocholangitis; autoimmune cholangiopathy; PSC]):
            1. clinical: like PBC but neg. AMA [S-04-4874; L08-3230]
            2. NASH: there can be apparent biliary changes within portal chronic inflammation that is apparently just part of the NASH process.
            3. serological: high ANA; sometimes p-ANCA pos.; neg. AMA; may also have positive ASMA [L-04-10922; L06-2337]
            4. chemical: slight ALT (SGOT) increase
            5. histology: nonsuppurative destructive cholangitis; 70% with granulomas; bile duct lesions and ductopenia; lower grade fibrosis than PBC; may need to use ck7 and ck19 to hunt residual cholangiocytes
          • overlap syndrome of PBC & AIH (OLS...a hepatitic variant of PBC):
            1. clinical: ; it is possible to have serological "overlap" with disproportionate or negative corresponding histological overlap [L08-3332]; overlap is in 20% of patients with autoimmune liver disease5, criteria:[LMC-02-4640] ...
              • 2 of 3 PBC features (pos. AMA, florid duct lesion, AP 5x uln)
              • 2 of 3 AIH features (pos. ASMA, severe interface cellularity, ALT 5x uln, serum IgG 2x uln)
            2. serological: high ANA [homogeneous]; pos. AMA
            3. chemical: significant ALT elevation
            4. histology: ;45% with granulomas.
          • idiopathic adulthood ductopenia:
        2. vs. hepatocytes: autoimmune hepatitis (AIH):
          • AIH first described in 1950s as "lupoid hepatitis" because had pos. ANA
          • usually insidious; rarely acute
          • selective elevation of serum IgG when pure etiology
          • as many as 20% present (2005) without currently known & detectable auto antibodies (ANA, ASMA, anti-LKM-1, p-ANCA) [LMC-04-6010].
          • ASMA can be significantly elevated in other situations.
          • at least 24 medications are implicated as drug-induced AIH.
          • IAIHG 1999 report, formula to calculate whether AIH (J. of Hepatology 31:929-938, 1999)
          • AIH type I:
            1. clinical: young or middle-aged females
            2. serological: strong titers ASMA, or ANA, or both [LMC-02-747]; ASMA (anti-SMA) & ANA (anti-nuclear antibody) can be negative but should have positive anti-SLA (soluble liver antigens), p-ANCA, and/or anti-ASGP-R (asialoglycoprotein rector).
            3. chemical: significant ALT (SGOT) elevation; serum gamma globulins elevated.
            4. histology: prominent piecemeal & confluent lobular injury; <10% granulomas; portal plasma cells and eos.
          • AIH type II2:
            1. is liver-kidney microsomal antibody positive AIH (usually > 1:320) ; if not positive, then anti-LC1 (liver cytosolic protein type 1) should be positive (and/or anti-SLA and/or anti-GOR) but ANA & ASMA negative20.
            2. reported in 1987 & common in southern Europe; rare in northern Europe and USA
            3. commonly HLA DR4 common
            4. an aggressive, poorly responsive variety of AIH
            5. attacks at young age, female, usually no other auto-Abs except maybe low titer ANA (may be "fine speckled"), often associated with other autoimmune disorders
              • if associated IgA deficiency, poor candidate for liver transplant
          • AIH type III:
            • is AMA and SLA positive, maybe with ASMA but not ANA or LKM20.
          • AIH type IV:
            • is mostly children with high ASMA but negative for SLA or AMA20.
      • toxic:
        1. alcoholic hepatitis
      • reactive: such as in association with an episode of acute pancreatitis where you see a few portal lymphocytes, eosinophiles, and polys [LMC-03-3790]
      • medication:
        1. acetaminophen (Tylenol) toxicity: central necrosis with prominently elevated ALT & LDH [FA-95-36; A97-15; A-80-518].
        2. old tetracycline: microvessicular fatty liver.
        3. methotrexate [grading the injury].
        4. minocycline: "hepatitis", AIH & otherwise; as a tetracycline like med, possibly microvesicular fatty change [L07-8935].
        5. Lovastatin: hepatocellular injury.
      • bacterial:
        1. acute ascending cholangitis: polys in biliary lumen or epithelium (biliary tract infection)
        2. acute ascending pericholangitis: polys in portal tracts (abdominal infection...or inflammation...with lymphatic spread up the portal lymphatics: from PID, UC, etc.) [LMC-05-6894]; polys can be induced into the area by tumor mmetastases [L13-14894].
      • fungal:
      • parasitic:
        1. amebic abscess (ameba hist. serology should be positive)
    • Storage or metabolic disease:
      • hemochromatosis (obvious on iron stain): when significant numbers of hepatocytes have granular positivity...whether heavy or not (whether low or high iron load or not), genetic hemochromatosis is possible, and the finding is grounds for genetic testing [L07-6489]. The serum iron profile is used to interpret the total body iron status. Heavy metal analysis of quantitative iron in the liver biopsy can help (Mayo Clinic.
      • alpha-1 antitrypsin deficiency (visible with d-PAS stain...sometimes H&E and round globules)[LMC-03-2385; LMC-04-7655; LMC-05-7512]
      • NAFLD/NASH: fatty liver whether it is macrovesicular or microvesicular or even so fine-calibre as to be "foamy degeneration " (a nomenclature pigeon-hole implying "fat" & lumped in the broader category of ballooning degeneration of hepatocytes [L-06-6796]); seen in people of normal weight but mostly in the overweight & needs management to prevent progression to cirrhosis; "non-alcoholic fatty liver disease "/"non-alcoholic steatohepatitis " = (1) NAFLD, simply a fatty liver; (2) NASH, a fatty liver which also has a little on-going injury of liver cells. If no evidence of hepatocyte injury (no elevation of ALT & few or no d-PAS fine-granule-positive sinusoidal or portal macrophages) = non-alcoholic steatohepatosis. An important cause of presence of fat in the liver is the atherogenic "metabolic syndrome" 25(central obesity, hypertriglyceridemia, increased insulinemia due to insulin resistance, below normal HDL cholesterol resulting in (1) CVD, (2) increased sympathetic vascular tone (HTN), (3) renal sodium retention (HTN), (4) a low grade thrombophilia due to tissue inflammatory injury (increasing hs-CRP), (5) renal uric acid retention (sometimes first discerned in surgical pathology exam of joint tissue), (6) polycystic ovaries, (7) acanthosis nigricans, and (8) hyperadrogenism.  Brunt grading.
        1. An interesting web site and another
        2. AST:ALT ratio usually <1.06
    • Clinical presentations:
      • portal hypertension or cirrhosis workups ("portal venopathy"17):
        1. cirrhosis associated: pretty obvious on biopsy.
        2. non-cirrhosis associated 8 (peripheralized triad venule and maybe zones of heaptocyte atrophy17):
          • pre-sinusoidal causes increased pressure/obstruction: portal venule problems which either (1) "restricted flow" (prehepatic, intrahepatic, or posthepatic) or (2) "increased flow" due to noncirrhotic splenomegally or some type of aterio-portal shunt (likely to only see peripheralized triad venule [LMC-07-389]). Increased flow due to extramedullary hematopoiesis causes sinusoidal fibrosis which leads then to restricted flow [L11-12010].
          • sinusoidal causes increased pressure/obstruction:
          • such as amyloidosis or fibrosis (HPS)[L-04-11140; L11-12010].
          • post-sinusoidal (central) causes increased pressure/obstruction: largely cardiac failure or hepatocaval thrombosis which produce increased right-sided caval venous pressure [L12-2959].
      • clinically jaundiced:
      • clinical hepatitis:
      • incidental discovery elevated liver function tests:
      • patient presents in coma:



  1. Ludwig & Batts, Practical Liver Biopsy Interpretation, 2nd Ed., ASCP Press, [Mayo Clinic pathologists] 1998.
  2. LKM-Positive AIH in the Western US: A Case Series, Scripps Clinic,  A. J. Gastroent. 95(11):3238-3241, 2000.
  3. International Autoimmune hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis, Journal of Hepatology 31:929-938, 1999.
  4. Frank Mitros' web at top of this page
  5. Pathology of the Liver, 4th Ed., 2002, MacSween, et. al.
  6. Burke, MD, "Liver function: test selection and interpretation of results", Clinics In Laboratory Medicine, 22:377-390, 2002.(EBS's office)
  7. Snover Dale C., "Liver Pathology", morning workshop, 11th Annual "Seminar in Pathology", Pittsburgh, April 28-May 2, 2004.
  8. Roskams T, et. al., "Histopathology of Portal Hypertension: a Practical Guideline", Histopathology 42:2-13; January 2003 (EBS's office).
  9. Kakar S, et al, "Histologic Changes mimicking biliary disease in liver biopsies with venous outflow impairment", (Mayo Clinic), Modern Pathology 17(7):874-878, July 2004.
  10. R. G. Lee's on-line liver pathology book
  11. Stone JH, et. al., Human Monocytic Ehrlichiosis, JAMA 292(18):2263-2270, 10 Nov. 2004.
  12. Rodger Haggitt consult re: cancer of saccules of Beale, 1998.
  13. Japanese J. of Surgery 19(6):691-698, 1989.
  14. Annals of Surgery 219(3):267-274, 1994.
  15. Japanese J. of Clin. Onc. 29(5): 252-255, 1999.
  16. Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. Odze, Goldblum, & Crawford, 1067 pages, 2004. [EBS]
  17. Mozaic Pathology pathologist (or other experts) tips by phone, fax, letter, or e-mail.
  18. CR Price, JM Crawford, " Sinusoidal Dilatation in Human Liver Biopsies Rarely Results from Hepatic Venous Outflow Obstruction", University of Florida, Gainesville, FL USCAP Annual Meeting March 26, 2007 Poster # 187
  19. MacSween 4th Ed. liver textbook.
  20. Geller & Petrovic, Biopsy Interpretation of the Liver, 442 pages, 2004.
  21. Acalculous cholecystopathy, eMedicine website.
  22. Patel S, et. al., "Hyalinizing...", AJSP 35(8):1104-1113, 2011.
  23. Albores-Saavedra J, Keenportz B, Bejarano PA, Alexander AA, Henson DE, "Adenomyomatous hyperplasia of the gallbladder with perineural invasion: revisited.", Am J Surg Pathol, 10:1598-1604, 31 Oct. 2007. HERE
  24. Pierre D. Maldjian, Nasrin Ghesani, Shahida Ahmed and Yiyan Liu, "Adenomyomatosis of the Gallbladder: Another Cause for a 'Hot' Gallbladder on 18F-FDG PET", AJR 189(1), July 2007. HERE
  25. Winter WE, "Metabolic Syndrome", CAP meeting CME CP101, 13 October 2013, Gaylord Palms hotel, Kissimmee, Fla.
(posted 2001; latest slight addition 6 April 2014)

© Copyright 1999 - 2006, all rights reserved, Pathology Associates Of Lexington, P.A.