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. Those are 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. In our area of the USA, fatty liver, hepatitis C, and multiple legitimate use of medicinals and herbals are all 3 quite prevelant. So, it makes sense that we will not infrequently encounter liver biopsies with multifactorial histological changes (such as HCV in a person with fatty liver²³). Presence of plasma cells suggests an autoimmune component (especially if ASMA serological positivity). Presence of steatosis suggests a steatohepatitic component. And presence of eosinophiles suggest presence of a drug/herbal sensitivity component. A rare granuloma might herald early PBC; if, epithelioid, maybe also think of sarcoid. Sarcoid & fatty liver might coexist,for example. And, remember the possibility of autoimmune "overlap" situations of mixed autoimmune hepatic disease. Having said the above, one can see how important it is to have serological information (ANA, AMA, ASMA) and/or the liberty to just recover any patient's serum in the lab and do these 3 if the information is needed.

A 2010 REVIEW of hepatic needle biopsies we processed in Nov. & Dec. 2009 & Jan. 2010 found 75 cases (5 taken during gallbladder or bariatric surgery): 15 were of masses or small lesions seen during surgery (1 of them histologically suggesting a medical problem), 6 were fatty liver workups, 3 were hemochromatosis workups, 14 were HBV/HCV workups (two possibly being not HCV due to false positive HCV serological testing), and 34 (45%) were for elevated LFTs (and uncertain liver problem or liver looks odd at surgery). Out of this last group, there were 5 more with siderosis.

Web Links:

• Dr. Randall G. Lee's out-of-print, on-line liver textbook, U. of Pittsburgh, highly recommended by Dr. Shari Taylor, is apparently no longer on-line as of early 2010.
• liver lab tests on-line source Practice Guidelines

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 non-cirrhotic idiopathic extrahepatic "increased flow" portal hypertension (look for peripheralized portal triad venules & rule out splenomegally).
  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].

Topics:

• Gastric emptying & GB function tests
• Standard Hepatic Function (LFTs) info
• Histology review
• 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].

EXTRA-HEPATIC TUMORS & ABNORMALITIES:

• Benign:
• gallbladder (GB)¹⁶ & cholecystodynia causes: Murphy's sign by physical exam is when the examining hand is pressed gently beneath the right subcostal margin at expiration & causes pain there upon inspiration, while sonographic Murphy's sign is pain elicited as the sonographic probe presses over the GB.
  • cholelithiasis (stones, grit, sludge) and cholecystitis (acute, subacute, chronic). 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]; there can be associated "hyperplastic cholecystopathy" [L09-2797], see below. "Stones" may not be visible but can be detected by smearing the bile between gloved fingers & feeling the "grit" ("microlithic cholelithiasis": confirmed by polarized light microscopy and with abdominal U/S showing echogenic bile without shadowing [L09-9676]).
    • without histological abnormality:
  • with cholecystitis:
    1. usual: chronic inflamation, musculomural thickening, mucinous metaplasia, A-R sinuses.
    2. chronic: with stones; or without (acalculous...may see thickly inspissated bile) stones; may include extramuscular liposclerosis or scleredema thickening; may be acalulous & without muscular thickening but with prominent cholesterolosis [L10-984].
    3. subacute: eosinophiles ; extramuscular liposclerotic stromo-vascular thickening.
    4. acute: suppurative, necrotizing, or gangrenous.
    5. xanthogranulomatous cholecystitis: thick & sometimes "tumefactive" with visible yellowish histiocytic zones on cut surface.
    6. lymphoid follicular cholecystitis: impressive follicular nodules of mucosa [L09-6547, L10-1334].
    7. sclero-calcific cholecystopathy: calcified gallbladder (a type of potentially clinically palpable "Courvoisier gallbladder" L09-7360).
  • cholecystopathy without inflamatory cells: muscular thickening [L10-2183].
  • complcated: by such processes²² as sytemic mastocytosis, eosinophilic cholecystitis in those with hypereosinophilic syndrome and/or eosinophilic gastroeneteritis, atypical mycobacterial diffuse histiocytic infiltration, and Langerhan cell histiocytosis; and by hyperplastic cholecystopathy.
  • cholecystopathy (cholecystosis); chronic acalculous gallbladder disease²¹: advances in radiology with ultrasound and 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 during the prior year. Muscular thickening & A-R sinuses (herniations) imply dyskinetic or organic obstructive influences on bile expulsion from GB.
  • surgeon removed the stones: the GB comes to the lab with some sort of opening & the operative note may not state that the surgeon removed the stones to show to the family [L09-3832].
  • stones were spontaneously passed: in the interval between imaging demonstration of small stones, the patient can pass them unbeknownst to anyone [L09-3832]; or there are changes of borderline muscle thickening & maybe some few transmural lymphs (with or without associated cholesterolosis) & you infer & therefore propose prior stones being made & passed [L09-6649, L09-15208, L10-984]; or changes are so striking that you are confident that there were prior stones [L09-6581] and use DX of "acalculous, calculous-associated chronic cholecystitis".
  • abnormal kinetic function is demonstrated: (decreased 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]. Usually assumed to be due to "cystic duct syndrome" wherein the duct constricts rather than relaxing when the GB squeezes. But couldn't amyloidosis deposits or diabetic effects cause dyskinesia?
  • abnormal function IS NOT demonstrated (HIDA scan not done or is normal but not really high ejection fraction) & no histological chronic inflammation [L08-13447; L10-976] 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 = doubtful cholecystopathy. Surgery may have found another etiology for pain and the GB incidentally removed because did not appear to be perfectly normal [L09-596]. Really concentrated, thick bile might result in poor function in vivo even though CCK test normal [L09-2253 "thick bile dyskinesia"]. Otherwise, being all normal, one might warn surgeon, et. al., in your report to think of (1) fatty liver abdominal pain, (2) hereditary angioneurotic edema if episodes of N&V are prominent (HAE), (3) non-cutaneus "shingles" (VZV) neuropathy, or (4) 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] and gone ahead and removed the GB because the GB was the pre-operative target.
  • "acalculous serosal pericholecystic adhesive cholecystopathy": when the only abnormallity is surgically demonstrated adhesions [L09-6551] which probably "tug" and cause pain when the GB expresses bile, & diagnosis is affirmed when pain turns out postoperatively to have been cured.
  • "acalculous hyperplastic cholecystopathy": mucosal hyperplasia may be present to a varying degree and alone account for this DX if "lush" enough; but at least one other of the following should be additionally impressively expressed in cases with a lesser degree of hyperplasia.
    1. adenomyomatosis (mural thickening and very prominent Aschoff-Rokitansky...Rokitansky-Aschoff...sinuses [A-R sinuses]) [L07-324; L07-1966; L09-2797]: A-R "sinus" formation 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).
    2. metaplasia: pyloric or mucinous; intestinal (to include Paneth).
    3. papillary hyperplasia: highly velvety mucosa due to mucosal elongations (can be focal, segmental, diffuse [L09-6028]).
    4. cholesterolosis to the extent of significant mucosal thickening.
  • 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: one lesion [L09-4391] or multifocal, incidental adenomatous change of mucosa [LMC-02-3532]. Adenomatous change denotes a "field effect" for the component of the entire biliary tract that is chronically inflammed (if you see it in the chronic GB, then the at-risk field has been removed by cholecystectomy [L09-10946])²³.
  • adenosis: incidental focal mucosal adenosis [L08-11597; L09-470].
  • mucosal papilloma.
  • cholesterolosis polyp(s): range from 1-5mm; when impressive enough (e. g., seen on pre-op U/S), may warrant a term such as "acalculous, polypoid-cholesterolosis cholecystopathy" [L10-1134].
  • mucosal lymphoid hyperplasia: "chronic lymphoid follicular cholecystitis" when inflammation present [L09-6547].
  • fundic adenomyoma: admixture of benign A-R-sinus-like (A-R = Aschoff-Rokitansky) epithelium & smooth muscle [LMC-05-6849] forming a plaque; can centrally ulcerate [L09-1778].
  • mucocele: cystic duct obstruction so complete & chronic that GB distended with mucous. An end stage of this is the murally calcified porcelain gallbladder.
  • heterotopia (ectopic, ectopia, choristoma): normal tissue in abnormal location...gastric, pancreatic nodule [LMC-07-361], hepatic, thyroid, adrenal cortical.
  • ciliated foregut cyst.
  • cystic duct lymph node enlarged: this may be due to nonspecific hyperplasia, sarcoid, lymhoma, metastatic carcinoma or oleogranulomatous lympadenopathy [L09-3729].
  • coincidental pathology: occlusive arteriolopathy [L09-6183].
• uncertain biological behavior:
• carcinoid: a 3 mm incidental (surgery & pathologist) cystic duct carcinoid in 79 y/o female [LMC-02-2548].
• 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 radiate^13,14.
2. common bile duct adenocarcinoma:
   1. proximal = Klatskin tumor [T-06-182]
   2. distal
   3. ampulla of Vater (is there any history of colonic familial adenomatous polyposis (FAP)?
3. malignant carcinoid: some can be pigmented (1.1 cm melanin-containing carcinoid of common duct in 48 y/o [S-02-3904] husband of our employee).
4. adenoendocrine (mixed exocrine endocrine; amphicrine; adenocarcinoid) carcinoma: worse actor than pure neuroendocrine tumor. Tumors composed of a mixture of endocrine and exocrine cells have been recognized especially in the digestive tract¹⁵.

INTRAHEPATIC TUMORS :

• BENIGN:
• MALIGNANT:
  • carcinoma:
    • iopsies of an "atypical hepatocellular proliferation: sometimes the reticulin stain pattern is OK, hepatocytes are not seriously dysplastic, & serum AFP levels are normal[L10-85].
    • hepatocellular (HCC):
      • varicoid HCC: CT images suggest hemangioma because of prominent vascular component that fails to show up with tagged RBC study (L10-85).
    • biliary:
      • pure cholangiocarcinoma:
      • cholangio with intrahepatic nodules vs. met. adenoca. [CN09-12].
• metastatic malignancies:
• lymphoma:
• sarcoma:

MEDICAL DISEASES:

• 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.
     inclusions:
     • Mallory bodies:
     • 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. SPE with increased globulins & beta-gamma electrophoretic bridge and decreased albumin hints at chronicity.
• lobule (hepatocytes as groups):
  1. hepatocyte cell change:
     • balooning change: cytoplasmic edema.
     • feathery degeneration: cholestatic ballooning, see above.
     • foamy cell change: fatty ballooning, see above.
     • syncytial change (poor cell membrane definition) of hepatocytes: alcoholic hepatitis.
     • steatosis:
       • macrovesicular: common...AFLD; NASH/NAFLD.
       • microvesicular: more acute toxic
  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 right-sided systemic venous pressure, see VOI, below, gives dilation of central sinusoids (due to hepatic vein, IVC, cardia, right heart failure [L08-13713], constrictive pericarditis...anything that increases venous pressure from central vein to proximal, intrahepatic or extrahepatic). BUT, appearing dilated can also be due to general 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 deposition in post jejunoileal bypass for obesity: this also has macroves. fatty & portal tracts & septae may have polys & lymphs. When extramedullary hematopiesis induces increased hepatic blood flow, may get sinusoidal fibrosis [LMC-04-11140] which can lead to portal hypertension.
   • 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 & macrophages:
   • d-PAS stain needed to visualize: if single or clusters of lining cells contain positive, fine granules, this is a sign of hepatocyte necrosis within the past 6 months
   • H&E obvious with pigment: ceroid histiocytosis reflects injury and has been seen in the early days of intravenous hyperalimentation & may be an injury pattern one might see among people with high stress lives taking lots of herbals & suppliments [L09-3817].
   • as xanthoma clusters: [L09-9473; L09-9701].
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:
  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 reserve ; is apparently irreversible; check patient for hypercoagulation (some think this may be part of the etiology).[S04-4874]
  4. artery: being adjacent to bile duct and/or "naked arterioles" may indicate ductopenia
  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: imply an autoimmune component.
     • eosinophiles: imply an allergic (drug or suppliment allergy)
     • polys: in bariatric post-bypass cases, see above; drawn to area any time there is bile ductule proliferation; medication induced vs. ascending cholangitis vs. ascending pericholangitis [L06-2862].
• 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.].
       • biliary ductular epithelial injury: reflected as a type of cellular pleomorphism & anisonucleosis & often seen on HCV.
       • 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.
       • Knodell hepatic damage scoring table (HERE).
    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 negative...no 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]
    3. NASH: there can be apparent biliary changes within portal chronic inflammation that is apparently just part of the NASH process.
  • autoimmune (spectrum)...(AJCP 114:705-711, 11/2000): while there are full blown situations which are diagnostic, we often get biopsies "early" in the course of an ilness. So, one has to pay close attention to the serum biochemical & serological information. Is there any AIH (hepatocyte injury) component AND is there any biliary-injury component (the former treated with steroids & possible overlap component watched to see if responds to the anti-AIH steroid Rx and, if not, an Rx may be added to protect the biliary component [L10-1408]).
    1. vs. biliary cells: could come to BX very early with elevated LFTs, especially some elevation of alk. phos., and a couple of cores be negative or maybe just show a very subtle granuloma (if so, see if AMA elevated; order serology if need be); nonsuppurative destructive cholangitis (florid duct lesion); evidence of cholangiocyte injury (and it can be subtle [L09-4800])...
       • 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:  diagnostic = 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/or ck19 to hunt residual cholangiocytes; periportal hepatocytes may be swollen and contain copper. But, biopsies early in the course may be very subtle; but a positive AMA serology keeps you focused on the possibility.
       • AIC (autoimmune cholangitis [immunocholangitis; autoimmune cholangiopathy; PSC]):
         1. clinical: like PBC but neg. AMA [S-04-4874; L08-3230, L08-3332]
         2. serological: high ANA; sometimes p-ANCA pos.; neg. AMA; may also have positive ASMA [L-04-10922; L06-2337; L09-4800].
         3. chemical: slight ALT (SGOT) increase & may have very slight, if any, increase in GGTP or alk phos.
         4. 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 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; L10-1408] ...
            • 2 of 3 PBC features (pos. AMA, florid duct lesion, AP 5x uln) = full blown.
            • 2 of 3 AIH features (pos. ASMA, severe interface cellularity, ALT 5x uln, serum IgG 2x uln) = full blown.
         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.
       • as many as 20% present without detectable auto antibodies (ANA, ASMA, anti-LKM-1, p-ANCA) [LMC-04-6010].
       • ASMA can be significantly elevated in other situations than AIH.
       • 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).
       • there can be an autoimmune component to a number of other hepatidites as reflected by presence of plasma cells and/or ASMA positivity.
       • 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]: fatty & fibrous change.
    4. minocycline: "hepatitis", AIH & otherwise; as a tetracycline like med, possibly microvesicular fatty change [L07-8935].
    5. cimetidine: cholangiocentric lymphocytes and biliary epithelial reactive change & even to ductopenia.
    6. Lovastatin: statins & many meds cause hepatocellular injury & usually not having histologically discernable changes.
  • 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]
  • 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]. There can be hemochromatosis due to rare, as-yet-undefined genetic abnormalities [L09-13591]. There can be hepatic siderosis which is not genetic hemochromatosis. Bile duct epithelial cell siderosis is one of the more specific markers of genetic hemochromatosis.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 trichrome...as round globules)[LMC-03-2385; LMC-04-7655; LMC-05-7512]
  • NAFLD/NASH: fatty liver whether 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); "non-alcoholic fatty liver disease "/"non-alcoholic steatohepatitis "...NAFLD, a fatty liver; NASH, a fatty liver which also has a little on-going injury of liver cells...seen in people of normal weight as well as overweight...needs management. If no evidence of hepatocyte injury (no elevation of ALT & few or no fine-granule-positive sinusoidal or portal macrophages) = non-alcoholic steatohepatosis. Brunt grading.
    1. An interesting web site and another
    2. AST:ALT ratio usually <1.0⁶
• Clinical presentations:
  • portal hypertension workups ("portal venopathy"¹⁷):
    1. cirrhosis associated: pretty obvious on biopsy.
    2. non-cirrhotic causes⁸ (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.
       • sinusoidal causes increased pressure/obstruction:
       such as amyloidosis or fibrosis (HPS)[L-04-11140].
       • post-sinusoidal causes increased pressure/obstruction: largely cardiac failure or hepatocaval thrombosis.
  • clinically jaundiced:
  • clinical hepatitis:
  • incidental discovery elevated liver function tests:
  • patient presents in coma:

 

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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 site...link 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, no longer generally on line as of early 2010.
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.
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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. CAP 2006 on-line CME Case of The Month [HERE].
23. Shari Taylor, MD, expert GI pathologist, personal communications.
24. Vidhya Nair, MD, et. al., "Non–Viral-Related Pathologic Findings in Liver Needle Biopsy Specimens From Patients With Chronic Viral Hepatitis", AJCP 133(1):127-132, Jan. 2010.