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Hepatobiliary Diseases

Web Links:

• Dr. Randall G. Lee's out-of-print, on-line liver textbook,  U. of Pittsburgh , highly recommended by Dr. Shari Taylor.
• 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].
• abnormal liver or LFT history and biopsy looks "normal": think of non-cirrhotic idiopathic extrahepatic "increased flow" portal hypertension (look for peripheralized portal triad venules & rule out splenomegally).

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:
  • gallbladder¹⁶:
    • shape abnormality: phrygian cap (of distal body...area bulges or protrudes like a broad diverticulum due to a mural/mucosal fold).
    • multifocal, incidental adenomatous change of mucosa [LMC-02-3532].
    • mucosal papilloma .
    • cholesterolosis polyp: range from 1-5mm.
    • mucosal lymphoid hyperplasia.
    • xanthogranulomatous cholecystitis
    • fundic adenomyoma: admixture of benign A-R-sinus-like...Aschoff-Rokitansky...epithelium & smooth muscle [LMC-05-6849].
    • hyperplastic cholecystosis or cholecystoses:
    1. cholesterolosis.
    2. adenomyomatosis (mural thickening and very prominent Aschoff-Rokitansky...Rokitansky-Aschoff...sinuses [A-R sinuses]) [L07-324; L07-1966]: 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.
    3. metaplasia: pyloric or mucinous; intestinal (to include Paneth).
    4. papillary hyperplasia: highly velvety mucosa due to mucosal elongations (can be focal, segmental, diffuse).
    • Mucocele: cystic duct obstruction so complete & chronic that GB distended with mucous.
    • heterotopia (ectopic, ectopia, choristoma): normal tissue in abnormal location...gastric, pancreatic nodule [LMC-07-361], hepatic, thyroid, adrenal cortical.
    • ciliated foregut cyst.
  • uncertain:
    • 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):
    • 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] & 57 y/o male []L08-6031]; resect and radiate^13,14.
    • common bile duct adenocarcinoma:
    1. proximal = Klatskin tumor [T-06-182]
    2. distal
    3. ampulla of Vater
    • 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).
    • 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.

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) .
2. apoptotic body: fragment of an acidophile body.
3. 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), or feathery degeneration when due to cholestasis.
     • 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.
  2. inclusions:
     • Mallory bodies:
     • megamitochondria:
     • pigment:
  3. 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] (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, constrictive pericarditis...anything that increases venous pressure from central vein to proximal, intrahepatic or extrahepatic).BUT, appearing dilated can also be due to portal vein or hepatic artery insuffciency¹⁸! 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:
   • 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:
  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:
     • eosinophiles:
     • polys: in bariatric post-bypass cases, see above; any time there is bile ductule proliferation; medication induced; ascending cholangitis; 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.]
       • 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 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]
  • 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 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
       • as many as 20% present without detectable auto antibodies (ANA, ASMA, anti-LKM-1, p-ANCA) [LMC-04-6010]
       • 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]
         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)
         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
  • 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]
  • 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 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:

 

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 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
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.