Medical liver disease

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This article deals with medical liver disease. An introduction to the liver and approach is found in the liver article.

Every differential in liver pathology has "drugs" -- if it isn't clearly malignancy.

Liver neoplasms are dealt with in the liver neoplasms article.

Hepatitis A

  • Infection is self-limited, i.e. not persistent.
  • Usually asymptomatic in children.[1]
  • Serology is diagnostic.

Hepatitis B

General

  • May lead to hepatocellular carcinoma without cirrhosis.
  • High prevalence.
  • Diagnosis is by serology.

Histology

Hepatitis C

General

  • Leads to hepatocellular carcinoma in the setting of cirrhosis.
  • Tends to be chronic; the "C" in "hepatitis C" stands for chronic.
  • Diagnosis is by serology.

Histology

  • Lobular inflammation - this is non-specific finding.
  • Periportal steatosis in genotype 3.[2]
    • Steatosis in hepatitis C is usually a secondary pathology, i.e. a separate pathologic process.[3]

Congestive hepatopathy

  • Liver failure due to (right) heart failure.
  • AKA cardiac cirrhosis - a term used by clinicians.
    • Generally, it does not satisfy pathologic criteria for cirrhosis.[4]

Gross

  • "Nutmeg" liver - yellow spotted appearance.

Histologic

Features:[5]

  • Zone III atrophy.
  • Portal venule (central vein) distension.
  • Perisinusoidal fibrosis - progresses to centrilobular fibrosis and then diffuse fibrosis.
  • Dilation of sinusoids in all zone III areas - key feature.[6]

Alcoholic liver disease

  • Acute and/or chronic liver changes due to alcohol use.
  • Includes ASH (alcoholic steatohepatitis).

Classic lab findings in EtOH abusers

  • AST & ALT elevated with AST:ALT=2:1.
  • GGT elevated.
  • MCV increased.

Gross pathology/radiologic findings

  • Classically micronodular pattern.
    • May be macronodular.

Histopathology

See:

Features:

  • Often zone III damage.
  • Neutrophils (often helpful to differentiate) -- few other things have PMNs.
  • Cholestatsis common, i.e. yellow staining.
  • Fibrosis starts at central veins.

Notes:

  • If portal inflammatory infiltrates more than mild, r/o other causes i.e. viral hepatitis.
  • Mallory bodies once thought to be characteristic; now considered non-specific and generally poorly understood.[7]
  • Some consider alcoholic liver disease a clinical diagnosis, i.e. as a pathologist one does not diagnose it.[8]

Non-alcoholic fatty liver disease

  • Abbreviated NAFLD.
  • Fatty liver that is not due to alcohol; includes obesity-related fatty liver, metabolic disease/diabetes-related fatty liver.

NASH

  • Non-alcoholic steatohepatitis - see steatohepatitis section.
  • Histologically indistinguishable from ASH.
  • NASH is a clinical diagnosis based on exclusion of alcohol.

Steatohepatitis

  • Steatohepatitis is a label for a set of histopathologic findings.
    • May arise due to numerous etiologies, e.g. alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH).
  • Fat accumulation in hepatocytes.
    • It may be a pattern seen in drug toxicity, e.g. methotrexate toxicity.[9]

Histology

Features:

  • Steatosis (usually macrovesicular) - key feature.
    • If less than 10% ... consider alt. diagnosis/disease process.
  • Hepatocyte injury:
    • Ballooning degeneration - key feature (see introduction to liver).
    • Mallory bodies.
      • Mallory body wannabes: "occasional cytoplasmic clumping".
  • +/-Chicken-wire perisinusoidal fibrosis +/- zone III (centrilobular) fibrosis (early).
    • Late-stage disease - portal bridging.[10]

Grading steatohepatitis

Grading inflammation:[11]

  • Grade 1 - steatosis, occ. ballooning degen., PMNs.
  • Grade 2 - obvious ballooning, obvious PMNs, chronic inflammation.
  • Grade 3 - panacinar steatosis.

Autoimmune hepatitis

General

  • Abbreviated AIH.
  • Several criteria exist to diagnose.

Diagnosis

Simplifed diagnostic criteria (2008):[12]

  1. Antibody titer.
  2. Elevated IgG.
  3. Liver pathology.
  4. Exclusion of viral hepatitis.

Details (scoring):[12]

  • ANA or SMA 1:40 1 point.
  • ANA or SMA 1:80 2 points.
  • LKM 1:40 2 points.
  • IgG upper normal 1 point.
  • IgG 1.1x upper limit 2 points.
  • Histology compatible 1 point.
  • Typical AIH histo. 2 points.
  • No viral hepatsis 2 points.

Interpretation: Definite >= 7. Probable = 6.

Notes:

  • Autoantibodies may be seen in HCV.[12]
  • A normal IgG is very unusual in AIH - but may be seen in atypical variants with zone III involvment.

Abbreviations:

  • ANA = anti-nuclear antibody.
  • SMA = smooth muscle antibody.
  • LKM-1 = liver kidney microsomal type 1 antibody.

Histology

Classification:[12]

  • Typical:
    • Interface hepatitis (zone 1).
      • Lymphocytic/lymphoplasmacytic infiltration of portal tracts + lobule.
    • Emperipolesis - one cell penetrates into another one.
    • Hepatic rosette.
  • Compatible
    • Chronic hepatitis - with lymphocytic dominant.
  • Atypical:
    • Signs of other disease.

Notes:

  • PAS may be useful - find plasma cells. (???)
  • Atypical Autoimmune hepatitis may have zone III involvment (lymphoplasmacytic infiltrate)[13] and a normal IgG.[14]

Micrographs:

Treatment

  • Immunosuppresants (prednisone, azathioprine).[13]

Primary biliary cirrhosis

  • Abbreviated PBC.

Epidemiology

  • Female>male (~9:1).[15]
  • Usually middle age.
  • Associated with other autoimmune conditions (Sjogren's syndrome, progressive systemic sclerosis, celiac).

Etiology

  • Autoimmune.

Serology

  • AMA+.

Classic presentation

  • Pruritis.

Pathophysiology

  • Septal bile duct attacked.

Histopathology

  • Intraepithelial lymphocytes - in bile duct key feature.
  • Bile duct epithelial cells with eosinophilic cytoplasm.[16]
  • Plasma cells.
  • Granulomas - close to bile duct.
    • Seen in classic presentation -- often not present or poorly formed.
  • Focal damage (may be missed on biopsy -- due to sampling).
  • "Garland" cirrhosis -- has irregular border (unlike in EtOH).
    • Garland originally "wreath of flowers" (in French).[17]

Images:

DDx:[18]

  • Sarcoidosis (if granulomas present).
  • PSC, viral hepatitis, AIH, drugs, Hodgkin's lymphoma[19]

Staging

PBC is staged according to Ludwig:[20]

  • Stage 1: Portal - inflammation or bile duct abnormalities.
  • Stage 2: Periportal - periportal fibrosis (enlargement of portal tracts) +/- inflammation.
  • Stage 3: Septal - septal fibrosis +/-inflammation in septa.
  • Stage 4: Cirrhosis - nodules of hepatocytes +/- inflammation.

Notes:

  • There can be significant variation in staging on biopsy - due to variability of fibrosis in a PBC liver.[21]
    • "Worst area" in biopsy specimen is used to determine stage.

Treatment

  • Ursodeoxycholic acid.
  • May be indication for transplant.


Autoimmune hepatitis-primary biliary cirrhosis overlap syndrome (AIH-PBC OS)

Epidemiology

  • Rare.

Serology

  • AMA+, anti-dsDNA+.[22]


Primary sclerosing cholangitis

Diagnosis

  • Diagnosed radiologically.
  • Liver biopsy is rarely useful diagnostically[25] - as the disease may be patchy.
    • The utility of the biopsy is staging.

Treatment

  • None very good.
  • May be indication for transplant.

Histopathology

  • Classic: "onion-skinning" - cells layer around the bile ducts; "onion skin" present in approx. 40% of cases.[26]
    • Not pathognomonic for PSC[26] - but not too much else looks like this on microscopy (ergo good fellowship exam question).
  • +/-Ductopenia.
  • +/-Ductal proliferation.

DDx:

  • Big.

Micrographs:

Staging

Features:[27]

  • Stage I - focal portal inflammation, +/- duct abnormalities, no fibrosis.
  • Stage II - portal enlargement (fibrosis), +/- inflammation.
  • Stage III - bridging fibrosis + necrosis.
  • Stage IV - cirrhosis.

Notes:

  • Similar to PBC staging.

Hereditary hemochromatosis

Epidemiology/General

  • Genetic defect.
    • One mutation (C282Y mutation) in up to 12.5% of people in populations of northern and central European origin[28]
  • Onset in males earlier than females (due to menses).
  • Mutation thought to confer survival advantage - several theories (increased resistance to TB, S. typhi vs. decr. iron def./incr. iron absorption)[28]

Pathophysiology

  • Iron overload --> cirrhosis. (???)

Histopathology

  • Periportal changes (early), i.e. no iron centrilobular.
    • Late stage disease has diffuse iron deposition.
  • Brown granular -- may look like lipofuscin on H&E.

Diagnosis suggested by positive iron stain.

  • Light blue haze is not enough.
    • NOT siderosis -- in Kupffer cells.

Notes:

  • Iron in the bile ducts and endothelium used to be though specific of hereditary hemochromatosis.[29]
    • It is now thought to just reflect the severity of iron deposition, i.e. if the bile ducts and endothelium have iron - it is severe.

DDx

  • Myelodysplastic syndrome.
  • Chronic hemolysis.
  • Alcohol.

Wilson's disease

Epidemiology

  • Rare autosomal recessive - mutation in copper-transporting adenosine triphosphatase (ATPase) gene (ATP7B).[30]
    • Heterozygote carrier rate approximately 1/100 persons.[30]
  • Young individuals - usually 12-23 years old.

Clinical

  • Kayser-Fleischer rings --> on slit-lamp examination (green eyes).
  • May present to psychiatry or appear to be abusing EtOH.
  • Serum ceruloplasmin - lower than normal.

Etiology

  • Excess copper -- due to genetic defect.

Histopathology

  • Nothing specific.
  • Steatosis.
  • Portal fibrosis.

Staining:

  • Copper staining positive in ONLY 15%.
    • Other stains: rhodinine, orecin.


Alpha-1 antitrypsin deficiency

  • AKA 'alpha1-antiprotease inhibitor deficiency'.

Etiology

  • Genetic defect.

Causes

  • Lung and liver injury.
    • Lung -> emphysema.

Histopathology

  • Pink globules in zone 1.
    • Globules not seen in children.
    • May not be present in late stage (cirrhotic).
    • Best seen on PAS-diastase.
    • Can be seen on H&E -- if one looks carefully.


Drug toxicity

  • Can do almost anything; may include: granulomata, bile duct injury, cholestasis, ischemic type injury.
  • Effects can be delayed -- temporal relationship not always obvious.

Microscopic:

  • Non-specific findings.
    • +/-Eosinophils.[31]
    • +/-Steatosis - periportal macrovesicular, microvesicular.

Common

Acute hepatits:

  • Related to Rx - most often antibiotics.

Acetaminophen:

  • Zone 3 necrosis.

Methotrexate - chronic use:

  • Histology:[32]
    • Features of steatohepatitis.
      • Zone III steatosis.
      • Ballooning degeneration.
    • Portal inflammation with mixed population (lymphocytes, macrophages, PMNs).
    • Nuclear atypia (hyperchromasia, pleomorphism, vacuolation).
      • Described as just nuclear size variation by some.[33]

Focal nodular hyperplasia

  • Abbreviated FNH.
  • Not commonly seen by pathologists.
  • Benign lesions.
  • Associated with oral contraceptive pill (OCP) use.

Imaging

  • FNH enhances on the arterial phase in triphasic imaging, i.e. triphasic CT or MRI.[34]

Gross

Features:[35]

  • Well circumscribed, but no capsule.
  • Lighter than surrounding parenchyma, may be yellow.
  • +/-Stellate central scar with thick vessels.

Note: Usually a solitary lesion.[34]

Histopathology

Features:[36]

  • Stellate scar has large arteries with fibromuscular hyperplasia.
    • Thin fibrous septa radiate from the central scar - surrounded by lymphocytes & bile ductules.
      • Normal hepatocytes between fibrous septae.

DDx

  • May be difficult to distinguish from hepatic adenoma if no scar and no ductal proliferation.[37]


Nodular regenerative hyperplasia

  • Associated with renal transplants, bone marrow transplants and vasculitities.[38]
  • Can lead to portal hypertension and many of the associated complications.

Etiology

  • Arterial hypervascularity secondary to loss of hepatic vein radicles (loss of central venule in hepatic lobule).[39]

ASIDE: radicle = ramulus - smallest branch or vessel or nerve.[40]

Gross

  • Diffuse nodularity - whole liver.

Histopathology

Features:[41]

  • "Plump" hepatocytes surrounded by atrophic ones.
  • No fibrosis.


Sinuosoidal obstruction syndrome

  • Term for obstruction due to toxicity from a chemotherapeutic agent.[42]
  • May be referred to as Hepatic veno-occlusive disease.[43]

Polycystic kidney disease and the liver

Complications of PKD in the liver:[44]

  1. Infected cyst.
  2. Cholangiocarcinoma.
  3. Cholestasis/obstruction due to duct compression.[45]

Cysts:

  • Cysts in the liver, like the kidney, are thought to enlarge with age.

Microscopic

Features:[46]

  • Von Meyenburg complexes (bile duct hamartoma):
    • Cluster of dilated ducts with "altered" bile.
    • Surrounded by collagenous stroma.
    • Separate from the portal areas.[47]

Images:

Notes:

  • Appearance on ultrasound[48] and CT (hypodense)[49] - similar to metastases.

See also

References

  1. ↑ PMID 20068336.
  2. ↑ Yoon EJ, Hu KQ. Hepatitis C virus (HCV) infection and hepatic steatosis. Int J Med Sci. 2006;3(2):53-6. Epub 2006 Apr 1. PMID 16614743. Avialable at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1415843. Accessed on: September 9, 2009.
  3. ↑ OA. September 2009.
  4. ↑ [1]
  5. ↑ http://emedicine.medscape.com/article/151792-diagnosis
  6. ↑ Suggested by OA. September 2009.
  7. ↑ Jensen K, Gluud C (November 1994). "The Mallory body: theories on development and pathological significance (Part 2 of a literature survey)". Hepatology 20 (5): 1330-42. PMID 7927269.
  8. ↑ MG. September 2009.
  9. ↑ MG. 22 September 2009.
  10. ↑ Gramlich, T.; Kleiner, DE.; McCullough, AJ.; Matteoni, CA.; Boparai, N.; Younossi, ZM. (Feb 2004). "Pathologic features associated with fibrosis in nonalcoholic fatty liver disease.". Hum Pathol 35 (2): 196-9. PMID 14991537.
  11. ↑ Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Am J Gastroenterol. 1999 Sep;94(9):2467-74. PMID 10484010.
  12. ↑ 12.0 12.1 12.2 12.3 Scoring systems for the diagnosis of autoimmune hepatitis: past, present, and future. Wiegard C, Schramm C, Lohse AW. Semin Liver Dis. 2009 Aug;29(3):254-61. Epub 2009 Aug 12. PMID 19675998
  13. ↑ 13.0 13.1 Non-classical phenotypes of autoimmune hepatitis and advances in diagnosis and treatment. Czaja AJ, Bayraktar Y. World J Gastroenterol. 2009 May 21;15(19):2314-28. Review. PMID 19452572.
  14. ↑ FW. 21 September 2009.
  15. ↑ DCHH P.162.
  16. ↑ OA. 11 September 2009.
  17. ↑ http://dictionary.reference.com/browse/garland
  18. ↑ DCHH P.163.
  19. ↑ Vanishing bile duct syndrome and Hodgkin disease: a case series and review of the literature. Pass AK, McLin VA, Rushton JR, Kearney DL, Hastings CA, Margolin JF. J Pediatr Hematol Oncol. 2008 Dec;30(12):976-80. PMID 19131796.
  20. ↑ PBC. eMedicine.com. URL: http://emedicine.medscape.com/article/171117-diagnosis. Accessed on: 22 September 2009.
  21. ↑ J Clin Pathol. 1996 July; 49(7): 556-559. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=500569. Accessed on: September 22, 2009.
  22. ↑ The serological profile of the autoimmune hepatitis/primary biliary cirrhosis overlap syndrome. Muratori P, Granito A, Pappas G, Pendino GM, Quarneti C, Cicola R, Menichella R, Ferri S, Cassani F, Bianchi FB, Lenzi M, Muratori L. Am J Gastroenterol. 2009 Jun;104(6):1420-5. Epub 2009 Apr 28. PMID 19491855.
  23. ↑ Khurana V, Singh T. Primary sclerosing cholangitis. eMedicine.com. URL: http://emedicine.medscape.com/article/187724-overview. Accessed on: 29 November 2009.
  24. ↑ Jesudian, AB.; Jacobson, IM. (2009). "Screening and diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis.". Rev Gastroenterol Disord 9 (2): E41-7. PMID 19668124.
  25. ↑ Khurana V, Singh T. Primary sclerosing cholangitis. eMedicine.com. URL: http://emedicine.medscape.com/article/187724-diagnosis. Accessed on: 29 November 2009.
  26. ↑ 26.0 26.1 Steele et al. URL: http://www.medscape.com/viewarticle/552500_6. Accessed on: 29 November 2009.
  27. ↑ Steele et al. URL: http://www.medscape.com/viewarticle/552500_6. Accessed on: 29 November 2009.
  28. ↑ 28.0 28.1 Weinberg ED (2008). "Survival advantage of the hemochromatosis C282Y mutation". Perspect. Biol. Med. 51 (1): 98-102. doi:10.1353/pbm.2008.0001. PMID 18192769.
  29. ↑ MG. 17 September 2009.
  30. ↑ 30.0 30.1 http://emedicine.medscape.com/article/183456-overview
  31. ↑ DCHH P.166.
  32. ↑ MacSween 5th Ed. P.715.
  33. ↑ MG. 23 September 2009.
  34. ↑ 34.0 34.1 http://emedicine.medscape.com/article/368377-overview
  35. ↑ PBoD P.922.
  36. ↑ PBoD P.922.
  37. ↑ STC. 19 Jan 2009.
  38. ↑ PBoD P.922.
  39. ↑ PBoD P.922.
  40. ↑ Dorlands2
  41. ↑ PBoD P.922.
  42. ↑ Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome. Helmy A. Aliment Pharmacol Ther. 2006 Jan 1;23(1):11-25. Review. PMID 16393276.
  43. ↑ Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). DeLeve LD, Shulman HM, McDonald GB. Semin Liver Dis. 2002 Feb;22(1):27-42. Review. PMID 11928077.
  44. ↑ MacSween 5th Ed. PP. 174-5.
  45. ↑ URL: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=9184868. Accessed on: 23 September 2009.
  46. ↑ MacSween 5th Ed. P.176.
  47. ↑ Meyenburg complex. Stedman's Medical Dictionary. 27th Ed.
  48. ↑ Bile duct hamartomas--the von Meyenburg complex. Salles VJ, Marotta A, Netto JM, Speranzini MB, Martins MR. Hepatobiliary Pancreat Dis Int. 2007 Feb;6(1):108-9. PMID 17287178.
  49. ↑ [The von Meyenburg complex] Schwab SA, Bautz W, Uder M, Kuefner MA. Rontgenpraxis. 2008;56(6):241-4. German. PMID 19294869.
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