Hepatomegaly: Difference between revisions

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'''For patient information on this topic, click [[Hepatomegaly (patient information)|here]].'''
'''For patient information on this topic, click [[Hepatomegaly (patient information)|here]].'''
{{Hepatomegaly}}
{{Hepatomegaly}}
{{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}}
{{CMG}}; '''Associate Editor-In-Chief:''' {{SMP}},{{IQ}}<br>
 
{{SK}} Enlarged liver; liver enlargement
{{SK}} Enlarged liver; liver enlargement


==[[Hepatomegaly overview|Overview]]==
== Overview ==
The '''liver''' is an [[Organ (anatomy)|organ]] present in [[Vertebrate|vertebrates]] and some other animals. The adult human liver normally weighs between 1.4 to 1.6 kilograms (3.1 to 3.5 pounds), and it is a soft, pinkish-brown "boomerang shaped" organ. It is located on the right side of the upper [[Human abdomen|abdomen]] below the [[Diaphragm (anatomy)|diaphragm]]. The size of the liver increases with age and ranges between 5 cm to 15 cm in adulthood. A normal liver is less than 16 cm on ultrasound evaluation. Hepatomegaly may be found during physical examination or on imaging studies. Imaging is more accurate in determining liver size.<ref name="pmid475535">{{cite journal| author=Sapira JD, Williamson DL| title=How big is the normal liver? | journal=Arch Intern Med | year= 1979 | volume= 139 | issue= 9 | pages= 971-3 | pmid=475535 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=475535  }} </ref><ref name="pmid6622701">{{cite journal| author=Niederau C, Sonnenberg A, Müller JE, Erckenbrecht JF, Scholten T, Fritsch WP| title=Sonographic measurements of the normal liver, spleen, pancreas, and portal vein. | journal=Radiology | year= 1983 | volume= 149 | issue= 2 | pages= 537-40 | pmid=6622701 | doi=10.1148/radiology.149.2.6622701 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6622701  }} </ref> In some conditions normal liver may be palpated as enlarged liver including thin people, during deep [[Inhalation|inspiration]], right [[pleural effusion]], and [[emphysema]] resulting in hyperinflation of the chest with diaphragmatic descent and downward displacement of the [[liver]]. Common pathological causes that may result in hepatomegaly are [[hepatitis]], [[Storage Disease|storage disorders]], impaired venous outflow, infiltrative disorders, and [[biliary obstruction]].


==[[Hepatomegaly pathophysiology|Pathophysiology]]==
== Causes ==
Various causes of hepatomegaly may be classified on the basis of etiology into hepatitis, storage disorders, impaired venous outflow, infiltrative, and obstructive causes.<ref name="pmid10970452">{{cite journal |vauthors=Wolf AD, Lavine JE |title=Hepatomegaly in neonates and children |journal=Pediatr Rev |volume=21 |issue=9 |pages=303–10 |year=2000 |pmid=10970452 |doi= |url=}}</ref><ref name="pmid16454833">{{cite journal |vauthors=Chau TN, Lai ST, Tse C, Ng TK, Leung VK, Lim W, Ng MH |title=Epidemiology and clinical features of sporadic hepatitis E as compared with hepatitis A |journal=Am. J. Gastroenterol. |volume=101 |issue=2 |pages=292–6 |year=2006 |pmid=16454833 |doi=10.1111/j.1572-0241.2006.00416.x |url=}}</ref><ref name="pmid23485521">{{cite journal |vauthors=Bernstein DL, Hülkova H, Bialer MG, Desnick RJ |title=Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease |journal=J. Hepatol. |volume=58 |issue=6 |pages=1230–43 |year=2013 |pmid=23485521 |doi=10.1016/j.jhep.2013.02.014 |url=}}</ref><ref name="pmid16625098">{{cite journal |vauthors=Torbenson M, Chen YY, Brunt E, Cummings OW, Gottfried M, Jakate S, Liu YC, Yeh MM, Ferrell L |title=Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus |journal=Am. J. Surg. Pathol. |volume=30 |issue=4 |pages=508–13 |year=2006 |pmid=16625098 |doi= |url=}}</ref><ref name="pmid8982149">{{cite journal |vauthors=Chatila R, West AB |title=Hepatomegaly and abnormal liver tests due to glycogenosis in adults with diabetes |journal=Medicine (Baltimore) |volume=75 |issue=6 |pages=327–33 |year=1996 |pmid=8982149 |doi= |url=}}</ref><ref name="pmid28043933">{{cite journal |vauthors=Mukewar S, Sharma A, Lackore KA, Enders FT, Torbenson MS, Kamath PS, Roberts LR, Kudva YC |title=Clinical, Biochemical, and Histopathology Features of Patients With Glycogenic Hepatopathy |journal=Clin. Gastroenterol. Hepatol. |volume=15 |issue=6 |pages=927–933 |year=2017 |pmid=28043933 |doi=10.1016/j.cgh.2016.11.038 |url=}}</ref><ref name="pmid11025794">{{cite journal |vauthors=Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, Rosenbloom BE, Scott CR, Wappner RS, Weinreb NJ, Zimran A |title=The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease |journal=Arch. Intern. Med. |volume=160 |issue=18 |pages=2835–43 |year=2000 |pmid=11025794 |doi= |url=}}</ref><ref name="pmid18312287">{{cite journal |vauthors=Drebber U, Kasper HU, Ratering J, Wedemeyer I, Schirmacher P, Dienes HP, Odenthal M |title=Hepatic granulomas: histological and molecular pathological approach to differential diagnosis--a study of 442 cases |journal=Liver Int. |volume=28 |issue=6 |pages=828–34 |year=2008 |pmid=18312287 |doi=10.1111/j.1478-3231.2008.01695.x |url=}}</ref><ref name="pmid14530778">{{cite journal |vauthors=Park MA, Mueller PS, Kyle RA, Larson DR, Plevak MF, Gertz MA |title=Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients |journal=Medicine (Baltimore) |volume=82 |issue=5 |pages=291–8 |year=2003 |pmid=14530778 |doi=10.1097/01.md.0000091183.93122.c7 |url=}}</ref><ref name="pmid8943863">{{cite journal |vauthors=Cooke CB, Krenacs L, Stetler-Stevenson M, Greiner TC, Raffeld M, Kingma DW, Abruzzo L, Frantz C, Kaviani M, Jaffe ES |title=Hepatosplenic T-cell lymphoma: a distinct clinicopathologic entity of cytotoxic gamma delta T-cell origin |journal=Blood |volume=88 |issue=11 |pages=4265–74 |year=1996 |pmid=8943863 |doi= |url=}}</ref><ref name="pmid870368">{{cite journal |vauthors=Long RG, Scheuer PJ, Sherlock S |title=Presentation and course of asymptomatic primary biliary cirrhosis |journal=Gastroenterology |volume=72 |issue=6 |pages=1204–7 |year=1977 |pmid=870368 |doi= |url=}}</ref><ref name="pmid19501929">{{cite journal |vauthors= |title=EASL Clinical Practice Guidelines: management of cholestatic liver diseases |journal=J. Hepatol. |volume=51 |issue=2 |pages=237–67 |year=2009 |pmid=19501929 |doi=10.1016/j.jhep.2009.04.009 |url=}}</ref>
{| class="wikitable"
!Etiology
!
!Disease
|-
| rowspan="11" |[[Hepatitis]]
| rowspan="4" |Infections
|Acute and chronic [[hepatitis|viral hepatitis]]
|-
|Bacterial [[liver abscess]]
|-
|[[Parasitic infections]]
|-
|[[Granulomatous hepatitis]]
|-
|[[Ischemia]]
|[[Ischemic hepatitis]] ("[[shock liver]]")
|-
|Toxins
|[[Alcoholic hepatitis]]
|-
| rowspan="2" |[[Steatosis]]
|[[Alcoholic liver disease|Alcoholic fatty liver disease]]
|-
|Nonalcoholic [[Fatty liver|steatohepatitis]]
|-
|[[Medication|Medications]]
|[[Drug induced liver injury]] (DILI)
|-
|Immune mediated [[hepatitis]]
|[[Autoimmune hepatitis]]
|-
|Copper deposition
|[[Wilson's disease|Wilson disease]]
|-
| rowspan="6" |Storage disorders
| rowspan="2" |Glycogen
|[[Glycogen storage disease|Glycogen storage disorders]]
|-
|[[Diabetes mellitus]]
|-
| rowspan="2" |Lipid
|[[Gaucher's disease|Gaucher disease]]
|-
|[[Nonalcoholic steatohepatitis]]
|-
|Protein
|[[Alpha 1-antitrypsin deficiency|Alpha-1 antitrypsin deficiency]]
|-
|Iron
|[[Hemochromatosis]]
|-
| rowspan="6" |Impaired venous outflow
| rowspan="2" |Cardiac
|[[Right heart failure]]
|-
|[[Constrictive pericarditis]]
|-
| rowspan="2" |Hepatic vein
|[[Budd-Chiari syndrome|Hepatic vein thrombosis]]
|-
|[[Inferior vena cava]] web
|-
| rowspan="2" |Intrahepatic
|[[Sinusoidal obstruction syndrome]]
|-
|[[Peliosis hepatis]]
|-
| rowspan="11" |Infiltrative diseases
| rowspan="3" |Benign primary liver tumors
|[[Diffuse neonatal hemangiomatosis|Hemangiomas]]
|-
|[[Adenoma|Adenomas]]
|-
|[[Focal nodular hyperplasia]]
|-
| rowspan="4" |Malignant primary liver tumors
|[[Hepatocellular carcinoma]]
|-
|[[Cholangiocarcinoma]]
|-
|Fibrolamellar carcinoma
|-
|[[Hemangioendothelioma]]
|-
| rowspan="4" |Metastatic or disseminated tumors
|[[Multiple myeloma|Myeloma]]
|-
|[[Lymphoma]]
|-
|[[Leukemia]]
|-
|[[Metastatic solid tumors]]
|-
| rowspan="3" |Biliary obstruction
| colspan="2" |[[Primary biliary cirrhosis]]
|-
| colspan="2" |[[Primary sclerosing cholangitis]]
|-
| colspan="2" |[[Biliary atresia]]
|-
| rowspan="3" |Other
|Anatomic variations
|[[Riedel's lobe]]
|-
| rowspan="2" |Cystic liver disease
|[[Polycystic liver disease]]
|-
|[[Caroli's disease]]
|}


==[[Hepatomegaly causes|Causes]]==
== Differential Diagnosis ==
Patients with hepatomegaly need to be differentiated from other patients presenting with similar complaints such as abdominal pain.<ref name="pmid10970452">{{cite journal |vauthors=Wolf AD, Lavine JE |title=Hepatomegaly in neonates and children |journal=Pediatr Rev |volume=21 |issue=9 |pages=303–10 |year=2000 |pmid=10970452 |doi= |url=}}</ref><ref name="pmid16454833">{{cite journal |vauthors=Chau TN, Lai ST, Tse C, Ng TK, Leung VK, Lim W, Ng MH |title=Epidemiology and clinical features of sporadic hepatitis E as compared with hepatitis A |journal=Am. J. Gastroenterol. |volume=101 |issue=2 |pages=292–6 |year=2006 |pmid=16454833 |doi=10.1111/j.1572-0241.2006.00416.x |url=}}</ref><ref name="pmid23485521">{{cite journal |vauthors=Bernstein DL, Hülkova H, Bialer MG, Desnick RJ |title=Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease |journal=J. Hepatol. |volume=58 |issue=6 |pages=1230–43 |year=2013 |pmid=23485521 |doi=10.1016/j.jhep.2013.02.014 |url=}}</ref><ref name="pmid16625098">{{cite journal |vauthors=Torbenson M, Chen YY, Brunt E, Cummings OW, Gottfried M, Jakate S, Liu YC, Yeh MM, Ferrell L |title=Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus |journal=Am. J. Surg. Pathol. |volume=30 |issue=4 |pages=508–13 |year=2006 |pmid=16625098 |doi= |url=}}</ref><ref name="pmid8982149">{{cite journal |vauthors=Chatila R, West AB |title=Hepatomegaly and abnormal liver tests due to glycogenosis in adults with diabetes |journal=Medicine (Baltimore) |volume=75 |issue=6 |pages=327–33 |year=1996 |pmid=8982149 |doi= |url=}}</ref><ref name="pmid28043933">{{cite journal |vauthors=Mukewar S, Sharma A, Lackore KA, Enders FT, Torbenson MS, Kamath PS, Roberts LR, Kudva YC |title=Clinical, Biochemical, and Histopathology Features of Patients With Glycogenic Hepatopathy |journal=Clin. Gastroenterol. Hepatol. |volume=15 |issue=6 |pages=927–933 |year=2017 |pmid=28043933 |doi=10.1016/j.cgh.2016.11.038 |url=}}</ref><ref name="pmid11025794">{{cite journal |vauthors=Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, Rosenbloom BE, Scott CR, Wappner RS, Weinreb NJ, Zimran A |title=The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease |journal=Arch. Intern. Med. |volume=160 |issue=18 |pages=2835–43 |year=2000 |pmid=11025794 |doi= |url=}}</ref><ref name="pmid18312287">{{cite journal |vauthors=Drebber U, Kasper HU, Ratering J, Wedemeyer I, Schirmacher P, Dienes HP, Odenthal M |title=Hepatic granulomas: histological and molecular pathological approach to differential diagnosis--a study of 442 cases |journal=Liver Int. |volume=28 |issue=6 |pages=828–34 |year=2008 |pmid=18312287 |doi=10.1111/j.1478-3231.2008.01695.x |url=}}</ref><ref name="pmid14530778">{{cite journal |vauthors=Park MA, Mueller PS, Kyle RA, Larson DR, Plevak MF, Gertz MA |title=Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients |journal=Medicine (Baltimore) |volume=82 |issue=5 |pages=291–8 |year=2003 |pmid=14530778 |doi=10.1097/01.md.0000091183.93122.c7 |url=}}</ref><ref name="pmid8943863">{{cite journal |vauthors=Cooke CB, Krenacs L, Stetler-Stevenson M, Greiner TC, Raffeld M, Kingma DW, Abruzzo L, Frantz C, Kaviani M, Jaffe ES |title=Hepatosplenic T-cell lymphoma: a distinct clinicopathologic entity of cytotoxic gamma delta T-cell origin |journal=Blood |volume=88 |issue=11 |pages=4265–74 |year=1996 |pmid=8943863 |doi= |url=}}</ref><ref name="pmid870368">{{cite journal |vauthors=Long RG, Scheuer PJ, Sherlock S |title=Presentation and course of asymptomatic primary biliary cirrhosis |journal=Gastroenterology |volume=72 |issue=6 |pages=1204–7 |year=1977 |pmid=870368 |doi= |url=}}</ref><ref name="pmid19501929">{{cite journal |vauthors= |title=EASL Clinical Practice Guidelines: management of cholestatic liver diseases |journal=J. Hepatol. |volume=51 |issue=2 |pages=237–67 |year=2009 |pmid=19501929 |doi=10.1016/j.jhep.2009.04.009 |url=}}</ref>


==[[Hepatomegaly differential diagnosis|Differentiating Hepatomegaly from other Diseases]]==
<span style="font-size:85%">'''Abbreviations:'''
'''[[RUQ]]'''= Right upper quadrant of the abdomen, '''LUQ'''= Left upper quadrant, '''LLQ'''= Left lower quadrant, '''RLQ'''= Right lower quadrant, '''LFT'''= Liver function test, SIRS= [[Systemic inflammatory response syndrome]], '''[[ERCP]]'''= [[Endoscopic retrograde cholangiopancreatography]], '''IV'''= Intravenous, '''N'''= Normal, '''AMA'''= Anti mitochondrial antibodies, '''[[LDH]]'''= [[Lactate dehydrogenase]], '''GI'''= Gastrointestinal, '''CXR'''= Chest X ray, '''IgA'''= [[Immunoglobulin A]], '''IgG'''= [[Immunoglobulin G]], '''IgM'''= [[Immunoglobulin M]], '''CT'''= [[Computed tomography]], '''[[PMN]]'''= Polymorphonuclear cells, '''[[ESR]]'''= [[Erythrocyte sedimentation rate]], '''[[CRP]]'''= [[C-reactive protein]], TS= [[Transferrin saturation]], SF= Serum [[Ferritin]], SMA= [[Superior mesenteric artery]], SMV= [[Superior mesenteric vein]], ECG= [[Electrocardiogram]], US = [[Ultrasound]]</span>


==[[Hepatomegaly risk factors|Risk Factors]]==
{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
 
! rowspan="3" align="center" style="background:#4479BA; color: #FFFFFF;" |Organ system
==[[Hepatomegaly natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
! rowspan="3" style="background:#4479BA; color: #FFFFFF;" align="center" |Disease
 
| colspan="7" rowspan="1" style="background:#4479BA; color: #FFFFFF;" align="center" |'''Clinical manifestations'''
==Diagnosis==
! colspan="2" rowspan="2" style="background:#4479BA; color: #FFFFFF;" align="center" |Diagnosis
 
! rowspan="3" style="background:#4479BA; color: #FFFFFF;" align="center" |Comments
[[Hepatomegaly history and symptoms|History and Symptoms]] | [[Hepatomegaly physical examination|Physical Examination]] | [[Hepatomegaly laboratory findings|Laboratory Findings]] | [[Hepatomegaly CT|CT]] | [[Hepatomegaly MRI|MRI]] | [[Hepatomegaly ultrasound|Ultrasound]] | [[Hepatomegaly other imaging findings|Other Imaging Findings]] | [[Hepatomegaly other diagnostic studies|Other Diagnostic Studies]]
|-
 
| colspan="5" rowspan="1" style="background:#4479BA; color: #FFFFFF;" align="center" |'''Symptoms'''
==Treatment==
! colspan="2" rowspan="1" style="background:#4479BA; color: #FFFFFF;" align="center" | Signs
 
|-
[[Hepatomegaly medical therapy|Medical Therapy]] | [[Hepatomegaly surgery|Surgery]] | [[Hepatomegaly prevention|Prevention]] | [[Hepatomegaly cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Hepatomegaly future or investigational therapies|Future or Investigational Therapies]]
! style="background:#4479BA; color: #FFFFFF;" align="center" |Abdominal Pain
 
! colspan="1" rowspan="1" style="background:#4479BA; color: #FFFFFF;" align="center" | Fever
==Case Studies==
! style="background:#4479BA; color: #FFFFFF;" align="center" |Nausea or vomiting
[[Hepatomegaly case study one|Case #1]]
! style="background:#4479BA; color: #FFFFFF;" align="center" |Jaundice
 
! style="background:#4479BA; color: #FFFFFF;" align="center" |Weight loss
==Related Chapters==
! style="background:#4479BA; color: #FFFFFF;" align="center" |Hypo-
tension
! style="background:#4479BA; color: #FFFFFF;" align="center" |Rebound Tenderness
! colspan="1" rowspan="1" style="background:#4479BA; color: #FFFFFF;" align="center" | Lab Findings
! style="background:#4479BA; color: #FFFFFF;" align="center" |Imaging
|-
! rowspan="3" align="center" style="background:#4479BA; color: #FFFFFF;" |Pancreato-biliary disorders
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |[[Pancreatic carcinoma]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Epigastric]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* ↑ [[Alkaline phosphatase]]
* ↑ [[Bilirubin|serum bilirubin]]
* ↑ [[gamma-glutamyl transpeptidase]]
* ↑ [[CA 19-9]] 
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Computed tomography|MDCT]] with   [[Positron emission tomography|PET]]/[[Computed tomography|CT]]
* MRI
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
[[Skin]] manifestations may include:
* [[Bullous pemphigoid]]
* [[Mucous membrane pemphigoid|Cicatricial pemphigoid]]
* [[Thrombophlebitis|Migratory superficial thrombophlebitis]] (classic [[Trousseau's syndrome]])
* [[Panniculitis|Pancreatic panniculitis]]
|-
| colspan="1" rowspan="1" style="padding: 5px 5px; background: #DCDCDC;" align="center" |[[Primary biliary cirrhosis]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[RUQ]]/[[Epigastric]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Increased [[AMA]] level
* Abnormal [[LFTs]]
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* ERCP
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Pruritis
|-
| colspan="1" rowspan="1" style="padding: 5px 5px; background: #DCDCDC;" align="center" |[[Primary sclerosing cholangitis]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[RUQ]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Increased liver enzymes
* Increased [[IgM]], [[IgG]]4
* [[Anti-neutrophil cytoplasmic antibody]] ([[p-ANCA]])
* [[Anti-nuclear antibody]] ([[ANA]])
* [[Anti-smooth muscle antibody]] (Anti-Sm)
* Anti-endothelial antibody
* [[Anti-cardiolipin antibodies|Anti-cardiolipin antibody]]
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |ERCP and MRCP shows
* Multiple segmental [[strictures]]
* Mural irregularities
* [[Biliary]] dilatation and diverticula
* Distortion of biliary tree
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* The risk of [[cholangiocarcinoma]] in patients with primary sclerosing cholangitis is 400 times higher than the risk in the general population.
|-
| rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" |'''Systemic disease'''
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |[[Whipple's disease]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Diffuse
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | ±
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | ±
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | ±
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Thrombocytopenia]]
* [[Hypoalbuminemia]]
* [[Small intestinal]] [[biopsy]] for [[Tropheryma whipplei]]
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |[[Whipple's disease other diagnostic studies|Endoscopy]] is used to confirm diagnosis.
Images used to find complications
*[[Whipple's disease x ray|Chest and joint x-ray]]
*[[Whipple's disease CT|CT]]
*[[Whipple's disease MRI|MRI]]
*[[Whipple's disease ultrasound|Echocardiography]]
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |Extra intestinal findings:
* [[Uveitis]]
* [[Endocarditis]]
* [[Encephalitis]]
* [[Dementia]]
* [[Hepatosplenomegaly]]
* [[Hepatosplenomegaly]]
* [[Arthritis]]
* [[Ascites]]
|-
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |[[Hemochromatosis]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |RUQ
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
* >60% TS
* >240 μg/L SF
* Raised LFT
* Hyperglycemia
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
* Ultrasound shows evidence of cirrhosis
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Extra intestinal findings:
* Hyperpigmentation
* Diabetes mellitus
* Arthralgia
* Impotence in males
* Cardiomyopathy
* Atherosclerosis
* Hypopituitarism
* Hypothyroidism
* Extrahepatic cancer
* Prone to specific infections
|-
! rowspan="3" align="center" style="background:#4479BA; color: #FFFFFF;" |Hematologic causes
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |Myeloma
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Diffuse
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | ±
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | ±
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Anemia]]
* Elevated ESR and CRP
* Proteinuria
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Mainly in old age
* Back pain
* Kidney involvement
|-
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |Lymphoma
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Diffuse
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | ±
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Anemia
* Elevated ESR and CRP
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
|-
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |Leukemia
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Diffuse
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | ±
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | ±
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Anemia
* Elevated ESR and CRP
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
|-
! align="center" style="background:#4479BA; color: #FFFFFF;" |
! style="background:#4479BA; color: #FFFFFF;" align="center" |Disease
! style="background:#4479BA; color: #FFFFFF;" align="center" |Abdominal Pain
! style="background:#4479BA; color: #FFFFFF;" align="center" |Fever
! style="background:#4479BA; color: #FFFFFF;" align="center" |Nausea or vomiting
! style="background:#4479BA; color: #FFFFFF;" align="center" |Jaundice
! style="background:#4479BA; color: #FFFFFF;" align="center" |Weight loss
! style="background:#4479BA; color: #FFFFFF;" align="center" |Hypo-
tension
! style="background:#4479BA; color: #FFFFFF;" align="center" |Rebound Tenderness
! style="background:#4479BA; color: #FFFFFF;" align="center" |Lab Findings
! style="background:#4479BA; color: #FFFFFF;" align="center" |Imaging
! style="background:#4479BA; color: #FFFFFF;" align="center" |Comments
|-
! rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" |Cardiac causes
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |Heart failure
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Diffuse/ RLQ/LLQ
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | ±
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* CBC
* Increased BNP and Pro BNP
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Echocardiography
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Exertional dyspnea
* Chest pain
* Edema
|-
! style="padding: 5px 5px; background: #DCDCDC;" align="center" |Constrictive pericarditis
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Diffuse/ RLQ/LLQ
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |±
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |−
! style="padding: 5px 5px; background: #F5F5F5;" align="center" |-
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
* Echocardiography
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |
* Exertional dyspnea
* Chest pain
* Edema
|-
! rowspan="4" align="center" style="background:#4479BA; color: #FFFFFF;" |Hepatic causes
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |[[Hepatitis|Viral hepatitis]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[RUQ]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | Positive in fulminant hepatitis
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Abnormal LFTs
* Viral serology
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* US
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Hep A and E have fecal-oral route of transmission
* Hep B and C transmits via blood transfusion and sexual contact.
|-
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |[[Liver abscess]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |RUQ
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | ±
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* CBC
* Blood cultures
* Abnormal [[Liver function test|liver function tests]]
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* US
* CT
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
|-
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |[[Hepatocellular carcinoma]]/[[Metastasis]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |RUQ
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | +
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |<nowiki>+</nowiki>
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* High levels of [[Alpha-fetoprotein|AFP]] in serum
* Abnormal [[Liver function test|liver function tests]]
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* US
* CT
* Liver biopsy
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
Other symptoms:
* [[Splenomegaly]]
* [[Variceal bleeding]]
* [[Ascites]]
* [[Spider nevi]]
* [[Asterixis]]
|-
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |[[Budd-Chiari syndrome|Budd-Chiari syndrome]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[RUQ]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | ±
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | ±
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="center" | −
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |
*Elevated [[Aspartate aminotransferase|serum aspartate aminotransferase]] and [[alanine aminotransferase]] levels may be more than five times the upper limit of the normal range.
*Elevated serum [[alkaline phosphatase]] and [[Bilirubin|bilirubin levels]], decreased [[Albumin|serum albumin level]].
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |CT scan findings:
* Early enhancement of the [[caudate lobe]] and [[central liver]] around the [[Inferior vena cavae|inferior vena cava]]
*Delayed enhancement of the peripheral [[liver]] with accompanying central low density (flip-flop appearance)
| style="padding: 5px 5px; background: #F5F5F5;" align="left" |[[Ascitic tap|Ascitic fluid examination]] shows:
*[[Total protein]] more than 2.5 g per deciliter
*[[White blood cells]] are usually less than 500/μL.
|-
|}


==External links==
==References==
* [http://www.nlm.nih.gov/medlineplus/ency/ National Institute of Health's Medline Plus Medical Encyclopedia]
{{Reflist|2}}
* [http://www.nlm.nih.gov/medlineplus/ency/article/003275.htm Hepatomegaly]
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Latest revision as of 22:08, 29 July 2020

Hepatomegaly

For patient information on this topic, click here.

Hepatomegaly Microchapters

Home

Patient Information

Overview

Causes

Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Seyedmahdi Pahlavani, M.D. [2],Iqra Qamar M.D.[3]
Synonyms and keywords: Enlarged liver; liver enlargement

Overview

The liver is an organ present in vertebrates and some other animals. The adult human liver normally weighs between 1.4 to 1.6 kilograms (3.1 to 3.5 pounds), and it is a soft, pinkish-brown "boomerang shaped" organ. It is located on the right side of the upper abdomen below the diaphragm. The size of the liver increases with age and ranges between 5 cm to 15 cm in adulthood. A normal liver is less than 16 cm on ultrasound evaluation. Hepatomegaly may be found during physical examination or on imaging studies. Imaging is more accurate in determining liver size.[1][2] In some conditions normal liver may be palpated as enlarged liver including thin people, during deep inspiration, right pleural effusion, and emphysema resulting in hyperinflation of the chest with diaphragmatic descent and downward displacement of the liver. Common pathological causes that may result in hepatomegaly are hepatitis, storage disorders, impaired venous outflow, infiltrative disorders, and biliary obstruction.

Causes

Various causes of hepatomegaly may be classified on the basis of etiology into hepatitis, storage disorders, impaired venous outflow, infiltrative, and obstructive causes.[3][4][5][6][7][8][9][10][11][12][13][14]

Etiology Disease
Hepatitis Infections Acute and chronic viral hepatitis
Bacterial liver abscess
Parasitic infections
Granulomatous hepatitis
Ischemia Ischemic hepatitis ("shock liver")
Toxins Alcoholic hepatitis
Steatosis Alcoholic fatty liver disease
Nonalcoholic steatohepatitis
Medications Drug induced liver injury (DILI)
Immune mediated hepatitis Autoimmune hepatitis
Copper deposition Wilson disease
Storage disorders Glycogen Glycogen storage disorders
Diabetes mellitus
Lipid Gaucher disease
Nonalcoholic steatohepatitis
Protein Alpha-1 antitrypsin deficiency
Iron Hemochromatosis
Impaired venous outflow Cardiac Right heart failure
Constrictive pericarditis
Hepatic vein Hepatic vein thrombosis
Inferior vena cava web
Intrahepatic Sinusoidal obstruction syndrome
Peliosis hepatis
Infiltrative diseases Benign primary liver tumors Hemangiomas
Adenomas
Focal nodular hyperplasia
Malignant primary liver tumors Hepatocellular carcinoma
Cholangiocarcinoma
Fibrolamellar carcinoma
Hemangioendothelioma
Metastatic or disseminated tumors Myeloma
Lymphoma
Leukemia
Metastatic solid tumors
Biliary obstruction Primary biliary cirrhosis
Primary sclerosing cholangitis
Biliary atresia
Other Anatomic variations Riedel's lobe
Cystic liver disease Polycystic liver disease
Caroli's disease

Differential Diagnosis

Patients with hepatomegaly need to be differentiated from other patients presenting with similar complaints such as abdominal pain.[3][4][5][6][7][8][9][10][11][12][13][14]

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram, US = Ultrasound

Organ system Disease Clinical manifestations Diagnosis Comments
Symptoms Signs
Abdominal Pain Fever Nausea or vomiting Jaundice Weight loss Hypo-

tension

Rebound Tenderness Lab Findings Imaging
Pancreato-biliary disorders Pancreatic carcinoma Epigastric + + +

Skin manifestations may include:

Primary biliary cirrhosis RUQ/Epigastric +
  • ERCP
  • Pruritis
Primary sclerosing cholangitis RUQ + + ERCP and MRCP shows
  • Multiple segmental strictures
  • Mural irregularities
  • Biliary dilatation and diverticula
  • Distortion of biliary tree
  • The risk of cholangiocarcinoma in patients with primary sclerosing cholangitis is 400 times higher than the risk in the general population.
Systemic disease Whipple's disease Diffuse ± ± + ± Endoscopy is used to confirm diagnosis.

Images used to find complications

Extra intestinal findings:
Hemochromatosis RUQ
  • >60% TS
  • >240 μg/L SF
  • Raised LFT
  • Hyperglycemia
  • Ultrasound shows evidence of cirrhosis
Extra intestinal findings:
  • Hyperpigmentation
  • Diabetes mellitus
  • Arthralgia
  • Impotence in males
  • Cardiomyopathy
  • Atherosclerosis
  • Hypopituitarism
  • Hypothyroidism
  • Extrahepatic cancer
  • Prone to specific infections
Hematologic causes Myeloma Diffuse ± + ±
  • Anemia
  • Elevated ESR and CRP
  • Proteinuria
  • Mainly in old age
  • Back pain
  • Kidney involvement
Lymphoma Diffuse + + ±
  • Anemia
  • Elevated ESR and CRP
Leukemia Diffuse + ± + ±
  • Anemia
  • Elevated ESR and CRP
Disease Abdominal Pain Fever Nausea or vomiting Jaundice Weight loss Hypo-

tension

Rebound Tenderness Lab Findings Imaging Comments
Cardiac causes Heart failure Diffuse/ RLQ/LLQ + ±
  • CBC
  • Increased BNP and Pro BNP
  • Echocardiography
  • Exertional dyspnea
  • Chest pain
  • Edema
Constrictive pericarditis Diffuse/ RLQ/LLQ + ± -
  • Echocardiography
  • Exertional dyspnea
  • Chest pain
  • Edema
Hepatic causes Viral hepatitis RUQ + + + + Positive in fulminant hepatitis +
  • Abnormal LFTs
  • Viral serology
  • US
  • Hep A and E have fecal-oral route of transmission
  • Hep B and C transmits via blood transfusion and sexual contact.
Liver abscess RUQ + + + + + ±
  • US
  • CT
Hepatocellular carcinoma/Metastasis RUQ + + +
  • US
  • CT
  • Liver biopsy

Other symptoms:

Budd-Chiari syndrome RUQ ± ± CT scan findings: Ascitic fluid examination shows:

References

  1. Sapira JD, Williamson DL (1979). "How big is the normal liver?". Arch Intern Med. 139 (9): 971–3. PMID 475535.
  2. Niederau C, Sonnenberg A, Müller JE, Erckenbrecht JF, Scholten T, Fritsch WP (1983). "Sonographic measurements of the normal liver, spleen, pancreas, and portal vein". Radiology. 149 (2): 537–40. doi:10.1148/radiology.149.2.6622701. PMID 6622701.
  3. 3.0 3.1 Wolf AD, Lavine JE (2000). "Hepatomegaly in neonates and children". Pediatr Rev. 21 (9): 303–10. PMID 10970452.
  4. 4.0 4.1 Chau TN, Lai ST, Tse C, Ng TK, Leung VK, Lim W, Ng MH (2006). "Epidemiology and clinical features of sporadic hepatitis E as compared with hepatitis A". Am. J. Gastroenterol. 101 (2): 292–6. doi:10.1111/j.1572-0241.2006.00416.x. PMID 16454833.
  5. 5.0 5.1 Bernstein DL, Hülkova H, Bialer MG, Desnick RJ (2013). "Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease". J. Hepatol. 58 (6): 1230–43. doi:10.1016/j.jhep.2013.02.014. PMID 23485521.
  6. 6.0 6.1 Torbenson M, Chen YY, Brunt E, Cummings OW, Gottfried M, Jakate S, Liu YC, Yeh MM, Ferrell L (2006). "Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus". Am. J. Surg. Pathol. 30 (4): 508–13. PMID 16625098.
  7. 7.0 7.1 Chatila R, West AB (1996). "Hepatomegaly and abnormal liver tests due to glycogenosis in adults with diabetes". Medicine (Baltimore). 75 (6): 327–33. PMID 8982149.
  8. 8.0 8.1 Mukewar S, Sharma A, Lackore KA, Enders FT, Torbenson MS, Kamath PS, Roberts LR, Kudva YC (2017). "Clinical, Biochemical, and Histopathology Features of Patients With Glycogenic Hepatopathy". Clin. Gastroenterol. Hepatol. 15 (6): 927–933. doi:10.1016/j.cgh.2016.11.038. PMID 28043933.
  9. 9.0 9.1 Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, Rosenbloom BE, Scott CR, Wappner RS, Weinreb NJ, Zimran A (2000). "The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease". Arch. Intern. Med. 160 (18): 2835–43. PMID 11025794.
  10. 10.0 10.1 Drebber U, Kasper HU, Ratering J, Wedemeyer I, Schirmacher P, Dienes HP, Odenthal M (2008). "Hepatic granulomas: histological and molecular pathological approach to differential diagnosis--a study of 442 cases". Liver Int. 28 (6): 828–34. doi:10.1111/j.1478-3231.2008.01695.x. PMID 18312287.
  11. 11.0 11.1 Park MA, Mueller PS, Kyle RA, Larson DR, Plevak MF, Gertz MA (2003). "Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients". Medicine (Baltimore). 82 (5): 291–8. doi:10.1097/01.md.0000091183.93122.c7. PMID 14530778.
  12. 12.0 12.1 Cooke CB, Krenacs L, Stetler-Stevenson M, Greiner TC, Raffeld M, Kingma DW, Abruzzo L, Frantz C, Kaviani M, Jaffe ES (1996). "Hepatosplenic T-cell lymphoma: a distinct clinicopathologic entity of cytotoxic gamma delta T-cell origin". Blood. 88 (11): 4265–74. PMID 8943863.
  13. 13.0 13.1 Long RG, Scheuer PJ, Sherlock S (1977). "Presentation and course of asymptomatic primary biliary cirrhosis". Gastroenterology. 72 (6): 1204–7. PMID 870368.
  14. 14.0 14.1 "EASL Clinical Practice Guidelines: management of cholestatic liver diseases". J. Hepatol. 51 (2): 237–67. 2009. doi:10.1016/j.jhep.2009.04.009. PMID 19501929.

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