Mallory Bodies


Article Author:
Emir Kurtovic


Article Editor:
Faten Limaiem


Editors In Chief:
Linda Lindsay


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
7/30/2019 10:10:39 PM

Introduction

Mallory bodies (MB), also known as Mallory-Denk bodies (MDB), are cytoplasmic hyaline inclusions of hepatocytes, once thought to be specific for alcoholic hepatitis now occur in other liver diseases which include nonalcoholic steatohepatitis (NASH), cholestatic liver diseases, primary biliary cirrhosis (PBC) and hepatocellular carcinoma (HCC).[1][2] In 1911, Frank Burr Mallory (1862-1941) discovered these bodies while examining the hepatocytes of patients with alcoholic hepatitis. In 1975, Helmut Denk found the first animal model of Mallory bodies by feeding mice griseofulvin, which allowed further research on Mallory bodies resulted in the renaming to Mallory-Denk bodies (MDB).[1]

Issues of Concern

The development of Mallory-Denk bodies indicates that intracellular protein quality has failed.[3]

Causes

In general, Mallory-Denk body formation presents in liver diseases. Those include hepatitis B and C, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), HCC, PBC, chronic cholestasis, focal nodular hyperplasia Wilson disease, and copper toxicosis.[4]

However, it also presents in glucocorticoid therapy, intestinal bypass surgery for obesity, Weber-Christian disease, von Gierke disease, radiation pneumonitis, asbestosis, amiodarone, a beta lipoproteinemia, porphyria cutanea tarda, antitrypsin deficiency, Indian childhood cirrhosis, perhexiline maleate hepatitis, cirrhosis, 2′3′-dideoxyinosine diethylaminoetheoxyhex-estriol-induced hepatitis, hepatic adenoma, sclerosing hyaline necrosis in Bloom syndrome, congenital fibrosis.[5]

Rarely do Mallory-Denk bodies present in nonhepatic cells, but examples do exist which present as in asbestosis renal cell carcinoma and type 2 pneumocytes.[1]

Anatomical Pathology

P62 (a sequestosome), ubiquitin, and intermediate filament proteins keratins 8 and 18 (K8/18) are the significant elements that make up a Mallory body.[1] In normal conditions, K8 and 18 are present in a 1 to 1 ratio.[6] Protein misfolding, proteasome overload, a ratio of K8 greater than K18 and including transamidation of K8 contribute to MDB formation [7]. K8 is insoluble and not easily amenable to degradation, thus resulting in Mallory-Denk bodies. While overexpression of K18 inhibits MDB formation.[1] K8 is more likely to change its helical shape to cross-beta sheets resulting in Mallory-Denk body formation. Those that do not have K8 do not make MDB thus linking cross-beta sheets as a necessity for MDB development.[8]

Clinical Pathology

Cytoplasmic inclusion bodies intracytoplasmic hyaline bodies (IHB) and Mallory-Denk bodies can be present in HCC. MDB was linked steatohepatitis variant of HCC while intracytoplasmic hyaline bodies (IHB) was not. However, the presence of IHB correlates shorter survival than MDB.[9] MDB is distinguishable from other cytoplasmic inclusions such as IHB. For example, MDB consists of ubiquitin, p62, and keratin, while IHB has only ubiquitin and p62. IHBs have intracytoplasmic hyaline bodies been found to be a morphological precursor to MDB.[1]

Morphology

MDBs are cytoplasmic inclusions that are predominantly filamentous ranging from a diameter of 3 to 24 nm vs. 10 nm of classical IF.[1] Mallory-Denk bodies can be classified as type I (parallels filaments), II (randomly orient filaments), or III (granular and amorphous). Type II occurs in the periphery while type III occurs around the center. MDB occur in ballooned hepatocytes. They are visible via hematoxylin-eosin stain, however immunohistochemical staining to CK or ubiquitin is more sensitive. Pericellular fibrosis and neutrophil tend to surround the hepatocytes with MDB are called satellitosis.[1][10] Distribution of MDB in the cells suggests different stages of their formation. For example, small cytoplasmic globular structures are early, large para-nuclear inclusions are mature, and the ones located in the periphery are considered old.[1] MDB can be found in different zones of the liver and varies depending on the disease process. In primary biliary cholangitis and Wilson disease, it is seen in zone 1, whereas in ASH and NAFLD it is present in zone 3.[4]

Mechanisms

As Denk had used griseofulvin in his study to create MDB, recent studies have used diethyl-1, 4-dihydro-2, 4, 6-trimethyl-3, 5-pyridine dicarboxylate (DDC).[11] DDC induced MDB faster than griseofulvin. They have proposed that there are three mechanisms in the formation of MDB.

Before MDB occur, ballooning of hepatocytes occurs first, which are the response of oxidative stress, such as abnormal protein (heat shock proteins) or fat result in water accumulation into the hepatic cytoplasm.[4]  HSP formation indicated cellular dysfunction

The first mechanism is that epigenetics (acetylation, methylation, and ubiquitination of histones) contribute to hepatocyte memory during MDB formation.[12]

The second pathway is the shift from the 26s proteasome to the immunoproteasome. The 26S proteasome plays a part in degradation intracellular (cytosolic, nuclear and membrane) proteins.[13]  The way DDC induces MDB is that it changes 26s proteasome to immunoproteasome, thus resulting in protein accumulation.[7] When chaperones (i.e., heat shock protein 70), proteins that refold misfolded proteins, become flawed, inclusion bodies such as MDB form. Alcohol and DDC cause chaperons to become defected. Misfolded proteins are targeted by ubiquitination, which signals the molecule via p62 for proteasomal and autophagic degradation.[1]

The third is the chronic activation of the Toll-like signaling pathways which stimulate proinflammatory and cell growth pathways. IFN-gamma and TNF-alpha stimulate TLR receptors, which cause up-regulation of growth factor resulting in the proliferation of MDB forming cells. Drugs as well can create a shift to the formation of the immunoproteasome rather than the 26s proteasome.[7]

DDC stimulates tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) expression, which in turn activates the toll-like receptor (TLR). Proinflammatory cytokines TNF-alpha and IFN-gamma via TLR signaling cause up-regulation of the immunoproteasome and down-regulation of the 26s proteasome which results in undigested proteins and MDB formation.[7]

Clinicopathologic Correlations

Clinical findings of ASH (jaundice, leukocytosis, fever) may demonstrate classical histological finding of steatosis; however few or no MDB.  The opposite may be true, as well.[1] MDB is noted to be fewer and less developed in NASH, which tends to be less severe of the two. NASH in children often do not have MDB, which suggests aging may play a role as well.[1] MDB as a NAFLD marker depends on the histological scoring system. Matteoni et al. emphasized MDB while Kleiner et al., which is a more accepted scoring system, did not.[1] Some recommend for KRT8/K18 ratio to be a biomarker for HCC.[6] In alcohol using patient, a sensitive and specific test to detect MDB is Ub/immunostaining.[4]

Inclusions do occur in the liver, muscle, and neural tissues which suggest a common intracellular network of protein synthesis and degradation along with responsiveness to stressors. MBD can be considered a protective mechanism of cell injury or rather a step in the pathogenesis of liver damage.[4]

Clinical Significance

Abnormal protein folding is known to cause other diseases, including Alzheimer disease.  In a recent literature review,[5] there is common ground in the mechanism involved Alzheimer disease and MDB formation. Due to its similarities, the proposal was that future studies should test betaine or SAMe (methyl donors) effect on Alzheimer disease, as they have shown to prevent MDB formation. Beta sheets which are present in amyloid deposits are also present in MDB.[1]

Denk, in his publication, notes that MDB formation occurs secondary to abnormal hyperkeratosis, which has links to Vitamin A deficiency.  In his animal study, Vitamin A level was decreased from 30% at day 12 of treatment with Griseofulvin down to13% at 60 days.[14]

In patients with alcoholic liver disease, about 70 to 75% have MDB.  However, in patients with NAFLD, MDB ranges from 7% to 90%.[4] The wide range of MDB in NAFLD is likely the result of not having the specific amount which qualifies as excessive alcohol use, which would categorize the patient as alcoholic rather than non-alcoholic.

In severe alcoholic hepatitis, non-responders to corticosteroids had high histopathological findings of ballooning degeneration and MDB suggesting that histopathology findings can identify those who may respond to corticosteroids.[15] Studies have shown that autophagy contributes to MDB degradation along with other intracellular compartments.[16][17][18] Fenofibrate, a fibric acid derivative that lowers cholesterol, prevented MDB formation by preventing disruption of intermediate filament.[19]

Methyl donors like Betaine and SAMe prevent MDB formation. SAMe prevents demethylation of histones, which occurs with DDC while Betaine prevents MDB formation by preventing the changes in methionine metabolism and by betaine-homocysteine methyltransferase (BHMT) methionine increases from homocysteine.[12][7][20] TLR and p62 pathways are prevented by betaine and SAMe as well.


  • Image 11258 Not availableImage 11258 Not available
    Image courtesy Dr Chaigasame
Attributed To: Image courtesy Dr Chaigasame

Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Mallory Bodies - Questions

Take a quiz of the questions on this article.

Take Quiz
What is the composition of Mallory bodies?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 40-year-old female with a history of alcohol use, hyperlipidemia was evaluated outpatient for liver biopsy. Immunostaining of the hepatic sample has confirmed Mallory-Denk bodies (MDB). What proteins were found that also constitute intracytoplasmic hyaline bodies (IHB)?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 60-year-old obese male had an abdominal ultrasound performed for abdominal pain which demonstrated cirrhosis of the liver and a hepatic lesion. A biopsy confirmed hepatocellular carcinoma (HCC) with Mallory-Denk bodies present as well. With what variant of HCC is this associated?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 50-year-old female with a history of alcohol abuse and hepatitis C presents to the clinic with fatigue, non-bloody diarrhea, and vision disturbance at night. Vital signs show a temperature of 100.9 F, blood pressure of 106/77 mmHg and pulse 105/minute. Physical exam reveals jaundice and scleral icterus. Labs demonstrate white blood cell count 21,000/microL, aspartate aminotransferase 154 U/L, alanine aminotransferase 70 U/L and total bilirubin 5.2 mg/dl. Liver biopsy shows Mallory-Denk bodies. The vitamin deficiency responsible for night blindness in this patient is necessary for the formation of what molecule?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 17-year-old male with no significant past medical history presents with fatigue and jaundice. Vitals signs are stable. Physical exam reveals jaundice and a dark ring encircling the iris. Labs demonstrate alkaline phosphatase 53 IU/L, alanine aminotransferase 210 IU/L, aspartate aminotransferase 244 IU/L, and total bilirubin 6 mg/dl. Immunohistochemistry staining of the liver biopsy is positive for p62, ubiquitin, and keratin. Which test should be ordered for this disease?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 55-year-old woman undergoes right hepatectomy for a tumor. Histologically, the neoplasm is composed of atypical hepatocytes arranged predominantly in a trabecular and pseudoacinar pattern having pleomorphic vesicular nuclei, prominent nucleoli, and moderate cytoplasm. In the cytoplasm of tumor cells, there are irregular, ropelike eosinophilic intracytoplasmic strings. Immunohistochemistry shows positive staining of these intra-cytoplasmic inclusions for CK8 and CK18. What are the intra-cytoplasmic structures seen in the cytoplasm of tumor cells?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Mallory Bodies - References

References

Afifiyan N,Tillman B,French BA,Sweeny O,Masouminia M,Samadzadeh S,French SW, The role of Tec kinase signaling pathways in the development of Mallory Denk Bodies in balloon cells in alcoholic hepatitis. Experimental and molecular pathology. 2017 Oct;     [PubMed]
Zatloukal K,French SW,Stumptner C,Strnad P,Harada M,Toivola DM,Cadrin M,Omary MB, From Mallory to Mallory-Denk bodies: what, how and why? Experimental cell research. 2007 Jun 10;     [PubMed]
Aishima S,Fujita N,Mano Y,Iguchi T,Taketomi A,Maehara Y,Oda Y,Tsuneyoshi M, p62 Hyaline inclusions in intrahepatic cholangiocarcinoma associated with viral hepatitis or alcoholic liver disease. American journal of clinical pathology. 2010 Sep;     [PubMed]
Basaranoglu M,Turhan N,Sonsuz A,Basaranoglu G, Mallory-Denk Bodies in chronic hepatitis. World journal of gastroenterology. 2011 May 7;     [PubMed]
French SW,Mendoza AS,Peng Y, The mechanisms of Mallory-Denk body formation are similar to the formation of aggresomes in Alzheimer's disease and other neurodegenerative disorders. Experimental and molecular pathology. 2016 Jun;     [PubMed]
Golob-Schwarzl N,Bettermann K,Mehta AK,Kessler SM,Unterluggauer J,Krassnig S,Kojima K,Chen X,Hoshida Y,Bardeesy NM,Müller H,Svendova V,Schimek MG,Diwoky C,Lipfert A,Mahajan V,Stumptner C,Thüringer A,Fröhlich LF,Stojakovic T,Nilsson KPR,Kolbe T,Rülicke T,Magin TM,Strnad P,Kiemer AK,Moriggl R,Haybaeck J, High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype. Translational oncology. 2019 Feb;     [PubMed]
French SW,Bardag-Gorce F,Li J,French BA,Oliva J, Mallory-Denk body pathogenesis revisited. World journal of hepatology. 2010 Aug 27;     [PubMed]
Mahajan V,Klingstedt T,Simon R,Nilsson KP,Thueringer A,Kashofer K,Haybaeck J,Denk H,Abuja PM,Zatloukal K, Cross β-sheet conformation of keratin 8 is a specific feature of Mallory-Denk bodies compared with other hepatocyte inclusions. Gastroenterology. 2011 Sep;     [PubMed]
Aigelsreiter A,Neumann J,Pichler M,Halasz J,Zatloukal K,Berghold A,Douschan P,Rainer F,Stauber R,Haybaeck J,Denk H,Lackner C, Hepatocellular carcinomas with intracellular hyaline bodies have a poor prognosis. Liver international : official journal of the International Association for the Study of the Liver. 2017 Apr;     [PubMed]
Denk H,Stumptner C,Zatloukal K, Mallory bodies revisited. Journal of hepatology. 2000 Apr;     [PubMed]
Denk H,Franke WW,Eckerstorfer R,Schmid E,Kerjaschki D, Formation and involution of Mallory bodies (     [PubMed]
Harada M, Autophagy is involved in the elimination of intracellular inclusions, Mallory-Denk bodies, in hepatocytes. Medical molecular morphology. 2010 Mar;     [PubMed]
Harada M,Hanada S,Toivola DM,Ghori N,Omary MB, Autophagy activation by rapamycin eliminates mouse Mallory-Denk bodies and blocks their proteasome inhibitor-mediated formation. Hepatology (Baltimore, Md.). 2008 Jun;     [PubMed]
Ke PY, Diverse Functions of Autophagy in Liver Physiology and Liver Diseases. International journal of molecular sciences. 2019 Jan 13;     [PubMed]
Nikam A,Patankar JV,Somlapura M,Lahiri P,Sachdev V,Kratky D,Denk H,Zatloukal K,Abuja PM, The PPARα Agonist Fenofibrate Prevents Formation of Protein Aggregates (Mallory-Denk bodies) in a Murine Model of Steatohepatitis-like Hepatotoxicity. Scientific reports. 2018 Aug 28;     [PubMed]
Oliva J,Bardag-Gorce F,Li J,French BA,Nguyen SK,Lu SC,French SW, Betaine prevents Mallory-Denk body formation in drug-primed mice by epigenetic mechanisms. Experimental and molecular pathology. 2009 Apr;     [PubMed]
Yuan QX,Marceau N,French BA,Fu P,French SW, Mallory body induction in drug-primed mouse liver. Hepatology (Baltimore, Md.). 1996 Sep;     [PubMed]
Bardag-Gorce F,Oliva J,Villegas J,Fraley S,Amidi F,Li J,Dedes J,French B,French SW, Epigenetic mechanisms regulate Mallory Denk body formation in the livers of drug-primed mice. Experimental and molecular pathology. 2008 Apr;     [PubMed]
Livneh I,Cohen-Kaplan V,Cohen-Rosenzweig C,Avni N,Ciechanover A, The life cycle of the 26S proteasome: from birth, through regulation and function, and onto its death. Cell research. 2016 Aug;     [PubMed]
Shasthry SM,Rastogi A,Bihari C,Vijayaraghavan R,Arora V,Sharma MK,Sarin SK, Histological activity score on baseline liver biopsy can predict non-response to steroids in patients with severe alcoholic hepatitis. Virchows Archiv : an international journal of pathology. 2018 Apr     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of NP-Genetics. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for NP-Genetics, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in NP-Genetics, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of NP-Genetics. When it is time for the NP-Genetics board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study NP-Genetics.