What is Acute liver failure?

Acute liver failure (ALF) is a disorder in which severe acute impairment of liver function, with or without alteration of consciousness in association with liver cell damage in a child with no recognised underlying chronic liver disease
 

What are the symptoms of acute liver failure?

Symptoms of acute liver failure can be like those of a virus infection such as loss of appetite, nausea, vomiting, yellowing of skin and eyes, and a tired feeling all the time. These symptoms rapidly progress to bleeding tendency, irritability, excessive sleeping and even unconsciousness (encephalopathy).
Alteration of consciousness or encephalopathy occurs when a child has sudden and severe liver failure. Infants up to 28 days old may not have many noticeable signs of encephalopathy, although, they may have other symptoms as described above. Infants older than 28 days may be irritable, have crying spells and can't be made to feel better, or they might want to sleep more during the day than at night.
 

What are the causes of Acute liver failure in India?

 Causes of acute liver failure include:

• Viral causes like Hepatitis A, B, E, Dengue and other rarer viruses
• Drugs such as anti-tubercular drugs, pain killers such as nimesulide, anti-convulsants such as sodium valproate
• Toxins such as Carbon tetrachloride, Iron and paracetamol overdose
• Metabolic causes: Galactosaemia, Fructosaemia, Tyrosinaemia, Mitochondrial disorders.  Wilson disease is the commonest metabolic cause seen in India
• Autoimmune hepatitis
• Infiltrative: Leukaemia, Haemophagocytic lymphoistiocytosis, Haemangioendothelioma, Lymphangioendothelioma    
• Ischaemic: Budd-Chiari syndrome,  Heat stroke
• Cryptogenic -when the cause cannot be determined

 How is Acute liver failure diagnosed?

• Investigations should be aimed at establishing the diagnosis and finding the cause of acute liver failure. It is important to exclude conditions not treatable by liver transplantation
• Bone marrow examination is done to exclude: Haemophagocytic lymphohistiocytosis (HLH), Leukaemia, Lymphoma, Storage disorders and Mitochondrial Disorders
• Histopathology of the liver in children with acute liver failure does not contribute much to the management and is usually not performed.

What are the treatment options available?

 Supportive care: There are some patients who will get better on their own and need organ dysfunction to be temporarily supported as the liver is able to regenerate itself into a healthy organ.
Medication: When the acute liver failure is caused by acetaminophen or certain metabolic diseases, medications may be able to reverse the condition if irreversible damage has not yet occurred.
Liver Transplant: Approximately half of all children with acute liver failure need a liver transplant in order to survive. 
 

What are the general measures for management of acute liver failure?

 General Measures include; nursing the patient in quiet environment, avoiding any stimulation and pain, avoid hypoglycaemia (low blood sugars) and electrolyte imbalance. Role of Lactulose is not known, Sucralfate and Ranitidine are given. Nutrition supplementation of 1 gm/kg of protein is provided to the patient.
Assisted ventilation support is provided if the patient has hypoxia (low oxygenation), altered consciousness (encephalopathy) or before transferring patient to intensive care. 
 

What are the treatable causes of liver failure?

Management of treatable causes are as follows:

• Mushroom Poisoning              Penicillin
• Tyrosinemia                            NTBC
• Galactosemia                          Galactose free diet
• Herpes infection                      Acyclovir
• Paracetamol                           NAC
• Haemochromatosis             Antioxidant cocktail and IV Immunoglobulin in pregnancy

What is the management for the complications of acute liver failure?

• Encephalopathy is managed by using ammonia lowering agents, protein restriction, lactulose and gut decontamination. .
• Raised ICP (Intracranial pressure) is managed by giving Mannitol. It acts as osmotic diuretic and increases cerebral blood flow.
• Infections: Prophylactic treatment is provided to prevent infections. Bacterial and fungal infections can lead to sepsis causing death.
• Bleeding: Fresh frozen plasma is given if patients have bleeding from any site (as clotting factors are not produced by the liver) or an invasive procedure needs to be performed. 

Which disorders are not ‘cured’ by transplant?

• Mitochondrial disorders with neurological involvement (beware of valproate toxicity!)

• Niemann - Pick disease type C
• Giant-cell hepatitis with Coombs’ positive haemolytic anaemia
• Haemophagocytic lymphohistiocytosis
• Leukaemia - Lymphoma

Is there anything like a liver artificial support or liver dialysis?

 Yes. This system is called MARS. This is useful as a bridge to transplant, in order to tide over the crisis for few days. It is not a replacement for transplantation.
 

When is the patient advised a liver transplant for acute liver failure?     

Several criteria including the King's College criteria are used to decide on the need for transplantation. It is advised when the predicted outcome of OLT is better than that of underlying disease and there is no severe brain damage
 

What is Auxiliary Liver Transplant?

 When the original diseased liver is not removed and a small part of the donor liver is transplanted into the patient, the process is referred to as an auxiliary liver transplant. It acts as a bridge for recovery of the native liver. After the native liver regenerates, the immunosuppressive drugs (those administered for preventing the rejection of the new liver) are withdrawn, and the new liver shrinks away. This is specifically used sometimes in patients with acute liver failure.
 

Is liver transplant feasible in emergency?

 An organ donation from a deceased donor is usually not feasible at short notice in the Indian setting; therefore most patients would undergo a living related liver transplant where the donor is a close family member. It is feasible but there are several ethical issues in obtaining an informed consent in an emergency setting.
 

What is the long term prognosis of the child suffering from ALF?

 Prognosis depends on the cause of the liver failure. However early identification of the disease and timely care in a specialized center dedicated to pediatric liver disease can improve survival. Liver transplant early in the course of the disease has survival upto 75% at 5 years.

 Important Articles on Acute Liver Failure

1. Etiology and Prognostic Factors of Acute Liver Failure in Children.
    http://www.ncbi.nlm.nih.gov/pubmed/23255683
    Kaur S, Kumar P, Kumar V, Sarin SK, Kumar A.  
    Indian Pediatr. 2012 Nov 5. doi:pii: S097475591200142. [Epub ahead of print]   
    PMID: 23255683 [PubMed - as supplied by publisher]     
 
2. Ribavirin therapy for hepatitis E virus-induced acute on chronic liver failure: a
    preliminary report.
    http://www.ncbi.nlm.nih.gov/pubmed/22910532
    Goyal R, Kumar A, Panda SK, Paul SB, Acharya SK.      
    Antivir Ther. 2012;17(6):1091-6. doi: 10.3851/IMP2317. Epub 2012 Aug 16.       
    PMID: 22910532 [PubMed - indexed for MEDLINE]          
                             
3. Hepatic stellate cells are involved in the pathogenesis of acute-on-chronic liver failure
    (ACLF).
    Rastogi A, Bihari C, Maiwall R, Ahuja A, Sharma MK, Kumar A, Sarin SK.         
    Virchows Arch. 2012 Oct;461(4):393-8. doi: 10.1007/s00428-012-1291-2. Epub 2012 Aug
    PMID: 22886437 [PubMed - indexed for MEDLINE]          
                             
4. Persistent hyperammonemia is associated with complications and poor outcomes in
    patients with acute liver failure.
    http://www.ncbi.nlm.nih.gov/pubmed/22521861
    Kumar R, Shalimar, Sharma H, Prakash S, Panda SK, Khanal S, Acharya SK.  
    Clin Gastroenterol Hepatol. 2012 Aug;10(8):925-31. doi: 10.1016/j.cgh.2012.04.011.
    Epub 2012 Apr 17. 
    PMID: 22521861 [PubMed - indexed for MEDLINE]          
                             
5. Neuropathology of acute liver failure.
    http://www.ncbi.nlm.nih.gov/pubmed/22198438
    Thumburu KK, Taneja S, Vasishta RK, Dhiman RK.        
    Neurochem Int. 2012 Jun;60(7):672-5. doi: 10.1016/j.neuint.2011.10.013. Epub 2011 Dec 16.
    Review.      
    PMID: 22198438 [PubMed - indexed for MEDLINE]          
                             
 6. Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of
     patients with acute-on-chronic liver failure.
     http://www.ncbi.nlm.nih.gov/pubmed/22119930
     Garg V, Garg H, Khan A, Trehanpati N, Kumar A, Sharma BC, Sakhuja P, Sarin SK.   
     Gastroenterology. 2012 Mar;142(3):505-512.e1. doi: 10.1053/j.gastro.2011.11.027.
     Epub 2011 Nov 23.           
     PMID: 22119930 [PubMed - indexed for MEDLINE]       
 
7. Dengue fever presenting as acute liver failure--a case report.  
    http://www.ncbi.nlm.nih.gov/pubmed/21771479
    Jhamb R, Kashyap B, Ranga GS, Kumar A.         
    Asian Pac J Trop Med. 2011 Apr;4(4):323-4. doi: 10.1016/S1995-7645(11)60095-3.
    Epub 2011 May 29.
    PMID: 21771479 [PubMed - indexed for MEDLINE]          
 
8. Acute on chronic liver disease in children from the developing world: recognition and
    prognosis.
    http://www.ncbi.nlm.nih.gov/pubmed/21691224
    Jagadisan B, Srivastava A, Yachha SK, Poddar U.          
    J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):77-82. doi: 10.1097/MPG.0b013e318228d7da.   
    PMID: 21691224 [PubMed - indexed for MEDLINE]          
 
9. Predictors of outcome in acute-on-chronic liver failure in children.
    http://www.ncbi.nlm.nih.gov/pubmed/21484110
    Lal J, Thapa BR, Rawal P, Ratho RK, Singh K.    
     Hepatol Int. 2011 Jun;5(2):693-7. doi: 10.1007/s12072-010-9217-z. Epub 2010 Dec 28.
     PMID: 21484110 [PubMed] Free PMC Article
           
10. Tenofovir improves the outcome in patients with spontaneous reactivation of
     hepatitis B presenting as acute-on-chronic liver failure.
     http://www.ncbi.nlm.nih.gov/pubmed/21294143
     Garg H, Sarin SK, Kumar M, Garg V, Sharma BC, Kumar A.      
      Hepatology. 2011 Mar;53(3):774-80. doi: 10.1002/hep.24109. Epub 2011 Feb 3. Erratum in:
      Hepatology. 2011 Sep 2;54(3):1114.
      PMID: 21294143 [PubMed - indexed for MEDLINE]      
 
11. Intensive care management of children with acute liver failure.
      http://www.ncbi.nlm.nih.gov/pubmed/20799075
      Bhatia V, Lodha R.          
      Indian J Pediatr. 2010 Nov;77(11):1288-95. doi: 10.1007/s12098-010-0167-1. Epub
      2010 Aug 27.
      PMID: 20799075 [PubMed - indexed for MEDLINE]        
         
12. Non-hepatic insults are common acute precipitants in patients with acute on chronic
      liver failure (ACLF).
      http://www.ncbi.nlm.nih.gov/pubmed/20721624
      Duseja A, Chawla YK, Dhiman RK, Kumar A, Choudhary N, Taneja S.
       Dig Dis Sci. 2010 Nov;55(11):3188-92. doi: 10.1007/s10620-010-1377-0. Epub 2010 Aug 19. 
       PMID: 20721624 [PubMed - indexed for MEDLINE]     
                               
13. PFIC type III in infant presenting as acute liver cell failure.
      http://www.ncbi.nlm.nih.gov/pubmed/20551550
      Zaki SA, Shanbag P, Amarapurkar A.    
      Indian J Pathol Microbiol. 2010 Apr-Jun;53(2):334-6. doi: 10.4103/0377-4929.64326.
      PMID: 20551550 [PubMed - indexed for MEDLINE] Free Article            
                               
14. Antituberculosis therapy-induced acute liver failure: magnitude, profile, prognosis, and
      predictors of outcome.
      http://www.ncbi.nlm.nih.gov/pubmed/20196116
      Kumar R; Shalimar, Bhatia V, Khanal S, Sreenivas V, Gupta SD, Panda SK, Acharya SK.           
       Hepatology. 2010 May;51(5):1665-74. doi: 10.1002/hep.23534.
       PMID: 20196116 [PubMed - indexed for MEDLINE]     
                               
 15. Fulminant hepatic failure in an infant with severe dengue infection.
       http://www.ncbi.nlm.nih.gov/pubmed/20140763
       Soundravally R, Narayanan P, Bhat BV, Soundraragavan J, Setia S.  
       Indian J Pediatr. 2010 Apr;77(4):435-7. doi: 10.1007/s12098-010-0027-z. Epub 2010 Feb 8.        
       PMID: 20140763 [PubMed - indexed for MEDLINE]     
         
16. An unusual cause of acute liver failure.
      http://www.ncbi.nlm.nih.gov/pubmed/22767474
      Agrawal P, Gandhi V, Nagral A, Nagral S.         
      BMJ Case Rep. 2010 Aug 26;2010. doi:pii: bcr0320102837.                              
      PMID: 22767474 [PubMed - in process] Free PMC Article        
                               
17. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific
      Association for the study of the liver (APASL).
     http://www.ncbi.nlm.nih.gov/pubmed/19669378
Sarin SK, Kumar A, Almeida JA, Chawla YK, Fan ST, Garg H, de Silva HJ, Hamid SS, Jalan R, Komolmit P, Lau GK, Liu Q, Madan K, Mohamed R, Ning Q, Rahman S, Rastogi A, Riordan  SM, Sakhuja P, Samuel D, Shah S, Sharma BC, Sharma P, Takikawa Y, Thapa BR, Wai CT, Yuen MF.       
 Hepatol Int. 2009 Mar;3(1):269-82. doi: 10.1007/s12072-008-9106-x. Epub 2008 Nov 20.      
 PMID: 19669378 [PubMed] Free PMC Article      
                               
 18. Efficacy of L-ornithine L-aspartate in acute liver failure: a double-blind, randomized,
       placebo-controlled study.
       http://www.ncbi.nlm.nih.gov/pubmed/19505424
       Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK.        
       Gastroenterology. 2009 Jun;136(7):2159-68. doi: 10.1053/j.gastro.2009.02.050
       PMID: 19505424 [PubMed - indexed for MEDLINE]     
                               
 19. Parvovirus B19-induced thrombocytopenia and anemia in a child with fatal fulminant
       hepatic failure coinfected with hepatitis A and E viruses.
       http://www.ncbi.nlm.nih.gov/pubmed/19203989
       Kishore J, Sen M.          
       J Trop Pediatr. 2009 Oct;55(5):335-7. doi: 10.1093/tropej/fmp004. Epub 2009 Feb 8.
       PMID: 19203989 [PubMed - indexed for MEDLINE]     
         
20. Acute hepatic failure in an infant caused by acetaminophen (paracetamol) toxicity.
      http://www.ncbi.nlm.nih.gov/pubmed/19021948
      Ebenezer K, Agarwal I, Fleming D.Ann Trop Paediatr. 2008 Dec;28(4):301-3.
      doi: 10.1179/146532808X375495.           
      PMID: 19021948 [PubMed - indexed for MEDLINE]      
         
21. Aetiology, clinical profile and prognostic indicators for children with acute liver failure
      admitted in a teaching hospital in Kolkata.
      http://www.ncbi.nlm.nih.gov/pubmed/18384007
      Samanta T, Ganguly S. Trop Gastroenterol. 2007 Jul-Sep;28(3):135-9.
      PMID: 18384007 [PubMed - indexed for MEDLINE]      
 
22. Prevalence of dengue infection in north Indian children with acute hepatic failure.
      http://www.ncbi.nlm.nih.gov/pubmed/18376367
      Kumar R, Tripathi P, Tripathi S, Kanodia A, Venkatesh V.
      Ann Hepatol. 2008 Jan-Mar;7(1):59-62.
      PMID: 18376367 [PubMed - indexed for MEDLINE]      
                               
 23. TIPS can be lifesaving in acute liver failure associated with portal vein and inferior vena
       cava thrombosis in a case of Budd Chiari syndrome due to protein S deficiency.
       http://www.ncbi.nlm.nih.gov/pubmed/18046604
       Verma A, Sharma G, Mohan S, Saraswat VA, Baijal SS.           
       Cardiovasc Intervent Radiol. 2008 Jul;31 Suppl 2:S197-9. Epub 2007 Nov 27.
       PMID: 18046604 [PubMed - indexed for MEDLINE]     
                               
 24. Hepatic calcification following dengue virus-induced fulminant hepatic failure.
       http://www.ncbi.nlm.nih.gov/pubmed/17558076
       Saikia N, Talukdar R, Singal DK, Chaudhary D, Bhullar SS, Tandon RK.        
       Indian J Gastroenterol. 2007 Mar-Apr;26(2):90-2.          
       PMID: 17558076 [PubMed - indexed for MEDLINE]     
                               
25. Nimesulide-induced hepatotoxicity and fatal hepatic failure.
      http://www.ncbi.nlm.nih.gov/pubmed/17538762
      Tan HH, Ong WM, Lai SH, Chow WC.
      Singapore Med J. 2007 Jun;48(6):582-5.
      PMID: 17538762 [PubMed - indexed for MEDLINE] Free Article            
                               
26. Fulminant hepatic failure complicating visceral leishmaniasis in an apparently
      immunocompetent child.
      http://www.ncbi.nlm.nih.gov/pubmed/17526962
      Baranwal AK, Mandal RN, Singh R.       
      Indian J Pediatr. 2007 May;74(5):489-91.
      PMID: 17526962 [PubMed - indexed for MEDLINE]        
 
27. Early indicators of prognosis in fulminant hepatic failure: an assessment of the Model for
      End-Stage Liver Disease (MELD) and King's College Hospital criteria.
      http://www.ncbi.nlm.nih.gov/pubmed/17370333
      Dhiman RK, Jain S, Maheshwari U, Bhalla A, Sharma N, Ahluwalia J, Duseja A, Chawla Y.        
       Liver Transpl. 2007 Jun;13(6):814-21.    
       PMID: 17370333 [PubMed - indexed for MEDLINE] Free Article         
                               
 28. Differential diagnosis of acute liver failure in India.
       http://www.ncbi.nlm.nih.gov/pubmed/17060870
       Deepak N A, Patel ND.
        Ann Hepatol. 2006 Jul-Sep;5(3):150-6. 
        PMID: 17060870 [PubMed - indexed for MEDLINE]     
                             
29. Fulminant hepatic failure following halothane anaesthesia.
      http://www.ncbi.nlm.nih.gov/pubmed/16085447
      Kumar GP, Bhat VJ, Sowdi V.    
      J Clin Forensic Med. 2005 Oct;12(5):271-3.        
      PMID: 16085447 [PubMed - indexed for MEDLINE]        
                             
30. Acute liver failure and severe hemophagocytosis secondary to parvovirus B19 infection.
      http://www.ncbi.nlm.nih.gov/pubmed/16041107
      Dutta U, Mittal S, Ratho RK, Das A.       
      Indian J Gastroenterol. 2005 May-Jun;24(3):118-9.        
      PMID: 16041107 [PubMed - indexed for MEDLINE]        
                                   
31. Predictive value of arterial ammonia for complications and outcome in acute liver failure.
      http://www.ncbi.nlm.nih.gov/pubmed/16024550
      Bhatia V, Singh R, Acharya SK. 
      Gut. 2006 Jan;55(1):98-104. Epub 2005 Jul 15.  
      PMID: 16024550 [PubMed - indexed for MEDLINE] Free PMC Article   
32. Hepatitis A in pediatric acute liver failure in southern India.
      http://www.ncbi.nlm.nih.gov/pubmed/15778534
      Bhowmick K, Mammen A, Moses PD, Agarwal I, Mathew L, Kang G.  
      Indian J Gastroenterol. 2005 Jan-Feb;24(1):34. No abstract available.          
      PMID: 15778534 [PubMed - indexed for MEDLINE]       
                             
 33. Severe falciparum malaria simulating fulminant hepatic failure.
       http://www.ncbi.nlm.nih.gov/pubmed/15757017
       Devarbhavi H, Alvares JF, Kumar KS.  
       Mayo Clin Proc. 2005 Mar;80(3):355-8.  
       PMID: 15757017 [PubMed - indexed for MEDLINE]     
                             
 34. Hepatocellular failure in glycogen storage disorder type 3.
       http://www.ncbi.nlm.nih.gov/pubmed/15656054
       Ingle SA, Moulick ND, Ranadive NU, Khedekar K.       
       J Assoc Physicians India. 2004 Feb;52:158-60. 
       PMID: 15656054 [PubMed - indexed for MEDLINE]       
                             
 35. Pulmonary aspergillosis in a child with hepatic failure.
       http://www.ncbi.nlm.nih.gov/pubmed/15246213
       Scott JX, Kumar TS, Sanghi S, Shah A, Moses PD.     
       Indian J Gastroenterol. 2004 Jul-Aug;23(4):147-8.         
       PMID: 15333974 [PubMed - indexed for MEDLINE]       
 
36. Prophylactic phenytoin does not improve cerebral edema or survival in acute liver failure-
      -a controlled clinical trial.
      http://www.ncbi.nlm.nih.gov/pubmed/15246213
      Bhatia V, Batra Y, Acharya SK.  
      J Hepatol. 2004 Jul;41(1):89-96.  
      PMID: 15246213 [PubMed - indexed for MEDLINE]        
                                   
 37. Hepatitis E virus and acute-on-chronic liver failure.
       http://www.ncbi.nlm.nih.gov/pubmed/15176533
       Jeyamani, Kurian G.       
       Indian J Gastroenterol. 2004 Mar-Apr;23(2):45-6. No abstract available.          
       PMID: 15176533 [PubMed - indexed for MEDLINE]       
                             
 38. Acute liver failure: prognostic markers.
       http://www.ncbi.nlm.nih.gov/pubmed/15025260
       Batra Y, Acharya SK.     
       Indian J Gastroenterol. 2003 Dec;22 Suppl 2:S66-8. Review.    
       PMID: 15025260 [PubMed - indexed for MEDLINE]       
                             
39. Role of transfusion-transmitted virus in acute viral hepatitis and fulminant hepatic failure
      of unknown etiology.
      http://www.ncbi.nlm.nih.gov/pubmed/15012777
       Das K, Kar P, Gupta RK, Das BC.          
       J Gastroenterol Hepatol. 2004 Apr;19(4):406-12.
      PMID: 15012777 [PubMed - indexed for MEDLINE]      
                             
40. Etiopathogenesis of acute hepatic failure: Eastern versus Western countries.
      http://www.ncbi.nlm.nih.gov/pubmed/12472948
      Acharya SK, Batra Y, Hazari S, Choudhury V, Panda SK, Dattagupta S.          
      J Gastroenterol Hepatol. 2002 Dec;17 Suppl 3:S268-73. Review.          
      PMID: 12472948 [PubMed - indexed for MEDLINE]        
                             
41. A pilot study of polyunsaturated phosphatidyl choline in fulminant and subacute hepatic
      failure.
      http://www.ncbi.nlm.nih.gov/pubmed/11273253
      Singh NK, Prasad RC.    
      J Assoc Physicians India. 1998 Jun;46(6):530-2.
      PMID: 11273253 [PubMed - indexed for MEDLINE]        
                             
42. Recommendations of the International Association for the Study of the Liver
      Subcommittee on nomenclature of acute and subacute liver failure.
      http://www.ncbi.nlm.nih.gov/pubmed/10355501
      Tandon BN, Bernauau J, O'Grady J, Gupta SD, Krisch RE, Liaw YF, Okuda K, Acharya SK.
      J Gastroenterol Hepatol. 1999 May;14(5):403-4. No abstract available.
      PMID: 10355501 [PubMed - indexed for MEDLINE]        
 
43. Prognostic evaluation of early indicators in fulminant hepatic failure by multivariate
      analysis.
      http://www.ncbi.nlm.nih.gov/pubmed/9635624
      Dhiman RK, Seth AK, Jain S, Chawla YK, Dilawari JB. 
       Dig Dis Sci. 1998 Jun;43(6):1311-6.       
       PMID: 9635624 [PubMed - indexed for MEDLINE]         
                                   
 44. Acute viral hepatitis types E, A, and B singly and in combination in acute liver failure in
       children in north India.
       http://www.ncbi.nlm.nih.gov/pubmed/8801280   
       Arora NK, Nanda SK, Gulati S, Ansari IH, Chawla MK, Gupta SD, Panda SK.
       J Med Virol. 1996 Mar;48(3):215-21.      
       PMID: 8801280 [PubMed - indexed for MEDLINE]         
                                   
45. Fulminant hepatic failure resulting from coexistent Wilson's disease and hepatitis E.
      http://www.ncbi.nlm.nih.gov/pubmed/8020819
      Sallie R, Chiyende J, Tan KC, Bradley D, Portmann B, Williams R, Mowat AP, Mieli-
      Vergani G.
      Gut. 1994 Jun;35(6):849-53.
      PMID: 8020819 [PubMed - indexed for MEDLINE] Free PMC Article