Liver & intrahepatic bile ducts

• Most chronic liver disease cannot be cured by removal of the affected native liver; the goal is to cure end stage liver disease / cirrhosis or fulminant acute hepatitis
• Brief overview of pathophysiologic mechanisms involved in recurrence
  • Recurrent hepatitis B and recurrent hepatitis C: virus persists in the patient's bloodstream if not cured pre-liver transplantation (LT) (Best Pract Res Clin Gastroenterol 2020;46:101689)
  • Recurrent autoimmune hepatitis, recurrent primary sclerosing cholangitis and recurrent primary biliary cholangitis: autoimmunity / inappropriately overactive immune system persists (Am J Clin Pathol 2021;155:435, Best Pract Res Clin Gastroenterol 2020;46:101688, Liver Transpl 2006;12:S73, Gastroenterology 2019;156:96)
  • Recurrent alcoholic liver disease: alcohol consumption may resume secondary to several factors (Liver Transpl 2020;26:25, World J Gastroenterol 2018;24:2785)
  • Recurrent metabolic dysfunction associated steatotic liver disease: metabolic dysfunction (obesity, diabetes, etc.) may persist if not appropriately addressed clinically (Best Pract Res Clin Gastroenterol 2020;46:101688)
  • Recurrent hepatocellular carcinoma: aggressive disease (e.g., with lymphovascular invasion) is more likely to recur (World J Gastroenterol 2023;29:1243)
• Diseases that do not recur include alpha-1 antitrypsin deficiency (as the defect lies within native hepatocytes) and Wilson disease (as the defect lies within native hepatocytes)
• Role of liver transplantation (LT) in curing hereditary hemochromatosis remains uncertain (Clin Liver Dis 2014;18:675)
  • One study reported no significant iron overload in liver biopsies after LT (Transplant Direct 2020;6:e560)

• Timing of recurrent liver disease (RLD) varies among different studies
• In addition to factors such as the original disease, immunosuppression scheme and epidemiologic factors, variables such as length of follow up and performance of protocol biopsies impact the determination of the timing of disease recurrence
• RLD can occur at any time in the allograft but each RLD has an average onset and a median time to graft loss (see table below)
• Recurrent hepatitis C
  • ~50% of patients remain asymptomatic during the first 12 months post-LT
  • Most patients will show histologic features of hepatitis
  • Success of HCV treatment has changed the epidemiology of liver transplantation (decline of HCV liver transplants) and correlates with improved graft survival (Transplant Direct 2019;5:e427)
• Recurrent autoimmune hepatitis
  • More common in children (Clin Liver Dis 2017;21:381)
• Recurrent alcoholic liver disease
  • Although there is no consensus about definition of harmful drinking post-LT, abusive drinking is less common after LT (about 10% of patients)

Average onset of recurrent diseases and median time to graft loss (Transpl Int 2008;21:459)

Recurrent disease	Average onset	Median time to graft loss in days (years)
Recurrent hepatitis B	1 - 1.5 years	717 days (~2 years)
Recurrent hepatitis C	First hours and days	1429 days (~4 years)
Recurrent autoimmune hepatitis	> 1 year	525 days (~1.5 years)
Recurrent primary sclerosing cholangitis	2 - 3 years	1342 days (~4 years)
Recurrent primary biliary cholangitis	2 - 5 years	2833 days (~8 years)
Recurrent alcoholic liver disease	1 - 2 years	2543 days (~7 years)
Recurrent metabolic dysfunction associated steatotic liver disease	3 - 10 years	1123 days (~3 years)
Recurrent hepatocellular carcinoma	1 - 2 years	581 days (~1.5 years)

Contributed by Lidiane Vieira Marins, M.D., Ph.D.

• Patients may be asymptomatic
• Signs and symptoms: fatigue, jaundice, pruritus, abdominal pain, hepatomegaly
• Patients with primary sclerosing cholangitis (PSC) may present with concomitant inflammatory bowel disease (IBD), especially ulcerative colitis (UC)
• Important to investigate alcohol consumption and all medications, herbs and supplements the patient is taking
• Specific recurrent liver disease (RLD) diagnosis, genetic profile and immunosuppression status are some of the factors that determine recurrence
• In some studies, RLD accounts for 19% of deaths following LT (Ann Hepatol 2012;11:415)

• Liver function assessment includes
  • Liver enzyme tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT)
  • Total bilirubin, direct bilirubin, indirect bilirubin and albumin
  • Prothrombin time and complete blood count
• Depending on the pretransplant disease and clinical suspicion of recurrence, additional laboratory tests may be performed
• Recurrent hepatitis B (World J Hepatol 2018;10:352, JHEP Rep 2023;5:100728)
  • HBV DNA quantification in serum
  • Serum hepatitis antigens (HBsAg, HBeAg, HBcAg, others)
• Recurrent hepatitis C (Ann Gastroenterol 2013;26:304, Nat Rev Gastroenterol Hepatol 2014;11:710)
  • HCV RNA quantification in serum
• Recurrent autoimmune hepatitis (Clin Liver Dis 2017;21:381, World J Transplant 2022;12:59)
  • There is no specific marker for diagnosis
  • The International Autoimmune Hepatitis Group criteria, developed in the nontransplant setting, is also applied post-liver transplantation (LT) (Liver Transpl 2001;7:285, J Hepatol 2022;77:84)
  • Increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
  • Hypergammaglobulinemia, particularly elevated IgG
  • Diagnostic utility of autoantibody testing (e.g., anti-smooth muscle antibodies [ASMA]) is considered uncertain
    • Patients transplanted for AIH may have positive autoantibodies with no other abnormalities
    • Patients transplanted for non-AIH etiologies can develop autoantibodies after LT
• Recurrent primary sclerosing cholangitis (Transplant Direct 2017;3:e334)
  • Autoantibodies such as antinuclear antibodies (ANA) and ASMA may help, although they are not specific to PSC
  • Assessment of IBD / UC related markers: antineutrophil cytoplasmic antibodies (ANCA) positivity, elevated levels of C reactive protein (CPR), elevated levels of fecal calprotectin, abnormal colonoscopy
• Recurrent primary biliary cholangitis (Gastroenterology 2019;156:96, Best Pract Res Clin Gastroenterol 2020;46:101688)
  • Autoantibodies such as antimitochondrial antibodies (AMA), particularly the AMA M2 subtype
  • Hypergammaglobulinemia, particularly elevated IgM
• Recurrent alcoholic liver disease (World J Gastroenterol 2018;24:2785, Liver Transpl 2020;26:25)
  • Increased AST, ALT, GGT, ethyl glucuronide, serum carbohydrate deficient transferrin and bilirubin, thrombocytopenia and decreased serum albumin
• Recurrent metabolic dysfunction associated steatotic liver disease (Best Pract Res Clin Gastroenterol 2020;46:101688)
  • Total cholesterol, low density lipoprotein cholesterol (LDL C), high density lipoprotein cholesterol (HDL C), triglycerides, fasting blood glucose and insulin
• Recurrent hepatocellular carcinoma (World J Gastroenterol 2023;29:1243)
  • Elevated alpha fetoprotein (AFP), although not specific, may indicate HCC recurrence
  • Elevated des-gamma-carboxy prothrombin can be used in conjunction with AFP for monitoring

Contributed by Raul S. Gonzalez, M.D. and Lidiane Vieira Marins, M.D., Ph.D.

• Newly acquired viral infections (hepatitis A, hepatitis B, hepatitis C, hepatitis E, CMV, Epstein-Barr virus (EBV), herpes simplex virus (HSV) types 1 and 2, arboviruses and others) (Best Pract Res Clin Gastroenterol 2020;46:101689):
  • Liver transplantation (LT) patients are immunocompromised, raising the likelihood of subsequent infection
  • These mainly enter the differential diagnosis for acute recurrent hepatitis C, acute recurrent hepatitis B and acute recurrent autoimmune hepatitis
    • Histologic findings may be similar
    • Travel history, socioepidemiological factors and serological tests can provide valuable insights
    • Favoring HAV (hepatitis A virus), HEV (hepatitis E virus) and arboviruses: histology may show discrete / moderate findings (spotty necrosis and few / many apoptotic bodies) or severe alterations (massive hepatocellular necrosis) (Eur J Gastroenterol Hepatol 2020;32:916, Case Rep Transplant 2021;2021:5159934)
    • Favoring HCV: steatosis and hepatocellular ballooning (World J Gastroenterol 2014;20:2810)
    • Favoring HBV: ground glass hepatocytes (Liver Transpl 2006;12:S50)
    • Favoring CMV: reactive bile duct changes, lobular microabscesses, sinusoidal inflammatory infiltrate, CMV inclusions (Transpl Infect Dis 2006;8:21)
    • Favoring EBV: sinusoidal lymphocytosis (mostly B cells), portal infiltrate with immunoblasts and eosinophils (Hum Pathol 1993;24:1306)
    • Favoring HSV: geographic necrosis and nuclear inclusions
• Drug induced liver injury (DILI) (Liver Transpl 2020;26:1167):
  • Considered a differential diagnosis for all recurrent liver diseases (RLD)
  • Can mimic all major histologic patterns of liver injury
  • Excluded by a detailed investigation of medications taken by the patient
  • Association between DILI and RLD can occur
    • More easily diagnosed when the drug injury and the RLD have different histologic patterns of injury
• Some RLD have specific further differential diagnoses
• Recurrent hepatitis B and recurrent hepatitis C (World J Gastroenterol 2014;20:2810):
  • Acute recurrent hepatitis B / recurrent hepatitis C versus acute T cell mediated rejection (TCMR):
    • Clinical features, laboratory tests and timing of biopsy do not help to differentiate TCMR from acute recurrent hepatitis C but accurate diagnosis is crucial
      • Mild acute TCMR is not a major concern because it is not treated in most transplant centers
      • Detection of moderate / severe acute TCMR is important because it requires modification in the immunosuppressive regimen and may exacerbate recurrent hepatitis B / recurrent hepatitis C
    • Histologic findings are similar in both conditions: lymphocytes and eosinophils in the portal tracts, bile duct injury, endotheliitis
      • Favoring acute TCMR
        • Portal based injury
        • Activated and blastic lymphocytes, more prominent bile duct injury / ductitis, more prominent endotheliitis and many eosinophils in the inflammatory infiltrate
        • Important to meet the criteria for at least moderate acute rejection
      • Favoring acute recurrent hepatitis B / recurrent hepatitis C
        • Lobular based injury
        • Lobular inflammation, hepatocyte ballooning, steatosis, apoptotic bodies
  • Chronic recurrent hepatitis B / recurrent hepatitis C versus fibrosing cholestatic hepatitis (FCH) versus mechanical biliary stricture:
    • Histologic findings may be similar
    • Favoring chronic recurrent hepatitis B / recurrent hepatitis C
      • Portal based mononuclear inflammatory infiltrate, mild to moderate interface hepatitis, lobular inflammation, discrete ductular reaction, mild steatosis
    • Favoring mechanical biliary stricture
      • Prominent ductular reaction, mixed portal inflammatory infiltrate and bile plugs in bile duct lumina
      • Imaging studies may provide additional assistance
    • Favoring FCH
      • Prominent ductular reaction, mixed portal inflammatory infiltrate in the portal tracts, intense lobular disarray, hepatocyte ballooning, steatosis, pericellular fibrosis
      • High viral RNA levels
  • Chronic recurrent hepatitis B / recurrent hepatitis C with plasma cell rich infiltrate:
    • Resembles autoimmune hepatitis (AIH)
    • May represent an alloimmune response (especially if the patient has a previous history of interferon treatment)
• Recurrent autoimmune hepatitis (Am J Clin Pathol 2021;155:435):
  • Acute TCMR:
    • This dilemma is less critical, since increased immunosuppression is required in both conditions
    • Favoring recurrent autoimmune hepatitis
      • Prominent lobular inflammation and extensive lobular necrosis
• Recurrent primary sclerosing cholangitis (Liver Transpl 2006;12:S68):
  • Chronic ductopenic rejection (CR):
    • Favoring recurrent primary sclerosing cholangitis
      • Concentric onion skin periductal fibrosis, fibrotic scars in the portal tracts
    • Favoring CR
      • Lack of ductular reaction, senescent changes in bile ducts, foam cell arteriopathy
  • Complications related to biliary anastomosis and ischemic cholangitis:
    • Histologic findings are similar
    • Imaging studies may provide additional assistance
    • Favoring recurrent primary sclerosing cholangitis
      • Nonanastomotic structures, > 90 days post-LT
• Recurrent primary biliary cholangitis (Best Pract Res Clin Gastroenterol 2020;46:101688):
  • CR:
    • Recurrent primary biliary cholangitis and CR may both demonstrate ductopenia and chronic cholestasis
    • Favoring recurrent primary biliary cholangitis
      • Lymphocytic or granulomatous cholangitis
      • Lobular chronic inflammation
    • Favoring CR
      • Lack of ductular reaction, senescent changes in bile ducts, foam cell arteriopathy
  • Infectious granulomatous diseases:
    • Favoring infection
      • Large granulomas with necrosis
• Recurrent alcoholic liver disease and recurrent metabolic dysfunction associated steatotic liver disease (Liver Transpl 2020;26:25, World J Gastroenterol 2018;24:2785, Best Pract Res Clin Gastroenterol 2020;46:101688):
  • These 2 diseases share toxic metabolic pathways causing liver dysfunction and one can simulate the other
  • Favoring recurrent alcoholic liver disease
    • Ductular reaction, cholestasis, abundant Mallory-Denk bodies
• Recurrent hepatocellular carcinoma (World J Gastroenterol 2023;29:1243):
  • De novo development of new hepatocellular carcinoma
    • Important to verify the histologic subtype of hepatocellular carcinoma and tumor grade in the native liver
      • Different histologic subtype suggests de novo hepatocellular carcinoma

A 55 year old man with a history of chronic alcohol abuse underwent liver transplantation 2 years ago. He now presents with elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT). A history of depression and alcohol intake is noted by the clinician and he orders a liver biopsy, with findings as shown above. Which finding(s) help the clinician to consider recurrent alcoholic liver disease as the diagnosis in this setting?

1. Chronic inflammation in the portal tracts with granulomas in the histology
2. History of alcohol intake and chronic hepatitis with severe activity
3. History of alcohol intake and liver biopsy showing steatosis
4. Steatosis alone allows the diagnosis of recurrent alcoholic liver disease

C. History of alcohol intake and liver biopsy showing steatosis. The diagnosis of recurrent disease relies on the evidence that the same disease is happening again in the liver allograft. The diagnosis is multidisciplinary. The history of the patient's alcohol intake leads to clinical suspicion of recurrent alcoholic liver disease. If the liver biopsy shows steatosis, this is consistent with recurrent alcoholic liver disease, especially if other metabolic dysfunctions are excluded by the clinician (World J Gastroenterol 2018;24:2785, Best Pract Res Clin Gastroenterol 2020;46:101688). Answer A is incorrect because chronic inflammation in the portal tracts with granulomas in the histology is more common in primary biliary cholangitis and is not described in recurrent alcoholic liver disease. Answer D is incorrect because the histologic evidence of steatosis alone is not sufficient. A history of alcohol intake must be noted clinically. The diagnosis of recurrent alcoholic liver disease is multidisciplinary. Answer B is incorrect because recurrent alcoholic liver disease is linked to steatosis or steatohepatitis patterns of injury. If chronic hepatitis with severe activity is noted, the pathologist must consider the possibility of de novo autoimmune hepatitis.

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Reference: Recurrent disease

A 45 year old woman with autoimmune hepatitis underwent liver transplantation. After 14 months, she presents with elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT). She has not taken her immunosuppressive medicines for the last 2 months. Serologic testing reveals antinuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA). Which histologic feature is characteristic of recurrent autoimmune hepatitis (AIH) in the liver allograft?

1. Chronic hepatitis with moderate to severe interface activity
2. Chronic inflammation in the portal tracts with granulomas in the histology
3. Ductular reaction and periductal onion skin fibrosis
4. Severe steatosis

A. Chronic hepatitis with moderate to severe interface activity. Interface hepatitis, characterized by inflammation at the interface between hepatocytes and the portal tract, is a hallmark histologic feature of recurrent autoimmune hepatitis in the liver allograft, especially when it is moderate to severe. Other findings that may be seen in recurrent autoimmune hepatitis include prominent plasma cells, lobular activity with necrosis and perivenulitis (Ann Gastroenterol 2013;26:304, Liver Transpl 2009;15:S35). Answer B is incorrect because chronic inflammation in the portal tracts with granulomas in the histology is more common in primary biliary cholangitis and it is not part of the classic histologic pattern of recurrent autoimmune hepatitis. Answer C is incorrect because ductular reaction and periductal onion skin fibrosis are more common in primary sclerosing cholangitis and they are not part of the classic histologic pattern of recurrent autoimmune hepatitis. Answer D is incorrect because severe steatosis is not pathognomonic of recurrent autoimmune hepatitis, although steatosis can be noted because of toxic injury when the patient is being treated with steroids.

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Reference: Recurrent disease