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Patterns of liver injury and cytokine profiles in chronic hepatic GvHD after transplant: Refining current NIH consensus criteria

Sep 7, 2022
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Learning objective: After reading this article, learners will be able to cite a new development in GvHD.

Introduction

Chronic graft-versus-host disease (cGvHD) following allogeneic hematopoietic stem cell transplantation is a multi-organ condition with typical and atypical features. Immune dysregulation and immunodeficiency, driven by both autoimmune and alloimmune processes, lead to impaired organ function and end organ failure; this drives disease comorbidity and ultimately increases mortality.1

Hepatic cGvHD can be misdiagnosed as elevations in liver enzymes and bilirubin can be nonspecific, rising because of other posttransplant hepatobiliary challenges.1 Overdiagnosis can lead to unnecessary immunosuppressive treatments and adverse events, such as opportunistic infections.1

Published in Transplant and Cellular Therapy in 2022, Yang, et al.1 conducted a cross-sectional study (NCT00092235) to characterize liver dysfunction in cGvHD. The study investigated patterns of liver injury as assessed by histopathological findings, liver function tests, clinical data, and immune profiles to evaluate the accuracy of the National Institute of Health (NIH) consensus criteria2 and further elucidate predictors of hepatic cGvHD. Below, we summarize the key findings.

Study design

This was a cross-sectional, prospective multicenter trial recruiting patients through National Cancer Institute (NCI)-designated cGvHD centers. A diagnosis of hepatic cGvHD was made if alanine transaminase (ALT) or total bilirubin was >3 times the upper limit of normal, with no other clinical or biological explanation. cGvHD was scored as mild, moderate, or severe, according to NIH consensus criteria and assessment of the skin, eyes, mouth, liver, gastrointestinal tract, lungs, joints-fascia, and female genital tract (Figure 1). Prospective data collection included clinical and laboratory investigations, histopathology data from liver biopsy, and treatment information, such as immunosuppression intensity (Figure 1)

Figure 1. NIH global cGvHD score assessment and scoring of immunosuppression intensity as used in the cross-sectional study design* 

cGvHD, chronic graft-versus-host disease; NIH, National Institute for Health.
*Data from Yang, et al.1

Objectives

  • Identify clinical and biological prognostic markers to incorporate into the NIH consensus criteria

Inclusion criteria3

  • Aged ≥1 years
  • Referred by primary transplant physician for assessment of cGvHD

Exclusion criteria3

  • Other significant medical condition
  • Pregnancy
  • Life expectancy <3 months

Results

Overall, 302 patients were enrolled in the study; the baseline demographic and clinical features can be seen in Table 1. Most patients had undergone hematopoietic stem cell transplantation for hematologic malignancy, with over half (55%) receiving myeloablative conditioning. Of these patients, 55% underwent transplant from HLA-matched related donors. In total, 77% of patients received peripheral blood stem cell grafts. Most patients were receiving moderate to high-intensity immunosuppression at the time of their visit.

Table 1. Baseline demographic, clinical, and treatment characteristics of study participants*

Characteristic

Study participants

Median age at transplant, years (IQR)

41.5 (28.1–51.9)

Median age at GvHD, years (IQR)

42.4 (29.3–53.0)

Median age at entry, years (IQR)

45.4 (31.8–55.9)

Female, n (%)

128 (42.4)

Median BMI (IQR)

23.8 (20.5–27.1)

Time from transplant to cGvHD diagnosis, days (IQR), days

217 (141–367)

Underlying disease, n (%)

 

              Hematologic malignancy

257 (85)

              Non-malignant hematologic disease

30 (10)

              Non-hematologic malignancy

4 (1.4)

              Non-malignant disorder

11 (3.6)

Conditioning regimen, n (%)

 

              Myeloablative

165 (55)

              Non-myeloablative/reduced intensity

137 (45)

              Total body irradiation

111 (37)

NIH consensus criteria, n (%)

 

              Mild

4 (1)

              Moderate

85 (28)

              Severe

210 (70)

              Total Score

8 (5–11)

Organs involved

 

              Median number of organs involved (IQR)

5 (3–6)

              Liver, n (%)

148 (50)

              Gastrointestinal tract, n (%)

135 (45)

              Eyes, n (%)

231 (77)

BMI, body mass index; cGvHD chronic graft-versus-host disease; IQR, interquartile range; NIH National Institute of Health.
*Adapted from Yang, et al.1

Association of platelet count and cytokine levels with hepatic cGvHD

The median platelet count in this cohort was 39 U/ml (interquartile range [IQR], 27–71 U/ml). Using a platelet cutoff of 150 × 103 cells, lower platelet count was significantly associated with higher ALT, total bilirubin, increased portal vein diameters, and lower albumin. An association between liver disease and portal hypertension is suggested by a concurrent increase in portal vein diameter, ALT, and bilirubin in some patients. Several cytokines were associated with either hepatocellular or cholestatic pattern liver injury (Table 2).

Table 2. Cytokines associated with liver injury*

Affected organ

Cytokine

Hepatocellular injury

Serum amyloid A
IL-15
Matrix metalloproteinase 3
Tumor growth factor-α

Cholestatic injury

IFN-g
IFN g-induced protein 10
Monokine induced by IFN-g
IL-6
IL-7
IL-10
IL-13
Tumor growth factor-α

IFN, interferon; IL, interleukin.
*Data from Yang, et al.1
Hepatocellular liver injury was defined as an abnormal aspartate transaminase >34 U/L and alanine transferase >41 U/L.
Cholestatic liver injury was defined by an abnormal alkaline phosphatase >116 U/L or gamma-glutamyl transaminase >85 U/L.

cGvHD diagnosed on consensus criteria

In this study, 148 patients had hepatic cGvHD based on the National Consensus Criteria cGvHD consensus criteria (Table 3). Skin, eyes, and lungs were the most commonly affected organs (79%, 77%, and 76% of patients, respectively). According to the NIH cGvHD consensus criteria, the median total score was 8 (IQR, 5−11), with cGvHD graded severe, moderate, and mild in 70%, 28, and 1% of patients, respectively. A total of 50% of the patients had hepatic involvement of their cGvHD according to NIH consensus criteria, with a median of four other organs involved.

Table 3. The number of patients with an NIH consensus criteria hepatic score of 0–3*

NIH consensus criteria hepatic cGvHD score

Number of patients

0

150

1

99

2

47

3

2

cGvHD, chronic graft-versus-host disease; NIH, National Institute of Health.
*Data from Yang, et al.1

GvHD diagnosed on liver biopsy

Liver biopsy was performed in 32 patients. Hepatic cGvHD was identified in 16 patients (59%) on histology, of which six had isolated hepatic cGvHD compared to ten with other liver diseases (Table 4), including steatosis, iron overload, sinusoidal obstructive syndrome, and possible drug-induced liver injury. Only 50% of patients with clinically suspected hepatic cGvHD had histological confirmation. Clinical diagnosis of hepatic cGvHD confirmed on histology had low sensitivity, specificity, positive and negative predictive values of 50%, 27.3%, 50%, and 27.3%, respectively (Kappa,0.23; 95% confidence interval, 0.59 to 0.13). Demographic and clinical features of patients with and without histologically confirmed hepatic cGvHD were well matched. However, total cholesterol (76% vs 56%; p=0.024), and low-density lipoprotein (LDL) (63% vs 41%; p = 0.030) demonstrated a statistically higher prevalence in patients with cGvHD compared to those without.

Of the 27 biopsies taken, 26 were subject to univariate analysis identifying significant hepatic cGvHD association with higher ALP, total cholesterol, and LDL. Overall, 69% of patients had at least one abnormal liver function test. Multivariate logistic regression identified a significant association with ALP and total cholesterol (Table 4). Using total cholesterol in the diagnostic criteria with a cutoff of 220 mg/dL, the sensitivity, specificity, positive predictive value, and negative predictive value were improved to 75%, 25%, 60%, and 33.3%, respectively.

Table 4. Associations of biopsy-proven hepatic cGvHD versus non-hepatic cGvHD*

 

Non-hepatic cGvHD
(n = 10), mean (SD)

Biopsy-proven hepatic cGvHD
(n = 16), mean (SD)

p value from t‑test

Multivariable logistic regression

OR

LCI

UCI

p value

Total cholesterol

191 (56)

258 (76)

0.024

1.26

1.02

1.56

0.035

LDL

93 (41)

145 (63)

0.030

ALP

107 (56)

199 (113)

0.012

1.16

1.01

1.33

0.040

ALP, alanine phosphatase; LCI, lower confidence interval; LDL, low density lipoprotein; OR, odds ratio; ROC, receiver operative curve; UCI, upper confidence interval.
*Adapted from Yang, et al.1
Odds Ratio (OR) for a change in 10 units of alkaline phosphatase and total cholesterol. Area under ROC = 0.89 (0.77-1.00).

Study limitations

The authors identified several study limitations, including the cross-sectional design, which prevents longitudinal assessment of laboratory parameters. In addition, active treatment of patients may have masked hepatic cGvHD histopathological features or caused confounding drug-related events, such as hypercholesterolemia. Finally, there may have been an introduction of bias due to the physician rather than protocol-guided selection of patients for liver biopsy.

Conclusion

In conclusion, abnormal liver enzymes in cGvHD are non-specific and have poor correlation with histologic evidence for hepatic GvHD, highlighting the importance of histology. Cytokines provide an insight into the pathogenesis of hepatic cGvHD. Decreased platelet count was associated with factors associated with liver disease, including portal vein diameter, which may suggest progression of liver disease. This highlights the need of incorporating these factors into natural history studies and utilizing liver biopsy to understand the development of liver dysfunction in hematopoietic stem cell transplant, to develop better diagnostic instruments, and decrease hepatic cGvHD-related morbidity and mortality.

The authors conclude that while liver function tests are commonly elevated post-HSCT, they are often non-specific to hepatic cGvHD, and that the diagnosis of hepatic cGvHD is hard due to the insensitivity of current diagnostic criteria. Histologic findings must remain the gold standard to confirm diagnosis, with the incorporation of total cholesterol to improve the sensitivity and specificity of the criteria. The association of decreased platelet count with factors associated with liver disease, including portal vein diameter, demonstrated its potential utility as a surrogate marker for the progression of liver disease.

  1. Yang AH, Han MAT, Samala N, et al. Characterization of hepatic dysfunction in subjects diagnosed with chronic GvHD by NIH consensus criteria. Transplant Cell Ther. Online ahead of print. DOI: 10.1016/j.jtct.2022.07.017
  2. Martin PJ, Lee SJ, Przepiorka D, et al. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: VI. The 2014 clinical trial design working group report. Biol Blood Marrow Transplant. 2015;21(8):1343-1359. DOI: 1016/j.bbmt.2015.05.004
  3. ClinicalTrials.gov. National history study of clinical and biological factors determining outcomes in chronic graft-versus-host disease. https://clinicaltrials.gov/ct2/show/NCT00092235. Accessed Sep 9, 2022.

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