Acute cellular rejection, although common, is a rare cause of graft loss and liver retransplantation [1, 2]. LAR remains a histological diagnosis, usually occurring within 3 to 6 months after transplantation [7,8,9]. A systematic review including 9 studies reported that the incidence of LAR varied from 7 to 40%; however, only one study-related incidence was greater at 25% . This prevalence has decreased in recent years due to the new ISs [2,3,4,5,6,7,8,9].
Risk factors for LAR include inadequate IS, younger donor age, previous early acute rejection, previous graft failure, seronegative hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis prior to transplantation, while transplantation for viral disease seems to be protective [1, 10, 11]. D’Antiga et al.  reported that underlying liver disease, decreased immunosuppression, and poor compliance were the main factors predisposing patients to develop LAR. A US study found a high rate of LAR in female and young recipients and in patients with primary diagnoses of autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis . A recent study showed that younger recipients, primary biliary cirrhosis, and previous graft loss were significant independent predictors of LAR (P < 0.001) . Inadequate IS due to a significant decrease in SI was the only risk factor for LAR found in our observation. This decrease in SI was the result of a gradual discontinuation of immunosuppressive drugs following hematological and renal side effects. Therefore, any reduction in SI should be closely monitored within 6 months of any dose change .
The diagnosis of LAR is more difficult to make than that of early acute rejection, as histological abnormalities are less classic and differential diagnosis is broader [1, 7,8,9], hence the need for a systematic investigation as described in our case report, including a detailed pretransplant, pertransplant, posttransplant, and donor history . Our case, LAR, was discovered following ALFTs with a predominance cholestasis, which was consistent with the literature review . Jung et al.  observed a predictive increase in transaminase levels prior to routine biopsies in patients with histologic evidence of late acute rejections. However, LAR can be clinically asymptomatic and incidentally discovered during a routine liver biopsy. Hence, the systematic search for LAR during posttransplant follow-up even in the absence of ALFTs requires at least one systematic liver biopsy during the first 12 months posttransplant . Histology remains fundamental for the diagnosis of acute rejection and the evaluation of its severity in order to adapt the management. We have retained the diagnosis of LAR for our patient on biochemical, radiological, and histological arguments, associating ALFTs with histological lesions compatible with acute rejection. The severity of the rejection is assessed histologically by the Banff criteria and classified into 3 categories: mild (0–3), moderate (4–6), and severe (>6) [2, 7, 8]. In our case, the score was 6, classifying it as moderate. The moderate form remains the most common. Moderate LAR accounted for more than half of the patients (63%) with LAR in an English study .
LAR is a potentially serious complication with a risk of graft loss (HR 1.71; 95% CI 1.23–2.37; P = 0.001), progression to chronic rejection (3–28% of cases), and decreased patient survival (HR 1.89; 95% CI 1.35–2.65; P=0.001) [1, 2, 5, 7]. According to Thurairajah et al. , the rate of developing chronic rejection after a single episode of LAR was 28%, with an overall rate of graft failure of 6%. The causes of mortality included end-stage liver failure from chronic rejection, sepsis, malignancy, recurrent of primary disease, hepatic artery thrombosis, and cardiovascular deaths, hence the need for urgent, prompt, and adequate management. According to the literature, acute rejection usually responds to corticosteroid boluses. Rejection resistant to corticosteroids is rare [2, 11]. However, Nakanishi et al.  had already reported a case of steroid-resistant LAR, but rescue therapy with deoxyspergualin was used successfully. One study showed that as few as 51% of treated LAR patients completely respond to high-dose steroids . In an English study, in which the majority of patients with rejection were treated with high-dose pulsed corticosteroids (prednisolone 200 mg/day for 3 days), a complete normalization of serum transaminase levels in 23 (22%) cases, a partial response in 42 (40%) cases, and no response in 18 (17%) cases were reported . The management of acute rejection depends on the degree of liver injury and histological grading. Optimization of basic immunosuppressive drugs is sufficient for mild acute rejection, while moderate and moderately severe acute rejection requires corticosteroid, boluses combined with intensification of the basic IS . Our patient had moderate LAR and responded well to corticosteroid bolus combined with intensification of the basic IS.