Clinical Practice Guidelines for Liver Transplantation in Saudi Arabia

Graft failure in extended criteria donors

Donor risk index

The overall survival after LT has steadily improved over the last 20 years.⁵⁰ Nevertheless, the increasing demand for organ availability causes augmented use of high-risk or ECD organs. During procurement and LT, donor-recipient matching occurs, and an extensive process is involved in choosing and finalizing an organ for LT.^51,52 Thus, identifying the donor-related factors that may derive from poor post-LT outcomes is extremely important. Furthermore, different regions have different donor characteristics and differences in medical management across organ procurement institutions, which have the potential to affect the post-LT results.⁵²

Organ-specific DRI are introduced to estimate graft survival among different donor and recipient features. The use of livers with high DRI associates with amplified healthcare expenses that are risk-independent to patients.⁵²

Graft failure risk can be substantially increased due to:

• recipient’s age (more than 40 years)

• racial group (African versus White)

• death reason (cardiovascular [CV] injuries)

• type of graft (partial or split LDLT)

• height (by means of 10 cm reduction)

Besides, cold ischemia time and locality where the donor resides are regarded with respect to where the recipient is living.¹² Liver steatosis is not taken into account in DRI, which is a crucial limitation.¹²

BAR score

The BAR score recognizes a few significant predictors of recipient survival after transplantation and a study confirmed the superiority of the BAR score as compared to the other scoring systems.⁴⁸ Partial LTs (split and living donor LT), donation after circulatory death (DCD), and combined LTs are not considered. These predictors are: MELD score and age of recipient, age of donor, cold ischemia time, earlier transplantation, and pre-transplant life assistance dependency.

Rise in BAR scores implies reduced patient survival. Balance of risk score has a threshold, after which the mortality increases exponentially at BAR,¹⁸ while it stays stable below 16.¹² The BAR score is suitable to explain the threshold when there is increased LT risk. This is especially advantageous when allocating ECD livers to sick patients, which is a common occurrence in KSA.

Liver steatosis

The frequency of steatosis in donors for LT is increasing over time. The prevalence of this condition in the Saudi population is predicted to be 25%.⁵⁴ Still, the SCOT statistics show that steatosis is the primary cause of unrecovered extinct livers of qualified donors agreed for donating between 1994 and 2017 (45.6%).⁴ The rise in demand to increase the donor liver graft availability results in the possible inclusion of steatotic livers as donors. Although related to poor post-LT outcomes, the inclusion of steatotic livers has conflicting results in the literature, and further investigation is needed.⁵⁷

In spite of poor outcomes than that of nonsteatotic donor livers, steatotic are the most common marginal donor livers presented in the recent 2 decades because of the scarcity of donor organs. Liver steatosis is not against cadaveric LT all the times.⁵⁸ Mild steatotic donor livers in LT could not substantially raise the risk for unfortunate outcomes after LT.⁵⁹ Metabolic syndrome especially obesity and diabetes negatively affected the number of living donors.⁶⁰ Increasing the donor pool needs proper introduction of novel approaches, including the use of living non-related liver donors under strict policies.

The classification of steatosis can range from mild (10-30%), moderate (30 to 60%), and severe (>60%), based on the proportion of hepatocytes that contain cytoplasmic fat droplets.^55,56 Moderate and severe steatotic donor livers can be considered for recipients in comparatively better clinical status but having an desperate requirement for LT. Moderately and severely steatotic donor livers used for LT were reported to cause higher occurrence of primary non-function and a drift to rise 1-month recipient death rate. Still, the outcomes over on a more extended period were comparatively similar. This outcome led to the suggestion that recipients with good health might endure weak graft function in the beginning or severe post-LT difficulties and further supports the use of moderate and severe steatotic donors for LT.⁵⁹ Furthermore, it has been shown that microvesicular steatosis of donor livers has no adverse effect on the postoperative outcome after LT.⁶¹

The results from a study that combined the 2 major LT databases (United States and Europe) into one complete model to foresee outcome after LT, which focused on the effect of the existence of graft steatosis, showed that hepatic steatosis can be included in modern liver allocation models. Using the BAR score, microsteatosis or less than 30% of macrosteatotic grafts are safer to use until BAR score <18, while grafts with >30% macrosteatosis need to be used for BAR score of 9 or inferior.⁶² These results are helpful, considering the current high prevalence of steatosis in LT donors in KSA.

Use of anti-HBc positive donors

Hepatic grafts from donors positive for anti-HBc antibody are frequently associated with HBV infection transmission to recipients, even in the absence of serological markers of active infection.⁶³ De novo HBV infection is mainly caused by transplanting anti-HBc positive grafts, and care must be taken by the LT centers when using these organs.

Studies have shown that use of hepatitis B immunoglobulin (HBIg) during the surgery along with the use of nucleos(t)ide analogs (NUCs) therapy for longer duration, like lamivudine, can prevent HBV infection in those who received hepatic allografts from those having anti-HBc positivity.^63,64

De novo HBV infection developed in 19% of recipients with hepatitis B surface antigen (HBsAg)-positivity is not common in anti-HBc/hepatitis B surface antibody (anti-HBs) positive recipients (15%) than HBV naïve non-prophylactic patients (48%). Anti-HBV prophylaxis decreased the rates of such infections in anti-HBc/anti-HBs positive and HBV naïve recipients (3% and 12%). Liver grafts from that donors having anti-HBc positivity are safer to use, especially in recipients with HBsAg or anti-HBc/anti-HBs positivity. Recipients with HBsAg negativity must get lamivudine prophylaxis, similar to recipients with anti-HBc and anti-HBs positivity.⁶⁵

In an international, European, multicenter retrospective analysis to measure the rates of HBV recurrence in LT recipients with HBV, it was shown that fewer recurrence incidents were reported when patients received HBIg and NUC as prophylaxis (4.3%) in the long-term of 7 years. The HBV-HCC recurrence rate was 9.5%.⁶⁶ However, lifelong HBIg use is both burdensome and costly, whereas sustained use of lamivudine for a longer time induces resistance formation. Lately, to bring in HBIg-free therapy regimens, highly efficacious NUCs, such as entecavir or tenofovir, were investigated either as a single-drug regimen or together with HBIg in a lower dosage with better outcomes.⁶⁷ The use of HbsAg donors is increasingly done in clinical practice and could help in expanding our local donor pool.⁶⁸

Hepatitis C virus positive donors

These donors have varying (mild to severe) forms of infection. However, choosing viremic donors and those with seropositivity are crucial to LT for an uninfected recipient. A viremic donor may pose a 100% transmission risk through LT. Nevertheless, an aviremic but seropositive-only donor possesses lesser threat in terms of HCV transmission (up to 16% risk).⁶⁹

Direct-acting antiviral therapy has proven to be highly effective in treating HCV infection. Its almost 100% cure rates suggest that organs with HCV positivity are safer to waitlisted patients who do not have HCV infection.⁷⁰

Excellent outcomes of antiviral agents against viral hepatitis have rendered the LT fraternity with the advent to utilize organs from donors with viral hepatitis that require simple treatment post-LT.⁶⁹ However, ethical concerns should be considered and require a rigorous process of obtaining informed consent from potential recipients.⁷⁰

Grafts from donors with viral hepatitis

During transplantation, stored fresh tissue grafts from donors, who are infected with HBV and HCV, are utilized for vascular reconstruction. This is how the recipients get infected and pose a risk of disease transmission.⁷¹ To avoid these constraints, it is not advisable to store these arterial and venous tissues for use in patients other than relevant organ.¹²

Present/past cancer in donors

Malignancy transferring from donor to recipient due to LT is often a severe complication in patients with less immunity and is challenging for both transplant experts and recipients.¹²

The tumor transmission risk to the recipient of DDLT from donors affected by central nervous system (CNS) cancer is less common. Because cancers of the CNS less frequently spread and affect outside the brain, marginal grafts can be used to increase the potential organ availability for LT. A recent study has shown that median survival of 40 months was attained in patients who received grafts from donors having a CNS cancer, and no donor-related cancer transformation has been found.⁷²

However, the available literature remains incomplete. Further investigation is needed to understand the actual tumor transmission risk, possible risk factors, and readiness to treat recipients in case of a transmission. For donors with various primary brain tumor groups, the considerations are as follows:⁷³

• Group I: organ donation is not contraindicated.

• Group II: organ donation can be considered when there are no risk factors present.

• Group III: organ donation is contraindicated, unless in cases of life-challenging emergency LT, in which the waiting-list death risk is higher compared to the risk of transmitting after the surgery.

The ultimate decision regarding LT from donors with primary brain tumor is with the specialists and other team members involved in the transplanting process, who should ponder the tumor transmission risk with the death risk during the waiting list period.⁷³

Careful risk and benefit assessments of using organs from those having a present or past history of cancer require cautious evaluation before performing LT.⁷⁴ Individuals with glioblastoma multiforme, colorectal carcinoma (>T3), melanoma, choriocarcinoma, breast cancer (>T1c), and lung carcinoma are not suitable as LT donors.¹²

Use of organs from infected donors

The risk of microbial infections can occur following LT. The European Association for the Study of the Liver (EASL) Guidelines used a risk classification to assess the safety and suitability of donors based on infection type¹² and considers as absolute contraindications or unacceptable risk: positive donors for HIV-1 and HIV-2, multidrug-resistant (MDR) infections caused by bacteria, or West Nile virus (WNV), encephalitis, tuberculosis (TB), or others; for such patients, a concrete treatment strategy is unavailable.

In contrast to the US Centers for Disease Control and Prevention policy principle of “zero” risk donor to recipient transmission, the European guidelines take a more practical and pragmatic approach in which the clinical context is considered.¹² This seems to be more suitable for the KSA population (Table 3).

Hepatitis B virus-related hepatic disease

Even though decompensated HBV cirrhosis is lessening globally because of extensive vaccination campaigns and the introduction of direct-acting antivirals, it is still considered a major cause of ESLD in KSA, with HCC being the third leading indication for LT.⁹ The HBV status of the recipient needs to be assessed. If HBV DNA is detectable, regardless of the level, antiviral treatment with NUCs should be started because interferon (IFN) is not to be used in those having decompensated cirrhosis. Entecavir or tenofovir are the drugs of choice (Grade II-2),⁷⁸ and they act by improving liver function and decreasing the risk of HBV recurrence after LT. They are efficacious and safe in patients with advanced liver disease.^79-81 The dose of NUCs should be modified in those with poor creatinine clearance.¹²

It is essential to note that a significant proportion of decompensated patients who initiate NUCs therapy show improved hepatic function, that may, at times, result in delisting from LT waitlist (Grade II-2).^82,83 A recent study from KSA revealed HBV/HDV coinfection rate of 24%; however, this did not negatively impact LT outcomes.⁹ On the other hand, one-third of patients may die within half a year due to hepatic function loss, irrespective of giving effective antiviral treatment,¹² and a precise prognosis is not available to predict patients who will not require LT for recovering and those who will succumb with no LT.

Hepatitis C virus-related hepatic disease

Hepatitis C virus infection is the leading LT indication. Hepatitis C virus genotype 4 (HCV-G4) is the most prevalent genotype in the Middle Eastern region.^84,85 In KSA, HCV forms approximately 29% of LT indications; of them, approximately 60% are related to HCV-G4.⁸⁶

Liver transplantation candidates need pre-LT antiviral agents to lessen the post-LT HCV recurrence (Grade I). Interferon-based regimens are not recommended due to issues with safety and tolerability.^87,88 Treatment with IFN-free antiviral drugs has shown improved liver function, with some patients being delisted (Grade II).^89,90

Treatment with sofosbuvir and ribavirin (RBV) for a few weeks before LT in patients with HCV genotype-1 (HCV-G1) or HCV-G4, compensated cirrhosis, and HCC prevented graft infection in the most patients⁹¹ (Grade II). Sofosbuvir/ledipasvir given along with RBV for 12 or 24 weeks was evaluated in patients with HCV-G1 or HCV-G4 and compensated or decompensated cirrhosis. The rates of sustained viral response (SVR) at 12 weeks (SVR12) were above 95% and 85% in individuals with compensated and decompensated cirrhosis, respectively (Grade II).⁸⁹ The same study showed improvement in MELD scores by 1-8 points in about 66% of patients with decompensated cirrhosis. Sustained viral response at 12 weeks rates of ~95% was obtained with the use of the combined drugs of ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir with RBV in compensated cirrhotic cases with HCV-G1 infection.⁹² Efficacy in those with compensated cirrhosis of all genotypes is obtained using the combined use of sofosbuvir, daclatasvir, and RBV (Grade II).⁹³ A report on patients infected with HCV-G4 concluded that the combination of ledipasvir and sofosbuvir, without RBV, is potent and safe in treating these patients, either in a pre- or post-LT setting.⁹⁴

Alcoholic liver disease (ALD)

It is most frequent in Western countries, where it is a common LT indication,¹² and LT for alcoholic cirrhosis has a favorable outcome.⁹⁵ A period of 6-month alcohol abstinence before LT is recommended (Grade II-3). This recommendation can result in improved liver function and delisting of the patient and is a good predictor of patient compliance.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

Due to epidemic levels of obesity and T2DM, NAFLD and NASH prevalence are emerging as serious health concerns in KSA.⁵⁴ Patients with NAFLD/NASH may progress to ESLD and require LT. The presence of metabolic syndrome is linked to many comorbidities, which increases the risk of complications related to surgery⁹⁶ and needs to be carefully evaluated. Conditions, such as obesity, hypertension, T2DM, and dyslipidemia require rigorous workup in the screening phase, and they may exacerbate in the post-LT phase (Grade III).⁹⁷

Primary biliary cholangitis

Survival of primary biliary cholangitis (PBC) patients hugely increased well with the extensive use of ursodeoxycholic acid. Nevertheless, approximately 33% of patients show treatment failure and continue to develop cirrhosis, necessitating LT as the final option.⁹⁸ Indications for LT in individuals with PBC do not differ from those in patients with other liver diseases; those with decompensated hepatic disease, portal hypertension of advanced, complex stage, and non-controllable and non-tolerable pruritus are indicated for LT¹² (Grade II-3). The optimal timing for LT in PBC is when the total serum bilirubin reaches around 10 mg/dL.⁹⁹

Primary sclerosing cholangitis (PSC)

In PSC cases, decompensated hepatic disease, complicated portal hypertension, and recurring occurrences of cholangitis must be indicated for LT (Grade II-3).¹² The cholangiocarcinoma risk rises approximately 10-15% post a 10-year PSC course,¹⁰⁰ and this bile duct cancer should be left out using pre-LT radiological and biological markers (Grade III). Colon cancer should be monitored by annual colonoscopy in patients with PSC and ulcerative colitis (Grade II-3).

Autoimmune hepatitis (AIH)

Autoimmune hepatitis affects more females than males, with the percentage of female patients in the KSA ranging from 60.8% in the central region to 75.7% in the Western region.¹⁰¹ The prevalence of AIH among LT patients from KSA is estimated to be approximately 14.3%, based on a single-center report.¹⁰² Liver transplantation is indicated for AIH in those with ESLD, or with acute hepatic failure during ineffective immunosuppressant therapy (Grade II-3).¹⁰³ The outcomes of LT for AIH patients are extremely good, with 1- (90%) and 5- year (80%) survival rates.¹⁰⁴

Wilson’s disease (WD)

Wilson’s disease is a rare autosomal recessive disease affecting copper metabolism. Only a few studies on WD patients of a small sample size have been conducted in KSA, mainly in regions where consanguineous marriages exceed 50%.¹⁰⁵ Wilson’s disease can manifest as acute, subacute, or even chronic hepatic failure, leading to ESLD. Acute stage (Grade III) or ESLD development may require LT, and candidates with neuropsychiatric symptoms need neuropsychiatric examination.¹²

Hereditary hemochromatosis (HH)

Hereditary hemochromatosis is an autosomal recessive disorder featured by iron overload. It is caused by a mutation in the HFE gene, the most common being p.C282Y and p.H63D. In the Saudi population, the frequency of p.C282Y is extremely low (<0.001), but the p.H63D mutation is relatively common.¹⁰⁶ Few HH patients (1%) transplant due to ESLD,¹² but they pose a higher risk of HCC than those affected by other cirrhosis causes.¹⁰⁷ Therapeutic phlebotomy is the generally recommended therapy for HH.¹⁰⁸ Iron overload mainly poses hepatic implications; nevertheless, it has the potential to develop multiple organ damage. The post-LT outcome for HH is favorable, with 1- (80.7%) and 5- year (74%) survival rates (Grade III).¹⁰⁹

Primary hyperoxaluria type 1 (PHT1)

This disease develops due to shortage of alanine:glyoxylate aminotransferase. It results in the accumulation of insoluble calcium oxalate salts in the kidney and other organs.¹¹⁰ Hemodialysis is inadequate for oxalate clearance, requiring LT and kidney transplantation (KT) to rectify the metabolic irregularity.¹¹¹ Isolated KT reinstates oxalate excretion but is linked to increased recurrence. Pre-emptive LT before end-stage kidney disease is thus a recommended strategy, as LT improves the metabolic defect and averts renal failure¹² (Grade III).

Hepatocellular carcinoma

Hepatocellular carcinoma is the most frequent hepatic cancer. In the KSA, HCC comprises 87.6% of all hepatic malignancies, and the median ages at cancer recognition are 65 and 60 years for males and females, respectively.¹¹² This HCC incidence in KSA is a consequence of the increased occurrences of 2 major risk factors, namely HBV and HCV infection. Indications for LT in HCC patients are liver cirrhosis, Milan criteria (one lesion <5 cm or <3 lesions <3 cm each), no proof of portal vein (PV) invasion or extrahepatic spread, and no contraindications for LT¹¹² (Grade I). When these criteria are applied, 5-year survival rate exceeding 70% can be predictable.¹¹³ To avert the patient from falling out of these criteria when on waiting list, local ablative treatment or chemoembolization can be given to resist cancer growth.

University of California San Francisco (UCSF) criteria have shown that the patients with the following measures possess a recurrence-less survival not substantially varied from those within the Milan principles: one nodule of <6.5 cm or many nodules with the hugest being <4.5 cm and the sum being <8 cm.⁸² Nonetheless, the Milan criteria serve as the yardstick for choosing HCC patients to undergo LT and the source for appraising new suggested criteria. A 5-year survival is to be attained after downstaging post-LT as similar as the HCC patients who fit the norms for LT with no need of downstaging.⁸⁵ Another criteria includes the alpha-fetoprotein (AFP) levels above 500 ng/ml or a hike of 15 ng/ml per month which are poor prognosis criteria.⁸³ Like the AFP model, other measures have been used, that consider the nodule counts and sizes along with the AFP level.⁸⁴

Cancer progression, downstaging, and bridging therapy make all patients estimated to wait for LT more than 6 months.^86,87

Non-cirrhotic patients with non-resectable HCC, who have a resection and an intrahepatic HCC recurrence, are regarded as suitable LT candidates when the non-existence of macrovascular invasion and extrahepatic spread has been confirmed.⁸⁸

Cholangiocarcinoma

It is the second most common hepatic neoplasia. A study on cancer incidence using data from the KFSHRC Tumor Registry program showed that 11% of cancer malignancies were due to cholangiocarcinoma.¹¹⁴ Cholangiocarcinoma often features a poor prognosis and is separated into intrahepatic, hilar, and distal. Liver transplantation in such cases is contentious as the disease may recur.¹¹⁵ For unresectable hilar cholangiocarcinoma, neoadjuvant chemoradiation and LT are considered a therapy strategy¹¹⁶ (Grade II-3), assisting in achieving lesser recurrences and more remarkable long-term survival than other available therapy strategies.¹¹⁶ Surgical removal is regarded as a suitable therapeutical option for extrahepatic cholangiocarcinoma.

Other hepatic malignancies

Liver transplantation can help treat other hepatic malignancies that do not feature extrahepatic metastatic spread, including fibrolamellar cancer and epithelioid hemangioendothelioma. Remarkable disease-free survival rates: 90% (one year), 82% (5 years), and 64% (10 years) (Grade II-3).¹¹⁷

Obesity

Overweight and obese patients have significantly increased morbidity in terms of infections after LT and, consequently, more prolonged hospitalizations.¹¹⁹ In obese patients (BMI >35), MDT discussion involving a diet specialist, psychology expert, hepatologist, anesthetic expert, and surgeon is needed. On the other hand, malnutrition is another major concern in cirrhotic patients; therefore, nutritional assessment and management of malnutrition are mandatory in the pretransplant setting.¹²⁰

Older age

Though LT does not have any specific age requirement, patients above 65 years need a MDT discussion to evaluate comorbidities (Grade III). Elderly patients (>70 years) having several comorbid conditions are regarded as relatively contraindicated LT by all 4 LT centers in KSA.³ However, 5-year death rate and graft loss in recipients above 70 years are similar to those in younger patients, signifying that patients need not be excluded based only on age, but these recipients develop a higher CV complications risk.¹²¹ The impact of old donor age is more pronounced in younger recipients, and age-matching between the donor and the recipient should be incorporated into allocation policies with a multistep approach.¹²²

Cardiovascular disease

Checking of CV function is essential in the assessment process. Traditional CV risk factors are associated with coronary artery disease (CAD) in candidates with hepatic disease, which are to be considered as indicators for cautious pre-LT assessment of coronary risk.¹²³ Electrocardiogram and transthoracic echocardiography need to be conducted in LT candidates to differentiate the pre-existing cardiac disease. To uncover asymptomatic ischemic heart disease, a cardiopulmonary exercise test is required if the candidate has several CV risk factors and is above 50 years (Grade II-3). In candidates with increased CV risk, a cardiology consultation is required for executing a coronary angiography when CAD is suspected. If the candidates received effective pre-LT CAD treatment, post-LT survival is not expressively varied between those having and not having obstructive CAD.¹²⁴

Respiratory diseases

All LT candidates may require pulmonary function tests and chest X-ray (Grade II-3). Hepatopulmonary syndrome (HPS) is found in up to 17% of cirrhotic patients resulting from intrapulmonary vascular dilatations and hypoxemia and is recognized by measuring the alveolar-arterial oxygen gradient and conducting contrast echocardiography.¹²⁵ Hepatopulmonary syndrome can be treated only by LT (Grade II-2/3). Severe HPS patients with <50 mmHg oxygen partial pressure without 100% reversibility pose a hazard of permanent pulmonary failure post-LT and high-risk perioperative death.¹²⁶ Hepatopulmonary syndrome betterment and reversibility may take months after surgery.¹²⁷

Portopulmonary hypertension (PPHTN) happens in 2% to 8% of cirrhotic patients. A disparity between vasodilators and vasoconstrictors may cause erroneous angiogenesis and pulmonary hypertension.¹²⁸ Portopulmonary hypertension is doubted when systolic pulmonary artery pressure is >30 mmHg on echocardiography, which needs to be established by right heart catheterization. Moderate (mean pulmonary artery pressure [MPAP] less than 35 mmHg) and severe PPHTN (less than 45 mmHg) are related to high post-LT death rates.¹²⁹ Managing PPHTN patients before surgery needs early disease detection and treatment using respiratory vasodilators epoprostenol (prostacycline) or endothelin receptor antagonist, or phosphodiesterase inhibitor type 5 (sildenafil), could support maintaining respiratory hemodynamics and had shown satisfactory results; though, long-term outcomes are yet to be known.¹³⁰ Hence, LT could be the treatment option in moderate PPHTN patients who show good response to clinical therapy and respiratory vasodilators and with moderate MPAP less than 35 mmHg (Grade II-2/3) under anesthetic consultation.¹³¹

Renal disease

Assessing kidney physiology is crucial for a LT candidate. Cirrhotic patients who suffer kidney impairment pose a 7-fold high mortality risk post-LT, with half of them dying within a month.¹³²

The hepatorenal syndrome, a reversible cause of kidney impairment, is defined as an acute decline in renal physiology manifested by increased serum creatinine (>0.3 mg/dl) to a percentage rise of 50% (1.5- fold) from baseline, caused due to pre-LT reasons other than those of acute kidney injury (AKI), including sepsis, decrease in blood volume, and parenchymal kidney disease.

Chronic kidney disease (CKD) is defined as a projected glomerular filtration rate (GFR) of less than 60 ml/min for more than 3 months.¹³³ Patients with ESLD having 1) GFR <30 ml/min, 2) hepatorenal syndrome wanting kidney replacement treatment over 8 to 12 weeks, and 3) kidney biopsy exposing >30% fibrosis and glomerulosclerosis, would be advantageous from getting both liver and renal grafts.¹³⁴ However, the requirement of combined LT-KT in those with creatinine clearance of 30-60 ml/min. The risk of deterioration of kidney function post LT alone needs to be balanced as a significance of LT and medication side effects, and the scarcity of renal grafts (Grade II-2).

Hepatocellular carcinoma

Initially, in 2002, a MELD exception was given based on Milan criteria, which included either one lesion <5 cm in maximum diameter or up to 3 lesions with a maximum diameter of any lesion of 3 cm. Stage I tumors (<2 cm size) and stage II lesions were granted a MELD score of 24 and 29, respectively, with an increase in MELD every 3 months, provided the tumor remains within Milan criteria for LT.¹¹³

Due to an inequitable increase in DDLT for HCC candidates compared to non-HCC patients, along with discrepancies in diagnosis and new drop-out rate data, several modifications to the original MELD score exception assigned to HCC patients were issued to reduce this advantage.

In 2003, OPTN/UNOS reduced the initial MELD scores except 20 for stage I HCC, and 24 for stage II HCC.¹⁶⁴ In 2004, the MELD exception priority for stage I lesions was eliminated.¹⁶⁵ Then, in 2005, the initial MELD exception score for stage II HCC was reduced from 24 to 22. Patients continued to receive a 10% increase in exception points every 3 months, provided they remained within Milan criteria.¹⁶⁶ In 2015 (“Delay and Cap HCC” policy), a patient listed with an actual MELD score like without HCC in the first 6 months was then given a MELD score of 28. Every 3 months, extensions are applied to increase the MELD score to 30, 32, and 34 as the maximum.¹⁶⁷ In 2017, it was allowed standard exception points to be granted to patients who were down-staged as per criteria set by the UCSF (up to 5 tumors with the largest being 4.5 cm and the sum of tumors being <8 cm), within Milan criteria, and restriction on standardized exception points for HCC patients with AFP levels >1000 ng/mL that do not decrease to <500 ng/mL with treatment.^168,169

Pulmonary complication of cirrhosis

Both HPS and portopulmonary hypertension (POPH), granted MELD score of 22 with an increase in MELD points equivalent to a 10% increase in mortality every 3 months, provided PaO₂ remains less than 60 mmHg, for patients with HPS and MPAP remains less than 35 mm Hg and pulmonary vascular resistance less than 400 dyn/s/cm for patients with POPH.¹⁷⁰

Progressive familial intrahepatic cholestasis (PFIC)

Progressive familial intrahepatic cholestasis is a group of autosomal recessive cholestatic disorders that presents intrahepatic cholestasis in children or early adulthood and often requires LT early in life. Our pediatric community in KSA is a leading referral for LT in children (Grade II-3).¹⁸⁹ Progressive familial intrahepatic cholestasis includes 3 major diseases characterized by failed secretion of bile acids (BAs) or phospholipids into the bile canaliculus to complete micelle formation.¹⁹² Three types of PFIC have been identified, PFIC1, PFIC2, and PFIC3, with an estimated incidence of 1/50,000 - 100,000.¹⁹³

Progressive familial intrahepatic cholestasis 1 and PFIC2 are caused by impaired secretion of bile salt or conjugated primary BAs into the canaliculi due, respectively, to defects in ATP8B1 gene encoding the FIC1 protein, and in ABCB11 gene encoding the bile salt export pump protein (BSEP). They are characterized by infantile presentation with jaundice, pruritus, and failure to thrive but low or normal gamma-glutamyl transferase (GGT) activity.

ABCB4 gene encodes MDR3 protein, a phospholipid transporter involved in biliary phospholipid excretion. Reduced phospholipid level causes inefficient inactivation of detergent bile salts and epithelial injury of cholangiocytes resulting in high GGT cholestasis, the classical features of PFIC3. In addition to causing PFIC3 (symptoms ranging from neonatal cholestasis to biliary cirrhosis in adult), ABCB4 mutations can also cause intrahepatic cholestasis of pregnancy and low phospholipid-associated cholelithiasis syndrome, and predispose an individual to medicine-induced cholestasis.¹⁹⁴

Indication for LT in PFIC includes liver decompensation, failure to thrive, portal hypertension, or intractable itching not responding to medical therapy.¹⁹⁵

Tight Junction Protein 2 (TJP2) & BA coenzyme A: amino acid N-acyltransferase (BAAT)

Tight Junction Protein 2 & BAAT mutation-positive cases present with normal GGT cholestasis, high serum BA, and progressive cholestasis to ESLD. The primary role of TJP2 is to avert the back diffusion of bile salts from the canaliculi to the blood circulation at the paracellular level, explaining the reason behind presence of normal GGT, high serum BA, and fat malabsorption in children. However, it is still unclear why they also have progressive cholestasis with high liver enzymes and bilirubin progressing to ESLD.¹⁹⁶ Indications for LT include liver failure and severe failure to thrive.

Bile acid synthesis defects (BASD)

Inborn errors of primary BA synthesis are rare inherited autosomal recessive disorders. The most frequent defects are the 3β-Δ5-hydroxy-C27-steroid oxidoreductase (3β-HSD) deficiency (OMIM 607765), which is due to mutations in HSD3B7; and to a lesser extent, the ∆4–3-oxosteroid-5β-reductase (∆4–3-oxo-R) deficiency, due to mutations in AKR1D1.¹⁹⁷ These defects in enzymes catalyzing key reactions in the formation of the primary BAs, namely cholic acid (CA) and chenodeoxycholic acid in humans, lead to an inadequate synthesis of primary BAs that are critical for bile formation and to the production and the accumulation of atypical and hepatotoxic BA intermediates. These deficiencies commonly manifest in neonates or infants as cholestasis and can progress to early cirrhosis and liver failure unless treated early with CA.¹⁹⁸

Alagille syndrome (ALGS)

Alagille syndrome, a multiorgan disorder, having a variety of changes in clinical complications, observed even between patients of a single family. Most common characteristics include bile duct paucity on liver biopsy, cholestasis, congenital cardiac imperfections (chiefly concerning pulmonary arteries), butterfly vertebrae, ophthalmologic irregularities (mainly posterior embryotoxon), and characteristic facial features. Abnormalities in kidney function, growth failure, developmental delays, splenomegaly, and vascular anomalies are also reported. Disease diagnosis is recognized in a proband who fulfills the required criteria and/or possesses a heterozygous pathogenic variant in JAG1 or NOTCH2 as diagnosed by molecular genetic testing. The primary indication for LT in ALGS is ESLD secondary to progressive cholestasis, followed by growth failure as the next indication. Some other primary indications are intractable pruritus, portal hypertension, and fractures (Grade III).¹⁹⁹

High disease burden of autosomal recessive cholestatic liver disease in KSA

Comparable with the local experience with other autosomal recessive disorders, most mutations were private young mutations that were rendered homozygous through the consanguinity loop (68%).²⁰⁰

However, the rest (32%) were founders based on their detection in apparently unrelated individuals, and the cumulative carrier frequency was 0.0115 (1 in 87). This translates into a minimum disease burden of cholestatic liver disease in KSA of 1:7246, a really high estimate even compared with countries with a high burden in children, such as Japan.²⁰¹

Biliary atresia

Biliary atresia is a fibroinflammatory disease of the intrahepatic and extrahepatic biliary tree. Surgical hepatic portoenterostomy may restore bile drainage, but the intrahepatic disease progression results in complications of portal hypertension and advanced cirrhosis in most children,²⁰² becoming one among the most common LT indications in children. Although improvements in biliary atresia surgical treatments, a majority of children require LT (Grade II-3).²⁰³ Indications for LT in biliary atresia include failed Kasai portoenterostomy, significant and recalcitrant malnutrition, recurrent cholangitis, and the progressive manifestations of portal hypertension. Extrahepatic complications of this disease, such as HPS and PPHTN, are also indications for LT.²⁰⁴

Urea cycle disorders (UCDs)

These are a cluster of monogenic inborn faults of liver metabolism that cause life-threatening hyperammonemia. Flaws in the urea cycle pathway cause a propensity for hyperammonemia and resultant neurological injury. Ornithine transcarbamylase (OTC) insufficiency is utmost familiar among the UCDs; others include argininosuccinate lyase insufficiency (argininosuccinic aciduria) and argininosuccinate synthetase deficiency (citrullinemia). All UCDs, except OTC deficiency, are autosomal recessive in inheritance. Quick and intrusive therapy is needed for survival. However, the prognosis is not strong relating to survival and neurological outcomes correlated with the number, severity, and duration of hyperammonemic episodes. The only known “cure” for UCDs is LT, which carries some significant morbidity and mortality (Grade III).²⁰⁵

Glycogen storage disorders (GSDs)

GSDs are inherited disorders in which the concentration and/or structure of glycogen in body tissues is abnormal. Essentially, all known enzymes involved in the synthesis or degradation of glycogen and glucose have been discovered to cause some type of GSD.²⁰⁶ Glycogen storage disorders types I, III, and IV can be associated with severe liver disease. The indications for LT in GSD I are either multiple liver adenomas bearing the risk of malignant transformation and/or poor metabolic controls.²⁰⁷ In GSD III, the LT indication is liver failure and HCC. In GSD IV LT, the indication is progressive liver cirrhosis with portal hypertension.²⁰⁸

Tyrosinemia type 1

Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems and long-term risks for HCC.²⁰⁹ The indications of LT in early life is liver failure that is not responded to medical therapy of NTBC [2-(2-nitro-4-trifluoromethylbenzoil)-1,3 cyclohxanedione]. After the age of 2 years, the indications are HCC and progressive liver disease with portal hypertension.

Conventional or standard liver transplantation

Whole-liver grafts are used and implanted in the position where the unhealthy liver in the right upper quadrant is located earlier. In many European nations, the piggy-back procedure is considered, preserving the patient’s inferior vena cava (IVC). The donor’s suprahepatic IVC is anastomosed to the recipient’s 3 hepatic veins (HVs), and the PV, hepatic artery (HA), and biliary tree are reconstructed by duct-to-duct anastomosis between the chief biliary tracts of donor and recipient¹² (Grade II-3). If the recipient’s IVC cannot be preserved or in some cases of malignancy, the surgery involves vascular reconstruction with end-to-end anastomoses between the donor’s IVC and the recipient’s infra- and suprahepatic IVC. Standard LT is classified depending on the donor type (brain dead or cardiac death), but in KSA, only brain dead donations are available.

Domino liver transplantation

The most common domino LT indication is familial amyloidotic polyneuropathy (FAP) (Grade II-3). The patient with FAP gives liver to another while getting a deceased organ.²²⁰ The FAP liver recipient should be above 55 years to reduce the risk of emerging FAP.¹² A graft with 3 distinct suprahepatic veins involving bench surgery for reconstruction is required in FAP patient to preserve IVC. The entire hepatectomy in the FAP donor is conducted because the blood circulation is preserved; however, complications are less if there is no portal hypertension.²²¹

Partial graft transplantation

It is performed when there is a requirement for partial support to manage a specific or complete metabolic insufficiency. The graft volume should be enough to withstand the post-LT life of the patient. The ratio of patient’s weight to the graft must be a minimum of 0.8%, indicating that an 80-kg patient may require a 640g graft at least.¹² This might cause an issue in adult living donors, and it is usually addressed using the right lobe for LT.²²²

Auxiliary liver transplantation

It can be performed orthotopically or heterotopically and is used in 2 types of situations: 1) patients with acute hepatic failure with the partial graft supporting the unhealthy liver while recovering, the graft is removed, and immunosuppression is reserved,²²³ and 2) patients with functional congenital or metabolic disorders disturbing the otherwise healthy liver (Grade II-3). Curing metabolic disorder to evade a full LT may require implanting a partial liver graft while maintaining the function of native liver.²²⁴ Decent outcomes are observed in young patients with acute hepatic failure (mostly viral or autoimmune),²²⁵ but inferior results are seen with Budd-Chiari syndrome and WD.²²⁶ Acute HBV infection remains a debatable indication due to the danger of graft reinfection.²²⁷

Split liver transplantation

Split liver transplantation involves splitting the liver into 2 parts, and how this division is made depends on who the recipients will be. If the liver is intended for one adult and one pediatric patient, it will be separated into a right lobe that also contains segment IV and a partial left lobe that comprises segments II and III^228,229 (Grade II-2). If the liver is intended for 2 adult patients, it will be separated into the right lobe (segments V-VIII) and left lobe (segments I-IV). Usually, the left lobe has a size of around 450g, which only allows it to be implanted in low-weight (50-55 kg) patients^230,231 (Grade II-2). Split liver transplantation is technically demanding and may increase perioperative complications; therefore, critical evaluation of donor livers suitable for splitting and careful screening of recipients is extremely important.²³²

Living donor liver transplantation

Living donor liver transplantation was first introduced to address the scarcity of pediatric sized cadaver donor livers, which bring about an inadmissibly increased rate of pediatric deaths on the waitlist. Pediatric LDLT became an alternative in these cases, where the living adult donor’s segments II and III are relocated into a child.²³³

In Asia, including the KSA, because of the lack of deceased donors, the usage of LDLT slowly extended, terminating with the technique of adult recipients getting entire right lobe grafts (segments V-VIII) from living donors.^3,234 Right hepatectomy is considered safe for the donor²³⁵ and needs careful dissection in which the right HA, right PV, right bile duct, and right suprahepatic vein are separated.¹² Graft/recipient weight ratio must be of at least 0.8% to ensure viability²²² (Grade III). The recipient process is perplexing because of the anastomoses’ size. Nevertheless, the outcomes are good and identical to patients who received whole grafts from deceased donors.²³⁶ However, the main challenge is the significant morbidity in 38% of donors and causing death in 0.18%.²³⁶ One-third of donors experience complications; most have type I or II on the Clavien-Dindo classification system.²³⁷ The most common complications are biliary fistulas, which are generally treated conservatively; however, a few require hospitalization and surgery again.^238,239 Complication in the right lobe donors is more than that of donors of the opposite lobe, with the latter also showing more rapid normalization of serum bilirubin levels and prothrombin time.²⁴⁰

Vascular complications Arterial complications

The incidence of hepatic artery thrombosis (HAT) is approximately 3% in adults and as high as 8% in children;²⁴¹ graft dysfunction is the most common feature.¹² This can dramatically alter the graft survival time lowering up to 27.4% at 5 years, in contrast with 76.4% for non-HAT patients.²⁴² Re-intervention and revascularization can be the treatment option for 50% of HAT patients, whereas the other half requires re-LT²⁴³ (Grade III). The most severe long-term complication is the incidence of ischemic biliary lesions or ischemic cholangiopathy (IC), which can require re-LT.²⁴⁴

Early identification is crucial, particularly in the pediatric population. This can be achieved with serial surveillance with Doppler ultrasound, which has a sensitivity of >90%.²⁴⁵ Permissive hemodilution (hematocrit 20-25%), anticoagulation, and antiplatelets are non-standardized preventive measures practiced variably by transplant centers for the pediatric population.²⁴⁶ Hepatic artery stenosis (HAS) can be a precursor to HAT, with an incidence in children of 2.8%.²⁴⁷ It is diagnosed by Doppler ultrasound imaging, and the gold standard is angiography and is best managed by angioplasty and endovascular interventions.²⁴⁸

Venous complications

Stenosis or occlusion of the IVC is an uncommon but serious problem, with 1-6% incidence and, mostly, concerning intimal hyperplasia or fibrosis at the place of anastomosis.²⁴⁹ The piggy-back technique (preservation of the IVC) may reduce the rate of complications arising due to anastomotic stenosis,²⁴⁹ and endovascular techniques are the therapy of choice²⁵⁰ (Grade II-3).

The use of the piggy-back technique, with the resultant requirement for anastomosis of the 3 HVs result in outflow problems affecting 30% of recipients.¹² This complication is now very rare due to the performance of anastomosis between the combination of the 3 HVs of the recipient and the IVC of the donor.²⁵¹ Patients receiving LDLT/SLT grafts are at particular risk, and graft positioning at the time of the transplantation is critical to minimize the incidence. HV obstruction clinically bears similarity to Budd-Chiari syndrome. Hepatic veins outflow obstruction is common terminology used to reflect HV obstruction instigated by compression or twisting of the anastomosis due to graft regeneration or intimal hyperplasia and fibrosis at the sites of anastomosis. Management by interventional radiology dilation with or without stenting resolves the obstruction.²⁵² Clinical problems, such as ascites, renal failure, lower limb edema, and splenomegaly, can resolve after endovascular interventions.

Portal vein thrombosis has an incidence of 2.1-26% in patients undergoing LT,²⁵³ mainly due to complications such as smaller PV diameter, technical, size mismatch between the donor’s and recipient’s PV, and atretic or hypoplastic recipient PV in biliary atresia.²⁵⁴ In patients with previous PVT, LT is associated with higher surgical complexity, and surgical alternatives include portocaval transposition, renoportal anastomosis, mesentericoportal anastomosis, and multi-visceral transplantation.¹² These, however, are associated with higher morbidity and mortality, with the rate of re-thrombosis reaching 13%, and short-term anticoagulation is therefore recommended.²⁵³ Early PVT presents with graft dysfunction, bleeding, and ascites, and it is managed by thrombectomy, while late PVT showing symptoms of portal hypertension and can be managed by Meso-Rex or selective portosystemic shunts. Alternatively, it can be managed with interventional radiology. Symptomatic PV stenosis is best managed by interventional radiology. In up to half of the PV, stenosis requires more than one dilatation.²⁵⁴

Biliary tract complications

Biliary complications remain the Achilles heel of LT, with a reported incidence of up to 30% and include biliary leaks and biliary strictures. Biliary leaks can be anastomotic or, in cases of LDLT/SLT, from the cut edge of the liver. Leaks occur as an early postoperative complication and increase morbidity and mortality after LT. Presentation can be with peritonitis, irritability, vomiting, fever, bilious output from drains, and elevated liver enzymes. The cause can be technical or secondary to HA complications and timely surgical or radiologic intervention is advised to prevent septic complications.

The incidence of biliary leakage is approximately 5%.²⁵⁵ Depending on its cause, it may have a comparatively convenient option that includes ERCP procedure and sphincterotomy, temporarily placing a prosthesis, and many more solutions¹² (Grade II-3). For partial graft, the leak is occasionally located on the superficial split liver and is produced by tubules with a gradually decreasing flow. Very infrequently, tubular embolization or re-surgery is needed.²⁵⁶

Ischemic bile duct injuries

These may have various etiologies, such as ABO incompatibility, artery thrombosis, ischemia/reperfusion injury, among others,¹² and are among the most common complications (15-37%) in patients who received livers from DCD donors.²⁵⁷ Additional cause is the reappearance of PSC (20-30%).^258,259 These injuries are presented by intrahepatic strictures chiefly disturbing their confluence, making a beaded appearance, with stenosis and dilatation of the entire biliary tract; cholestasis with intractable pruritus and recurrent cholangitis of liver abscesses are the chief manifestations.¹² Re-LT is suggested in these patients (Grade II-3).²⁶⁰

Anastomotic stenosis

Anastomotic stenosis occurs²⁶¹ in few adults (4-9%), while in children, it can be as high as 25%.^262,263 The pre-existing reasons for anastomotic strictures are related to suboptimal operation procedures or biliary leak, and their majority presents in the post-LT year, albeit it rises gradually later.²⁶⁴ Late biliary strictures generally appear as a result of graft ischemia; a radiological examination differentiates HAT. Ischemic biliary strictures usually occur more than one time and upset the entire biliary tree. However, solitary biliary strictures are generally related to surgical anastomosis. The earliest indications are 5 to 10 times increased alkaline phosphatase and GGT levels.²⁶⁵ Biliary dilatation is often absent in ultrasound, but diagnosis can be made by MRCP, with a sensitivity and specificity nearing 90%,²⁶⁶ but the treatment ability is not sufficient. The regular treatment strategy involves endoscopic procedure with balloon dilatation and applying a stent, showing a better success rate (70-100%).^261,267 Percutaneous transhepatic cholangiogram is kept for patients who did not benefit from endoscopic therapy or those with complicated hepatico-jejunostomies and possesses a lesser success rate (50-75%).²⁶⁸ When patients do not respond to either therapy, a hepatico-jejunostomy needs to be conducted (Grade II-3).¹²

Complications associated with partial grafts

The most common complication associated with partial grafts is anastomotic stenosis. An important related factor is the presence of bile leak,²⁶⁹ and even though the underlying process is unknown, it may be associated with the local bile inflammatory effect or with weak local vascularity.¹² Some research reports relate duct-to-duct anastomosis size with the presence of stenosis.²⁷⁰ The incidence of anastomotic stenosis can affect half of partial liver graft recipients, and although it may not disturb long-term survival, the quality of life may be impacted.²⁶¹ The success rate of endoscopic treatment (60-75%) is lesser compared to anastomotic stenosis after whole-LT.²⁷¹ Interventional radiology serves as a good therapy option through dilatation or stent insertion.¹² Around half of the cases need re-surgery, and the duct-to-duct anastomosis becomes a hepatico-jejunostomy (Grade III).²⁵⁶

Bowel perforation

Bowel perforation is a potentially devastating complication after LT in the pediatric population. Post-Kasai procedure recipients are particularly at risk, while other risk factors include high-dose steroid therapy, CMV infection, prolonged procedure, and re-operation for postoperative bleeding. The diagnosis can be challenging in this age group, with abdominal distention being the only symptom presenting. The incidence is reported to be 10-20%.^272,273 Emergency laparotomy, washout, and repair are indicated.

Re-liver transplantation

Approximately 7-10% of adult patients lose transplanted grafts,²⁷⁴ and re-LT is the only suitable therapy for these patients (Grade II-2).²⁷⁵ The main causes of graft loss can be divided into early (HAT or main graft not functioning) and late-onset (IC, chronic rejection, or reappearance of the primary liver disease).¹² The re-LT rate in KSA is 3.7%, lower than worldwide rates, which vary between 5-22%,²⁷⁶ and this can be attributed to the severe shortage of deceased donor grafts. Small-for-size syndrome is the leading indication for re-LT in KSA, followed by HAT, recurrence of the original disease, chronic rejection, and late vascular complications.²⁷⁶ The timing of re-LT is a crucial time for patient and graft survival. Those with a re-LT time of fewer than 30 days have lower survival times than those with later re-LT,^276,277 and re-LT has higher morbidity and mortality compared with LT.²⁷⁴ Currently, there is no consensus for defining specific survival outcomes in which re-LT should be avoided, and only the MELD score provides an objective stratification for re-LT candidates.¹² Re-LT recipients having MELD score >25 showed a reduced short-term survival (<60%), while those with MELD score >30 had a 20-40% survival rate.²⁷⁸ The key parameter in establishing treatment success of re-LT is allograft quality, with aged donors and lengthy cold ischemia time are regarded as crucial aspects.¹²

Hepatitis C virus was regarded as an independent risk factor for re-LT. However, several studies show that re-LT can give an optimal survival time, with no significant differences in survival time between HCV positive, cryptogenic, cholestatic, or ALD patients when attuned to MELD scores and age (Grade II-3).^279-281

The selection of recipients for re-LT needs to be integrated with disease severity, time since first LT, and graft quality, which are imperative than the cause of re-LT.¹²

Calcineurin inhibitor

Tacrolimus is the medicine of choice and main CNI in post-LT patients. A meta-analysis comparing tacrolimus with cyclosporin has shown that tacrolimus is better than cyclosporin in terms of improving survival and avoiding graft loss or rejection. However, no difference in renal function has been found.^284,285 The main side effects of CNI therapy are renal impairment, infections, gout, hypertension, hypercholesterolemia, glucose intolerance, hypomagnesemia, hyperkalemia, and tremor.²⁸⁵

Calcineurin inhibitor neurotoxicity post-LT is a rare but serious event, especially associated with posterior reversible encephalopathy syndrome (PRES) due to endothelial dysfunction secondary to CNIs. In a retrospective cohort of 1923 adult LT recipients, PRES was diagnosed radiologically in 19 patients (1%), with most cases occurring early post-LT.²⁸⁶ A sustained-release formulation of tacrolimus was introduced, which offers a once-daily dosing option, but showing efficacy and safety identical to the twice-daily dosing regimen.^287,288 Such a formulation may help achieve patient medication adherence.²⁸⁹

Azathioprine (AZA) and mycophenolate mofetil

In LT, both the antimetabolites, AZA and MMF, are widely used. These drugs reduce purine synthesis, impacting T and B lymphocyte proliferation, and they are used in combination with a CNI for preventing graft rejection. The use of these drugs has increased in the last 2 decades as they serve the purpose of decreasing the CNI’s dose, especially in patients with kidney impairment, minimizing the effect of CNI nephrotoxicity. Mycophenolate mofetil has increasingly become the highly utilized antimetabolite drug, albeit no differences were observed with AZA regarding patient and graft survival.^147,290,291 Major side effects of MMF include diarrhea, leucopenia and bone marrow suppression. The enteric-coated formulation of mycophenolate sodium (EC-MPS) reduces the gastrointestinal side effects, but the LT data is limited.^292,293 A small size single-arm study in LT showed that the conversion from MMF to EC-MPS was related to substantial progress in gastrointestinal symptoms,²⁹¹ but no high-level evidence is existing as such.

Sirolimus (SRL) and everolimus (EVR)

Sirolimus and EVR inhibit the mammalian target of rapamycin (mTORi), blocking interleukin (IL)-2 and IL-15 induced proliferation of T and B lymphocytes. The main side effects of mTORi are thrombocytopenia, leucopenia, impaired wound healing, hyperlipidemia, proteinuria, possible increased risk of HAT.²⁹⁴ The use of EVR in combination with reduced tacrolimus dose prevents renal impairment post-LT.²⁹⁵ It reduces the HCC recurrence rate in one year, as shown in a randomized multicenter study of LDLT.²⁹⁶

Basiliximab

Basiliximab is an induction agent, IL-2 receptor (CD25) monoclonal antibody used to decrease the side effects of immunosuppressants by diminishing or delaying the use of CNIs. This agent is used especially when the recipient has renal impairment prior to transplant, although studies have not found differences in patient and graft survival. A meta-analysis of 18 studies showed that LT patients receiving IL-2R antagonists had lesser acute rejection, steroid-resistant acute rejection, and no functioning of kidneys when related to decreased or late CNI use.²⁹⁷

Corticosteroids

Corticosteroids are part of the standard immunosuppression regimen with CNI and antimetabolite agents, starting with the induction in the immediate operative phase and then continuing with taper protocols. Steroids may be tapered by 2 months in patients at low risk for rejection, uncontrolled diabetes, severe osteoporosis, sepsis, or delayed wound healing. However, low-dose steroids should continue in autoimmune disease to try to prevent disease recurrence. Steroids have many side effects, including infections, hypertension, T2DM, and osteoporosis. Therefore, minimizing the corticosteroids regimen with time is prudent.²⁹⁸ Table 6 summarizes the side effects of immunosuppressive drugs.

The choice of immunosuppressive drugs varies between individuals and depends on many factors that include time after transplant, indication for transplant, rejection episodes, risk of cancer, renal impairment, risk of infections, and comorbid diseases.^283,299 In addition, drug-drug interactions must be considered during the use of immunosuppressive agents (Table 7).

Early post-liver transplantation and long-term follow-up

Most deaths happen in the initial days after LT, and the causes differ based on the time after LT. Almost 60% of deaths are related to infections and intra- and perioperative surgical complications. Graft losses in the initial year post-LT and de novo cancers and cardiovascular manifestations are key mortality causes after this period.¹² Increased, adequate, and safer use of immuno suppressive agents may prevent acute rejections or graft loss, while chronic ductopenic rejection poses a lesser prognosis without re-LT.³⁰⁰

The increasing prevalence of NAFLD and aged LT recipients, de novo diabetes and metabolic bone disease, are diagnosed after LT. De novo malignancy and PTLD, although less common, are associated with significant mortality in NAFLD recipients. Earlier diagnosis, immunosuppression treatment modification, and rarely re-LT in the context of irreversible graft rejection and KT in end-stage renal disease (ESRD) are important for patient outcomes.^118,300

Hepatitis C virus recurrence: management and treatment post-liver transplantation

It is expected that HCV may recur post-LT in approximately 33% of LT patients who are HCV-infected, increasing the risk of clinical decompensation and graft loss.^301,302 Early antiviral treatment is suggested in these patients. Sustained viral response is related to better patient outcomes.^12,306 (Grade II-1). For genotype 1- and 4- infected LT recipients, such as patients with compensated cirrhosis, an initial treatment regimen with a sofosbuvir-based therapy or a combination of glecaprevir/pibrentasvir for 12 weeks is recommended with high SVR rates. While for decompensated cirrhosis, the treatment will be sofosbuvir-based therapy with RBV for 12 -24 weeks, as per the HCV guidelines: (https://www.hcvguidelines.org).

Preventing and treating hepatitis B virus recurrence

The recurrence of post-LT HBV causes allograft dysfunction, allograft cirrhosis, and graft failure.³⁰⁹ Hepatitis B virus-related cirrhotic patients pose increased graft infection risk (~70%), hepatitis D virus-related cirrhotic patients have moderate (~40%) risk, and those with acute hepatic failure has comparatively lower (<20%) risk. The key cause of HBV recurrence is increased HBV DNA levels during the LT procedure.^12,310 Liver transplantation for HBV-related cirrhosis currently has exceptional long-term outcomes, with 5-year SVR ≥80%.^84,311,312

The use of antivirals for patients waiting for LT subdues allograft HBV replication and recurrence. Thus, HBV patients with decompensated cirrhosis must require entecavir or tenofovir prior to LT.³⁰⁹ Currently, >90% of patients with recurrent HBV infections require antiviral agents.³⁰⁹

Hepatitis B virus recurrence can be prevented by a combination of HBIg and antiviral drugs in high-risk patients. However, low dose HBIg, HBIg-free protocols, and monoprophylaxis with high-efficacy antiviral drugs can also be used in low-risk cases.³⁰⁹ Because of the increased expenses related to HBIg therapy, many research projects have evaluated the efficacy of HBIg in reduced doses or even withdrawal in chosen patients. These approaches, along with NUCs, have successfully prohibited HBV recurrence and seem to be a possible strategy for HBeAg-negative in LT candidates with non-detectable HBV DNA traces. Besides, these regimens dramatically reduce costs when compared to high-dose intravenous HBIg regimens.¹² Five years after receiving intramuscular injections of HBIg (400 IU to 800 IU per month) along with lamivudine, the recurrence was merely 4%.³¹³ A randomized study has shown that a small dosage regimen of HBIg along with lamivudine, trailed by lamivudine monotherapy, has yielded good results in patients with undetectable HBV DNA levels during LT.³¹⁴

Although recent studies have questioned the need for HBIg since NUCs have become more efficient, data is not consistent concerning HBV graft infection and HBV recurrence.³¹⁵

Patients who got liver transplantation from anti-hepatitis C virus positive donors

The impact of anti-HBc positive liver grafts on survival and de novo HBV infection risk post-LT continue to be debatable.³¹⁶ Liver transplantation patients who received transplant from an anti-HBc positive donor must receive antiviral therapy soon after LT (Grade II-2).³¹⁷

In terms of cost-effective treatment, lamivudine monotherapy is the best option. A recent study comparing lamivudine and entecavir monotherapy prophylaxis in HBsAg negative recipients that received anti-HBc positive grafts showed that de novo HBV was exceptionally infrequent, particularly with entecavir prophylaxis.³¹⁶ Hepatitis B immune globulin must not be given in HBsAg negative patients who received LT from an anti-HBc positive donor (Grade II-2).¹²

Managing patients transplanted for alcoholic liver disease

Liver transplantation candidates with ALD have a similar survival rate compared to those without ALD, but the post-LT death rate is high in patients with comorbid ALD.²⁸³ Post-LT alcohol relapse in ALD patients varies a lot (10%-90%), and patients with an earlier disease detection of ALD must be advised to avoid alcohol at all (Grade II-2) and undergo psychiatric treatment or consultation if they start back alcohol consumption in the post-LT period (Grade II-3).^12,283

Advice on smoking cessation must be considered. The risk of cardiovascular disease and associated manifestations or new-onset malignancies of the airway, pulmonary tract, or upper digestive tract, particularly in cigarette smokers, requires caution.³¹⁸

Recurrence of NAFLD

Both NAFLD and NASH, recurrent and de novo, are common after LT.⁹ Pre- and post-LT BMI, T2DM, arterial hypertension, and hyperlipidemia are the major risk factors for post-LT NAFLD/NASH.^12,318,319 Liver biopsy is required to confirm recurrent or de novo NAFLD/NASH, recognize fibrosis, and exclude alternate causes of altered liver chemistry tests (Grade III). Avoiding extreme weight gains and keeping hypertension, dyslipidemia, and T2DM in control are recommended (Grade III).^12,318

Recurrence of cholestatic hepatic disease

Autoimmune hepatitis, PBC, and PSC recurrence differ from 10% to 50% and must be confirmed by liver biopsy and/or cholangiography (PSC) (Grade II-3).¹² Primary sclerosing cholangitis recurrence is common and leads to graft failure after LT for PSC. Keeping an inactive inflammatory bowel disease status may guard against PSC recurrence.³²⁰ There is no convincing data to support the ursodeoxycholic acid prophylaxis in patients who underwent LT for PBC and PSC (Grade III).¹²

Managing hepatocellular carcinoma recurrence

The risk of HCC recurrence following LT affects between 15% and 20% of the cases. It is generally observed during a couple of years initially after LT, with a median survival lesser than a year.^321,322 The recurrence risk depends on numerous factors related to the tumor, patient, and treatment.³²³

Factors such as the histopathological characteristics of the tumor, AFP levels, and waiting time are well established. However, other biological factors related to tumor behavior and treatment must be identified since they can be used to refine selection criteria of transplant candidates to reduce recurrence.³²³

In patients who developed hepatic cirrhosis due to HCC recurrence, de novo HCC may progress, similar treatment protocol used for immunocompetent patients needs to be adhered, that may include hepatic resection, radiofrequency ablation or TACE (when possible) and, when indicated, re-LT.¹² Surveillance for de novo HCC needs to be carried out with radiological investigation of the abdomen every 6 months to one year.³¹⁸

Currently, there is no supporting data suggesting that long-term (>5 years) recurrence-free survival is achieved using SRL (Grade I); however, it seems to be effective in 3-5 years, time in HCC patients within Milan criteria (Grade I). Therefore, an immunosuppressant treatment plan that comprises SRL starting many weeks post-LT must be used for patients who are affected due to HCC.^12,283

Several studies have attempted to demonstrate that sorafenib, a multikinase inhibitor, might be associated with benefits in survival and safety profiles; however, based on the current data, a recommendation for its use cannot be established.^12,324-326 Thus, it is recommended that therapy for HCC recurrence post-LT be personalized, and there is no evidence to utilize sorafenib in patients with disseminated recurrence (Grade III).¹²

Managing kidney dysfunction

Most LT recipients, who survive the initial 6 months, develop CKD.³²⁷ The causes of CKD in LT patients (Table 8) depend on many factors that include long-time use of CNIs: hypertension, T2DM, obesity, atherosclerosis, hyperlipidemia, chronic HCV infection, pretransplant renal dysfunction, and perioperative AKI.³¹⁸

Immediately after LT, incessant observing of kidney function is mandatory for detecting and managing CKD, including treating possible risk factors (Grade II-2).¹² Quantifying urinary protein by means of protein to creatinine concentration ratio is required a minimum once a year post-LT.³¹⁸ Reducing or completely withdrawing CNI-associated immunosuppression or using CNI-free treatment regimens is an appropriate regimen in LT recipients with abnormal kidney function (Grade I).^12,318 Kidney transplantation is helpful in improving survival and can be regarded as the ideal therapeutic option for LT patients with ESRD (Grade II-3).^12,318

Preventing and treating infections

Infections are a serious concern following LT, as around two-thirds of the LT patients get them postoperatively. Therefore, preventing infections and using aggressive disease recognizing approaches are essential depending on the time after LT¹² (Table 8).

Infections may highly occur during 2-6 months post-LT with opportunistic agents, such as herpesviruses (especially CMV, herpes zoster and simplex, and EBV), fungi (Aspergillus and Cryptococcus), and more not-common bacterial infections (Nocardia, Listeria, and Mycobacteria). Therefore, assessing infections following LT should consider implementing prophylactic antimicrobials, avoid high-risk exposures, and minimize immunosuppression therapy.³¹⁸

Following the 3 months after LT, with the reduction of immunosuppression regimens, the risk of infection becomes lower. After this period, infections in intra-abdominal, lower respiratory tract, or by community-acquired pathogens, such as enteric Gram-negative infections, S. pneumonia, and respiratory viruses, are quite common.³¹⁸ Bacterial pathogens cause most infections post-LT, particularly Gram-negative bacteria, including Escherichia coli and Enterobacter, Pseudomonas.¹² Surgical site, abdominal cavity, urinary tract, and bloodstream are the common locations. Intra-abdominal infections are related to graft loss and increased mortality.³²⁸

Cytomegalovirus, infection is the most common opportunistic infection in LT recipients. Although satisfactory prophylaxis has been shown to expressively lessen its incidence, it still involves pertinent illness. The most common syndromes are viremia, bone marrow suppression, colitis, and hepatitis.³²⁹ For at least 3 months post-LT, CMV prophylaxis should be given to patients who have high CMV infection risk (Grade II-2).

Postulate lymphoproliferative disorder must be doubted in LT patients, particularly in patients who show seropositivity to EBV before LT or are treated with anti-lymphocyte globulin, an aggressive immunosuppressive agent, as they are at an increased risk of progressing PTLD (Grade III).³³⁰ Treatment for PTLD needs reducing immunosuppressants. Further treatments include rituximab, chemotherapy, radiation, and surgery if no response is received by immunosuppressant reduction.¹²

Fungal infections have been reported over the last 2 decades, with a substantial reduction in invasive candidiasis and an insignificant rise in invasive aspergillosis in LT recipients.³³¹ Risk factors associated with invasive fungal infections are decreased length of LT surgery, transfusion needs during LT, cold ischemic time, usage of roux-en-Y biliary anastomosis, PVT, biopsy-proven rejection episodes, re-LT, and kidney replacement treatment.^331-333 Therapy protocol consists of reducing immunosuppressive therapy and using antifungal agents. Oral prophylaxis to counter Candida species is recommended in the initial months, as it lessens death rates resulting from fungal infection (Grade II-3). Prophylaxis for countering aspergillus is only endorsed in high-risk scenarios (Grade II-3).¹²

Pneumocystis jirovecci, the agent that causes pneumocystis pneumonia, is infrequent during trimethoprim-sulphamethoxazole (TMP-SMX) prophylaxis. However, TMP-SMX might cause kidney toxicity, and corticosteroids are helpful as an adjunctive treatment to decrease respiratory inflammation and fibrosis occurring after infection (Grade II-3).^12,334 Prophylaxis to counter Pneumocystis jirovecci with TMP-SMX is required in LT patients for 6 months to one year (Grade II-2).¹²

Liver transplantation patients may experience active TB (0.47-2.3%), particularly in the first year after surgery.^335,336 This infection has a high mortality rate, and treatment for latent TB is relevant. Isoniazid regimen for 9 months (along with vitamin B6) is the typical treatment option. It needs to be indicated in the following scenarios: PPD positive skin test, history of untreated TB, or chest radiography findings suggesting TB.¹² Treating active TB in LT recipients is complicated due to drug interactions between anti-TB and immunosuppressants, plus the liver toxicity related to the first-line TB treatment. Patients on anti-TB therapy should be observed for possible side effects relevant to liver and acute rejection (Grade II-3). Treatment of non-severe TB must include isoniazid and ethambutol, and no rifamycins. Levofloxacin can be chosen instead of isoniazid. Severe form of TB must consist of treatment with rifamycin in the earlier and maintenance stages.¹² Table 9 outlines the prophylactic strategies underlying the common microorganisms that affect LT recipients.

Managing metabolic syndrome

One year following LT, complications associated with cardiovascular risks and metabolic syndrome become increasingly relevant.²⁹⁹ The number of LT recipients with underlying metabolic syndrome rises as the population’s median BMI grows.³³⁷ The clinical characteristics of metabolic syndrome, namely insulin-resistant (type 2) diabetes mellitus, obesity, dyslipidemia, and arterial hypertension, aid in delayed morbidity and mortality. It is estimated that the occurrence of metabolic syndrome in the LT population is between 50-60%.^12,338

Liver transplantation recipients have a higher risk of cardiovascular disease, representing almost one-fourth of mortality in the post-LT, long-term follow-up.^339,340 Data has shown that the immunosuppressant treatment protocols exacerbate underlying systemic and metabolic disorders and de novo arterial hypertension after surgery, hyperlipidemia, T2DM, and obesity.³³⁹ Hence, adequate therapy for modifiable risk factors by means of lifestyle and behavioral modifications, drug treatments, and changes to the immunosuppressive drugs are essential to prevent serious cardiovascular manifestations (Grade III).¹² Drug treatments in parallel with a balanced diet and routine physical exercise need to be implemented earlier to control arterial hypertension, hyperlipidemia, T2DM, and obesity (Grade II-3). Balanced diet and physical exercise initiatives can effectively help (Grade III).¹²

Bone disease

Bone loss increases in the first 6 months following LT and is related to higher fracture risk inducing obvious morbidity and poor quality of life.³⁴¹ Following the initial 6-12 months post-LT, bone loss reverses, and bone density increases. Annual examination of bone mineral density is advisable for patients with underlying osteoporosis and osteopenia. Similar examination is suggested every 2-3 years in those with normal values. After that, checking relies on how bone mineral density and associated risk factors change over time (Grade II-3).¹²

When the diagnosis of osteopenic bone disease is established or atraumatic fractures surge, associated risk factors for bone disease need to be evaluated. Particularly, calcium intake and 25-hydroxy-vitamin D need to be assessed. Gonadal and thyroid function evaluation, along with thoracolumbar radiography, need to be carried out. Besides, a complete medication history needs to be checked.³¹⁸

For the osteopenic LT recipient, regular weight-bearing exercises in combination with calcium and vitamin D supplements should be performed (Grade II-3). Bisphosphonate must be used in LT recipients with osteoporosis or recent fractures (Grade II-2).^12,318

De novo malignancies

The incidence of de novo cancers is higher in the LT population than a control population (age- and sex-matched non-LT) (Table 10). The incidence of de novo cancer following LT may increase up to 34% at 15 years after LT.^340,342,343

The increased incidence of de novo malignancies is because of the loss of immunovigilance induced by immunosuppressants and other associated risk factors, such as viral infections with oncogenic capability (namely, EBV, human papillomavirus), PSC, cigarette smoking, and alcohol consumption.¹² Post-LT malignancy screening protocols are required, especially in patients at high risk to notice de novo malignancies at an initial and possibly curative phase (Grade II-2). Several risk factors associated with de novo cancers cannot be altered, such as age or pre-existing hepatic disease. Thus, routine oncology surveillance initiatives have been suggested, although the optimal surveillance protocol still needs to be defined.¹² The most common de novo malignancy in LT patients is skin malignancy. The most frequent are non-melanoma cancers, such as squamous and basal cell carcinoma.³⁴⁴ Besides having a higher frequency, they tend to be more aggressive and metastasize more frequently in LT recipients than in a control population.³⁴⁵ Many risk factors aid in the progression of non-melanoma skin malignancies post-LT and include advanced age, prolonged sun exposure, sunburn, fair skin, and skin malignancy history.³⁴⁵ After surgery, LT recipients must attain dermatology consultation to evaluate cutaneous lesions with yearly assessments after five years or more post-LT (Grade I-1).

Malignancy in the upper gastrointestinal oropharyngeal-laryngeal and pulmonary cancers are particularly increasing in patients with alcoholic cirrhosis. These recipients should be subjected to a comprehensive surveillance strategy for identifying these malignancies (Grade II-3).³⁴⁰ Pre- and post-LT history of smoking additionally raises the risk of head/neck and pulmonary de novo malignancies, stressing the significance of quitting smoking by LT patients.³⁴⁶ Post-LT lymphoproliferative disorder is frequent in LT recipients and should be suspected when patients present with fever, weight loss, and night sweats, even without lymphadenopathy.¹² Epstein-Barr virus-associated PTLD was observed to be the most frequently encountered de novo malignancy after LT in a KSA transplant center during 2001-2010. Chemotherapy, along with reduced immunosuppression, serve as the treatment option.³⁴⁷

Patients who underwent LT for PSC with related bowel disease must take colonoscopy with biopsies every year to check and detect colorectal cancer (Grade II-3).^12,283 If dysplasia is diagnosed in a colonic biopsy, colectomy, including continence-preserving pouch procedures, must be tried.²⁸³