Main factors influencing long-term outcomes of liver transplantation in 2022

Table 1 Screening protocols proposal for the surveillance of de novo neoplasms in liver transplantation population

Malignancy	Screening proposal
Skin cancer	Annual dermatological visit[4], shorter follow up interval for high risk patients (i.e. every six months)
Lung cancer	Annual thoracic X-Ray; CT-scan in active or past smokers[282]
Colorectal cancer	Perform baseline colonoscopy on patients > 50 years old; annual fecal occult blood test in younger patients or if colonoscopy is negative; annual colonoscopy if patient affected by PSC + inflammatory bowel disease[1]
Ear, nose, and throat cancers	Annual otolaryngological visit in patient with active or past alcohol and/or smoking habit[124]
Renal cancer	Annual abdominal ultrasound
Cervical cancer	Annual papanicolau-test; annual gynecological visit
Breast cancer	Annual mammography, ultrasound evaluation if needed
Prostate cancer	Annual PSA and PSA ratio evaluation

CT: Computed tomography; PSC: Primary sclerosing cholangitis; PSA: Prostate specific antigen.

Table 2 Maintenance immunosuppressants main adverse effects

Drug class	Adverse effects
CNI	Nephrotoxicity[283], recurrence of HCC[188,284], risk of de novo neoplasia[285-287], new onset diabetes mellitus (TAC more than CyA)[288,289], hypertension (CyA more than TAC)[290], dyslipidemia[291] (CyA more than TAC)[292], neurotoxicty[293], weight gain[294,295]
Antimetabolites	Leukopenia, thrombocytopenia, gastrointestinal disturbances (MMF and AZA) diarrhea, CMV reactivation (MMF)[296], pancreatitis, hepatotoxicity, risk of de novo neoplasia (AZA)[296,297]
mTORi	Leukopenia, dyslipidemia[298,299], cutaneous and mucosal alterations[300], wound complications, lymphocele[301], hypertension[302]

CNI: Calcineurin inhibitors; HCC: Hepatocellular carcinoma; TAC: Tacrolimus; CyA: Cyclosporine; MMF: Mycophenolate mofetil; AZA: Azathioprine; mTORi: Mammalian target of Rapamicin inhibitors.

Table 3 Comorbidity/risk factors impairing long-term survival with suggested follow-up and management

Risk Factor/Comorbidity	Follow-up	Management
Metabolic syndrome	(1) Electrocardiogram and transthoracic echocardiography before transplantation. If patient older than 50 and has multiple cardiovascular risk factors, perform a cardiopulmonary exercise test. If coronary disease is suspected, coronary angiography should be executed[1]; and (2) Repeatedly perform a cardiovascular risk stratification after transplantation (for example, every 6 mo)[1].	(1) Aggressive and rapid management of metabolic risk factors in the form of lifestyle changes, pharmacological therapies and modifications of the IS[1]; (2) Dietary counseling for all LT patients[4]; and (3) Consider bariatric surgery in patients who failed behavioral weight-loss programs[4].
Sarcopenia	(1) Sarcopenia evaluation before LT (for example, measuring skeletal mass from CT scan, even required for other reasons)[23]; and (2) New assessment at 1 year after transplantation (possibly using the same method and the same CT machine, in order to compare results. Consider also 24-CER evaluation[20]).	(1) Manage sarcopenia with lifestyle modification and nutritional interventions both pre and post transplantation[1,28]; (2) Consider nutritional counseling after transplantation; and (3) Consider nutritional supplementations (e.g. with HMB)[29].
Osteoporosis	(1) Regular measurement of bone mineral density pre- and post- LT, with a follow up timing dependent on the severity of the disease; and (2) If osteopenic bone disease is confirmed or if atraumatic fractures are present, assess calcium intake, vitamin D levels, gonadal and thyroid function, a full medication history, and thoracolumbar radiography[4].	(1) Manage osteoporosis with calcium and vitamin D replacement (if deficient), consider a weight-bearing exercise pre-operative program[1]; and (2) Consider bisphosphonate therapy (for example, Neridronate, at the dose of 25 mg i.m./mo for 12 mo)[40].
Psychological health and QoL	Actively look for depressive symptoms since the early post-transplantation period[1].	(1) Treat promptly depressive symptoms with adequate pharmacotherapy[54]; (2) Consider psychological support by a specialist if needed; and (3) Propose lifestyle modifications (in particular, personalized aerobic and strength training programs)[55].
Renal dysfunction	(1) Continuous monitoring of renal function with serum creatinine and glomerular filtration rate measurements[1]; and (2) Urinary protein quantification at least once yearly[4].	(1) Treat potential risk factors (diabetes, hypertension); (2) Avoid nephrotoxic drugs[1]; (3) Adjustment of the IS; reduction or withdrawal of CNI or use alternative CNI-free protocols as soon as possible in impaired renal function (for example, EVR combination regimens starting 1 mo after transplantation[67,68]; and (4) Consider kidney transplantation in end-stage renal disease[4].
Infectious risk	Hepatologist accurate counseling to increase the percentage of vaccinated patients[81].	(1) Perform HAV, HBV, varicella, Pneumococcus, influenza and tetanus vaccinations prior to transplantation; (2) Administer inactivated influenza vaccine starting one month after transplantation during community influenza outbreak; (3) Annual influenza vaccination in liver transplanted patients[4]; and (4) Consider Oseltamivir prophylaxis during periods of local influenza circulation[86].
De novo malignancies	Define and follow a surveillance protocol with individualized emphasis laid on patients’ particular risk profiles[1].	(1) Treating modifiable risk factors: stop smoking, alcohol withdrawal[99], metabolic syndrome management[100], avoid sunbed use and sun exposure[101], promote HPV vaccination[102]; and (2) Use mTOR- based therapy if possible[1] or a CNI-mTOR combined therapy always at the lowest effective dose.
Smoking	(1) Assess smoking status at each visit, focusing on those with particular risk of relapse (ALD); and (2) Use of biomarkers (serum Cotinine)[116].	(1) Encourage to undertake smoking cessation[4]; and (2) Referral for behavioral/pharmacological therapy[125,126].
Adherence to therapy	Self- and collateral-reported non-adherence, trough levels (considering graft-function and concomitant use of other drugs)[136,139] with particular attention to younger patients and those missing clinic appointments, with a history of substance or alcohol use, mental health needs, divorced or high regimen complexity[131,137,140].	Multidisciplinary measures developed by professional educators, supported by psychologists, and coordinated by physicians[1,136].
Alcohol abuse relapse	(1) Assessing alcohol use at each clinic visit, with particular attention to those transplanted for ALD with pre-transplant abstinence of less than 6 mo, with psychiatric comorbidities, smoking, noncompliant with clinic appointment or medication and lacking social support[147,149,150]; and (2) Assessment by self-reported alcohol use, liver function tests and metabolites of alcohol, such as urinary ethyl glucuronide[157,158].	(1) Preventive structured management by a multidisciplinary team including transplant hepatologist, clinical psychologists and psychiatrists with expertise in alcoholism and social workers[159,160]; (2) Encouraging smoking cessation; and (3) Referral to psychiatric treatment or counselling in case of relapse[1,4].
HCC recurrence	(1) Thoracic CT – abdominal CT or MRI and AFP levels with 3- to 6-mo intervals in the first 2 or 3 years, increasing the interval between exams from that date[194]; (2) Selection of patients who needs a stricter follow-up using prognostic criteria such as: AFP levels, the presence of microvascular invasion, the diameter of the largest viable tumor and the number of viable tumors[202]; and (3) Particular attention to patients transplanted outside of Milan Criteria[176].	(1) Minimizing overall IS; consider adding mTORi[108]; (2) Individualized management of HCC discussed in a multidisciplinary team[303]; and (3) Surgical treatment when feasible[204,205].
Autoimmune disease recurrence	(1) Monitoring liver function tests[223,229] and performing liver biopsy and/or cholangiography when deemed necessary[1]; and (2) Exclude mimicking conditions (ischemia related biliary insults, hepatic artery thrombosis and/or chronic ductopenic rejection, infectious cholangitis for PSC, rejection histological mimicking for PBC and AIH)[223].	(1) AIH: Treatment of active cirrhosis and normalization of transaminases and IgG in the pre-transplantation period plus long-term corticosteroid use after LT; (2) PBC: Use of preventive Ursodeoxycholic Acid; and (3) PSC: Control of IBD and considering pre- or post-transplant colectomy in patients with difficult to control PSC[240].
NASH recurrence	(1) Early identification of Metabolic Syndrome components pre- and post-transplant[304]; (2) Annual screening with US and liver function tests; (3) Noninvasive testing and liver stiffness measurement in case of alterations at the annual screening; and (4) Biopsy in case of suspected fibrotic disease[259].	(1) Management as for other NAFLD/NASH patients (multidisciplinary approach with diet and lifestyle modification, pharmacological treatment and bariatric surgery when necessary[252,257]; (2) Treating metabolic syndrome components)[265,266]; and (3) Corticosteroids and CNI minimization when possible[108].
Viral hepatitis recurrence	(1) Liver function test monitoring; (2) HCV-RNA titres[111]; (3) HBV DNA and HBsAg monitoring[1,275]; (4) Regular assessment of graft damage[1]; and (5) Particular attention to patients transplanted for HCC with HBV recurrence/reactivation[277,278].	(1) Treating HCV before LT when possible; use of DAA[1,164]; and (2) HBIG and NUCs to prevent HBV recurrence/reactivation[1,272].

LT: Liver transplantation; CT: Computed tomography; CNI: Calcineurin inhibitors; EVR: Everolimus; HAV: Hepatitis A virus; HBV: Hepatitis B virus; HPV: Human papilloma virus; mTORi: Mammalian target of Rapamicin inhibitors; ALD: Alcohol-related liver disease; HCC: Hepatocellular carcinoma; AFP: Alpha fetoprotein; PSC: Primary sclerosing cholangitis; PBC: Primary biliary cholangitis; AIH: Autoimmune hepatitis; NASH: Non-alcoholic steatohepatitis; HCV: Hepatitis C virus; HBIG: Hepatitis B immunoglobulin; NUCs: Nucleos(t)ide analogues.