Abstract
The frequency and severity of TPH liver complications have decreased sharply in the last decade, with some complications that have completely disappeared, such as, for example, Candida liver abscesses.
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1 Introduction
The frequency and severity of TPH liver complications have decreased sharply in the last decade, with some complications that have completely disappeared, such as, for example, Candida liver abscesses. The development of more effective strategies to preventing SOS/VOD and GVHD has had a marked effect on its clinical presentation (see Chaps. 25 and 49). Finally, prophylaxis with antiviral and antifungal drugs has greatly reduced the incidence of the most common liver infections (Hockenbery et al. 2016). The major liver complications after HSCT are:
2 Sinusoidal Obstruction Syndrome
2.1 Definition
SOS, formerly called veno-occlusive disease of the liver (VOD), is the term used to designate the symptoms and signs that appear early after HSCT because of conditioning regimen-related hepatic toxicity. This syndrome is characterized by jaundice, fluid retention, and tender hepatomegaly appearing in the first 35–40 days after HSCT (Carreras 2015).
2.2 Pathogenesis
The hepatic metabolism of certain drugs (e.g., CY) by the cytochrome P450 enzymatic system produces several toxic metabolites (e.g., acrolein). These toxic metabolites are converted into stable (nontoxic) metabolites by the glutathione (GSH) enzymatic system and then eliminated. When this process occurs in patients with a reduced GSH activity, caused by previous liver disease or by the action of agents such as BU, BCNU, or TBI, which consume GSH, toxic metabolites are not metabolized. Toxic metabolites are predominantly located in area 3 of the hepatic acinus (around the centrilobular veins) because this area is rich in P450 and poor in glutathione. Consequently, damage to hepatocytes and sinusoidal endothelium occurs predominantly in this zone. Many other factors (see risk factors) can also contribute to endothelial injury.
The first events after endothelial injury caused by toxic metabolites are loss of fenestrae in sinusoidal endothelial cells (SEC), formation of gaps within and between SEC, and rounding up or swelling of SEC. Consequently, red blood cells penetrate into the space of Disse and dissect off the sinusoidal lining, which embolize downstream and block the sinusoids, reducing the hepatic venous outflow and producing post-sinusoidal hypertension. The changes observed in coagulation factors in these patients seem to be a consequence of the endothelial injury and probably play a secondary role in SOS pathogenesis, despite contributing to the sinusoidal occlusion (Carreras and Diaz-Ricart 2011).
2.3 Clinical Manifestations of SOS
Classical manifestations | Weight gaina/edema/ascites/anasarca Painful hepatomegaly/jaundice Consumption of (not refractoriness to) transfused plateletsb |
Manifestations of MOF | Pleural effusion/pulmonary infiltrates Renal, cardiac, and pulmonary failure Neurological symptoms (encephalopathy, coma) |
2.4 EBMT Diagnostic Criteria for Adults (Mohty et al. 2016)
Classical SOS (Baltimore criteria)a | Late-onset SOSb |
---|---|
In the first 21 days after HSCT Bilirubin ≥2 mg/dLc and ≥ 2 of the following – Painful hepatomegaly – Weight gain >5% – Ascites | Classical SOS beyond day 21, OR Histologically proven SOSOR ≥2 of the classical criteria AND ultrasound (US) or hemodynamical evidence of SOS |
2.5 EBMT Diagnostic Criteria for Children (Corbacioglu et al. 2018)
No limitation for time of onset of SOSa |
The presence of two or more of the followingb • Unexplained consumptive and transfusion-refractory thrombocytopeniac • Otherwise unexplained weight gain on 3 consecutive days despite the use of diuretics or a weight gain >5% above baseline value • Hepatomegaly (best if confirmed by imaging) above baseline valued • Ascites (ideally confirmed by imaging) above baseline valued • Rising bilirubin from a baseline value on 3 consecutive days or ≥2 mg/dL within 72 h |
2.6 Incidence
Variable depending on the diagnostic criteria used, center experience, type of patients, and year of HSCT
2.7 Risk Factors for SOS
Patient-related risk factors a,b | |
Age | Younger < older |
Sex | Male < female |
Karnofsky index | 100–90 < lower than 90 |
Underlying disease | Nonmalignant < malignant < some specific diseases c |
Status of the disease | Remission < relapse |
AST level before HSCT | Normal < increased |
Bilirubin level before HSCT | Normal < increased |
Prior liver radiation | No < yes |
Liver status | Normal < fibrosis, cirrhosis, tumor |
Iron overload | Absent < present |
CMV serology | Negative < positive |
Prior treatment with | Gemtuzumab or inotuzumab ozogamicin |
Concomitant drugs | Progestogens, azoles |
Genetic factors | GSTM1-null genotype, MTHFR 677CC/1298CC haplotype, etc. |
Transplant-related factors | |
Type of HCT | Syngeneic/autologous < allogeneic |
Type of donor | HLA-identical sibling < unrelated |
Grade of compatibility | Match < minor mismatch < major mismatch |
T-cell in the graft | T-cell depleted < non-T-cell depleted |
Type of conditioning | NMA < RIC < TRC < MAC |
Busulfan | IV < oral targeted < oral CY-BU < BU-CY |
TBI | Fractionated < single dose Low-dose rate < high-dose rate Less than 12 Gy < more than 12 Gy Time between CY to TBI 36 h < CY to TBI 12 h |
Fludarabine | Not included < included |
GvHD prophylaxis | CNI (TAC < CSA)< CNI + sirolimus |
HSCT number | First < second HSCT |
2.8 How to Confirm the Diagnosis?
SOS is a syndrome and must be diagnosed clinically, but several tools can help us | |
Transjugular hemodynamic study | Permits a safe measurement of the hepatic venous pressure gradient (HVPG), which evaluates the presence of intrahepatic post-sinusoidal hypertension. A HVPG >10 mmHg is highly specific (>90%) and moderately sensitive (60%) for SOS |
Transvenous liver biopsies | Transvenous biopsies may be obtained during hemodynamic studies, but false-negative results could be obtained due to the patchy nature of SOS. However, biopsies carry a risk of hemorrhagic complications (e.g., into the peritoneum and biliary tract). Consequently, they are only indicated when a crucial differential diagnosis is required (e.g., SOS versus GVHD?) |
Imaging techniques | They may be helpful to confirm hepatomegaly and/or ascites (relevant in overweight patients) and for the differential diagnosis. Baseline and serial US may be useful for early detection of SOS The US abnormalities observed in SOS (hepatomegaly, splenomegaly, gallbladder wall thickening, ascites) are not specific. Decrease in velocity or reversal of the portal venous flow is considered more specific for SOS but usually occurs late in the disease (reviewed in Dignan et al. 2013) |
Composite biomarkers | Recently some composite markers have shown a prognostic value at day 0 (L-Ficolin, HA, VCAM-1) and at diagnosis (ST2, ANG2, L-Ficolin, HA, VCAM-1) (Akil et al. 2015) |
2.9 EBMT Criteria for Severity Grading
Classically the severity of SOS was stablished, prospectively, based in a mathematical model or, retrospectively, based on its evolution (resolution or not at day +100). Later, SOS may be classified as severe with the development of multiorgan failure MOF. Several systems have been proposed for early prognostication of SOS using scales, including the following elaborated by the EBMT (Mohty et al. 2016).
Mild | Moderate | Severe | Very severe | |
Time since first symptoms | >7 days | 5–7 days | ≤4 days | Any time |
Bilirubin mg/dL | ≥2 to <3 | ≥3 to <5 | ≥5 to <8 | ≥8 |
Bilirubin kinetics | Doubling in 48 h | |||
Transaminases (× N) | ≤2 | >2 to ≤5 | >5 to ≤8 | >8 |
Weight gain (%) | <5 | ≥5 to <10a | ≥5 to <10a | ≥10 |
Renal function (× baseline at HSCT) | <1.2 | ≥1.2 to <1.5 | ≥1.5 to <2 | ≥2 or other data of MOF |
This severity grading must be applied once SOS/VOD has been diagnosed applying the criteria mentioned in 49.2.4 Patients belong to the category that fulfills ≥2 criteria. If patients fulfill ≥2 criteria in two different categories, they should be classified in the most severe category In the presence of two or more risk factors for SOS, patients should be in the upper grade |
2.10 Prophylaxis (Dignan et al. 2013; Carreras 2015)
Non-pharmacological measures | |
Avoid modifiable risk factors: Treat Iron overload (chelation); treat viral hepatitis; delay HSCT if active hepatitis; reduce intensity of conditioning; use CY + BU instead of BU + cy; try to avoid CNI (if not possible use TAC instead CSA) for GVHD prophylaxis; avoid hepatotoxic drugs (progestogens) | |
Pharmacological | Drug (degree of recommendation) |
Not recommended | Sodium heparin (2B), low-molecular-weight heparin (2B), antithrombin III (2B), prostaglandin-1 (1B), pentoxifylline (1A) |
Suggested | Ursodeoxycholic acid (2C)a Defibrotide: In high-risk adult patients (2B) |
Recommended | Defibrotide: In high-risk children (1A) [25 mg/kg/d] |
2.11 Treatment (Degree of Recommendation) (Dignan et al. 2013; Carreras 2015)
Methylprednisolone (2C):
Used by some authors. Recommended doses not defined (and range from high to low) and results difficult to analyze. Main risk: to delay treatment with defibrotide, the only agent with proved effectiveness.
Defibrotide (1B):
Despite the absence of randomized studies, it is the only agent approved by FDA and EMA to treat severe SOS (>80% mortality). In these patients: 50% of complete remission and > 50% SRV at day +100. Early treatment strongly recommended. Dose: 6.25 mg/kg q6h in 2 h during ≥21 days, depending on the response.
3 Hepatitis After HSCT
Despite the reduction in the incidence of liver complications after HSCT, there remain multiple hepatic causes of elevations of serum alanine aminotransferase (ALT). In addition to the acute viral hepatitis, other noninfectious causes must be considered:
VZV, CMV, EBV, HHV-6 | Infrequent (see Chap. 38) |
HBV, HCV, HEV | (see Chap. 38) |
Drug-induced hepatitis | Very frequent. Wide range of severity (see Sect. 49.3.1) |
Hepatic GvHD | Exceptional. AST/ALT >2000 U/L usually observed in patients without or with minimal IS (or receiving DLI) (see Chaps. 43 and 44) |
Autoimmune hepatitis | True autoimmune hepatitis or GVHD? Often difficult to differentiate (see Sect. 49.3.2) |
Other causes | Severe SOS (see Sect. 49.2), hypoxic liver injury (septic or cardiac shock or respiratory failure), acute biliary obstruction |
3.1 Drug Induced Hepatitis
Druga,b | Comments |
---|---|
Thiazole antifungalsc | Cholestaticd or hepatocellular hepatitise, liver failure |
Echinocandins | Cholestatic hepatitis or mild-moderate hepatocellular hepatitis |
Fluoroquinolones | Hepatocellular hepatitis |
Liposomal AmB | Mild-moderate elevation of alkaline phosphatase |
TMP/SMX | Hepatocellular hepatitis |
CSA, tacrolimus | Cholestasis. Dose-dependent effect |
Rapamycin | Hepatocellular damage, increased risk of SOSf |
Anticonvulsants | Hepatitis, hepatocellular or cholestatic |
NSAIDs | Hepatitis, hepatocellular or cholestatic |
Acetaminophen | Hepatocellular hepatitis. Dose-dependent effect |
Antidepressants | Hepatocellular hepatitis. Unrelated to drug dosage |
Ranitidine | Cholestatic hepatitis, eosinophilic infiltration |
Amoxicillin-clavulanic acid | Cholestatic and/or hepatocellular hepatitis |
Antihypertensive drugs + lipid-lowering agents + oral hypoglycemics | Drugs usually associated in patients with metabolic syndrome (see Chap. 55) |
3.2 Autoimmune Hepatitis (AIH)
The main problem with this hepatitis is how to differentiate them from a hepatic GVHD, since pathogenesis, clinical manifestations, and biological changes are practically identical (Dalekos et al. 2002).
Autoimmune hepatitis | Hepatic GVHD | |
---|---|---|
Jaundice | Usually mild | Various degrees |
Other symptoms | Fatigue, malaise, many times asymptomatic | Hepatic tenderness, dark urine, acholic stools, anorexia, usually GVHD in other organs |
Pathology | Inflammatory infiltrate in portal area, often penetrating lobes | Inflammatory infiltrate, loss of small bile duct, degeneration of bile ductular epithelium, cholestasis |
Cirrhosis | May be present | Rare |
>AST | Moderate to severe | Less striking |
>GGT | Marked | Usually normal o decreased |
Auto-Ab | Type AIH-2 (ALKM, ALC-1) | Often found (AIH-1) (ANA, ANCA, etc.) |
Response to steroids | Excellent | Depends on severity |
4 Cirrhosis and Heparocellular Carcinoma
Cirrhosisa | – In HSCT with HBV: exceptional – In HSCT with HCV: 11% at 15 years; 20% at 20 years (Peffault de Latour et al. 2004)b – In HSCT with HEV: frequency not known but rapidly progressive cases have been reported (see Chap. 38) – Poorly compensated cirrhosis is a contraindication for HSCT because of the prohibitive risk of developing SOS after MAC. Even compensated cirrhosis has a high likelihood of hepatic decompensation after NMA (Hogan et al. 2004) |
Carcinoma | In patients with chronic HCV: 5% at 20 years of new cases per year (Peffault de Latour et al. 2004). These patients should undergo surveillance with six monthly liver ultrasound scans according to international guidelines |
5 Other Less Frequent Hepatic Complications
5.1 Nodular Regenerative Hyperplasia
After HSCT, occasionally observed in patients with a previous SOS/VOD.
Pathogenesis:
Probable consequence of changes in liver blood flow with atrophy of zone 3 of the acinus and hypertrophy of zone 1 (without fibrosis).
Clinical Manifestations:
Silent evolution (occasionally increase of AP) until the appearance of portal hypertension (ascites, splenomegaly, thrombocytopenia).
Diagnosis:
Investigated by imaging (primarily MRI). Liver biopsy can rule out carcinoma and cirrhosis; need for a needle biopsy (not transjugular or fine-needle biopsy).
5.2 Focal Nodular Hyperplasia
In one series (Sudour et al. 2009) of HSCT survivors undergoing liver MRI, these lesions were observed in 12%.
Pathogenesis:
The likely cause is sinusoidal injury caused by myeloablative conditioning regimens.
Clinical Manifestations:
Asymptomatic.
Diagnosis:
By MRI, lesions have characteristic central scars that differentiate them from hepatocellular carcinoma and fungal lesions.
5.3 Idiopathic Hyperammonemia
Very rare. Observed after conditioning (Frere et al. 2000)
Diagnosis:
Severe hyperammonemia (>200μmol/L) with minimal alteration of other LFTs.
Clinical Manifestations:
Lethargy, motor dyscoordination, and alkalosis.
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Ruutu, T., Carreras, E. (2019). Hepatic Complications. In: Carreras, E., Dufour, C., Mohty, M., Kröger, N. (eds) The EBMT Handbook. Springer, Cham. https://doi.org/10.1007/978-3-030-02278-5_49
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