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:

Early after HSCT (<100 days)

Late after HSCT (months-years)

SOS/VOD

Acute GVHD (see Chap. 43)

Acute hepatitis

Pharmacological toxicity

Chronic GVHD (see Chap. 44)

Autoimmune hepatitis

Chronic viral hepatitis (see Chap. 38)

Cirrhosis and hepatocellular carcinoma

Iron overload (see Chap. 46)

Other less frequent

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)

  1. aPositive fluid balance not explained by excessive hydration
  2. bDifficult to demonstrate by expected thrombocytopenia

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

  1. aThese symptoms/signs should not be attributable to other causes
  2. bMainly observed after conditioning including several alkylating agents (e.g., BU, MEL, or TT)
  3. cObserved in almost 100% of adults but absent in up to 30% of children

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

  1. aUp to 20% of children present late SOS
  2. bWith the exclusion of other potential differential diagnoses
  3. cWeight-adjusted platelet substitution/day to maintain institutional transfusion guidelines
  4. dSuggested: imaging (US, CT, or MRI) immediately before HSCT to determine baseline value for both hepatomegaly and ascites

2.6 Incidence

Variable depending on the diagnostic criteria used, center experience, type of patients, and year of HSCT

Author (period analyzed) (study type)

Auto-HSCT

Allo-HSCT

Coppell et al. 2010 (1979–2007) (R)

8.7%

13%

Carreras et al. (1998) (P)

3.1%

8.9%

Corbacioglu et al. 2012 (2006–2009) (P)a

6%

14%

Carreras et al. 2011 (1997–2008) (R)b

–

MAC, 8%/RIC, 2%

  1. R retrospective study, P prospective study
  2. aOnly children and young adolescents
  3. bOnly adults

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

  1. Bold characters indicate the most relevant factors
  2. aMany factors have been associated with an increased risk of SOS, with those in bold letters seem the most relevant
  3. bRemember that the presence of several risk factors in a patient has an additive effect
  4. cDue to unknown causes, some malignant or nonmalignant diseases, osteopetrosis, adrenoleukodystrophy, thalassemia, hemophagocytic lymphohistiocytosis, or neuroblastoma are associated with a higher incidence of SOS

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)

  1. HA hyaluronic acid, VCAM-1 vascular cell adhesion molecule-1, ST2 suppressor of tumorigenicity-2, ANG2 angiopoietin-2

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

  1. N normal values
  2. aWeight gain ≥5% and <10% is considered as a severe SOS. However, if the patient does not fulfill other criteria for severe SOS, it is therefore considered a moderate SOS

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]

  1. aIn two randomized trials, UDCA reduce the incidence of SOS but in other two this effect was not observed. However, in all them, patients with UDCA have a lower TRM

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)

  1. AMB amphotericin B, TMP/SMX trimethoprim-sulfamethoxazole, NSAID nonsteroidal anti-inflammatory drug
  2. aOther than cytostatic drugs
  3. bOnline resources for the consultation of toxicities and interactions: https://livertox.nlm.nih.gov
  4. cVoriconazole, posaconazole
  5. dLiver damage with predominant elevation of bilirubin and alkaline phosphatase
  6. eHepatic damage with predominant elevation of transaminases
  7. fEspecially if associated to CNI

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

  1. In bold letter main differential data

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

  1. aThese data correspond to the times when new antiviral agents were not available. No updated data are available
  2. bThe cumulative incidence of severe liver complications in HSCT infected with the HCV was 11.7% at 20 years in multicenter cohort (Ljungman et al. 2012)

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.