Non-infectious complications after bone marrow transplant: liver complications

What every physician needs to know about non-infectious complications after bone marrow transplant: liver complications:

Liver complications of hematopoietic cell transplantation (HCT) are common and multi-factorial. We will discuss the most frequent complications.

Definition

Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS)

VOD is an early complication (usually by day +30) of HCT. It is a clinical diagnosis based on tender hepatomegaly, fluid retention (e.g., ascites), weight gain (greater than 2 or 5%), and elevated serum bilirubin.

Iron overload (IO)

IO has recently received more clinical attention. It can contribute to liver dysfunction and induce fibrosis by itself, but it can also exaggerate other complications of transplantation such as VOD, infections, cardiac toxicity, and mortality.

Drug-induced liver toxicity (DILT)

Many drugs can cause abnormal liver function tests and can be diagnosed clinically by excluding other etiologies.

Infections

Hepatitis from hepatitis B, C, A, Cytomegalovirus (CMV), adenovirus, or fungi can all complicate HCT.

Incidence

VOD

The incidence of VOD has been reported as 5-50%. This is a wide range because diagnostic criteria are not very specific and there is not sensitive non-invasive test to diagnose. After reduced intensity conditioning (RIC), VOD incidence is lower (5 to10%).

Transfusion-related iron overload occurs in up to 30 to 60% of alloHCT patients. Prior diagnoses requiring many red blood cell (RBC) transfusions (e.g., myelodysplastic syndrome (MDS), thalassemia, sickle disease, acute myeloid leukemia (AML) increase its pre-HCT frequency.

DILT

Due to the polypharmacy of HCT, this is a very common complication.

Risk factors

VOD

– Conditioning regimen agents:

High dose cyclophosphamide (CY), higher dose of TBI (total body irradiation), busulfan (Bu) (by inducing oxidative stress rather than direct toxicity), gemtuzumab ozogamicin, and busulfan and melphalan based regimens.

Extensive prior chemotherapy or prior irradiation
Genetic factors affecting relevant drug metabolism
Other drugs including antifungal “azoles”
Iron overloadPrior myeloablative transplant
History of pre-transplant hepatitis or liver injury: History of hepatitis B virus (HBV) does not always increase the risk for VOD of the liver if HBV is not active. Hepatitis B or C may increase risk of VOD in patient receiving hepatotoxic myeloablative regimens, but appear safer in patients receiving RIC, particularly fludarabine plus low dose TBI.

Frequent red blood cell transfusions; (hemachromatosis [recognized or not]).

DILT

Many drugs can cause abnormal liver function tests, including immunosuppressive drugs cyclosporine and tacrolimus (mainly elevated direct bilirubin due to inhibition of bilirubin transport), total parenteral nutrition (TPN), antimicrobiological agents including trimethoprim/sulfamethoxazole (mainly cholestasis), or antifungal azoles (itraconazole, voriconazole, posaconazole) which cause transaminitis.

What features of the presentation will guide me toward possible causes and next treatment steps:

Clinical symptoms and signs

Veno-occlusive disease

The syndrome presents with tender hepatomegaly, ascites and weight gain, and elevated serum bilirubin. The diagnosis of VOD depends on the presence of these symptoms and signs.

Iron overload or drug-induced liver toxicity

IO or DILT may be asymptomatic, but show only laboratory abnormalities.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Liver function tests, including aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyltransferase (GGT), alkaline phosphatase, total and indirect bilirubin, albumin and prothrombin time are appropriate. Transaminitis is more prominent than cholestasis (bilirubin and alkaline phosphatase) in viral hepatitis and DILT. On the other hand, an increase in bilirubin and alkaline phosphatase may be more prominent, compared to transaminitis, in acute graft-versus-host disease (GVHD), chronic GVHD, sepsis, extrahepatic biliary duct obstruction, cyclosporin A (CsA), and TPN (e.g., obstructive pattern).

Blood cultures and viral specific tests should be ordered to rule out viral or other infections.

What conditions can underlie non-infectious complications after bone marrow transplant: liver complications:

Differential diagnosis for veno-occlusive disease

– Viral hepatitis

For example, hepatitis B virus (HBV), hepatitis C virus (HCV), Cytomegalovirus (CMV), herpes simplex virus [HSV], adenovirus, varicella zoster virus [VZV]. Also evaluate history of viral infections and immigration relevant to other infectious processes.

Sepsis
Acute or chronic GVHD (look for other clinical evidence such as rash, diarrhea, dry mouth/eye, etc.)
Cholecystitis, biliary duct obstruction, or cholangitis
Iron overload (ferritin levels greater than 1,000ng/ml)

However, ferritin can be elevated as an acute phase reactant; order transferrin saturation in addition if elevated. Magnetic resonance imaging (MRI) of the liver (quantitative iron measures) or liver biopsy should be considered in patients in whom IO is highly likely because of history of many blood transfusions.

When do you need to get more aggressive tests:

Veno-occlusive disease

Liver biopsy: Percutaneous or transabdominal needle biopsy of the liver may provide sufficient histologic material for diagnosis and may allow determination of wedge hepatic venous pressure gradient (greater than 10mm of mercury is associated with VOD with a 91% specificity), but may be associated with hemorrhagic complications, particularly since many patients are thrombocytopenic.

Histopathology

VOD:

Injury in hepatic sinusoids is usually but not always the first event, followed by occlusion of hepatic venules and damage to surrounding centrilobular hepatocytes (zone 3).

IO:

Measure iron content as well (normal levels are 530-900 mcg/g dry weight).

Viral hepatitis:

Hepatocellular necrosis, sometimes with viral specific inclusions.

What imaging studies (if any) will be helpful?

Abdominal imaging

VOD:

Ultrasonographic Doppler flow studies can be useful by demonstrating reversal of portal flow or a higher portal vein resistive index. It will also rule out extrahepatic biliary duct obstruction.

DILT and IO:

DILT and IO most likely will have normal ultrasound findings. Liver MRI with quantitative iron estimates is a useful imaging test for IO.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Veno-occlusive disease

Treatment success depends on severity of VOD and the presence of other organ failure.

Mild VOD patients can be treated successfully with management of water-sodium balance and paracentesis to insure intravascular volume, and to prevent renal failure.

Moderate VOD patients require treatment such as diuretics or pain medications, but mostly resolve completely.

For severe VOD patients, intravenous defibrotide appears to be the best drug available (it is newly available in the United States) with a complete response of 30-46%. Complete remission rate was 35-40% by day 100 in patients with severe VOD and/or multiple organ dysfunction. This was significantly better than patients receiving supportive therapy (25%). Similarly, survival at day 100 was improved with defibrotide. Although its mechanisms of action in VOD treatment remain unknown, defibrotide has profibrinolytic and antithrombotic effects and leads to elevation of prostaglandin I and E levels.

Iron overload

Treatment of iron overload is evolving. Treatment options for those with satisfactory hemoglobin and erythropoiesis is phlebotomy. For anemic patients, iron chelation therapy (oral deferasirox or parenteral deferoxamine, both of which approved by FDA) may help but the impact on survival is unknown. The treatment guidelines are not standardized. Some recommend the following:

Patients with liver iron content (LIC) greater than 7,000-15,000 mg/g dry weight, should be treated aggressively; prefer phlebotomy,
Patients with LIC under 7,000mg/g dry weight, treatment is indicated only if there is evidence of liver disease,
In patients with ongoing transfusion needs after HCT, concurrent chelation therapy is often given but its effect on survival is unknown.

Drug-induced liver toxicity

Hold or replace culprit drug(s). Transaminases elevations may improve promptly (within 7-10 days) but drug-induced cholestasis may improve more slowly.

What other therapies are helpful for reducing complications?

Preventive measures for VOD

Alterations in the conditioning regimens such as limiting the dose of liver toxic chemo/radiation in conditioning regimens (RIC [reduced intensity conditioning]). Fractionation of the TBI dose could reduce the risks of VOD, particularly in heavily pre-treated patients.

Administration of busulfan following, rather than preceding, cyclophosphamide.

Monitoring busulfan serum levels to allow dose adjustment and limit excessive exposure.

Pharmacologic preventive measures have not been established, but ursodiol may be promising to limit peri-HCT liver injury.

Other agents, including defibrotide, low-dose heparin, low molecular weight heparin, prostaglandin E, fresh frozen plasma (FFP), pentoxifylline (to decrease inflammation and block TNF-α [tumor necrosis factor]), have been tested in prophylaxis of VOD, with no clear determination as to their benefit.

What should you tell the patient and the family about prognosis?

Prognosis of VOD is variable. Depending on severity of weight gain, bilirubin level, peripheral edema, ascites, platelet transfusion requirements, and multiorgan failure, mortality can approach 90% in severe cases. There is a much better prognosis for mild to moderate VOD.

Patients who have advanced VOD (for example, multiorgan dysfunction such as central nervous system, renal, or respiratory failure) and central vein thrombosis have a very poor prognosis. In addition, hepatic wedge pressure greater than 20 mm Hg and PAI-1 elevation are poor prognostic findings. Mortality can be greater than 80% in severe patients.

“What if” scenarios.

Severe VOD

For patients with severe VOD, no established treatment is available. Results are unsatisfactory, but defibrotide shows promise.

Recombinant tissue plasminogen activator, antithrombin III (check serum levels before administrating) and activated protein C, intravenous N-acetylcysteine, prostaglandin E1, transjugular portosystemic shunts, even liver transplant has been used with rare success.

Pathophysiology

Direct toxicity of chemotherapy drugs, in particular busulfan, to sinusoidal endothelial cells and hepatocytes is important. This may result in subsequent deposition of fibronectin and factor VIII/von Willebrand factor at the site of damaged endothelium, and thus to local activation of the coagulation system and subsequent sinusoidal obstruction with fibrin.

Along with these local histological changes, abnormalities in the coagulation system such as increased plasminogen activator inhibitor (PAI-1), decrease in plasma protein C levels, lower antithrombin III levels, and elevated factor VIII and fibrinogen levels can be found. Increased cytokines (including tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-b, interleukin (IL)-6, and IL-8, as well as decreased nitric oxide and matrix metalloproteinases levels) may also contribute to VOD.

Preventive measures for viral hepatitis: There are potent antiviral agents effective to prevent Hepatitis B reactivation, and thus viral hepatitis after transplantation during immunosuppression. Entecavir resulted in significantly lower hepatitis B reactivation compared to lamivudine.

What other additional laboratory studies may be ordered?

MRI of the liver or MR elastography of the liver might be helpful in differential diagnosis.

What’s the Evidence?

McDonald, GB, Hinds, MS, Fisher, LD. “Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients”. Annals of Internal Medicine.. vol. 118. 1993. pp. 255-267. (One of the defining studies of VOD.)

DeLeve, LD, Shulman, HM, McDonald, GB.. “Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease)”. Seminars in liver disease.. vol. 22. 2002. pp. 27-42. (One of the defining articles of VOD.)

Ramasamy, K, Lim, ZY, Pagliuca, A. “Incidence and management of hepatic venoocclusive disease in 237 patients undergoing reduced-intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT)”. Bone Marrow Transplantation.. vol. 38. 2006. pp. 823-824. (Demonstrates lower incidence of VOD after RIC HCT.)

Majhail, NS, Lazarus, HM, Burns, LJ.. “A prospective study of iron overload management in allogeneic hematopoietic cell transplantation survivors”. Biology of blood and marrow transplantation.. vol. 16. 2010. pp. 832-837. (Describes iron overload management in a prospective trial.)

Lee, JH, Lee, KH, Kim, S. “Relevance of proteins C and S, antithrombin III, von Willebrand factor, and factor VIII for the development of hepatic veno-occlusive disease in patients undergoing allogeneic bone marrow transplantation: a prospective study”. Bone Marrow Transplantation.. vol. 22. 1998. pp. 883-888. (Demonstrates the importance of some coagulation system abnormalities in VOD.)

Ustun, C, Koc, H, Karayalcin, S. “Hepatitis B virus infection in allogeneic bone marrow transplantation”. Bone Marrow Transplantation.. vol. 20. 1997. pp. 289-296. (Demonstrates the outcome of HBV after alloHCT.)

Ustun, C, Idilman, R, Gurman, G. “Hematopoietic stem cell transplantation from non-replicative hepatitis B virus carriers is safe”. J Hepatol.. vol. 31. 1999. pp. 202-209. (Demonstrates the outcome of alloHCT in which HBV carriers are used as a donor.)

Cantoni, N, Gerull, S, Heim, D. “Order of application and liver toxicity in patients given BU and CY containing conditioning regimens for allogeneic hematopoietic SCT”. Bone Marrow Transplantation. vol. 46. 2010. pp. 344-349. (Describes cyclophosphamide administration before busulphan decreases VOD.)

Richardson, PG, Soiffer, RJ, Antin, JH. “Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial”. Biology of blood and marrow transplantation.. vol. 16. 2010. pp. 1005-1017. (Describes defibrotide efficacy and side effects.)

Richardson, P, Tomblyn, M, Kernan, N. “Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure”. Blood.. vol. 127. 2016. pp. 1656-65. (Demonstrates efficacy of defibrotide in VOD.)

Bearman, SI, Shuhart, MC, Hinds, MS, McDonald, GB.. “Recombinant human tissue plasminogen activator for the treatment of established severe veno-occlusive disease of the liver after bone marrow transplantation”. Blood.. vol. 80. 1992. pp. 2458-2462.

Shang, J, Wang, H, Sun, J. “A comparison of lamivudine vs entecavir for prophylaxis of hepatitis B virus reactivation in allogeneic hematopoietic stem cell transplantation recipients: a single-institutional experience”. Bone marrow transplantation.. vol. 51. 2016. pp. 581-586. (Demonstrates the safety and efficacy of tPA [tissue plasminogen activator] in VOD.)

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Non-infectious complications after bone marrow transplant: liver complications