Question 26.2

A 45-year-old male received an allogeneic bone marrow transplant for acute lymphatic leukaemia (ALL). Twenty-six days after the transplant he developed severe gastroenteritis and a maculopapular skin rash and respiratory insufficiency.

The following investigations were performed:

Test	Value	Normal Adult Range
Haemoglobin*	94G/L	110 – 150
WCC*	2.3 x 109/L	4.0–10.0
Platelets*	54 x 109/L	150 – 300
Sodium*	132 mmol/L	135 – 145
Potassium*	3.4 mmol/L	3.5–5.0
Urea*	8.2 mmol/L	4.0–6.0
Creatinine	100 µmol/L	40 – 120
Bilirubin*	67 µmol/L	<25
ALP*	265 IU/L	<125
AST	40IU/L	<40
ALT*	51IU/L	<40

Coagulation profile: Normal

Stool:

Microscopy: WCC ++
Cultures: No growth
C.difficile toxin: Not detected

a) List three possible diagnoses.

Over the next 3 weeks, he developed generalized oedema predominantly in the trunk and lower extremities.

An ultrasound Doppler study of the abdomen revealed dilated portal vein and inferior vena cava and the following pressure measurements were obtained:

Test	Value	Normal Adult Range
Portal pressure*	18 mmHg	8– 10
Infrahepatic IVC*	20 mmHg	9– 11
Hepatic vein*	8 mmHg	9– 10
Suprahepatic IVC	8 mmHg	7– 8
Right atrium	6 mmHg	5- 10

Give the likely explanation for these findings.
List two treatment measures.

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College Answer

Sepsis
CMV infection
Graft v Host disease

Veno-occlusive disease of the liver

TIPS procedure
Diuretics
Fluid restriction

Discussion

Somewhat unfairly, the college has presented us with a patient suffering from some nonspecific symptoms. This young man is anaemic, thrombocytopenic, and has raised LFTs which may explain the high bilirubin. On the plus side, he seems to have engrafted.

Differentials would have to include GVHD (given the rash), CMV infection (given the gastroenteritis) and maybe sepsis - but DIC is ruled out by the absence of coagulopathy.

Generally speaking, the manifestatations of GVHD are as follows:

Rash, ranging from maculopapular to bullous erythroderma
Raised bilirubin
Diarrhoea and abdominal pain, progressing to ileus

The college reminds us to think broad by throwing a sepsis and a CMV in there. Manifestations of CMV infection following bone marrow transplant are protean, and may include all of the features mentioned in the college question.

For example:

CMV retinitis
CMV mucositis
CMV encephalitis
CMV pneumonitis
CMV myocarditis
CMV hepatitis
CMV colitis
CMV nephritis
CMV pancreatitis

Is there an organ system it does not affect?

The suddenly increased portal pressure (normal is 5-10mmHg) is suggestive of veno-occlusive disease of the bone marrow transplant recipient. These pressure measurements are not diagnostic values, however. There are the Seattle criteria and there are the Baltimore criteria, neither of which actually mention any pressures at all - they demand hepatomegaly, ascites and raised bilirubin.

However, the pressure values are given for a reason.

The RA pressure is normal, which should give the candidate the impression that there is no cardiac congestive hepatopathy present.
The portal pressure is raised, up from the normal 5-10mmHg.
The data given to us does not allow us to calculate the hepatic venous pressure gradient, which would require a WHVP (wedged hepatic venous pressure). However, the pressure in the IVC and the pressure in the portal vein are so different that one might infer the HVPG is elevated.

The current BCSH/BSBMT guidelines suggest the following management options:

Defibrotide
Methylprednisolone
Careful fluid management (which means basically diuretics and fluid restriction)
TIPS
Liver transplant

References

Baron, Frédéric, Manuel Deprez, and Yves Beguin. "The veno-occlusive disease of the liver." Haematologica 82.6 (1997): 718-725.

Dignan, Fiona L., et al. "BCSH/BSBMT guideline: diagnosis and management of veno‐occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation." British journal of haematology 163.4 (2013): 444-457.

Richardson, Paul G., et al. "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 16.7 (2010): 1005-1017.

Couriel, Daniel, et al. "Acute graft‐versus‐host disease: Pathophysiology, clinical manifestations, and management." Cancer 101.9 (2004): 1936-1946.

Ljungman, Per, Paul Griffiths, and Carlos Paya. "Definitions of cytomegalovirus infection and disease in transplant recipients." Clinical Infectious Diseases 34.8 (2002): 1094-1097.

Bearman, Scott I. "The syndrome of hepatic veno-occlusive disease after marrow transplantation." Blood 85.11 (1995): 3005-3020.

Coppell, Jason A., et al. "Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome." Biology of Blood and Marrow Transplantation 16.2 (2010): 157-168.

Mcdonald, George B., et al. "Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors."Hepatology 4.1 (1984): 116-122.

Jones, Richard J., et al. "Venoocclusive disease of the liver following bone marrow transplantation." Transplantation 44.6 (1987): 778-783.

Kumar, Ashish, Praveen Sharma, and Shiv Kumar Sarin. "Hepatic venous pressure gradient measurement: time to learn." Indian J Gastroenterol 27.2 (2008): 74-80.

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