# Hepatitis B Associated Monoclonal Gammopathy That Resolved after Successful Liver Transplant

Authors: P. Sreenivasan; S. Nair
Journal: Journal of Transplantation
 (2009)

---

## Abstract

Monoclonal gammopathy of undetermined significance (MGUS) has been most commonly associated with diseases like multiple myeloma, Waldenstrom's macroglobulinemia, primary systemic amyloidosis, HIV, and other lymphoproliferative disorders. There has been an isolated report of MGUS in patients coinfected with HIV and Hepatitis B, as the work by Amara et al. in 2006.  Here, we report a case of IgA-kappa light chain gammopathy secondary to Hepatitis B infection, which resolved after liver transplantation. To our knowledge, this is the first reported case of M protein spike seen in the context of Hepatitis B infection only.


---

## Body

## 1. Case

Mr. SD, a 45-year-old Caucasian male, was referred for evaluation for liver
transplantation because
of end-stage liver disease caused by Hepatitis B. He had
been well until six months prior to his initial visit, when he started losing
weight and developed severe fatigue. During the six-month period, he had lost
25 kilograms.His past
medical history was significant for non-Hodgkin's lymphoma that was diagnosed
eleven years ago. He was treated with 8 cycles of CHOP chemotherapy and had
been in remission since then.On examination, the patient appeared mildly icteric. The abdomen was
soft with some tenderness in the right upper quadrant and ascites. The spleen was mildly enlarged. The remainder of the examination was
normal. No enlarged lymph nodes were
detected.Complete
blood count showed a leukocyte count of 2500 cells/mm3, hemoglobin
of 9.8 gm/dL, and platelet count of 29 000 cells/mm3. His liver
function tests were abnormal with a total bilirubin of 5 mg/dL (normal, 0.2–1.2 mg/dL), ALT:
361 U/L (normal, 17–63 U/L), AST: 750 IU/L (normal, 15–40 U/L), total
protein: 15.4 g/dL (normal, 6.1–7.9 g/dL), albumin: 2.9 g/dL (normal, 3.9–4.8 g/dL), and an
INR of 1.9. Serological tests for viral hepatitis were as follows: Hepatitis B
surface antigen positive (HbsAg), Hepatitis B surface antibody negative
(antiHBs), HBe antigen negative, HBe antibody positive, IgM antibody to
Hepatitis B core antigen positive, IgG antibody to Hepatitis B core antigen
positive, and HBV DNA 4 150 000 IU/mL (by PCR). Antibodies against hepatitis
delta virus and hepatitis A virus were negative. HCV antibody was negative.
Hepatitis C RNA was undetectable. Cytomegalovirus IgG and IgM were negative.
Ebstein Barr virus IgM was negative and IgG was positive. He had a negative antinuclear
antibody and a negative antismooth muscle antibody. HIV antibody was negative.
Esophagogastroduodenoscopy revealed mild esophagitis and erythema of the
gastric body. The duodenal biopsies were normal. Colonoscopy was normal. CT
scan and ultrasound examination of the abdomen showed a small liver with
moderate ascites, splenomegaly, patent portal, and hepatic veins. There were no
enlarged lymph nodes on CT scan. Liver biopsy confirmed cirrhosis from HBV.The striking elevation in his globulin fraction (12.5 g/dL)
was further worked up. Serum protein electrophoresis showed the presence of a
large monoclonal protein spike (M protein) in the gamma region which on
immunofixation electrophoresis (IFE) was identified to be IgA-kappa type (see Figure 1). The IgA levels were increased at 6730 mg/dL (reference range 70–400 mg/dL) and
the IgG and IgM levels were decreased at 466 mg/dL (reference range 700–1600 mg/dL) and
25.6 mg/dl (reference range 40–320 mg/dL),
respectively. Urine was negative for M
protein. Cryoglobulins were negative. Serum viscosity was 3.3 (normal, 1.4–1.8). A bone
marrow biopsy on two separate occasions showed normocellular bone marrow with
less than 2 percent population of plasma cells. The plasma cells were
predominantly kappa light chains on the in situ hybridization. Bone marrow
cytogenetics did not detect any abnormalities. These results were reproduced on
2 repeat bone marrow biopsies. Metastatic bone survey showed no myelomatous
lesions. Full body positron emission tomography (PET) scan and CT scan were
performed, and no focus suspicious for lymphoma or myeloma or infection was
identified. Whole body MRI was unremarkable. On retrospective review, the
patient had an elevated total protein (12 g/dL) approximately six months prior
to initial visit.Within the
next few weeks, the patient continued to deteriorate, and he developed
worsening ascites with hyponatremia. It was clear that the patient had
progressive liver disease from chronic Hepatitis B with a relatively high MELD
score of 23, and he would benefit from a liver transplantation. Our dilemma
before proceeding with liver transplantation was whether he had an underlying
hematological malignancy that was causing the monoclonal gammopathy. This was
even more relevant given his prior history of lymphoma. We were also concerned
about potential vascular complications after liver transplant given his
increased viscosity. However, due to his deterioration and absence of any
clear-cut evidence of malignancy, it was decided to place the patient on the
liver transplant wait list. We chose not to anticoagulate him since he already
had an elevated INR.Anti-HBV
therapy was initiated with a combination of entecavir (0.5 mg/day) and
tenofovir (300 mg/day) to decrease his HBV DNA to the lowest possible level
before transplantation. However, he was on this antiviral therapy for less than
a month as he received a deceased donor liver transplant ten days after
listing. In the period between listing and liver transplantation, his bilirubin
continued to trend up from 3.3 mg/dL to 4.6 mg/dL, and his total protein level
fluctuated between 12.5 g/dL and 13.5 g/dL.Six weeks
after his liver transplant, his HBV DNA level was undetectable. He cleared his
Hepatitis B surface antigen four months after transplant. His IgA levels normalized. As per standard protocol in our
institution, he received two doses of rabbit antithymocyte globulin at 1.5 mg/kg during the time of transplant and on postoperative day 2. He also
received tacrolimus and mycophenolate mofetil for 3 months. Subsequently, the
mycophenolate mofetil was withdrawn, and he is currently on tacrolimus
monotherapy with trough levels between 3–5 mg/mL. He
continues to receive Hepatitis B immunoglobulin infusion every month along with
entecavir (0.5 mg/day), and his Hepatitis B antibody titre has been kept above
300 mIU/mL. He is currently 9 months posttransplant, his total protein levels
range 4-5 g/Dl, and he has had no detectable M protein spike.The temporal relation
of the liver transplant with disappearance of Hepatitis B surface antigen and
normalization of the monoclonal spike implicates Hepatitis B as the
possible cause of the M protein spike.


## 2. Discussion

There is very little data and uncertainty regarding the incidence and natural history of
M proteins in a person with Hepatitis B. It has been suggested that the immunological response elicited against Hepatitis
B virus in the host rather than the direct cytopathic effect of the virus may
be the basis for the pathogenesis of hepatic and nonhepatic manifestations [2]. Hepatitis B
virus seems particularly well suited to initiate a chronic immune disease
because of its tendency to persist in spite of a good immune response. This may cause clonal expansion of the
immunoglobulin secreting cells and may explain the above phenomenon.
Alternately, the M protein spike could represent increased serum
immunoconglutinin titres. It has been previously suggested that elevated serum
immunoconglutinin titers in patients with acute and chronic hepatitis B virus
infection may represent a physiological autoimmune response to HbsAg/anti-HBs
immune complexes [3]. Although our patient did not have the anti-HBs antibody,
it has been suggested that in the light of massive antigenemia present in
chronic HbsAg carriers, it is possible that anti-HBs exists in the form of
HbsAg/anti-HBs immune complexes. This would make it difficult to detect
anti-HBs in serum samples by conventional serological methods [4].There were several intriguing aspects to this patient. The primary issue was whether
he was eligible for liver transplantation in the presence of an increasing M
protein. The fact that he had lymphoma 10 years ago complicated this
evaluation. Additionally, an association between Hepatitis B infection
and non-Hodgkin's lymphoma has been previously described [5]. However, he had had regular follow-ups every six months
after remission of lymphoma, and also his malignancy workup prior to transplant
was negative. Moreover, the M protein spike was noticed only 6 months prior to
transplant and this coincided with the elevation of his liver function tests.
Surprisingly, his IgM antibody to Hepatitis B core antigen was positive, as was
his total core antibody. He did have active hepatitis and this can be deduced
by the fact that he had an ALT level that was 10 times the upper limits of
normal; his explanted liver showed significant inflammatory activity. His
biopsy also revealed frank cirrhosis. By putting all this together, it was felt
that most likely he had a flare of his chronic HBV, which might have triggered
the elevation in M protein.Because
of his elevated M protein and an urgent need for liver transplantation, we
decided to initiate dual therapy with a nucleoside (entecavir) and nucleotide
(tenofovir) analogue to decrease his HBV DNA. However, he was on therapy less than a month before a suitable organ
became available. We decided to accept the organ because of high MELD score
rather than to wait for HBV DNA disappearance. Since we were planning to
continue therapy posttransplant along with HBIG (target anti-HBs titers >500 IU/mL first three months and levels of >300 IU/mL after three months),
we believed that the risk of recurrence of HBV was very small. Unfortunately in
the time period before the transplant and after initiation of antiviral therapy,
we failed to follow his IgA levels and HBV DNA levels. However, his protein levels remained
unchanged suggesting that there may have been very little change in his
gammopathy, and this is not surprising given the fact that nucleos(t)ide
therapy seldom leads to HBsAg clearance in that time frame.After
liver transplantation and with clearance of the Hepatitis B surface antigen,
the M protein levels became normal. There are two potential explanations for
the disappearance of the M protein spike. One and the most likely reason is the
removal of antigen source with native hepatectomy. His Hepatitis B surface
antigen, M protein, and total protein levels remain within normal limits 1 year
after transplantation. The second possibility is the impact of thymocyte, given
at the time of transplant, on plasma cells. Antithymocyte globulin has been
used in treatment of plasma cell dyscrasias [6] due to its activity against
several plasma cell antigens. This is less likely in our patient because
thymocyte globulin was used only as induction therapy at the time of
transplantation. The elimination half time of thymoglobulin is 2-3 days and is
unlikely that its effect on plasma cell is sustained for a year [6]. In
conclusion, this case demonstrates that monoclonal gammopathy can be associated
with chronic Hepatitis B infection and can be eliminated after successful
transplantation.Figure 1
Total protein and IgA levels.



---

*Source: 103784-2009-02-24.xml*