Concurrent primary biliary cirrhosis and autoimmune hepatitis presenting as subfulminant hepatic failure

Abstract

Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) overlap syndrome may be found in a significant percentage of patients with either PBC or AIH. However, it is conceivable that most cases of PBC-AIH overlap syndrome are a concurrent manifestation of both diseases which therefore requires treatment of both disease entities. While most cases are found in asymptomatic patients or in patients who have been previously diagnosed with PBC, our patient presented with concurrent PBC and AIH resulting in subfulminant liver failure that responded to treatment with prednisone and ursodeoxycholic acid (UDCA). Extended 4-year follow-up and treatment with UDCA confirmed the diagnosis of PBC and demonstrated serological resolution of AIH.

BACKGROUND

Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) are the two most prevalent autoimmune diseases of the liver.¹ The syndrome observed in patients with overlapping features of both PBC and AIH has been given many names, such as overlap syndrome, autoimmune cholangiopathy and hepatitic form of PBC.² Controversy remains as to the precise definition as well as the nature of the disease. It is as yet unknown whether this syndrome is an intermediate in a spectrum between PBC and AIH, a hepatitic form of PBC, a cholangitic form of AIH, or a coincidence of two distinct diseases. AIH may flare, and these episodes are manifested as marked elevations in transaminases or even fulminant liver failure. There are no universally accepted diagnostic criteria for PBC-AIH overlap syndrome, but it is usually diagnosed in patients with features of both diseases.

CASE PRESENTATION

A 50-year-old African American man presented to our hospital with jaundice. For the preceding 2 months, he had experienced increasing fatigue, nausea and non-bloody, non-bilious vomiting. Three weeks prior to presentation, he noticed scleral icterus and generalised jaundice. He denied any similar symptoms previously and was in his usual state of health 2 months before presentation. He denied any medications including over the counter medications, specifically acetaminophen. He denied fevers, pruritus or abdominal pain. The patient did not have any other significant medical history but did have a history of remote non-intravenous cocaine use. His reported alcohol use was less than 25 g per day. He had no family or previous personal history of autoimmune disorders or liver disease. On initial examination, he was icteric and jaundiced. He was not encephalopathic, nor did he have gross ascites or other findings to suggest chronic liver disease. He did not have hepatosplenomegaly or abdominal tenderness.

INVESTIGATIONS

Laboratory findings at presentation and on follow-up are shown in table 1. His laboratory investigations showed a markedly elevated alkaline phosphatase at 12 times the upper limit of normal (ULN), total bilirubin at 11 times the ULN, alanine transaminase at four times the ULN and aspartate aminotransferase at six times the ULN. Both IgG and IgM were markedly elevated at nearly one and a half times the ULN and auto-antibodies were positive for anti-nuclear antibody (ANA) of 1:640 with a centromere pattern, and anti-mitochondrial antibody (AMA) of 1:40, subtyped to be against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). Endoscopic retrograde cholangiopancreatogram did not show intrahepatic or extrahepatic biliary changes or obstruction. Liver biopsy showed plasma cell infiltration and ductopenia, consistent with both AIH and PBC (fig 1) and no evidence of cirrhosis.

Table 1.

Laboratory investigations on admission, at 6 months and at 4-year follow-up

	Admission	6-Month follow-up	4-Year follow-up
Total bilirubin (mg/dl) (0.2–1.2)	13	4.3	2.8
Albumin (g/dl) (3.4–5.0)	3.3	3.4	3.3
Alkaline phosphatase (IU/l) (32–126)	1520	620	336
Alanine transaminase (IU/l) (10–63)	281	269	56
Aspartate aminotransferase (IU/l) (10–42)	262	140	51
IgM (mg/dl) (46–304)	522	419	440
IgG (mg/dl) (751–1560)	1970	1310	1120
IgA (mg/dl) (82–453)	427
Anti-nuclear Ab	1:640	1:640	Negative
Anti-mitochondrial Ab	1:40		1:40
Anti-smooth muscle Ab	Negative
Anti-liver-kidney microsomal Ab	Negative
Anti-Smith Ab	Negative
Haemoglobin (g/dl) (12–18)	12.8
Platelets (K/cmm) (150–450)	312
PT	14.1		15.6
INR	1.1		1.21

The ranges of normal values are given in parentheses.

Figure 1.

(A) H&E stain (×100): liver with chronic inflammation in portal tract and focal bile duct loss. (B) H&E stain (×400): portal tract with lymphohistiocytic infiltrates including plasma cells (arrow).

TREATMENT

Due to the presumptive diagnosis of a concurrent diagnosis of PBC and AIH, both prednisone 40 mg daily and ursodeoxycholic acid (UDCA) 13 mg/kg/day were initiated simultaneously. Within weeks of initiation of therapy the patient showed a significant improvement in transaminases and his jaundice subsided with improvement in fatigue.

OUTCOME AND FOLLOW-UP

During extended 4-year follow-up and treatment with UDCA, the patient still has laboratory abnormalities consistent with cholestatic liver disease. Interestingly, despite discontinuation of prednisone all serological markers of AIH are negative and his IgG is within normal levels.

DISCUSSION

Discussion of diagnosis

To the best of our knowledge, this represents the first well characterised case of PBC presenting with acute, subfulminant liver failure and features of AIH in an African American man with long term follow-up. We feel this case strongly illustrates the concurrent presentation of both diseases resulting in subfulminant failure. There are only two poorly documented published case reports of patients with PBC or overlap syndrome who presented with acute fulminant or subfulminant hepatic failure. Van Leeuwen described a 38-year-old African American woman presenting with fulminant hepatic failure who required liver transplant.³ She had features primarily of AIH with a positive AMA with a titre of 1:320. However, her IgM and alkaline phosphatase were only mildly elevated, and the authors themselves are equivocal on the diagnosis of overlap syndrome as AMA positivity can be found in up to 20% of patients with AIH. Kayacetin presented a case of a 50-year-old woman with fulminant hepatic failure and clinical, serological and histological evidence of PBC-AIH overlap syndrome with a response to corticosteroids and UDCA.⁴

PBC is a slowly progressive autoimmune disease of the intrahepatic biliary ducts that eventually progresses to cirrhosis, and is most often seen in women of middle age. Patients may present with jaundice, pruritus or cholestasis, but most are asymptomatic at the time of diagnosis. Laboratory abnormalities are consistent with cholestasis. Transaminases are often elevated, but only mildly. Elevations of transaminases greater than five times normal may suggest another diagnosis, such as PBC-AIH overlap syndrome. Elevated levels of IgM are often seen. The hallmark histological finding in PBC is ductopenia – the absence of interlobular bile ducts in more than 50% of portal tracts.

A striking feature of PBC is the highly directed, highly specific AMA.⁵ Indeed, when recombinant autoantigens are used, the specificity of the AMA for PBC approaches 100%. Asymptomatic subjects with detectable AMA with this assay are at significant risk for the development of PBC in the future.⁵ The most difficult component in understanding autoimmunity is the issue of aetiology. In the case of PBC, the AMA reactivity undergoes substantial evolution, both quantitatively and qualitatively over time, so masking the identity of the original causative factor. However, considerable progress has recently been made in which chemically modified mitochondrial peptides have been shown to react as well or better as native autoantigen^6,7 and, in fact, autoimmune cholangitis can be produced experimentally in mice by immunisation with a chemical mimic of PDC-E2.⁸ Hence, the data reported on this case take on further significance in light of the clinical history that is manifest.

AIH can be an acute or fluctuating autoimmune disorder, classically affecting young women with rapid progression to hepatic failure or cirrhosis without early treatment. Patients typically present either asymptomatically with elevated transaminases, or with jaundice and acute hepatic failure with marked transaminase elevations. The presence of autoantibodies such as ANA, smooth muscle antibodies, antibodies to soluble liver antigen, liver-kidney microsomal antibodies or antibodies to asialo-glycoprotein receptor are often but not always present. Elevated IgG is also usually found in untreated patients.² The hallmark histological finding in AIH is interface hepatitis but is not pathognomonic. Interface hepatitis with predominantly lymphoplasmacytic infiltrate may also be seen, although these findings may be difficult to differentiate from chronic viral hepatitis.

As with PBC, many overlap patients are asymptomatic at the time of diagnosis. In patients who present with symptoms, fatigue is the most common complaint (21–85%), followed by pruritus (19–55%). The reported prevalence of PBC-AIH overlap syndrome developing in patients initially diagnosed with PBC ranges from 2% to 10%.^1,9,10 The prevalence of overlap syndrome in patients initially diagnosed with AIH has been reported to be around 13%, whereas 7.8% of patients with overlap syndrome have features of both PBC and AIH at the time of diagnosis.^9,11

LEARNING POINTS

• Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) are the two most prevalent autoimmune diseases of the liver.

• PBC-AIH overlap syndrome requires treatment with both immunosuppression and ursodeoxycholic acid to prevent long term complications.

• The serological markers of the autoimmune component of PBC-AIH overlap syndrome can resolve with immunosuppression and ursodeoxycholic acid.