Amyloidosis and Subacute Liver Failure

Acute liver failure (ALF) is a rare disorder defined by the clinical progression of jaundice to hepatic encephalopathy in the absence of preexisting liver disease in fewer than 28 days. Subacute liver failure (SALF) is defined as the occurrence of this progression in 28–72 days.¹ SALF, which is rare, is associated with seronegative hepatitis, drug-induced liver failure, autoimmune hepatitis, Budd-Chiari syndrome, and Wilson disease.² Once the criteria for poor prognosis have been met, the only effective treatment for this condition is emergency liver transplantation (ELT). The 1-year survival rate for patients who do not receive ELT is 10–15%, compared to approximately 79% for patients who do receive ELT.³ Patient selection for ELT is most commonly determined by the King's College Hospital criteria.⁴ These criteria differ based on the cause of the ALF: acetaminophen (paracetamol) or non-acetaminophen (nonparacetamol; Table 1). The cardinal features of SALF are jaundice, hepatic encephalopathy, and coagulopathy. Malignant processes causing ALF have been previously described but are uncommon.⁵

Table 1.

King's College Hospital Criteria for Emergency Liver Transplantation

ALF caused by acetaminophen (paracetamol)

pH <7.3 (irrespective of hepatic encephalopathy grade)

OR all of the following criteria:

• PT >100 sec

• Hepatic encephalopathy grade >3

• Creatinine level >300 μmol/L]

ALF caused by nonacetaminophen (nonparacetamol)

PT >100 sec (irrespective of hepatic encephalopathy grade)

OR any 3 of the following criteria:

• Age <10 years or >40 years

• Bilirubin level >300 μmol/L

• PT >50 sec

• Non-A and non-B hepatitis of unfavorable etiology, halothane hepatitis, idiosyncratic drug reactions

• Duration of jaundice prior to hepatic encephalopathy >7 days

ALF=acute liver failure; PT=prothrombin time.

The case reported by Hydes and Aspinall involves a 50-year-old man who presented to his primary care physician with fatigue.⁶ The main abnormality identified at this consultation was proteinuria. Due to this condition, the patient was referred to a nephrologist and underwent a renal biopsy, which led to the diagnosis of amyloid light-chain (AL) amyloidosis. Prior to the commencement of chemotherapy, the patient's condition worsened. At this time, findings from the patient's liver function tests were noted to be abnormal. The patient had jaundice, and his serum alkaline phosphatase (ALP) level was significantly elevated. In the absence of biliary obstruction, a high AL level is associated with primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced liver injury, infiltrative processes (including sarcoidosis), lymphoma, and tumors (primary or secondary). If there is significant bone involvement, the presence of multiple myeloma may also have an impact on ALP level. It would be interesting to know the patient's γ-glutamyltranspeptidase level at this time.

The patient's abdominal pain and hepatomegaly prompted consideration of Budd-Chiari syndrome. The presence of heavy proteinuria may lead to deficiency in anticoagulant factors, including anti-thrombin III, protein C, and protein S. Although Budd-Chiari syndrome has been described in the presence of myeloma, it was not the diagnosis in this patient.⁷

The patient's liver function test results continued to worsen; at this point, perhaps liver tissue could have been obtained to secure a histologic diagnosis. At the time of presentation, the patient's aspartate aminotransferase level was elevated (57 IU/mL). The authors do not disclose information that may have been pertinent to this elevation, particularly the patient's alcohol history and risk factors for fatty liver disease or other metabolic liver diseases. It is conceivable that the patient may have had underlying liver cirrhosis and may have suffered an acute-on-chronic decompensation precipitated by alcohol, drug ingestion, or sepsis in addition to the AL amyloidosis. The presence of heavy amyloid deposition on serum amyloid P scintigraphy likely ushered the clinical team away from a liver biopsy (LB). In the past, there have been concerns of an increased bleeding risk from percutaneous LB in patients with amyloidosis, although this risk may have been overstated; nevertheless, the bleeding risk in these patients remains higher than for other LB indications.^8,9 If there were concerns regarding this risk, a transjugular LB could have been performed, particularly because of the patient's worsening coagulopathy.¹⁰ A LB may have identified cirrhosis (thereby excluding ELT) and could have demonstrated hepatic amy-loidosis and hepatic necrosis (as a consequence of SALF).

A LB may also have identified hepatic monoclonal plasma cell infiltration of myeloma. This condition has been reported in up to 40% of cases and responds to corticosteroids.^11–14 The King's College Hospital Acute Liver Failure Group described a case of hepatic amyloi-dosis secondary to myeloma that led to SALF without hepatomegaly in the presence of a normal serum ALP level, a negative test result for bence jones protein (a protein that is positive in 20% of cases), and a normal erythrocyte sedimentation rate. In this case, the presence of amyloidosis and myeloma was only determined from liver and bone marrow histologic examination on autopsy, highlighting the importance of histology.¹⁵ Hepatic failure is an unusual consequence of myeloma-associated AL amyloidosis.^15–17 SALF is even rarer in amyloid-associated amyloidosis. Only a small number of such cases have been reported in the English language medical literature.^18–20

In the setting of ALF or SALF, the occurrence of acute renal failure is an ominous sign. According to O'Grady's criteria for poor prognostic factors in ALF, severe renal impairment and metabolic acidosis behold a poor outcome in the absence of ELT.⁴ Other possibilities for acute renal failure in this situation include dehydration, sepsis, drug-induced nephrotoxicity, myeloma kidney, nephrotic syndrome, and possibly hepatorenal syndrome (if the patient is cirrhotic).

Transfer to the intensive care unit and the subsequent need for intubation, broad-spectrum antibiotics, and vasopressors herald the onset of multiple organ failure (MOF). Outcomes for patients with MOF are abysmal in the setting of ALF and cirrhosis.^21,22 It has been postulated that sepsis often serves as the catalyst for clinical deterioration and MOF.²³ Prophylactic antibiotics and antifungal agents are routinely prescribed for the management of patients with ALF syndromes. This practice appears to reduce the risk of infection, but it does not necessarily influence overall survival.^24,25

Multiple myeloma is the second most common hema-tologic malignancy (13%) and constitutes 1% of all cancers. Primary amyloidosis arises from diseases with disordered immune cell function, such as multiple myeloma and other immunocyte dyscrasias. AL amyloidosis is the most common form of systemic amyloidosis. It occurs in 5—15% of individuals with multiple myeloma. Liver involvement is less common in myeloma (32%) than in other hemato-logic malignancies: 80—100% in chronic leukemia and myeloproliferative diseases, 60—70% in acute leukemia, and 50—60% in non-Hodgkin lymphoma. As in the case reported by Hydes and Aspinall, these patients often present with hepatomegaly, jaundice, and ascites; fulminant liver failure per se is rare.^6,26,27 The presence of intrahepatic cholestatic jaundice is considered to be a bad prognostic sign, as is the presence of ascites.^28,29 It should be noted that ascites is a feature of SALF and is not unique to cirrhosis in liver disease, although this distinction is difficult to discern via imaging alone.

A recently published series of all AL amyloidosis patients evaluated at the UK National Amyloidosis Centre who underwent liver transplantation between 1984 and 2009 reported 1-year and 5-year survival rates of 33% and 22%, respectively. These figures do not meet the minimum survival rate required to justify liver transplantation as a viable treatment modality (ie, a 50% chance of survival 5 years post—liver transplantation).³⁰ Nevertheless, there have been case reports of AL amyloidosis patients doing well with sequential liver and stem cell transplantations.^31–34 Therefore, liver transplantation may be indicated as a life-saving procedure in well-selected cases of rapidly progressing hepatic amyloidosis.

In summary, the interesting case reported by Hydes and Aspinall describes a rare cause of SALF attributed to AL amyloidosis.⁶ This case shows that ascites and features of portal hypertension do not develop only in the setting of decompensated cirrhotic liver disease but also in more acute settings. Failure to recognize these findings may prevent some patients from gaining access to life-saving ELT. The outlook for patients who undergo transplantation for AL amyloidosis is poor compared to other indications, but prolonged survival may be possible in well-selected cases. Finally, this case highlights the potential role of LB in the setting of SALF.