Multiple myeloma with hepatic amyloid light-chain amyloidosis manifesting as progressive liver failure

Abstract

We present a case of a 45-year-old man admitted to the hospital with new-onset ascites and bilateral subconjunctival haemorrhages. He was found to have elevated liver enzymes in a hepatocellular pattern and direct hyperbilirubinemia. A diagnostic paracentesis was consistent with portal hypertension (PH). Extensive workup for acute and chronic liver disease was unremarkable. In the absence of clinical evidence of cirrhosis to explain PH, a liver biopsy with hepatic venous pressure gradient was pursued, which revealed proteinaceous material and apple-green birefringence under polarised light consistent with amyloid deposits. Bone marrow biopsy revealed plasma cell neoplasm with proteinaceous deposits consistent with concomitant multiple myeloma with AL amyloidosis. He developed rapidly progressive liver failure and passed shortly after presentation despite treatment with chemotherapy. This case illustrates how primary hepatic amyloidosis can present with a physiology that mimics cirrhosis and can easily be missed.

Background

Amyloidosis is a systemic infiltrative disease that can affect nearly every organ in the human body. It is characterised by the deposition of misfolded protein within various tissues and organs.¹ Multiple subtypes of amyloidosis exist including secondary amyloidosis (AA) associated with inflammatory disorders, and familial amyloid transthyretin (ATTR) amyloidosis.² Amyloid light-chain (AL) amyloidosis is the most common subtype and is caused by extracellular deposition of misfolded immunoglobulin light chains secreted by clonal plasma cells in the bone marrow.³ Serum-free light-chain assay and immunofixation can assist in distinguishing AL amyloidosis from other subtypes. Patients will typically have isolated monoclonal gammopathy or smouldering myeloma, however less often, AL amyloidosis can present concomitantly with symptomatic multiple myeloma.⁴ Clinical signs and symptoms can vary depending on the extent of light-chain deposition and organs involved. This makes the diagnosis challenging without a high index of suspicion. Amyloid light chains most commonly damage the heart and kidneys, presenting with signs of cardiomyopathy or nephrotic syndrome.⁴ Liver involvement in amyloidosis is typically not associated with significant hepatic dysfunction and only a minority of patients exhibit clinical evidence of primary hepatic amyloidosis (PHA).¹ Although rare, PHA can present with potentially fatal complications, such as progressive liver failure or portal hypertension (PH).²

Non-specific symptoms that can be observed include abdominal pain, fatigue and decreased appetite.⁵ Due to the non-descript presentation and lack of specific clinical biomarkers, PHA can frequently be misdiagnosed.⁶ A tissue biopsy stained with Congo red demonstrating amyloid deposits with apple‐green birefringence is required for diagnosis.⁷ Patients with AL amyloidosis have a poor prognosis, and survival rates tend to be worse with hepatic involvement.⁸ Prompt recognition of this disease is essential so treatment is not delayed.

Case presentation

A 45-year-old African–American man with a medical history of hypertension and intellectual disability presented to the hospital accompanied by his family. He presented with worsening abdominal distension and decreased appetite, over several weeks. He also noted recent bruising and redness of his eyes, however, denied any trauma. A complete review of systems was otherwise unremarkable other than his presenting symptoms. Social history was negative for tobacco, alcohol or illicit drug use. On arrival, the patient was afebrile, normotensive, tachycardic (102 beats/min) and saturating well on room air. His home medications included atenolol and hydrochlorothiazide for hypertension. Physical examination revealed an alert and oriented man. Pupils were reactive to light and accommodation, with bilateral subconjunctival haemorrhages, and periorbital ecchymosis around the left eye. The rest of cardiopulmonary examination was normal. Abdomen was non-tender, but firm and distended on palpation with positive fluid wave and mild hepatomegaly. There were no stigmata of chronic liver disease and no asterixis. Labs notable for leukocytosis (23×10⁹L), normal haemoglobin level (15.4 g/L) and platelet count (288×10⁹/L). He had mild hypoalbuminemia (2.2 g/dL); however, there was no protein gap. Liver enzymes were elevated including aspartate aminotransferase (254 IU/L), alanine aminotransferase (106 IU/L), alkaline phosphatase (326 IU/L), elevated total bilirubin (3.4 mg/dL), elevated gamma-glutamyl transferase (251 U/L) and international normalised ratio (1.3) (table 1).

Table 1.

Evolution of liver function tests throughout admission

	Week 1	Week 2	Week 3	Week 4
AST	254 IU/L	297 IU/L	327 IU/L	2686 IU/L
ALT	106 IU/L	123 IU/L	130 IU/L	540 IU/L
Alkaline phosphatase	326 IU/L	469 34 IU/L	554 IU/L	601 IU/L
Total bilirubin	3.4 mg/dL	5.7 mg/dL	14.1 mg/dL	31.9 mg/dL
INR	1.3	3.5	4.2	7.6

ALT, alanine transaminase; AST, aspartate aminotransferase; INR, international normalised ratio.

Investigations

Initial imaging with CT abdomen revealed moderate abdominopelvic ascites, a slightly enlarged liver measuring up to 18.7 cm without splenomegaly. Ultrasound of the abdomen with doppler showed coarse echotexture of the liver parenchyma suggestive of hepatocellular disease with patent hepatic vasculature. Extensive workup for acute and chronic liver disease was negative including viral hepatitis panel, HIV, antinuclear antibodies, antismooth muscle antibody, iron panel, alpha-1 antitrypsin, ceruloplasmin and liver kidney microsomal antibody. Diagnostic paracentesis revealed and elevated serum to ascites albumin gradient (>1.1 g/dL), and low total protein concentration (0.2 g/dL) consistent with PH. Cytology of ascitic fluid was negative, and there was no evidence of spontaneous bacterial peritonitis. Grade I oesophageal varices were seen on oesophagogastroduodenoscopy. Transjugular liver biopsy with hepatic venous pressure gradient (HVPG) was performed to evaluate unexplained PH and liver disease in the absence of clinical findings of cirrhosis. HVPG was 32 mm Hg (normal 1–5 mm Hg) consistent with PH. Liver biopsy pathology revealed liver parenchyma with extensive deposition of proteinaceous material in a linear sinusoidal pattern (figure 1). Proteinaceous material demonstrated apple-green birefringence (Congo red stain preparation) under polarised light consistent with amyloid deposits. Serum protein electrophoresis and serum immunofixation showed no evidence of monoclonal paraprotein; however, urine immunofixation revealed a free lambda light-chain paraprotein. Free serum light chains showed both elevated kappa and lambda chains, with a decreased ratio at 0.17 mg/L. Bone marrow biopsy was significant for a plasma cell neoplasm (15%–20% of the marrow cells) with extensive proteinaceous deposits consistent with amyloidosis (figure 2). Transthoracic echocardiogram showed signs suggestive of cardiac amyloidosis including left ventricular hypertrophy, speckled myocardium, atrial enlargement and reduced longitudinal strain in basilar segments. N-terminal pro-brain natriuretic peptide (NT-pro BNP) was elevated at 420 pg/mL; however, ejection fraction was preserved.

Figure 1.

Liver with sinusoidal proteinaceous infiltrate, consistent with amyloidosis (H&E stain, 100×).

Figure 2.

Bone marrow with multilineage hematopoiesis and amyloidosis (H&E stain, 100×).

The patient was diagnosed with AL lambda light-chain amyloidosis with multiple myeloma.

Treatment

Haematology/oncology team was consulted, and the patient and his family elected for aggressive treatment. The treatment was initiated with bortezomib and dexamethasone. The patient received one cycle of chemotherapy, however, continued to decline clinically. Chemotherapy was discontinued after one cycle due to his worsening clinical status.

Outcome and follow-up

His condition rapidly deteriorated during his admission and he developed worsening hepatic and renal failure (table 1). His INR increased to (7.6), he experienced severe gastrointestinal bleeding with large amounts of melena and hematochezia requiring multiple blood transfusions and fresh frozen plasma. Total bilirubin increased to (31.9 mg/dL), alkaline phosphatase (601 IU/L). He became anuric and encephalopathic with estimated glomerular filtration rate (8 mL/min/1.73 m²). Encephalopathy worsened requiring endotracheal intubation and mechanical ventilation. Shortly after he was intubated, he developed sudden cardiac arrest and deceased. He survived a mere 3 weeks from the time his diagnosis was established.

Discussion

Multiple myeloma is a clonal plasma cell neoplasm and in 12%–15% of patients can present concomitantly with AL amyloidosis.⁹ This systemic infiltrative disease can affect nearly every organ in the human body with renal and cardiac being the most common affected systems.⁴ Approximately 30% of patients exhibit clinical evidence of hepatic involvement.⁶ However, this number is thought to be largely underestimated as autopsy studies have reported an incidence of up to 90% of hepatic involvement in patients with systemic amyloid.¹ Despite this, amyloidosis is not usually associated with significant liver fibrosis or liver dysfunction. In hepatic AL amyloidosis, monoclonal immunoglobulin light chains deposit primarily in the space of disse, the perisinusoidal space, liver parenchyma, vessel walls and stroma.⁶ As the amyloid deposits accumulate, the liver becomes engorged, compressing the hepatocytes and leading to cellular atrophy.¹⁰ However, the degree of deposition does not necessarily correlate with symptomatology.

The majority of patients with liver involvement present with subclinical disease, or non-specific symptoms such as abdominal pain, weight loss and fatigue.⁵ These non-specific findings are often misdiagnosed as alcoholic cirrhosis, viral hepatitis or congestive hepatopathy from heart failure. As these patients are largely asymptomatic without significant laboratory derangements, the diagnosis can be quite challenging. This case of mistaken identity leads to a delay in diagnosis, increasing morbidity and mortality.¹¹ Although hepatic involvement is not uncommon, PH from systemic amyloidosis is rare. Literature review reveals very few cases. The development of PH is thought to be the result of massive amyloid deposition in the perisinusoidal space leading to reduction in vasculature and increasing resistance to blood flow.¹² As PH progresses, so does its complications. Ascites in hepatic amyloidosis is usually secondary to concurrent heart failure rather than PH.¹ Therefore, a diagnostic paracentesis is necessary to rule out other causes that may confound the overall clinical picture and to manage the complications of PH, particularly oesophageal varices. Our patient had a serum-ascites albumin gradient (SAAG) >1.1 with low total protein consistent with PH but without clear evidence of cirrhosis as he initially lacked coagulopathy, thrombocytopenia, splenomegaly and had an unremarkable chronic liver disease workup, the aetiology of his PH remained unknown. As a result, it was decided to perform a transjugular liver biopsy with HVPG measurements, which revealed sinusoidal proteinaceous deposits, no fibrosis on trichrome stain and HVPG 32 (normal 1–5 mm Hg) consistent with non-cirrhotic PH. This lends to support prior evidence that hepatic AL amyloidosis is of the sinusoidal type and the development of PH is due to a reduction in hepatic sinusoids from amyloid deposition.¹² PH is diagnosed at HVPG >6 mm Hg and its complications arise at HVPG >10 mm Hg.¹³

Progressive liver failure is another rare complication of hepatic amyloidosis and has only been noted in a few individual case reports. Despite amyloid infiltration, the synthetic function of the liver is generally preserved. Liver failure would, thus, be attributable to severe PH, hepatic congestion or prolonged cholestasis.¹⁴ As in any case of acute or chronic liver disease, a workup should be pursued to evaluate cirrhosis from toxins/drugs, viral, metabolic and autoimmune conditions. In the absence of cirrhosis, imaging should be pursued to evaluate vascular causes such as portal vein thrombosis, Budd-Chiari and portosystemic shunting. If imaging is unremarkable, infiltrative diseases need to be considered, particularly in those patients lacking the typical findings in cirrhosis of coagulopathy, thrombocytopenia and splenomegaly. Therefore, it is imperative to consider a liver biopsy in all patients with unexplained acute or chronic liver failure. Unfortunately, the prognosis of hepatic amyloidosis with concomitant PH and/or liver failure is dire, with a median survival of 8.5 months.⁵ Markers associated with a worse prognosis include the presence of cardiac involvement, thrombocytosis (>500×10⁹/L) and hyperbilirubinemia (>20 mg/dL).² In order to confirm the diagnosis of amyloidosis, a positive biopsy must be obtained using Congo red stain in affected tissue or from a more accessible tissue site such as abdominal fat pad.⁷ Obtaining biopsies from a liver with amyloid involvement has been associated with increased risk of bleeding compared with a normal liver.¹⁵

In addition, our patient also presented with ocular symptoms (bilateral subconjunctival haemorrhages and periorbital ecchymosis) (figure 3). Subconjunctival haemorrhages may be an early sign of amyloidosis and is an unusual manifestation reported in the literature. Evidence suggests that this is the result of amyloid infiltration in the conjunctival vessels causing fragility and leading to haemorrhages.¹⁶ Although conjunctival biopsies were not obtained, his clinical course is supportive of the ocular manifestations being secondary to his systemic amyloidosis. Periorbital ecchymosis, known as amyloid purpura, appears in a minority of patients with amyloidosis, and can present with ‘raccoon eyes’ (figure 4). This is thought to be from the binding of factor X to amyloid fibrils causing a bleeding diathesis.¹⁷ Recognition of these rare ocular entities may lead to earlier diagnosis of systemic disease before patients present with more dramatic clinical presentations such as acute liver failure. In return, this could lead to earlier initiation of treatment, and may improve overall survival in these patients.¹⁸

Figure 3.

Ocular manifestations: bilateral subconjunctival haemorrhages.

Figure 4.

Ocular manifestations: periorbital ecchymosis around left eye.

Although treatments do exist for multiple myeloma with AL amyloidosis, the prognosis still remains dismal, and successful outcomes are limited. Patients should be evaluated to see if they are candidates for autologous haematopoietic stem cell transplantation (HSCT); however, only about 20% are eligible.⁸ Eligibility is determined based on age, performance status and organ involvement.⁸ Prospective studies have shown promising results in AL amyloidosis associated liver disease following high-dose intravenous melphalan and autologous stem cell transplantation.⁸ Patients who do not qualify for autologous HSCT should be evaluated for other chemotherapy regimens.⁷ Unlike in familial or transthyretin amyloidosis, the role of liver transplantation is not well established in AL amyloidosis.¹⁹

In conclusion, hepatic involvement is typically not the primary manifestation of amyloidosis; however, it is important for clinicians to consider infiltrative processes such as amyloidosis in a patient with unexplained liver failure or non-cirrhotic PH. Progressive liver failure remains an exceedingly rare complication of AL amyloidosis; however, knowledge of this potentially fatal complication is imperative. Unfortunately, the prognosis of hepatic amyloidosis with concomitant PH and/or liver failure still remains poor. Earlier recognition and diagnosis of this disease could lead to improved prognosis in the future.

Learning points.

• Portal hypertension is a rare clinical manifestation of hepatic amyloidosis and inclusion of infiltrative diseases must be in the differential diagnosis in patients presenting with unexplained ascites.

• Although hepatic involvement is common in patients with amyloid light-chain (AL) amyloidosis, the clinical manifestations are usually mild. Progressive liver failure is an unusual complication, and portends a poor prognosis.

• Subconjunctival haemorrhage and periorbital ecchymosis may be early signs of amyloidosis. This is due to capillary fragility from deposition of the amyloid protein.

• Systemic AL amyloidosis can be treated with multiple myeloma-type therapies. Patients who are candidates and receive stem cell transplants (SCT) tend to have increased survival.